Medicine & Health

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Now showing 1 - 10 of 11
  • (2022) Cao, Jun
    Thesis
    This thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.

  • (2022) Aishah, Atqiya
    Thesis
    Obstructive sleep apnoea (OSA) pathogenesis is multifactorial with contributions from anatomical and non-anatomical endotypes. Current anatomical-orientated therapies are often inadequate or poorly tolerated with no pharmacotherapies available for OSA. Recent research shows that a combination of noradrenergic and anti-muscarinic agents increases upper-airway muscle activity (key non-anatomical endotype) and reduces OSA severity. Thus, my thesis aimed to investigate alternate therapies for OSA including novel pharmacotherapies targeted towards non-anatomical OSA endotypes as well as combining with existing anatomical approaches based on OSA endotype characterisation. Study 1 investigated the effects of the noradrenergic agent atomoxetine combined with 2 different anti-muscarinics (solifenacin or biperiden) with different receptor-selectivity profiles. Previous studies combined atomoxetine with the antimuscarinic oxybutynin which has broad receptor-selectivity. The goal was to gain mechanistic insight into specific antimuscarinic receptor subtypes for OSA pharmacotherapy which may also have a better side-effect profile versus oxybutynin. The different anti-muscarinics plus atomoxetine improved upper airway function and perceived next-day sleepiness in people with OSA albeit to a lesser extent compared to oxybutynin. This suggests broad or at least M2 muscarinic receptor selectivity may be important in mediating the efficacy of this drug combination for OSA pharmacotherapy. Previous studies with noradrenergic and antimuscarinic agents have been short term (≤1 week) and have not included different doses. Accordingly, in study 2, I investigated longer term (1-month) safety, tolerability, and efficacy of different doses of atomoxetine plus oxybutynin (ato-oxy) versus placebo. 1-month of ato-oxy was generally well-tolerated with a side effect profile consistent with the known profile of each agent alone. An 80/5 mg dosage combination of ato-oxy reduced key OSA severity metrics by ~50%. In study 3 I aimed to investigate if OSA endotype characterisation can be used to inform targeted therapy to resolve OSA in the clinically relevant group of patients who have an incomplete therapeutic response to oral appliance alone (~50% of patients). In these individuals, I systematically added existing anatomical therapies and emerging non-anatomical therapies (i.e., ato-oxy) according to OSA endotype characterisation. OSA was controlled in 50% of participants with addition of other existing anatomical interventions. Almost all the remaining participants were fully treated with the addition of non-anatomical pharmacotherapies. These novel findings provide important insight for the development of novel pharmacotherapy and combination therapy approaches informed by underlying physiological mechanisms for future treatment and management of OSA.

  • (2023) Albanese, Bianca
    Thesis
    The incorrect use of child car restraint systems is a longstanding and widespread problem. While child restraints offer good protection, incorrect use increases the risk of death and injury to child occupants in a crash. Strategies to address incorrect use continue to be developed and implemented. However, no strategy has successfully addressed the complexity of interactions between the users i.e., the adult, the child, and the restraint. There is a need to engineer design-based solutions that target the ergonomics of child restraints from a user-centred approach. This thesis presents four interrelated studies evaluating the potential of targeted restraint design to reduce incorrect use. A multimethod, user-centred approach was used to identify restraint design features or clusters of design features with the lowest propensity for misuse by both adult and child users. A diverse range of methods were used to capture the breadth of interactions that occur between the child, the adult and the restraint. Methods include in-depth observation studies, a laboratory trial, a driving trial and the retrospective analysis of naturalistic driving data. Descriptive and complex multilevel statistical analysis techniques were used, including those that allow for the control of potential confounders and clustering of data, as well as content analysis for qualitative data. Results from this body of work demonstrate the substantial scope for reducing incorrect use of child restraints through attention to their design. To realise this reduction, there is a need to shift to user-centred design that recognises the usability of a restraint as a precedent to its utility. Design that incorporates features with a low propensity for misuse by both the adult and child users will ensure a system offers the level of crash protection for which it was designed. There is a need to further investigate different restraint systems, with different features, across all tasks of restraint use from a user-centred approach.

