Medicine (RMH) - Theses
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ItemOptimising patient outcomes in atrial fibrillation (AF) catheter ablation( 2022)Atrial fibrillation (AF) remains the most common arrhythmia worldwide with rising prevalence, driven by an aging population and the metabolic syndrome epidemic. AF is associated with morbidity and mortality risk, including reduced quality of life (QOL), congestive cardiac failure (CCF) and stroke. Sinus rhythm restoration has been shown to reduce hospitalisation rates, and improve patients’ QOL. Recent evidence also suggests that an early rhythm control strategy confers mortality benefit. Catheter ablation (CA) has been consistently shown to be superior to pharmacological rhythm control. Furthermore in patients with co-morbid AF and heart failure with reduced ejection fraction (HFrEF), there is now robust evidence for improved cardiovascular and survival outcomes with CA, thus firmly establishing the role of CA in these patients. Beyond CA, AF management has also broadened over the past decade to encompass a more holistic and multi-faceted approach. This includes an emphasis on addressing modifiable risk factors, including obesity, obstructive sleep apnoea (OSA), hypertension, and alcohol consumption, to both reduce the risk of AF occurrence and recurrence post CA. The aim of this thesis is to explore strategies to further optimize patient outcomes in AF ablation. The thesis could be divided into five major themes, underpinned by three randomised controlled trials (RCT). These themes are: i) novel ablation techniques; ii) novel ablation indication in cardiac comorbidity, specifically heart failure with preserved ejection fraction (HFpEF); iii) novel ablation technology; iv) role of coffee/ tea as modifiable risk factors; and iv) critical review of statistical methods/ data analyses to understand AF trials. Chapter 1 details our evolving understanding of focal arrhythmias and comparisons of mapping strategies, including multipolar mapping (MPM). We describe the pathogenesis of persistent AF (PsAF) and current ablation strategies utilized in the hope of improving arrhythmia outcomes. We discuss about radiofrequency (RF) ablation and various strategies for improving oesophageal safety, including the evidence for oesophageal temperature monitoring(ETM) and the biothermal physics and clinical evidence for high power short duration(HPSD) ablation. We explore the pathophysiologic relations between AF, HFpEF, and left atrial myopathy and the role of CA in this patient group. Current evidence on prevention of cardiovascular disease (CVD) through habitual coffee and tea intake is examined. In the current era of the COVID-19 pandemic we explore the various cardiac complications associated with COVID-19 disease, and management strategies including the use of prone electrocardiogram (ECG) for the detection of these complications. Chapter 2 explores the role of MPM in the context of a novel catheter, the High Density Grid (HDG) catheter, to guide CA in focal atrial and ventricular arrhythmias. MPM with the HDG catheter has been utilized in AF/ scar related ventricular tachycardia (VT) ablation, although its role in focal AT is undefined. We performed a case control study comparing MPM with conventional point-by-point (PbyP) in 54 patients. We concluded that MPM compared with PbyP mapping resulted in detection of electrograms(EGM) with earlier activation times, and shorter mapping and ablation durations, although clinical outcomes were equivalent. Chapter 3 describes important statistical concepts which clinicians should be cognisant of when designing and interpreting findings in AF outcomes studies. This is of particular relevance to this thesis given the undertaking of three RCTs. We explored concepts which were uniquely illustrated by previous major AF trials, including study designs, statistical analyses (intention to treat versus as treated versus per protocol), endpoint multiplicity, sample size calculations, and appropriate endpoint selections in AF trials. Chapter 4 describes the study design of the CAPLA study, which is a prospective, multi-centre, international RCT comparing two ablation strategies in PsAF patients undergoing their first ablation procedure, namely pulmonary vein isolation (PVI) versus PVI with posterior wall isolation (PWI). Adding PWI to PVI has been shown in early studies to improve arrhythmia free survival in PsAF patients, although further randomised data is needed to verify this finding. Chapter 5 represents the findings from the CAPLA study, the largest RCT to date to examine the role of adding PWI to PVI in PsAF patients. CAPLA was a prospective, international, multicentre RCT where 338 patients were randomised in a 1:1 ratio to either PVI alone or PVI with PWI, with the primary outcome of freedom from atrial arrhythmia from a single ablation procedure off AAD at 12 months follow up. We concluded that empirical PWI in PsAF did not improve arrhythmia recurrence outcomes compared to PVI alone. Chapter 6 explores the role of HPSD ablation in reducing the risk of oesophageal thermal injury (ETI), mediated through preferential resistive heating of local myocardial tissue or conductive heating of distal structures like the oesophagus. Studies have shown that HPSD is associated with improved procedural outcomes with no increase in complication risk. We performed a world-first RCT to directly compare HPSD with conventional lower power longer duration (LPLD) ablation on the posterior left atrial (LA) wall. In the Hi-Lo HEAT study we concluded that HPSD resulted in similarly