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(2022)ThesisEosinophilic chronic rhinosinusitis (eCRS) or type 2 dominant chronic rhinosinusitis (CRS) is a complex inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Management of this condition is often difficult, requiring multimodal approaches with local and systemic medications as well as surgical therapy. Biologic therapies, including mepolizumab (a monoclonal antibody targeting IL-5), have been successfully used in eosinophilic asthma and are emerging as a new treatment in CRS and eCRS, however there is limited data in this field. This thesis focuses on biomarkers and biologics in CRS. Firstly, identifying and assessing clinical biomarkers that are available to the guide management in patients with CRS and eCRS. Secondly, a prospective open-label single-arm single-centre study of the effectiveness of mepolizumab in patients with eCRS was performed. In this study, biomarkers as well as clinical, functional, and patient reported outcomes are assessed to determine the utility of mepolizumab as biologic treatment for eCRS.
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(2022)ThesisThe homeostatic regulation of amino acid concentrations is crucial for optimal brain function and development. Different amino acid transporters at cell membranes work together to facilitate the movement of amino acids into and out of the brain. Despite countless in vitro and in vivo research on these amino acids' activities, many fundamental concerns about their metabolic function in different brain areas and pathophysiological conditions remain unanswered. In the framework of this thesis, the effects of exogenous administration of several non-essential amino acids and the participation of their specific transporters in brain metabolism were investigated in Guinea pig cortical brain slices and mouse brain tissues using a targeted neuropharmacological and metabolomic strategy. Alterations in brain metabolism were analyzed using 1H and 13C nuclear magnetic resonance spectroscopy to evaluate changes in metabolite pools and 13C-enriched substrates. All the amino acid transporters mentioned in this study were addressed by the existing solute carrier (SLC) gene nomenclature system for amino acid transporters. The effect of exogenous L-aspartate, L-ornithine, and their salt, L-aspartate-L-ornithine (LOLA), on brain metabolism was investigated with or without an intact blood-brain barrier (BBB). The results indicated that neither L-aspartate, L-ornithine, nor LOLA, affected brain metabolism with an intact BBB. In cortical tissue slices L-aspartate increased brain metabolism concentration-dependently, L-ornithine significantly slowed it at higher concentrations (100 μmol/L), and the effects of LOLA was largely dependent on the balance of its two constituent amino acids. D-aspartate, another isoform of aspartate, produced a range of metabolic impacts, particularly on glutamatergic and GABAergic systems, with varying concentrations. In principal component analysis, the effects of D-aspartate were clearly distinguished from those of L-aspartate, indicating a metabolic pattern distinct from that of excitatory mechanisms. L-Proline administration significantly inhibited brain metabolism in Guinea pig cortical tissue slices, indicating a GABA-like effect; however, it was not a significant metabolic substrate. While it was actively taken up by cells in a concentration-dependent manner but was not completely metabolized. The metabolic pattern revealed that L-proline's effects clustered with 3-aminopropyl(methyl)phosphinic acid (SKF 97541), GABA, 1,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and (5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid) 1,1-dimethylethyl ester (RO194603) at lower concentrations (10 μmol/L) and with vigabatrin and RO194603 at higher concentrations (100 μmol/L); indicating that proline may act as a GABAB receptor agonist or GABAArho antagonist. Deletion of SLC6A17/NTT4 (neurotransmitter transporter 4) gene significantly impaired glutamate-glutamine cycle, reduced incorporation of 13C into Krebs cycle intermediates, and increased incorporation into lactate in the brain of mice lacking the gene. NTT4 knockout also altered several important metabolites in glutamatergic neurones, implying that it is a crucial transporter for maintaining brain amino acid homeostasis. Investigation of glutamine transport in cerebellum demonstrated that system A dominates glutamine transport in the cerebellum, with contributions from system N, which is inhibited by histidine and 2-(Methylamino)-2-methylpropionic acid (MeAIB) exerting the most metabolic influence. Inhibition of systems A and L by L-γ-Glutamyl-p-nitroanilide (GPNA) and 2-amino-4-bis(aryloxybenzyl)aminobutanoic acid (AABA) did not influence glutamine transport due to their low affinity for the transporters. Inhibition of systems L and B0 by 2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) showed little effect on fluxes from [1-13C]D-glucose but increased the flux of [1,2-13C]acetate into Glu C4,5 and Gln C4,5. Effects of cycloleucine were comparable to BCH but less powerful. This study provided new insight into the role of several non-essential amino acids in brain metabolism and also showed how brain metabolism is regulated in different brain regions.