  • (2023) Epiu, Isabella
    Thesis
    Across the world, altered breathing states like shortness of breathing are common presentations, more recently with millions infected during the COVID-19 pandemic. However, most people with chronic pulmonary diseases have longstanding shortness of breath. Dyspnoeic patients may suddenly become cognitively aware of their breathing difficulty, often in association with underlying infection, hypoxemia and/or hypercapnia, which are triggers to seek medical care. However, some patients with asthma and Chronic Obstructive Pulmonary Disease (COPD) lose lung function very slowly, adapt to it and present late in the course of their disease, without a preceding sudden deterioration. Therefore, further investigations to understand neural processing of respiratory stimuli in various respiratory diseases is paramount. In this thesis, I focus on respiratory motor impairments in COPD, one of the leading causes of morbidity and mortality worldwide. Novel investigations included swallowing assessment, inspiratory muscle responses to sudden airway occlusion, and neural perception including airway sensation, and EEG studies. I also built a decision analytic cost-effectiveness analysis model. Using bedside swallowing tests, I found lower tongue strength in this Australian sample, compared to the published weighted averages. The swallowing capacity was lower in the COPD than control groups, which also had a higher respiratory rate. Around 30% of the COPD group showed clinical signs of airway invasion, and their inhibitory reflex was delayed. The COPD group also had a reduced perception of the airway loads that could predispose them to aspirate, further increasing the risk of complications like pneumonia or acute exacerbations, which together reduce the quality of life of patients with COPD, some of whom may require intensive care unit (ICU) admission for respiratory failure and infection. This thesis provides further evidence of the swallowing, respiratory and cognitive impairments in COPD for targeted approaches to improve the neural control of breathing in this group. From the cost-effectiveness swallowing and respiratory sensation assessment (SwaRSA) model, the four SwaRSA strategies were all effective in reducing COPD exacerbations. The questionnaire based swallowing score alongside a modelled rehabilitation was the most cost-effective strategy, saving $8800 AUD per QALY gained. In people with COPD, SwaRSA testing, and a subsequent intervention appears costeffective relative to no-SwaRSA screening. The SwaRSA model is ready to be studied in a randomised trial to enable its implementation in routine practice at respiratory clinics and/or critical care units.

  • (2021) Barnet, Megan
    Thesis
    Effective anti-cancer response to checkpoint inhibitors can be paired with systemic immune activation, manifesting as auto-immune toxicity. This may represent a host predisposition to response (and toxicity); a genetic equivalent to the paired increased in response and toxicity seen with combination drug treatment. Germline contribution to anti-PD1 response and toxicity, however, is not well studied. Nucleotide-binding oligomerisation domain 2 (NOD2) is an innate immune receptor involved in maintaining immune homeostasis and its impairment is associated with autoinflammatory and inflammatory disease, most notably Crohn’s Disease; a form of inflammatory bowel disease. Germline variation in NOD2 could predispose to heightened response to anti-PD1 treatment. I identified compound heterozygous mutations within NOD2 (expected general population genotype frequency ~1 in 10,000) in a patient who experienced systemic “abscopal” response of metastatic melanoma following focal radiotherapy, simultaneously with a flare of Crohn’s colitis. To further explore the concept of germline contribution to anti-cancer response following immune stimulation, I then recruited 144 patients treated with single-agent anti-PD1/PD-L1 for metastatic non-small cell lung cancer (NSCLC). I selected patients with “high response” (n=40) or “non-response” (n=10) for germline whole genome sequencing. In these 50 individuals, rare and common variants were analysed and compared to general population and patients with NSCLC. To further explore the genetic association, we generated a translational mouse model truncating the candidate gene, NOD2, using CRISPR-Cas9 gene targeting (Nod2fs). Mice were transplanted subcutaneously with a syngeneic, mismatch repair deficient tumour (MC38). Tumour regression and time to progression following treatment with anti-PD1 antibody was improved in Nod2fs compared with wild-type (Nod2wt) animals and was accompanied by more effector memory subtype tumour infiltrating CD4 and CD8 T cells. Single cell gene expression analysis of Nod2fs compared with Nod2wt splenocytes provided insight into potential mechanism of the observed effect. Host predisposition to response and toxicity to immunotherapy represents an extensive and largely unexplored area. Further work is needed to define the potential role of germline immune variants as biomarkers for response and/or toxicity and as therapeutic targets. Germline analysis should be performed where possible alongside tumour analysis in order to identify novel tolerance checkpoints such as NOD2 with potential to modulate immune response to cancer.