low rates of ETI, with reduced procedural and RF ablation times. Furthermore arrhythmia recurrence was significantly lower in the HPSD group. Chapter 7 examines the impact of sinus rhythm restoration in patients with concomitant AF- HFpEF. Observational data suggest CA can improve haemodynamic outcomes and QOL. We performed a world-first RCT to directly compare CA with medical therapy in AF-HFpEF patients (STALL HFpEF). We concluded that CA resulted in significant reduction in peak pulmonary capillary wedge pressures (PCWP), improved exercise capacity and improved QOL. Furthermore sinus rhythm restoration reverses HFpEF in a proportion of patients. Chapter 8 describes the role of coffee and coffee subtype consumption on incident CVD, arrhythmia and mortality, utilizing data from the large scale UK Biobank cohort with long term follow up of over a decade. We concluded that increasing coffee intake was associated with a U-shaped relationship between incident CVD, arrhythmia and mortality, with the greatest benefit seen in those who consume 2-3 cups/day. Arrhythmia risk was reduced with ground and instant coffee, with neutral findings with decaffeinated coffee. All coffee subtypes reduced the risk of CVD and mortality. Chapter 9 explores a novel method of recording 12 lead ECGs in prone ventilated COVID-19 patients with severe respiratory distress, as these patients are at a higher risk of cardiac complications. The prone back (PB) ECG describes the placement of V1-V6 leads on a patient’s back in an exact mirror image to the position on the precordium. The PB ECG negates the need to turn over prone ventilated patients to record conventional supine ECG. We compared ECG findings between PB and supine positions in 100 patients. We concluded that the PB ECG was unreliable for detecting ST changes in anterior myocardial infarction (MI), although it was useful for ST/T wave abnormalities in limb leads, bundle branch block (BBB) detection and rhythm monitoring
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ItemOptimisation of Medical Therapies in Inflammatory Bowel Disease( 2022)Treatment expectations and outcomes for patients with IBD have greatly improved in recent decades due to the increased availability of highly effective medical therapies and the emergence of better strategies for using these agents. Concurrently, improvements in the personalisation of individual treatment decisions have occurred via the incorporation of numerous precision medicine tools into clinical practice. The optimisation of thiopurine immunomodulators has been enhanced via the use of pharmacogenomics and therapeutic drug monitoring. The use of concomitant allopurinol in thiopurine hypermethylators or patients with intolerance to thiopurine monotherapy has increased the efficacy and persistence of thiopurine therapy, although the exact mechanism of the favourable metabolic interaction remains to be confirmed. Despite an increased number of small molecule and biologic treatment options now available thiopurines will remain important medical therapies for IBD patients for the foreseeable future, hence their optimisation remains important. Anti-TNF agents have revolutionised the management of patients with luminal and fistulising disease, but their optimal dose and optimisation strategy remains to be determined. Reactive TDM in patients with secondary loss of response to anti-TNFs is now standard of care, although supportive data are stronger for infliximab than adalimumab. Proactive TDM of anti-TNFs, although intuitively appealing, is not supported by results from prospective studies, although recent results from studies involving multiple IMIDs are encouraging. Perhaps the proof of efficacy of proactive TDM will finally emerge from further refinement of dashboard-driven precision dosing pharmacokinetic models. Increased practicability of TDM should come from more widespread update of rapid testing, including remote sampling and monitoring. The modern-day potential to de-escalate medical therapies in IBD reflects the ability to first achieve prolonged objective remission in a substantial proportion of patients with current therapies. Data informing de-escalation treatment decisions have only emerged from recent studies, usually involving the cessation of either immunomodulators or anti-TNFs from patients receiving combination therapy. Although relapse rates are higher with anti-TNF withdrawal, the high anti-TNF re-treatment success rates demonstrated from recent well-designed studies suggest that biologic de-escalation, with its associated cost and safety benefits, may be considered in appropriate patients. To date the personalisation of IBD treatment decisions has been guided by outcomes research from epidemiological and clinical cohort studies and the results of clinical trials. More recently genome wide association studies and whole genome sequencing have increased the genotypic individualisation of patients, although the translation of this knowledge to clinical practice has been slow. Precision medicine tools have also expanded to include microbiome-based characterisation of disease phenotypes and predictors of treatment response, although the impact of this knowledge in clinical practice is only currently emerging. Future precision-medicine advances will incorporate the development of multiomics signatures of IBD into systems biology platforms that can be analysed and validated across multiple cohorts. This knowledge should help further personalise treatment decisions, and ultimately may be informative for the future prediction, and even prevention, of IBD.
