Medicine (St Vincent's) - Theses
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The role of cardiac output and fluid responsive measurements in improving outcomes after major abdominal surgery in adults
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.
A model of culturally informed integration of Diabetes Education and diabetic Eye disease Screening (iDEES) in Indigenous primary care settings
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.
Population level outcomes of advancements in diabetes care
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.
Addressing Controversies in the Management of Barrett’s Oesophagus Related Dysplasia
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.
Difficult to treat populations with hepatitis C infection: Prisoners, people who inject drugs, and viral resistance
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.
Virtual intracranial electroencephalography for epilepsy surgery: an ictal magnetoencephalographic study
Pharmaco-refractory focal epilepsy is a serious clinical problem. Epilepsy surgery is an effective approach to treat pharmaco-refractory focal epilepsy, particularly for complex cases with no clear lesion or an extensive lesion. However, surgical treatment is currently under-used and does not always render favourable outcomes. Invasive intracranial electroencephalography (iEEG) is the pre-surgical gold-standard to localise and circumscribe the epileptogenic zone (EZ). However, iEEG has several important limitations, such as constrained spatial sampling and invasiveness. More importantly, it is not always guaranteed that iEEG electrodes cover the entire EZ, which is believed to be one of the main reasons for unsuccessful surgeries. Non-invasive neuroimaging techniques mitigate the risks and limitations of iEEG by imaging brain structure and neural activity in a whole-brain fashion. Recent advances in electroencephalography (EEG), magnetoencephalography (MEG) and magnetic resonance imaging (MRI) combined with source imaging techniques allow to investigate neural dynamics at comparable temporal and spatial resolutions to iEEG but non-invasively. Solving forward and inverse problems are the two major missions of EEG and MEG source imaging. In this thesis, a study using realistic head model derived from individual MRI of a healthy subject and an epilepsy patient is conducted to understand the operating regime and limitations of constructing EEG and MEG forward models with compromise from brain lesion. Simulations using forward and inverse modelled ictal iEEG time-series and ictal MEG signals also offer crucial insights into reliably reconstructing ictal source signals that preserve important clinical characteristics, such as morphology and spatial patterns. Attempts have also been made to construct functional networks using ictal source signals reconstructed from MEG. There is a pressing need for non-invasive approaches that objectively characterise the EZ in presurgical evaluation. Dynamical network models using iEEG have demonstrated multiple successes in predicting the EZ and surgical outcomes. Combining non-invasive neuroimaging techniques with sophisticated dynamical network modelling approaches may offer valuable information to the current clinical localisation of the EZ such as iEEG. A novel approach, virtual iEEG (ViEEG), is proposed to non-invasively investigate ictal dynamics like iEEG without its limitations. The proof-of-concept study using 36 seizures captured MEG from 12 patients suggest dynamical network models applied to ictal ViEEG provide the valid characterisation of the EZ and non-ictogenic brain areas that are less likely to overlap the EZ. Moreover, solutions from ViEEG and dynamical network models using MEG alone predicts the iEEG seizure onset zone and the optimal source localisation solution that can only be offered using simultaneous EEG and MEG. The proposed approach and its findings demonstrate the feasibility of non-invasively and objectively characterising the EZ and motivate future work to optimise the current methods. The successful implementation of the proposed approach in the clinical setting would lead to significant benefit to people with refractory focal seizures: making surgery more available, minimising invasive recordings and therefore mitigation of risks, as well as improved surgical outcomes.