  • (2022) Kelly, Shane
    Thesis
    Autoimmune diseases represent a significant cause of morbidity and mortality, for which there is no cure. The pathogenesis of autoimmunity is unknown. Identifying and profiling antigen-specific lymphocytes has the potential to advance our knowledge of disease pathogenesis, and potentially offer more targeted therapy. The overall aim of this thesis was to identify antigen-specific cells in a range of autoimmune diseases and characterise them proteomically, transcriptomically and genomically using novel sequencing technologies. The experimental design comprised identifying pathogenic B cells from peripheral blood by flow cytometry, followed by single cell sorting and sequencing by G&T seq. Those cells confirmed as antigen-specific then underwent in depth genomic, transcriptomic and proteomic analysis. For the cryoglobulinaemia project I succesfully charcaterised antigen-specific B cells in a pateint who had a rare IgA RF-producing clone. It harboured nonsense mutations in TNFAIP3 and in BCL-10, both of which it is anticipated lead to increased NFKB signalling. For the MAG neuropathy project I successfully characterised antigen-specific B cells in all three patients. All had multiple IgM kappa clonal populations, although for two I was able to show that they arose from a common progenitor, despite being heavily mutated. Essentially all clones, irrespective of MAG specificity, harboured a MYD88p.L265P mutation. I also identified a number of other somatic mutations, including in CXCR4 in one patient, and in SIGLEC11 which was present in only one clonal branch of another patient. For the polyclonal models of autoimmunity project (ie PR3-AAV, MPO-AAV and Ro60+SjS) I was successful for two of the three diseases, although the cell frequency was exceedingly rare. In the one patient (who had PR3-AAV) where I isolated enough antigen-specific B cells to perform a meaningful analysis it was notable that they were enriched for IgG4, lambda, J6 gene usage, IGHE expression, and demonstrated low levels of somatic hypermutation. In summary in this thesis I was successful in most of my aims in identifying and multiomic profiling of antigen-specific B cells in a range of autoimmune diseases including cryoglobulinaemic vasculitis, MAG neuropathy and PR3-AAV. However given the significant challenges in isolating such cells in polyclonal models of autoimmunity, consideration needs to be given in sourcing alternative samples to peripheral blood and/or modifying the current experimental strategy.

  • (2023) Michniewicz, Filip
    Thesis
    Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable paediatric brain cancer, characterised by aggressive diffuse growth in the pontine region of the brain, preventing surgical resection and requiring targeted therapeutic intervention. Over 80% of DIPG patients possess epigenetic alteration H3 K27M, which substitutes a lysine for a methionine in the n-terminus tail of Histone H3, preventing the binding of methyl groups and therefore induces H3 K27 hypomethylation. This alteration partners with other mutations, notably TP53, PIK3CA, PDGFRα and other receptor tyrosine kinase associated alterations and ACVR1, complicating the application of targeted therapies. Over 200 clinical trials investigating various combinations of therapies have thus far failed to improve survival, with the majority of patients passing within a year of diagnosis. Copper is an essential metal ion which is widely incorporated into proteins and enzymes, which take advantage of its redox activity to catalyse reactions. Interestingly, copper is highly accumulated within the brain, is upregulated in several cancers, including brain cancers and is increasingly targeted by therapeutics. In particular, copper is known to influence RTK signalling in cancer, and in Wilson’s Disease has been linked to epigenetic alterations. A recent study also highlighted the redox ability of the H3-H4 tetramer. Upon this basis, it was hypothesised that reducing copper may represent a viable therapeutic strategy for DIPG. Interrogation of patient transcriptomic data revealed correlation between copper chaperones and epigenetic genes, and increased expression of copper chaperone MT1X. Copper reduction through copper chelator tetraethylenepentamine (TEPA) induced apoptosis in 3 DIPG cell lines and dose-dependently reduced phosphorylation of RTK associated proteins. Transcriptomic, proteomic and metabolomic analyses further revealed copper chelation activated inflammasome, impacted cell cycle proteins, impacted citric acid, cysteine and methionine, fatty acid, lipid, purine and pyrimidine metabolism, and dysregulated epigenetic mechanisms. Copper chelation also improved survival in an orthotopically injected PDX model of DIPG, and completely cleared the tumour in 25% of treated mice. This thesis outlines that copper chelation is a potential therapeutic strategy for DIPG, however further work is required to find combinations and more clearly define its cellular effects.

  • (2023) Affleck, Andrew
    Thesis
    Alzheimer’s disease is the most common type of dementia. It is an insidious, progressive, debilitating and ultimately fatal condition. It is pathologically characterised by the accumulation and progression of plaques and tangles through the brain which causes cell death. Despite it being known and studied for over 100 years, there is no treatment and no cure. A range of potentially modifiable risk factors for dementia have been identified, with the treatment of hypertension being acknowledged as likely the strongest of these. Furthermore, a significant proportion of individuals with Alzheimer’s disease also have cerebrovascular disease making hypertension, and its treatment, an ideal target. This thesis aimed to investigate the relationship between antihypertensive medication use during life and the histopathological brain changes seen after death. Alzheimer’s histopathology (chapter 3), cerebrovascular disease type changes (chapter 4) and astrocytic clearance processes (chapter 5) were assessed in 149 brain donor cases with pathological Alzheimer’s disease, cerebrovascular disease or were without significant neuropathology. The clinical records were retrospectively assessed for hypertension diagnosis and antihypertensive medication use and other metrics of significance such as clinical dementia rating. Chapter 3 showed that antihypertensive medication use associated with lower scores of plaque and neurofibrillary tangle progression through the brain. Chapter 4 assessed cerebrovascular disease, finding that antihypertensive medication use associated with less severe small vessel disease (mainly less dilated white matter perivascular space and rarefaction). Chapter 5 revealed that antihypertensive medication use normalised alpha-amylase levels (which related to pathologic tau levels in unmedicated individuals). In those taking antihypertensive medications, there were correlations between astrocytic reactivity around capillaries and pathological progression as well as between glymphatic insufficiency and perivascular space severity, glial fibrillary acidic protein (GFAP), and pathologic tau levels. In summary, the treatment of hypertension with antihypertensive medications, is associated with improved small vessel disease health and less Alzheimer’s disease spread through the brain. Astrocytes appear to function more optimally, supporting neurons to remove Alzheimer (and other) types of waste products more effectively and abating the spread of Alzheimer pathology.

