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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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(2021)ThesisAim: To determine the role of topical Caffeine, a Xanthine derivative in slowing myopia either as a single-drug or in combination with Atropine. Methods: A systematic review and meta-analysis for Atropine in myopia control was followed by a short-term dispensing trial to select a single Atropine concentration to use in combination with Caffeine. In a prospective, randomized, dispensing trial, children with myopia were assigned to daily use of either Caffeine-2%, Atropine-0.02% with Caffeine-2% or Atropine-0.02%. A parallel non-randomised group of spectacle lens wearers were controls. The six-month change in spherical equivalent, axial length, pupillary diameter, and accommodative amplitude were compared between groups. Finally, a validation trial monitored pupillary and accommodative amplitude changes over 24 hours with various concentrations of Atropine and Caffeine, either single or combined. Comparison between groups were performed using repeated measures Analysis of Variance with significance set at 5%. Post-hoc multiple comparisons conducted using Bonferroni correction. Results: Meta-analysis confirmed dose-dependent efficacy and side effects for all concentrations of Atropine excepting 0.01%. Similarly, short-term trial demonstrated no pupillary diameter/accommodative change with Atropine-0.01% in approximately 30% of eyes. Atropine-0.02% was selected to be used in combination with Caffeine and at six months, change in spherical equivalent/axial length was -0.20±0.34D/0.08±0.11mm, -0.20±0.30D/0.11±0.11mm, -0.39±0.38D/0.19±0.15mm and -0.33±0.29D/0.18±0.11mm with Atropine-0.02%, Atropine-0.02% with Caffeine-2%, Caffeine-2%, and single vision spectacles respectively. The pupillary diameter increase/reduction in accommodative amplitude was 1.20±0.85mm/-3.14±4.08D, 0.76±0.58mm/-2.84±4.35D, -0.07±0.47mm/-0.78±3.43D and -0.10±0.32mm/-0.22±3.81D respectively. Temporal observations of pupil diameter indicated, a) no significant variation with Caffeine, b) Post instillation to 60 minutes – Caffeine-2% combined with 0.05% and 0.1%-Atropine resulted in significantly fewer eyes reaching higher pupillary diameter compared to monotherapy with 0.05% and 0.1%-Atropine. There were no significant changes for accommodative amplitude. Conclusion: Caffeine-2% did not slow myopia when used either individually or in combination with Atropine. However, Caffeine in combination with Atropine significantly minimised the increase in pupillary diameter that occurs with use of Atropine.
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(2021)ThesisConcern about falling is a common and serious health concern for older people. However, older people's participation in proven interventions for reducing concern about falling remains low. Health literacy could be influential to older people’s long-term participation in health programs for concern about falling. This thesis aimed to understand the relationship between health literacy and concern about falling in community-living older people. Six studies were conducted: (i) proposed a multicomponent theoretical model on health literacy and concern about falling; (ii) conducted a systematic review and meta-analysis exploring the relationship between health literacy and physical activity; (iii) developed and validated the Falls Health Literacy Scale (FHLS), a health literacy instrument specific to falls; (iv) developed cut-points for the 30-item and 10-item Iconographical Falls Efficacy Scales (IconFES) and evaluated their construct and predictive validity to falls and reduced physical activity; (v) assessed the effectiveness of a six-week online cognitive behavioural therapy (CBT) program for reducing concern about falling; (vi) explored how health literacy affects adherence to a home-based exercise program. The main findings were: (i) health literacy is closely related to many determinants of concern about falling and greater efforts are needed to clarify the impact of health literacy on intervention adherence and decision-making of older people with concern about falling; (ii) older people with inadequate health literacy are less likely to engage in physical activity on ≥5 days per week than those with adequate health literacy; (iii) the FHLS is sensitive to levels of fall-related health literacy, with good validity in an older population; (iv) the developed IconFES cut-points were sensitive to variables associated with concern about falling and predicted fall incidence and physical activity restriction after one year; (v) online CBT is a feasible treatment method for older people, and a targeted program with a well-integrated psychoeducation module on concern about falling seems warranted to boost the therapeutic effects; (vi) education, history of falls, anxiety and neuroticism moderate the relationship between health literacy and adherence of older people to a home-based exercise program. The thesis findings elucidate key aspects of the relationship between health literacy and concern about falling in older people.