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ItemNo Preview AvailableClinical and Molecular genetic determinants of pituitary tumours( 2022)Pituitary tumours account for 10-15% of all intracranial neoplasms and may be functional (hormone producing 70-80%) or non-functional (20-30%). Functional pituitary tumours cause significant morbidity and mortality, however due to their rarity, there are few studies adequately assessing molecular genetics and clinical determinants for outcomes. Somatotrophinomas (growth hormone secreting) and corticotrophinomas (adrenocorticotrophic hormone secreting) account for 30-40% of all functional pituitary tumour and increased mortality rates are seen in those with on-going evidence of hormone hypersecretion. This thesis aimed to evaluate the effectiveness of different treatment modalities and identify clinical factors with prognostic value in patients with these tumour types, using data collected from two Australian tertiary centres. Furthermore, clinical and genetic analyses were performed for two rare forms of pituitary tumours, thyrotrophinomas (TSHoma) and ACTH-secreting pituitary carcinomas (PC), as the pathogenesis and clinical behaviour of these tumour types is poorly understood. High rates of metabolic complications including diabetes, hypertension, and hypercholesterolemia were seen in patients with both corticotrophinoma and somatotrophinoma. In multivariate analysis, microadenoma (<10mm) and older age at presentation were found to be predictors of sustained biochemical remission after initial operation in patients with corticotrophinomas. For somatotrophinomas, larger tumour size, and higher GH and IGF-1 levels at diagnosis were found to be predictors of persistent disease and worse clinical outcomes. The rate of disease recurrence was found to be higher in both tumour groups than is currently reported in the literature: 26% versus 15-18% in corticotrophinoma [median follow-up 6.5 years (IQR 2.3, 13.3)] and 20% versus 3.3-10.6% in somatotrophinoma [median follow-up 10.3 years (IQR 3.6, 21.3)], possibly attributable to the long duration of follow-up and higher proportion of macroadenomas (greater than 10mm) (26%) reported in this thesis. Surgery was the first line treatment for all patients included in this study and our results showed low complication rates. Remission rates following repeated surgery were suboptimal for patients with corticotrophinomas (28%) and somatotrophinomas (22%). Compared to somatotrophinomas, corticotrophinomas responded earlier to radiotherapy (RTx). A higher proportion of patients with corticotrohinomas than somatotrophinomas (80% versus 35%) achieved biochemical remission within a year after RTx. This difference was not evident after 10 years of follow-up. Tumour mass control post RTx was seen in both groups (97%) within the first year and the benefit was sustained long-term. Hypopituitarism was the most common complication of RTx, occurring in 33%. Approximately 20% of patients had multi-hormone deficiencies requiring long-term hormone replacement. Although the median time to onset of hypopituitarism after RTx was 3 years (IQR 0.5, 5), late onset of hypopituitarism (after 10 years) was seen. Given the low success rates with repeat surgery, early consideration of adjuvant medical therapy and/or RTx is reasonable for patients with persistent or recurrent disease, particularly if there is no clear surgical target. A high proportion of TSHomas were macroadenomas (88%) and the rate of disease recurrence was low (12%). Only a small proportion of the patients required adjuvant medical (18%) and/or RTx (9%) to achieve disease remission. Seven TSHomas had whole-exome sequencing (WES) analysis: no classical driver gene mutations were identified, and the incidence of somatic variants found were relatively low. Nine of the 96 genes with somatic variants identified (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary gland according to the GTEx database and these variants were novel in TSHomas. Mutations in these genes could contribute to tumourigenesis. Large scale copy number variations involving gain or loss of whole chromosomes, or chromosomal (chr) arms occurred in 86% of tumour samples. Targeted gene panel testing was performed on tumour tissue from a case of ACTH-secreting PC. Two novel somatic variants in the CDKN1b and DAXX genes were identified. Both variants were predicted to lead to nonsense mediated decay of DAXX and p27 proteins and immunohistochemistry (IHC) confirmed the absence of both proteins. Mutations of these genes have been detected in other tumour types, including pancreatic neuroendocrine tumours. Future studies are needed to determine if these gene mutations are implicated in pathogenesis. This thesis provides novel insights into the clinical characteristics and molecular pathogenesis of several functional pituitary tumours. Future research is required, and clinical studies should include long follow-up periods, while genetic studies should include copy number variation and epigenetic analysis, as direct DNA sequence mutations alone are unlikely to explain tumour development.