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(2022)ThesisPrimary total hip arthroplasty (THA) & total knee arthroplasty (TKA) are common, cost-effective surgeries that reduce the pain and disability caused by osteoarthritis. THA/TKA are associated with a small risk of complications, such as venous thromboembolism (VTE) and surgical site infection (SSI), resulting in poorer outcomes. VTE & SSI prophylaxis clinical practice guidelines exist, but it is unclear whether service providers comply, or whether this affects outcomes. Methods A prospective multi-centre cohort study was undertaken in consenting adults with OA having primary TKA/THA at one of 19 high-volume Australian public/private hospitals. Data were collected before and for one-year post-surgery. Compliance was calculated with the National Health & Medical Research Council (NHMRC) & Australian Orthopaedic Association (AOA) VTE clinical guidelines & Therapeutic Guidelines (TG) Antibiotic. Logistic and linear regression were undertaken to explore associations between clinical guideline non-compliance and complications and patient-reported outcomes (Oxford Hip/Knee Scores [OH/KS], EQ-5D), and cephalosporin prophylaxis and SSI. Results Data were analysed for 1875 participants. Clinical guideline non-compliance rates averaged 87% for TG Antibiotic, 65% for NHMRC VTE clinical guideline & 20.1% for AOA VTE clinical guideline. NHMRC VTE clinical guideline noncompliance was associated with an increased VTE risk (adjusted odds ratio [AOR]=2.83, 95%CI=1.59-5.28, p< 0.001) and with lower (worse) 1-year EQ-5D Index scores (β=-0.03, SE=0.008,p=0.002) & an inconsequential reduction in OH/KS (β=-0.76,SE=0.30,p=0.01). AOA VTE clinical guideline non-compliance reduced the risk of symptomatic 90-day VTE (AOR=0.1, 95%CI=0.0-0.4,p=0.01). TG Antibiotic noncompliance was associated with higher SSI risk (AOR=1.98, 95%CI=1.17-3.62,p=0.02) but not with PROMs. Reduced SSI risk was associated with cephalosporin dose (any SSI; AOR=0.68, 95%CI=0.47–0.99, p=0.05) and commencing antibiotics before skin incision (0-60 mins: any SSI, AOR=0.56,95%CI=0.36–0.89,p=0.01; DSSI, AOR=0.56,95%CI=0.36–0.89,p=0.01; ≥60 minutes: AOR=0.35, 95%CI=0.17-0.70,p=0.004; DSSI, AOR=0.35,95%CI=0.17-0.70,p=0.004). Changing dose (AOR=1.76, 95%CI=1.22–2.57,p=0.02) & receiving preoperative non-cephalosporin (AOR=1.35, 95%CI=1.01–1.81,p=0.04) increased SSI risk. Antibiotic prophylaxis duration was not associated with SSI. Summary Non-compliance with NHMRC VTE clinical guidelines & TG Antibiotic increased the risk of VTE & SSI. The contrary NHMRC & AOA VTE clinical guideline findings may be explained by AOA recommending aspirin. Increased compliance with high-quality VTE & antibiotic clinical guidelines may improve THA/TKA outcomes.
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(2022)ThesisThe adoption of the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988 (“the 1988 Convention”) has been widely viewed as the final step in establishing global drug prohibition. This thesis provides an examination of Australia’s decision to support and sign the Convention which has not been analysied before. It also provides a detailed history of the development of the Convention as Australia was a key participant in UN drug meetings at the time. This thesis is based on the first research to access archival files, primarily from Foreign Affairs but also from the AFP and Department of Health. Nearly 180 folders, totalling approximately 35,000 pages, were copied from the Australian archives. These files provide detailed reports of almost all meetings and drafts that progressed the 1988 Convention. Interviews with key participants were also conducted. It provides an interdisciplinary legal history of Australia’s involvement in the 1988 Convention using the lens of the international relations theory of neorealism and the political theory of historical institutionalism. Through process tracing, it uses the theories to examine whether neorealist geopolitical forces and institutional forces caused Australia to support and sign the Convention. The analysis finds that geopolitical considerations trumped early concerns that a third convention was not necessary. The analysis also demonstrates that institutional forces within the UN benefitted financially from drug prohibition and played an unusually strong role in encouraging the development of the 1988 Convention. It also finds that institutional forces within the Australian government, such as the AFP and Foreign Affairs, supported the new Convention to increase their own jurisdiction and powers. Lastly, it looks at whether alternative policies such as regulation or decriminalization were considered by key policymakers. It finds that key individuals did support decriminalization but were overpowered by institutional and geopolitical forces. The significance of the dissertation includes: large amounts of new data to explain the development of the 1988 Convention; it increases knowledge around the institutional forces of criminalization and global criminalization; it significantly increases our knowledge of the role of the United Nations in waging the War on Drugs; and it increases knowledge around how mid-level nations interact with global institutions.