  • (2023) Bradbury, Tom
    Thesis
    Background: Chronic Obstructive Pulmonary Disease (COPD) is a minimally reversible, inflammatory condition of the lower airways. Addressing exacerbations – acute episodes of symptom worsening - has emerged as a priority in the development of COPD management strategies and shapes the ethos behind trial design and concepts of efficacy in this field. Currently, there is poor consensus as to how the different aspects of exacerbations should be integrated into clinical trial outcomes. Furthermore, as COPD exacerbations are a relatively newly defined clinical entity there is a need to re-examine previous assumptions regarding the clinical efficacy of established interventions, incorporating updated knowledge and research methods. Aims: The aim of this thesis was to investigate how COPD exacerbations are represented and used as a measured outcome of efficacy and safety in past and current clinical trials of exacerbation prevention and management. The secondary aim was to develop a range of skills needed to conduct original research in this area. Methods: Five studies were conducted. These were a systematic literature review of exacerbation-based outcomes in published clinical trials, qualitative analysis of original interview data to assess COPD patient priorities in exacerbation treatment and future research, and a case series of an app-based exacerbation identification system. Quantitative analyses of the TASCS (Theophylline and Steroids in COPD Study) and PACE (Preventing Adverse Cardiac Events in COPD) trial datasets were performed to advance our understanding of how pharmacological agents modulate exacerbation properties in different COPD patient phenotypes. Results & Conclusions: The heterogeneity and evolving understanding of the pathophysiology of COPD is new knowledge which should be incorporated into clinical trial design and conduct. This was shown in the analyses of the TASCS and PACE trial data, where established understandings of exacerbations and different patient phenotypes were challenged by the findings. The results of the remaining three studies suggest that: (i) trial outcomes pertaining to exacerbations should be standardised and validated, and (ii) how these outcomes are defined, valued by patients, and measured should be clearly communicated and accurately cited. This will improve data quality, enhance representation of patient values in future research and minimise ambiguity in communicating research results.

  • (2023) Sehnert, Rebecca
    Thesis
    Cellular deficiencies in nicotinamide dinucleotide (NAD+) have been linked to a wide range of pathophysiologies. Boosting NAD+ levels via supplementation with its metabolic intermediates, such as nicotinamide mononucleotide (NMN), has been shown to be a potential treatment for many diseases. Notably, NMN administration is a promising solution to prevent female fertility damage due to chemotherapeutic insult. However, this strategy is severely limited due to a lack of drug delivery application methods. To address this need, we propose a drug-loaded hydrogel system that can be implanted at the location of interest. By chemically conjugating the NMN drug molecule to a poly (vinyl alcohol) (PVA) polymer via a linker of biodegradable ester bonds, it is hypothesised that we can prevent burst release while providing targeted, prolonged release duration through hydrolytic cleavage. PVA previously conjugated with photo-crosslinkable methacrylate pendants was chosen as the base system, as this allows for easy hydrogel formation. This work’s aim was to achieve conjugation of NMN into this PVA system, characterisation of the synthesis pathways utilised, as well as evaluation of the resultant hydrogel systems. It is proposed that a linear pendant containing multiple ester groups could be grown from the hydroxyl moieties on the PVA backbone via a series of carbodiimide reactions. Conjugation of the NMN to this pendant was investigated via three different synthesis pathways: 1) “Linear” amine building block, 2) “Reverse” amine building blocks and 3) “Fmoc” protecting group method. Each strategy has individual benefits and drawbacks, and each was evaluated for key parameters such as efficiency of reaction, maximum NMN loading achieved, and cytocompatibility. This work demonstrates the first known incorporation of NMN into a hydrogel system for the purpose of sustained drug release. These results demonstrate that NMN has been chemically conjugated into a PVA hydrogel system in a controlled, non-toxic and reproducible manner, allowing for eventual use in drug delivery applications.