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ItemInfluence of Alzheimer's disease proteinopathies in dementia with Lewy bodies( 2022)Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia in older adults, accounting for 15-20% of the dementia population. Clinically, people with DLB often present with progressive cognitive decline, accompanied by one or more of the DLB core clinical features, namely visual hallucinations, motor parkinsonism, cognitive fluctuations, and rapid eye movement sleep behaviour disorder. DLB is histologically characterised by abnormal accumulation of the synaptic protein alpha-synuclein as Lewy bodies and Lewy neurites in the brain. In addition, concomitant neuropathological changes, such as Alzheimer’s disease (AD) proteinopathies and cerebrovascular disease, often co-exist to varying degrees in people with DLB, but their clinical relevance is not well understood. For instance, approximately 50% of people with DLB have significant AD-related amyloid-beta depositions on neuroimaging, with the prevalence increasing with age. The overarching aim of this PhD is to investigate co-morbid neuropathological changes, particularly AD-related proteinopathies, in people with DLB and to evaluate their associations with clinical and imaging findings. The thesis examines the prevalence of amyloid-beta plaques, phosphorylated tau tangles and cerebral microbleeds in a prospective cohort of DLB participants using novel imaging and fluid biomarkers and explores their associations with clinical features and neurostructural changes. Understanding the role and influence of co-morbid neuropathologies in people with DLB is important as they may have important implications on clinical diagnosis, disease severity and prognosis.
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ItemBiological assessment of geriatric rehabilitation inpatients( 2022)Chronological age is a major risk factor for the development of chronic diseases and frailty. The growing ageing population has imposed a heavy burden on healthcare systems which are being inundated with geriatric patients. In clinical practice, older adults are assessed and managed by the Comprehensive Geriatric Assessment (CGA), a multidimensional and interdisciplinary clinical tool that evaluates medical conditions and functional capacity in multiple domains. While the CGA contains several detailed clinical tools, it currently does not involve any biological assessment. A biological assessment could identify individuals with an accelerated ageing process, provide additional information about their health status and ultimately help early diagnosis, prevention and recovery of age-related diseases. This PhD project investigated the biological determinants of adverse health outcomes in geriatric rehabilitation inpatients using clinical pathology data. The unresolved inflammation characterized by high C-reactive protein and low albumin, vitamin D deficiency and higher biological age determined by combined blood biochemistry markers were associated with frailty, institutionalization and mortality. In addition, a literature review that encompasses cell cycle regulators as cellular senescence markers in human peripheral blood cells was conducted, showing the potential as a biological assessment clinically. This thesis highlighted the predictive value of pathology parameters for adverse health outcomes and the importance of ensuring the resolution of inflammation and adequate levels of vitamin D during geriatric rehabilitation. Future studies are required to investigate the association of senescence burden in blood samples with clinical phenotype and rehabilitation outcomes, and evaluate the utility of CGA integrated with biological assessments in care planning.