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(2021)ThesisBackground: Cervical spine degenerative conditions effect up to two-thirds of the population and are the most common cause of acquired disability in patients over the age of 50. These disorders commonly present with axial pain, myelopathy, radiculopathy or a combination of these symptoms. Surgical intervention is generally indicated in with failure of conservative management or with evidence of cord compression or myelopathy. Anterior cervical discectomy and fusion (ACDF) is an effective option. It is not well established what factors contribute to dysphagia and recurrent laryngeal nerve palsy complications following ACDF surgery. Objective: 1. To determine the rates of dysphagia and recurrent laryngeal nerve complications following ACDF reported in the literature and potential associated factors. 2. To determine rates of dysphagia and recurrent laryngeal nerve injuries in a large Australian series of ACDF by a single surgeon. Methods: For the systematic reviews, electronic searches were performed using electronic databases. Relevant studies reporting the rate of dysphagia or recurrent laryngeal nerve injury as an endpoint for patients undergoing ACDF for degenerative disease, myelopathy, cervical canal stenosis or ossification of the posterior longitudinal ligament were identified according to prior inclusion and exclusion criteria. Statistical analysis was performed using odds ratio (OR) as the effective size. I2 was used to explore heterogeneity. For the retrospective chart review, consecutive patients undergoing ACDF from 2015 to 2019 for cervical radiculopathy and/or myelopathy were included. Univariate logistic regression analysis was performed to identify risk factors of RLN palsy, swallowing problems and adjacent-level ossification disease (ALOD). Results and conclusions: We found that based on pooled analysis that there was a higher rate of dysphagia for multiple-level ACDF (6.6%) compared with single-level ACDF (4%). The pooled incidence of recurrent laryngeal nerve palsy from the literature was 1.2%, with no difference between multiple- and single-level ACDF. These rates were similar to analysis of our retrospective series, with 1.8% patients having recurrent laryngeal nerve palsy and 4.0% with clinical dysphagia. We confirm based on our series that multi-level operation was associated with higher rate of RLN palsy, but this was not affected by other factors including age, gender, and the use of plate, internal fixation or number of screws.
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(2021)ThesisHuman papillomavirus (HPV) is one of Australia’s most common sexually transmissible infections and the primary cause of most cases of cervical cancer. HPV also causes other cancers, including penile, anal and oropharyngeal, and around 90% of all cases of genital warts. HPV-related cancers and genital warts are associated with a considerable health and economic burden. Australia became the first country in the world to implement a national school-based HPV vaccination program. Relatively high HPV vaccination coverage has been achieved in Australia, reaching just over 80% overall in 2017, yet this is still 10% lower than global recommendations by 2030, and considerably lower than targets of 95% for childhood immunisations. In Australia, analyses of HPV vaccination data to date have showed lower coverage in areas with lower socioeconomic status and in some geographical areas, but no studies have investigated variation in coverage across schools, which is where HPV vaccines are delivered. Adolescents should have equal access to the HPV vaccine course, irrespective of which school they attend. My thesis aimed to quantify the variation in HPV vaccination initiation across schools in three jurisdictions, and to understand school characteristics associated with lower coverage, particularly in schools where HPV initiation coverage was lower than for the dtpa vaccine (dtpa vaccine is co-administered and co-consented with HPV vaccine, so lower coverage for HPV would indicate HPV vaccine-specific hesitancy). My thesis also aimed to explore strategies to address the gaps identified. I undertook four interlinked studies using mixed quantitative and qualitative methods. The first study, a population-based ecological analysis of school-level data, identified that 23% of schools in the three jurisdictions in 2016/ 2017 school year had HPV initiation coverage at least 5% lower than for dTpa vaccine. This outcome was associated with schools with a higher proportion of adolescents from areas with higher socioeconomic advantage and from English-speaking backgrounds, and with smaller schools. The second study focused on using a school-level attributable risk measurement (taking the strength of the association and prevalence of school factors into account). This study found small schools, special education schools, schools with lower attendance and schools with higher enrolments of Aboriginal and Torres Strait Islander (Indigenous) students were most strongly associated with lower vaccination initiation coverage (<75%). Although special education schools had a lower school-level attributable risk measurement (as there was a small number of such schools), they had a much higher odds ratio than other school-level factors. My third study, a systematic review and meta-analysis, investigated the effectiveness of vaccine decision aids in decreasing decisional conflict regarding immunisations and increasing vaccination uptake with an inclusion period up to July 2019. The review found that decision aids slightly increased vaccination uptake and moderately increased intention to vaccinate, as well as a reduction in decisional conflict. However, there were no studies on HPV vaccination decision aids that met the inclusion criteria for the systematic review. The fourth study was an evaluation of a pilot intervention to determine the impact, acceptability and sustainability of an enhanced HPV vaccination catch-up program for Indigenous students who were missing at least one dose, which took place in term 3 and 4 in 2019. The study involved analysis of vaccination data, calculation of costs of the program and in-depth interviews conducted in term 1 2020, with immunisation providers delivering vaccinations in low HPV vaccination coverage schools. The evaluation demonstrated that the pilot intervention was considered beneficial with additional doses administered to Indigenous adolescents at a moderate extra cost; however, the process of following up with parents was very time consuming. Despite follow-up, some students did not attend the scheduled vaccine clinics, suggesting the need for additional strategies (e.g., out-of-school programs, more flexible vaccination clinics) to reach them. My research has identified the need for qualitative research to understand the reasons for low vaccination coverage in specific school settings, and the reasons for potential HPV vaccine-specific hesitancy. There is also a need to develop HPV vaccination-specific decision aids and evaluate their impact. Finally, future interventions should consider targeting students outside the school-based program. Overall, my thesis has highlighted the importance of collecting and analysing school-level data. It provides important insights that are needed to address the current gaps in the HPV vaccination program and to achieve equity in HPV vaccination coverage.
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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.