Responding to Urgency of Need - the Development of a Triage Tool for Palliative Care
Specialist palliative care services worldwide face the challenge of a workload that is growing in both volume and diversity. Simultaneously it is well recognised that timely access is crucial for the benefits of palliative care to be fully realized. When responding to a workload that at times may exceed resources, services must develop systems to prioritize patient care in a safe and fair manner. Significant efforts have been made to establish criteria defining which patients should receive specialist palliative care and at what point in the disease trajectory they should be referred, yet little is known about how patients should be prioritized once they have been referred. Unlike the field of emergency medicine and disaster response where systematic triage methods have been refined since World War I, limited attention has thus far been paid to how palliative care services should manage demand and consider urgency of response. A small number of studies have established that palliative care triage is a complex process embedded in organizational culture. Triage tools generated from these studies suffered from poor face validity and inter-rater reliability, and so have not been widely implemented into routine practice. This thesis therefore aimed to determine how the urgency of specialist palliative care needs should be assessed and compared between patients, with the practical outcome to ultimately develop an evidence-based, validated tool for palliative care triage – the Responding to Urgency of Need in Palliative Care (RUN-PC) Triage Tool. A series of studies were conducted, employing mixed methodologies to address various aspects of the research question and RUN-PC Triage Tool development. An initial qualitative study was undertaken to explore the attitudes and practices of palliative care providers towards triaging palliative care needs. This exploration led to a greater understanding of clinical decision-making that was used to develop a list of the key triage factors which formed the basis of the triage tool. These triage factors were then examined in the second study, a discrete choice experiment. This online international experiment determined the magnitude of effect that of each of the triage factors had on clinicians’ decision-making. These values became the scoring system for the RUN-PC Triage Tool. The third and final study was a validation study that demonstrated good intra- and inter-rater reliability and moderate to good correlation to expert opinion, which was used as the reference standard. This thesis paints a comprehensive picture of how palliative care clinicians approach the challenging task of triage and provides a practical tool to standardise the process that is evidence-based and validated. This research has significant implications for clinical practice internationally and represents an important step towards improving the transparency, consistency and efficiency of triage in palliative care, working towards equitable access for all.
Clinical, Immunological and Radiological Features of Endocrine Immune Related Adverse Events
Immune checkpoint blockade is a cancer treatment aimed at restoring and enhancing the ability of the immune system to combat a tumour. A recognised side effect is “collateral” immune damage to healthy tissue, or immune related adverse events (irAEs). Immune toxicity to endocrine glands can be rapid and irreversible and may result in the need for lifelong hormone replacement. A major challenge is identifying which patients will develop endocrine irAEs when treated with checkpoint inhibitors. The role of predictive biomarkers such as HLA type or autoantibodies has not been prospectively evaluated. The possibility of detecting pre-clinical endocrine dysfunction using MRI and PET imaging is described in small case series only. This project aims to 1. Define the clinical and immunological features of checkpoint inhibitor related diabetes, hypophysitis and thyroiditis in contrast to spontaneously occuring endocrine autoimminuty and 2. Explore ways to predict and detect endocrine toxicity early with biomarkers and imaging. First, I define the phenotype and immune mechanisms underlying checkpoint inhibitor related autoimmune diabetes. It was then relevant to discuss atypical or alternate phenotypes of diabetes and pancreatitis which have emerged over the past 2 years. This chapter concludes with a discussion of potential treatments aiming to reverse islet cell destruction, with a letter to the editor published in response to a case report. The next focus is the diagnostic evaluation of checkpoint inhibitor related hypophysitis. After hypothesising that the true incidence may be underappreciated, this chapter reviews the clinical, biochemical and radiological features in a cohort of patients monitored closely for this irAE. The third component of the thesis reviews the incidence and natural history of checkpoint inhibitor related thyroiditis. Defining the natural history provided important information guiding management of the hyperthyroid and hypothyroid phases respectively. This chapter includes a diagnostic accuracy study evaluating the role of FDG-PET/CT as a novel tool in the diagnosis of this irAE. In defining the natural history and diagnostic features of these three endocrine immune related adverse events, important recommendations about biochemical screening and the complementary role of routine cancer immaging are made. Importantly, treatment considerations relevant to oncologists and endocrinologists alike are outlined.