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ItemElucidating the Roles of CCL17 and CCL22 in Inflammatory Arthritis( 2022)Rheumatoid arthritis (RA) is a complex, autoimmune disease that targets the synovial joints. It is characterised by chronic and systemic inflammation and if left untreated, leads to debilitating pain, permanent cartilage degradation and bone erosion in the affected joints. There is no cure and while glucocorticoids reduce RA inflammation, their long-term use leads to adverse effects. How glucocorticoids induce their immunosuppressive effects remains to be fully elucidated. Various inflammatory mediators and cell types perpetuate this heterogeneous disease. C-C motif chemokine ligand 17 (CCL17) is upregulated by the pro-inflammatory cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), and both are highly elevated in the synovial fluid of patients. GM-CSF induces CCL17 production in monocytes and macrophages via the epigenetic demethylase, Jumonji domain-containing 3 protein (JMJD3), and the transcription factor, interferon regulatory factor 4 (IRF4). CCL17 is similarly upregulated by interleukin 4 (IL4); however, this anti-inflammatory cytokine is present at low levels in RA patients. Together, GM-CSF and IL4 can generate dendritic cells in vitro. The pro-inflammatory CD1c+ dendritic cell subset is elevated in the synovium of RA patients, and while expression of this population correlates with RA disease activity and CCL17 levels, whether these cytokines induce CCL17 production by CD1c+ dendritic cells is unknown. CCL17 is one of two functional CCR4 ligands but, the role and regulation of the other ligand, CCL22, has not been explored in RA. In contrast to CCL17, CCL22 is constitutively expressed but its levels are decreased in the RA synovial fluid. GM-CSF and IL4 can induce CCL22 production but whether JMJD3 and IRF4 are needed for its regulation is undetermined, and whether CCL22 promotes or prevents inflammatory pain and disease remains unknown. In this PhD thesis, the role and regulation of CCL22 was investigated and compared to that of CCL17. Both chemokines were upregulated by GM-CSF and IL4 in human monocytes/ macrophages and BMDMs but unlike CCL17, CCL22 dependence on JMJD3 and IRF4 varied between these cell types. CCL17 and CCL22 production also varied in monocyte-derived CD1c+ dendritic cells, generated with GM-CSF, alone or together with IL4. While GM-CSF-induced CD1c and CCL17 expression were not affected by IL4 in differentiating DCs, CCL22 production was further upregulated by IL4. The role of CCL22 in an acute inflammatory arthritis mouse model was also explored and, in contrast to CCL17-deficient mice, Ccl22-/- mice were not protected from pain and disease, developing even more pain than wild-type mice. Lastly, the mechanisms used by a synthetic glucocorticoid were investigated, and it was found to downregulate mediators of the GM-CSF signalling pathway, and ultimately CCL17 and CCL22 production. In conclusion, CCL17 and CCL22 were shown to be differentially regulated by GM-CSF and IL4 in monocytes/ macrophages, and this could account for their differential expression in RA patients. Moreover, these chemokines were shown to have contrasting roles in models of arthritic pain and disease, despite their shared chemotactic functions, and these differences could extend to their potential roles in RA pathogenesis.
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ItemExploring the Bi-directional Association between Depression and Diabetes: A Real-world Electronic Medical Records Based Study( 2022)Depression and type 2 diabetes are leading causes of disability and major contributors to the global disease burden. Clinical studies have suggested a bidirectional association between diabetes and depression: Individuals with type 2 diabetes have a higher risk of developing depression than individuals without diabetes, while individuals with depression have a significantly higher risk of developing type 2 diabetes than those without depression. The bidirectional nature of this comorbidity is often associated with adverse health outcomes in both diseases including reduced quality of life and increased risk of other complications and death. Identifying individuals and factors associated with the onset of both diseases may help clinicians to provide alternative management and preventive strategies, which will eventually have long-term positive effects on both mood and glycemic control. As of date, the temporal trends in the burden and risks of both diseases in people of different age groups, gender, and ethnicities are underreported. In addition, the role of related complications in the bidirectional association between the two diseases has not been addressed at the population level. This thesis used nationally representative electronic medical records from the UK (The Health Improvement Network database, THIN) and the US (General Electric Centricity Electronic Medical Record, GE CEMR) to examine the dynamism in the bidirectional association between type 2 diabetes and depression, and the interplay of cardiometabolic diseases and prognostic factors. To add to what is already known in the literature, emphases were laid on three main objectives: (i) Evaluation of risk factor distribution and long-term depression and cardiovascular risks in people with young-onset diabetes (diagnosed with type 2 diabetes at age less than 40 years) and usual-onset diabetes (diagnosis at age of 40 years or more); (ii) Evaluation of risk factor distribution, and the risk of type 2 diabetes in people with depression, and (iii) The real-world therapeutic management of people with depression. Chapter 1 introduces the key concepts of the mechanisms for the bidirectional link between depression and diabetes and presents the aims, research questions, and outline of the thesis. The second part of this thesis describes the database used and evaluates the representativeness of the US database