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(2022)ThesisBackground: Queensland’s infant mortality rate (IMR) is higher than other Australian jurisdictions and the disparity is under-researched, particularly for Sudden Unexpected Deaths in Infancy (SUDI). Informed by Triple Risk and Adverse Childhood Events (ACEs) constructs, and with a focus on shared infant sleep, this thesis analyses risk factors to identify opportunities for prevention. Methods: Three analytical chapters include: extraction and reconfiguration of reported demographic data to compare international and Australian jurisdictions; multivariate analysis of linked administrative data (a six-year Queensland births cohort) to analyse pre-natal risk factors for infant death; and analysis of findings from a series of SUDI and post-neonatal deaths, incorporating reviews by the Queensland Paediatric Quality Council expert panel. Results: I confirmed that Queensland’s IMR was significantly higher than the rest of Australia for neonatal, post-neonatal, ill-defined, and non-Indigenous deaths, but not Indigenous deaths. Perinatal factors significantly associated with acquired cause of death after multivariate analysis (young motherhood, higher birth order, smoking in pregnancy, late antenatal care, preterm gestation, maternal obesity, Male infant), were identifiable but not modifiable by mid-pregnancy. Indigeneity and residence in low socio-economic areas were not associated with acquired cause of death after adjustment for other factors. Correcting for post-conceptional age at SUDI shifts the peak incidence to age less than 44-weeks post-conception. Death scene description, post-mortem investigation, and clinico-pathological correlation were inadequate in more than 30 percent of SUDI cases. After panel review, deaths attributed to suffocation and undetermined causes increased, acknowledging the contributory role of unsafe sleep in almost all SUDI, and the rarity of other sufficient causes. SUDI occurred in the setting of high levels of multigenerational social adversity. Conclusion: SUDI is an important contributor to Queensland’s excess infant mortality. The vulnerability to SUDI of infants born before 40-weeks gestation provides a new focus for prevention. The association of maternal pre-natal risk factors with maternal ACEs is consistent with the multifactorial genesis of SUDI and warrants further research. Opportunities for prevention are hampered by inadequate death investigation. SUDI occur in families experiencing multigenerational adversity, for whom engagement and support may help to mitigate highly prevalent risk factors including unsafe sleep.
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(2022)ThesisThis 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.
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(2022)ThesisObstructive 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.
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(2022)ThesisDiabetes is a condition affecting 7.4% of Australians. Individuals with diabetes often develop complications, which include retinopathy, neuropathy, and kidney disease. Consequently, these individuals require multidisciplinary care. The provision of accessible and timely care is critical, especially with retinopathy, where eye examinations are required to prevent and delay visual impairment. Thus, the objective of the thesis was to assess the current standard of eye care and investigate new ways to enhance eye care for individuals with diabetes. This was explored over two sections. The first section comprised of three studies to explore current models and examine the efficacy of new models. The first study investigated wait lists at a public hospital ophthalmology clinic through a review of referrals. This study established that wait lists were encumbered by poorly targeted referrals for chronic ocular conditions, which could potentially delay access to eye care for individuals with diabetes. Subsequently, two studies were conducted to assess changes in access from two recently implemented models. The second study comprised of a randomised clinical trial that evaluated a metropolitan public hospital collaborative optometry-ophthalmology clinic. Low‑risk participants with diabetes examined by an optometrist experienced quicker wait times without affecting diagnostic accuracy. The third study evaluated a nationwide diabetic retinopathy screening programme operated at primary health care facilities. A survey of health care practitioners, and audit of photos graded by an optometry-led service revealed an increase in access to retinopathy screening. Evaluation of these models revealed that optometrists play a vital role in providing alternative pathways, and that the models improve access in both urban and non‑urban regions. The second section of the thesis comprised of two experimental studies investigating new uses of corneal confocal microscopy and optical coherence tomography which visualise the corneal nerves and retinal layers, respectively. Two cross-sectional studies were conducted to examine corneal and retinal changes in individuals with diabetes. These studies indicated reductions in corneal nerve morphology and retinal layer thicknesses. Since optometrists are familiar with these devices, there is potential to enhance eye examinations in the future by utilising these ocular imaging instruments to detect other diabetic complications.