Multidisciplinary Care of Functional Gastrointestinal Disorders
Functional gastrointestinal disorders are highly prevalent. They constitute the most common presentation for gastroenterology specialist consultation and are among the most common conditions seen by general practitioners. These disorders include irritable bowel syndrome, functional dyspepsia and constipation. Their treatment is associated with substantial costs to the healthcare system, while other costs include impaired workforce productivity. Functional gastrointestinal disorders are typically characterised by an absence of “organic” pathology. Psychological and dietary factors are thought to play some part. Despite the efficacy of psychologically-based, behavioural and dietary therapies they are rarely incorporated into specialist care, and rarely form first line therapy. The typical model of specialist care involves a gastroenterologist working in isolation; the outcome of such a model of care has not been adequately evaluated. This thesis involves a collection of studies which evaluate the outcome of gastroenterologist-only care for functional gastrointestinal disorders, other models of care, and a multi-disciplinary model of care. I have demonstrated that symptom outcomes twelve months after care in a gastroenterologist-only clinic is poor. The majority of patients were dissatisfied with care, continued to have symptoms, and were often absent from work due to symptoms. This is the first study to have evaluated the outcomes of a gastroenterologist-only clinic. In a systematic review of the literature I have evaluated the models of care which have been evaluated for functional gastrointestinal disorders. This is the first published evaluation of models of care for functional gut disorders and suggested the benefit of allied clinicians incorporated into the care of functional gastrointestinal disorders. To evaluate if a multi-disciplinary model of care is superior to a gastroenterologist-only clinic model I critically reviewed the literature regarding trial design. I then designed a comprehensive, pragmatic, randomised trial that evaluated symptoms, quality of life, psychological wellbeing and cost. The MANTRA (multi-disciplinary treatment of functional gastrointestinal disorders) study is the first randomised study to evaluate the benefit of a multi-disciplinary model of care for functional gastrointestinal disorders. It demonstrated clinically-relevant, statistically significant, superiority of a multi-disciplinary clinic compared with a gastroenterologist-only standard care clinic, with regards to symptoms, quality of life, psychological wellbeing and cost. The studies in this thesis demonstrate that the current specialist-only model of care for these highly prevalent and costly conditions is inadequate. The thesis also provides a clear rationale and evidence base for a multi-disciplinary clinic model for the treatment of functional gastrointestinal disorders with respect to all important outcomes.
Inflammatory bowel disease and pregnancy: patient education, assessment of disease activity and monitoring of drug therapies
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. The disease commonly impacts women during their reproductive years. IBD, particularly when active during pregnancy, is associated with worse maternofoetal outcomes. Pregnancy-related knowledge remains poor in many patients, with concerns regarding drug safety and a lack of understanding of the negative ramifications of active disease in pregnancy. Safe and effective monitoring of disease activity and drug therapies to control IBD throughout pregnancy are imperative. However, the utility and means of objective disease activity monitoring in pregnancy are unknown. The effect of pregnancy on the pharmacokinetics of immunosuppressant and biologic drugs in pregnancy remains undefined. This thesis presents a range of clinical research work as part of the prospective Pregnancy in Crohn’s and Colitis: Observations, Levels and Outcomes (PICCOLO) study. This study aimed to improve the pregnancy-related education and care of women with IBD; characterise the utility of objective disease activity monitoring including gastrointestinal ultrasonography in pregnancy; and examine the pharmacokinetics of thiopurine and biologic medications during pregnancy as well as infant outcomes following in utero medication exposure. I have explored the lived experience of IBD and pregnancy from the patient’s perspective using qualitative in-depth interviews. This research unearthed rich data relating to unique maternal fears and uncertainties around IBD medications and enduring a chronic illness throughout the pregnancy journey. I have demonstrated that a single individualised patient education intervention improves pregnancy-related knowledge among women with IBD. This novel intervention included a simple, accessible educational consultation for women with IBD who were pregnant or wishing to conceive. Pregnancy knowledge and quality of life scores were enhanced following the intervention and