with respect to the number of visits and the distribution of demographics, major cardiometabolic, and mental illnesses. The number of visits (designed to meet the need for objective and reliable information about the use of ambulatory medical care services) and the distribution of major cardiometabolic and mental illnesses (designed to assess the health and nutritional status) were compared with those from the US national surveys. Results from this section demonstrated the comparable distribution of office visits and major diseases including diabetes, obesity, and depression. Potential differences in gender and age distribution were observed and adjusted for in all downstream analyses. The results reaffirm the usability of the Centricity electronic medical records for conducting epidemiological studies while acknowledging major weaknesses inherent to all electronic medical records. Chapter 3 examines the trends in the bidirectional association between depression and type diabetes in different sociodemographic groups using the US database. Several key findings emerged. First, the prevalence of depression in people with type 2 diabetes increased significantly, especially among African Americans. Second, African Americans diagnosed with depression above the age of 50 years are the most likely to have type 2 diabetes, while white women with diabetes below 50 years had the highest probability of depression. The observed trend and sociodemographic disparity in both diseases imply a growing number of high-risk individuals with poorly managed depression and type 2 diabetes. This paved the way for further research pertaining to the real-world management of depression (chapter 4), and the understanding of factors that are contributing to the increase in depression and type 2 diabetes, including factors specific to demographic subgroups (chapters 5 and 6). The study in Chapter 4 explores the real-world population-based patterns and intensifications of specific antidepressant prescriptions targeting major depressive disorder, and the factors driving treatment intensifications after depression diagnosis. Findings from this research suggest more than a third of adults in the UK and the US diagnosed with depression are between the ages of 18-39 years with consistent increasing trends among men. It was also concluded that age, socioeconomic status, ethnicity, and cardiometabolic multimorbidity are the major sociodemographic and non-psychiatric risk factors for antidepressant prescription changes among adults with depression in the real world. In Chapter 5, two research studies were conducted involving cohorts of individuals newly diagnosed with type 2 diabetes. The first study found increasing trends in young-onset diabetes and the prevalence of cardiometabolic multimorbidity and depression in people with type 2 diabetes between 2012 and 2017. Importantly, this study also concludes that African Americans have significantly higher risks of cardiovascular diseases compared to White Caucasians (especially among young adults recording 42 – 88% higher risks). Findings from the second research work indicate a significant increase in the burden and risk of mental illnesses including depression in people with type 2 diabetes between 2006 and 2017. After adjusting for major confounders, the study also found younger adults with type 2 diabetes had 5 – 57% significantly increasing risks of depression onset irrespective of gender and baseline diabetic complications (cardiovascular diseases, cancer, retinopathy, neuropathy, chronic kidney diseases, obesity). Finally, Chapter 6 evaluates the role of cardiometabolic multimorbidity and obesity in the development of type 2 diabetes among African Americans and White Caucasians newly diagnosed with depression. Results from this chapter indicate a higher prevalence of cardiometabolic multimorbidity among African Americans and an increasing prevalence of obesity between 2006 and 2017 in both African Americans and White Caucasians with significantly higher values among African Americans. Compared with their white counterparts, African Americans had significantly higher risks of type 2 diabetes across all age groups with 17 – 35% of the increase attributed to differences in multimorbidity and 15 – 31% via the obesity pathway. To conclude, this dissertation provides a detailed exploration and valuable insights into the current burdens and rates of type 2 diabetes and depression in real-life settings. It also provides an updated algorithm for the identification and estimation of both diseases in the population to overcome the underestimation of the diseases from national surveys. This is of particular importance to public health considering the increasing prevalence of both diseases over the past decades. The thesis also identifies cohorts of individuals and risk factors associated with significant and/or greater increases in depression and type 2 diabetes over time, which could serve as a guide for allocating resources toward these cohorts in the management of the diseases in the population. With the increasing prevalence of diabetes coupled with longevity, especially in developed countries, the findings from this thesis could be recommended as part of a strategy to reduce the incidence of, and morbidity and mortality from, diabetes and its associated complications. For example, the Australian National Diabetes Strategy 2021 - 2030 has set aside 7 high-level goals in reducing diabetes in the community spanning prevention and awareness strategy; early detection and management; identification of high-risk individuals; and research agenda. The strategy identifies the most effective and appropriate interventions to reduce the impact of diabetes in the community and lead the way internationally in diabetes prevention, management, and research. Overall, this thesis advances current approaches to understanding the complexity of the bidirectional association between depression and type 2 diabetes.
