Medicine & Health

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  • (2022) Cao, Jun
    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
    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.

  • (2022) Kelly, Shane
    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.