patient satisfaction levels were very high. This work has defined the role of gastrointestinal ultrasonography as a feasible and accurate modality for monitoring IBD in pregnancy. Adequate intestinal views were obtained in most patients to the end of the second trimester. Gastrointestinal ultrasound delivered a high specificity and sensitivity when compared with matched faecal calprotectin concentrations as an objective marker of disease activity. The research has contributed substantially to the understanding of the pharmacokinetics of thiopurines and biologic medications including infliximab, adalimumab and vedolizumab during pregnancy. Thiopurine metabolite concentrations were studied longitudinally in patients with IBD across pregnancy and in exposed neonates. Significant shunting of maternal thiopurine metabolites can occur during pregnancy. This work has established that complete clearance of thiopurine metabolites occurs in exposed infants by six weeks of age. Unlike a previous study, this work has shown that there is no association with neonatal anaemia following antenatal exposure to thiopurines. However, I identified the novel findings of thrombocytosis and abnormal liver function tests in exposed infants from six weeks of age, which gradually improved; possible mechanisms behind these infant haematological and biochemical findings are uncertain. Maternal drug levels of infliximab, adalimumab and vedolizumab in pregnancy were also prospectively assessed. This work has demonstrated that adalimumab levels remain stable and infliximab levels display a small increase in pregnancy. This study has described the first data regarding vedolizumab levels in pregnancy and clearance time in infants exposed to vedolizumab in utero. I have identified that maternal vedolizumab levels may show a small decrease in pregnancy, while infant vedolizumab cord blood levels are lower than maternal levels. All infants had undetectable vedolizumab levels by sixteen weeks of age. I have also presented preliminary data regarding another newer biologic agent, ustekinumab, including maternal levels in pregnancy and placental transfer. Infant cord blood levels of ustekinumab were found to be higher than maternal levels in the small cohort to date. This series of studies has the potential to change the paradigm of pregnancy-related education, objective disease activity monitoring and optimal use of IBD therapies for pregnant women with IBD globally.
Clinical, molecular and psychosocial profiling of long-term survivors of glioblastoma
Glioblastoma is the most common and most aggressive primary brain tumor in adults. It affects approximately 5.5 per 100,000 people in Australia, with incidence increasing by 3% per year. It is the sixth leading cause of cancer burden in Australia and is associated with significant morbidity from diagnosis. Prior to 2005, the mainstay of treatment was maximal surgical resection followed by radiotherapy with three- and five-year survival rates of 4.4% and 1.9% respectively. In 2005, the addition of concurrent oral temozolomide chemotherapy to standard radiotherapy demonstrated a modest improvement in overall survival with three- and five-year survival rates of 16% and 9.8% respectively. This established combined therapy as standard treatment for this condition (Stupp protocol) and highlighted the prospect of longer term survival as a small but distinct possibility. Long-term survivors of glioblastoma have been defined as patients alive 18 months to 5 years following diagnosis, without clear consensus on an appropriate definition. Approximately 13.7% of all patients diagnosed with glioblastoma survive longer than 2 years. With improved surgical and radiotherapy techniques, and the introduction of new therapies such as targeted therapy, the numbers in this group may continue to grow. Predicting who these patients are and understanding the nature and experience of their survivorship becomes paramount. The purpose of this thesis is to gain a comprehensive understanding of long-term survivors of glioblastoma, defined as patients diagnosed with glioblastoma who survive at least two years. Using a mixed methods approach, it combines elements of quantitative research, such as chart reviews, quality of life questionnaires and neurocognitive assessment, with qualitative research, such as semi-structured interviews. Together, this thesis addresses three major facets. Firstly, to be able to recognise at diagnosis patients that are likely to survive longer. Secondly, to develop a detailed understanding of the lived experience and patient reported concerns faced by long-term survivors of glioblastoma. Thirdly, to increase the proportion of long-term survivors through targeted clinical trials. Ultimately, this thesis provides insight into the care needs of patients, facilitates the planning of treatment and supportive care by clinicians, identifies options for improving access to clinical trials and recognises the support networks required for both patients and their caregivers to uphold their quality of life.