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ItemIdentifying antibody responses associated with protection from malaria in pregnant women( 2022)Each year, over 100 million women become pregnant in malaria-endemic areas. Infection with the Plasmodium parasite can cause maternal anemia, premature delivery, low birth weight and infant mortality. Placental malaria pathogenesis is driven by the sequestration of Plasmodium falciparum-infected erythrocytes (iRBCs). iRBCs bind to the glycosaminoglycan chondroitin sulfate A (CSA) displayed on the placenta through VAR2CSA, a parasite-derived protein. However, antibodies to VAR2CSA have been associated with protection from placental malaria. Therefore, the overall objective of this work was to understand antibody responses to VAR2CSA expressing RBCs in three scenarios: 1) natural infection with P. falciparum parasites through mosquito bites, 2) immunization with the VAR2CSA-based vaccine candidate PAMVAC and 3) treatment with IPTp-type drugs. More specifically, we were interested: in 1) assessing the association between protection from placental malaria and levels of opsonizing antibodies that direct monocytes to phagocytose VAR2CSA expressing RBCs; 2) evaluating whether PAMVAC vaccine formulations elicited specific IgG antibodies with similar functions to those observed following natural infection; 3) exploring the dynamics and longevity of IgG antibodies to recombinant VAR2CSA antigens and 4) describing the in vitro effects of IPTp type drugs on monocytes ability to phagocytose VAR2CSA expressing RBCs in the absence of specific antibodies. The most important discoveries made in this project were: 1) at delivery, naturally acquired antibodies to VAR2CSA were associated with protection from placental malaria in women infected with P. falciparum; here, protection was associated with functional antibodies that directed monocytes for the phagocytosis of CSA binding parasites. 2) PAMVAC vaccine formulated with GLA-SE induces in nulliparous women living in a malaria endemic area, a similar functional antibody activity to that observed in natural infected women in 1). 3) levels of IgG antibodies to recombinant VAR2CSA antigens differ between infected and uninfected women, whether the infection is microscopic or submicroscopic, and were higher in women receiving IPTp with DHA-PQ; additionally, we found that, in the absence of reinfection, IgG antibodies to recombinant VAR2CSA were short-lived, particularly in those women infected at their first ANC visit. And last, we found that 4) both sulfadoxine and azithromycin are associated with higher levels of monocyte phagocytosis of CSA- binding parasites in vitro assays. All things considered, the findings presented in this work point to a promising path for controlling malaria in pregnancy by targeting one of the underlying causes of adverse birth outcomes: the sequestration of P. falciparum CSA parasites in the placental tissue.