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(2022)ThesisThe emergence of single cell RNA sequencing technologies has opened a vast number of strategies to look at various aspects of immunity to infectious diseases, especially into the adaptive immune system. Here, we applied scRNA-seq to study rare antigen-specific memory B cells in Hepatitis C and COVID-19 disease. Firstly, a tool for the reconstruction of single T cell and B cell receptor (TCR and BCR) sequencing method was developed that can obtain full-length repertoire from short read sequencing of T and B cell at single cell resolution. This tool, VDJPuzzle was able to report the detection of V(D)J genes, isotypes, somatic hypermutations, membrane vs secreted exon isoforms. VDJPuzzle showed highly accurate detection of V(D)J when benchmarked against available tools together. The utility of this tool to explore infection dynamics associated between BCR and disease outcome was then explored for two diseases: Hepatitis C (HCV) and COVID-19. In the HCV study, properties associated with rare HCV-specific memory B cells and varied HCV infection outcome in primary infection and reinfection were examined. In the primary infection cohort, a higher maturation of memory B cells and a reduced level of aromatic residues was observed in individuals that developed chronic infection. In the reinfection cohort, no association of BCR recall was observed, however transcriptomic differences were observed prior to re-infection across clearers and chronics where, clearers had a pre-existing enrichment of genes associated with the TNF-α signaling via NF-kB pathway. There was also a population of memory B cells with increased CD95 surface expression that showed migration of these cells towards effector long-lived plasma cells showing higher expression of ZBTB32, TBX21, FAS, ITGAX, etc. In the COVID-19 study, we successfully extracted rare SARS-CoV-2 specific memory B cells from mild/moderate and severely infected subjects, at 1 month and 4 months convalescence. Interestingly, the VDJPuzzle tool observed a higher percentage of dual kappa-lambda chains in SARS-CoV-2-specific B cells. The presence of unique phenotypes was also identified in SARS-CoV-2-specific memory B cells from subjects with severe disease. In particular, there was an increase in two populations defined as ‘actBC1’ (CD80hiTNFAIP3hi) and ‘actBC2’ (CD11chiCD95hi) which we hypothesized might be associated with increased longevity of the memory B cell response. The severe patients also maintained a higher level of activation genes associated with TNF-α signaling via NF-kB pathway, which may relate to the ‘cytokine storm’ that is often observed in severe SARS-CoV-2 infected individuals. Whereas, in mild/moderate infected individuals a decline in activated genes was observed over time. In summary, this thesis took advantage of unique sets of scRNA-seq techniques to identify the causes associated with HCV-specific memory B cells towards the clearance and chronic infection outcome in primary and reinfection cohort. Furthermore, we looked at the potential mechanistic insights associated with SARS-CoV-2-specific memory B cell response towards how transcriptome contributes towards the long-term immunity in a mild/moderate or severe infected individuals up to 4 months at convalescence.
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(2022)ThesisAlzheimer’s disease (AD) is the most common neurodegenerative disease characterised by the development of amyloid-beta (Aβ) plaques, neurofibrillary tau tangles and neurodegeneration. Currently, a definitive diagnosis is only possible with positron emission tomography imaging of amyloid-beta or the analysis of cerebrospinal fluid for AD biomarkers. Both approaches have limitations, namely they are expensive, not widely available and having limited repeatability. Magnetic resonance imaging (MRI) using magnetic nanoparticle contrast agents has opened the potential for less invasive and costly diagnosis. Moreover, magnetic particle imaging (MPI) is a novel tracer-based technology, which derives signal from magnetic nanoparticles to produce images with high sensitivity. While this technology is in the preclinical stages, its high spatial resolution and rapid image acquisition renders it a powerful new tool for neuroimaging research and diagnosis of AD. This thesis seeks to develop biocompatible Aβ-targeted magnetic nanoparticle for use as -MRI contrast agent and MPI tracer as tools for early AD diagnosis. Investigations were undertaken to examine the in vitro biocompatibility and imaging efficacy of Aβ-targeted spherical and cube nanoparticles stabilised with a dimercaptosuccinic acid (DMSA) coating and Aβ targeted spherical iron oxide nanoparticles coated with poly(maleic anhydride-alt-1-octadecene) (PMAO). Results indicated superior stability and MRI contrast enhancement of the PMAO-coated nanoparticles, and thus we employed these in subsequent in vivo analyses. Having established the efficiency of PMAO-coated nanoparticles, we sought to determine their in vivo biocompatibility and biodistribution, and evaluate the efficacy of the targeted nanoparticles as a dual-mode MRI and MPI tracer for AD diagnosis using a mouse model of AD. Critically, this study demonstrated that administration of Aβ-targeted PMAO-coated nanoparticles results in hypointensities in the MRI image and signal in MPI scans, which colocalise with Aβ plaques on histology. Furthermore, MPI is demonstrated as an effective and efficient tool for determining and quantifying nanoparticle biodistribution, establishing it as a powerful tool for research and diagnosis. The present work provides compelling preliminary investigation and evaluation of an Aβ-targeted MRI contrast agent which could facilitate more widespread availability early AD diagnosis, opening the window for more effective treatment and prevention of AD.