Determining how SRSF2 mutation leads to MDS and CMML and its genetic cooperativities in vivo and in vitro
Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal stem cell malignancies characterised by multilineage cytopenia and dysplasia. MDS mostly occurs in aged populations where there are limited therapeutic options. Compared to MDS, chronic myelomonocytic leukaemia (CMML) presents with a monocytosis feature and has a poor survival of 16 months for high-risk patients. In the past decade, several sequencing studies have defined the complex molecular landscapes of MDS and CMML. SRSF2, a component of RNA splicing machinery, is one of the most frequent mutations in MDS and CMML. To understand the consequences and effects of SRSF2P95H mutation on normal haematopoiesis, several groups, including our lab, have generated in vivo mouse models using various gene targeting strategies and Cre recombinases. These models demonstrated some effects of SRSF2P95H mutation on haematopoiesis, and described certain mis-splicing changes in the Srsf2P95H/+ cells. However, the mechanism and role of SRSF2P95H mutation in promoting and initiating MDS/CMML are still poorly defined. My thesis aimed to address key knowledge gaps by examining the cell of origin, transcriptomic/splicing changes, synthetic lethal genetic interactions, and co-operative interactions of SRSF2P95H/+ mutation in the initiation of MDS/CMML. In the first part of my thesis, I assessed the cell of origin in SRSF2P95H MDS by characterizing a conditional knock-in Srsf2P95H/+ mouse model, using LysM-Cre. After activating Srsf2P95H/+ mutation in myeloid progenitors, I observed no development of MDS even after prolonged ageing (up to 52 weeks) and only mild changes in haematopoiesis. Compared to the stem cell activation model (hScl-CreERT2) that we reported, the results of LysM-Cre demonstrated that a myeloid progenitor is not the cell of origin in SRSF2mut MDS. In the second part of my thesis, I analyzed the transcriptomic and splicing changes of Srsf2P95H/+ cells, using both purified stem and progenitor cell populations as well as Hoxb8 immortalized cell lines. The transcriptome analysis revealed up- and down-regulation of lineage associated genes and up-regulation of MDS associated pathways and the p38 MAPK kinase pathway. The splicing analysis demonstrated skipped exons as the most frequent alternative splicing event. In terms of specific mis-splicing targets, I examined exon inclusion in several reported transcripts and compared the most frequently mis-spliced genes across 12 human SRSF2mut and murine Srsf2mut datasets. Through this analysis, I found that mRNA processing and DNA repair represent the top mis-spliced pathways in Srsf2P95H/+ cells. I also present a pilot study of single cell RNA sequencing of Srsf2P95H/+ stem and primitive progenitor populations, which unveiled a myeloid-biased signature and enhanced myeloid differentiation of the Srsf2P95H/+ stem cells. In the third part of my thesis, I explored the synthetic lethality of Srsf2P95H/+ cells with a pooled CRISPR knock-out screen. I discovered that loss of DNA repair or cell cycle pathways was synthetic lethal with Srsf2P95H/+ mutation. Consistent with this genetic lethality, I demonstrated that Palbociclib, a CDK6 inhibitor, could preferentially target the Srsf2P95H/+ cells. This finding opens up new therapeutic windows beyond known spliceosome inhibitors for SRSF2mut MDS. In the fourth and last part of my thesis, I generated and characterized two multi-genic mutation models: Srsf2P95H/+ Tet2-/- and Srsf2P95H/+ Cbl-/-. In the Srsf2P95H/+ Tet2-/- model, I observed profound myeloid bias, B lymphoid suppression and increased ST-HSC percentages in the stem cell compartment after 52 weeks of activating/deleting mutations in the haematopoietic stem cells. Within the Srsf2P95H/+ Tet2-/- cohort, I also observed development of CMML in both native haematopoiesis and transplantation settings. So far, this is the first model to demonstrate synergistic interactions between Srsf2P95H/+ and Tet2-/- mutation, as well as initiation of CMML in vivo. For the Srsf2P95H/+ Cbl-/- model, I characterized a small cohort of mice due to prolonged breeding difficulties. Nevertheless, I discovered increased myeloid proliferation in the double Srsf2P95H/+ Cbl-/- and Srsf2P95H/+ Cbl+/- mutants. Collectively, the work included in this thesis creates an original contribution to understanding the role of SRSF2P95H mutation in MDS, its synthetic lethal genetic interactions, potential therapeutic targeting of SRSF2P95H cells, and how it co-operates with other recurrent mutations in initiation of CMML.