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ItemDietary Therapies For Adults With Epilepsy( 2022)Epilepsy is a chronic neurological condition, characterised by recurrent, spontaneous seizures. For the majority of people with epilepsy, their seizures will be controlled by anti-seizure medications. However, one-third of people with epilepsy will not have their seizures controlled, and in these patients with drug-resistant epilepsy, alternatives to medications should be considered. Ketogenic diet therapy is well-established in paediatric epilepsy care, however it has not been widely translated into adult practice. This thesis focuses on the feasibility, safety and efficacy of novel diets and dietary supplements as potential treatments for adults living with epilepsy in Australia, and emerging evidence for this approach as an adjunct treatment for super-refractory status epilepticus. The first aim of this thesis was to determine the feasibility and efficacy of novel dietary therapies for adults with drug-resistant epilepsy. To address this aim, we first conducted a 12-week randomised-controlled trial and 12-month open label extension study of oral triheptanoin oil as an add-on treatment for adults with drug-resistant epilepsy. Next, we investigated the feasibility and efficacy of the modified Atkins diet for epilepsy in adults in a 12-week randomised-controlled trial. Finally, we conducted a prospective audit of a newly established dietary therapy for epilepsy service embedded in a quaternary teaching hospital. The findings of these trials highlight challenges of conducting clinical trials of dietary therapy for epilepsy in adults, such as adherence and high attrition rate. We observed some adults with drug-resistant epilepsy may benefit from dietary therapy, with few serious adverse effects associated with its use. The second aim of this thesis was to investigate the emerging role of dietary therapy as treatment for super-refractory status epilepticus in adults. A review of the literature found a small number of retrospective, observational studies reporting use of the classical 4:1 ratio ketogenic therapy in this setting. We then conducted a retrospective cohort study at two quaternary teaching hospitals of patients treated with a 2:1 ratio ketogenic therapy for super-refractory status epilepticus. This lower ratio ketogenic therapy may be associated with fewer complications and better align with current critical care nutrition guidelines. The development and implementation of non-drug treatment options for epilepsy is crucial in the context of a multifaceted approach to improving seizure control and reducing disease burden. The research in this thesis demonstrated the safety, acceptability, practicality, and efficacy of dietary approaches as adjunct therapies for patients with drug-resistant epilepsy as an outpatient, and for critical care inpatients with super-refractory status epilepticus. There remains a significant need for ongoing research focusing on optimal dietary regimens and strategies to increase patient retention of dietary therapy long term for adults with epilepsy.
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ItemThe role of antibody, complement, and innate immune cells in protective immunity to malaria( 2022)Malaria continues to cause high morbidity and mortality worldwide. In Plasmodium falciparum malaria, the membrane of infected erythrocytes (IEs) is modified to express the parasite-derived protein, P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is the main antigenic target contributing to protective immunity through antibody development. Naturally acquired antibodies are key to protection from malaria that can inhibit parasite growth and neutralise parasites, but sterile immunity is never achieved. Therefore, it is important to dissect antibody features that best correlate with protective immunity. These antibody features are driven by the antibody constant (Fc) region that could generate protective immune responses against malaria. My thesis aimed to 1) dissect the role of antibody-mediated complement activation in immunity to Plasmodium falciparum infection, 2) understand in vitro the role of antibody-dependent phagocytosis (ADP) by phagocytic cells in peripheral whole blood in parasite clearance, and 3) assess the role of ADP of IEs by neutrophils and monocytes as a clinical correlate of protection against severe malaria in children and placental malaria in pregnant women from malaria-endemic areas. For this purpose, for the first time, we developed high throughput plate-based assays to simultaneously measure ADP of P. falciparum-IEs by peripheral blood leukocytes using prediluted whole blood. We also used the developed whole blood phagocytosis assays to assess clinical correlates of protection from placental malaria in pregnant women and severe malaria in young children from malaria-endemic regions and infected with P. falciparum. Our results suggested that opsonic antibody levels directed against P. falciparum-IEs promoted antibody-opsonic phagocytosis of IEs by neutrophils and monocytes in a malaria exposure-specific manner. We also showed that opsonising antibodies that promoted ADP of IEs in whole blood mainly targeted PfEMP1 on IEs, although antibodies also target secondary antigens on the IE surface, such as the most abundant band 3 proteins. Next, we showed that antibody-complement interactions are an integral immune mechanism contributing to enhanced phagocytic clearance of P. falciparum-IEs by neutrophils and monocytes from peripheral whole blood. However, complement did not induce antibody-mediated lysis in the presence of plasma from malaria-exposed pregnant women. In malaria-infected pregnant women, opsonising antibody levels against placental binding-IEs were associated with protection against placental malaria. But the same opsonising antibodies that recognised the recombinant DBL-3 domain of VAR2CSA were not protective against placental malaria. Thus, we suggest that opsonising antibody levels that indicate protection against placental malaria are conformation-specific. Last, our results demonstrated that in young children, opsonising antibody levels against EPCR-binding P. falciparum-IEs that promoted ADP by both neutrophils and monocytes were not associated with recovery from severe malaria. Our results suggested that whole blood assays could be exploited to understand antibody and complement interactions during P. falciparum infection that could be translated to low-resource settings to identify antibody correlates of protection in future vaccine design.