Medicine & Health

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  • (2022) Badge, Helen
    Thesis
    Primary 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.

  • (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.

  • (2022) Khou, Vincent
    Thesis
    Diabetes 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.

  • (2022) Ulanova, Marina
    Thesis
    Alzheimer’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.

  • (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) Lasschuit, Joel
    Thesis
    This era has seen exciting developments in diabetes care, however complications relating to bone and foot health are proportionately understudied. Spanning these domains is Charcot neuropathic osteoarthropathy (CN), a rare albeit potentially devasting complication of diabetes. Implementation of interdisciplinary High-Risk Foot Services (HRFS) remains a national priority, with the goal of improving diabetes-related foot complication outcomes. HRFSs deliver coordinated expert care, however literature formally evaluating their benefit is sparse. Chapter 2 comprises the first Australian publication to demonstrate lower inpatient cost, as well as Emergency Department avoidance, associated with HRFS involvement. While public health outcomes are important, there is great need to reduce the individual impact of bone and foot complications in diabetes. Calcaneal quantitative ultrasound (QUS) has emerged as a promising technology for the evaluation of bone health. Chapter 3 assesses calcaneal QUS measurement with foot repositioning and different operators, demonstrating high intra- and interobserver precision and reliability after rudimentary training. Chapter 4 investigates the influence of glycaemia and adiposity on calcaneal QUS measures, with these bone health determinants of relevance in type 2 diabetes. Longitudinal data was available and the cohort had been phenotypically well-defined. Sex-related differences are emphasised. Early detection of poor bone health may provide an opportunity for targeted intervention. In Chapter 5, calcaneal QUS is shown to provide comparable fracture risk prediction to the more traditional dual-energy x-ray absorptiometry, and this holds true in type 2 diabetes. Publication strengths were the prospective design, reliable fracture outcome data and long-term follow-up. Chapter 6 suggests that peripheral neuropathy may adversely impact bone health as measured by calcaneal QUS. In this publication the comparator group was balanced for confounders, a unique strength amidst relatively few similar studies. Finally, Chapter 7 presents learnings from amalgamated baseline data of the Charcot Foot Quantitative Ultrasound and Denosumab Study (CRUSADES). This ambitious multicentre randomised controlled trial (RCT) monitors calcaneal QUS over 18-months with denosumab used as a novel therapeutic in acute CN. CRUSADES is the first Australian RCT in acute CN, and one of three registered RCTs investigating denosumab in CN internationally.

  • (2023) Dhenni, Rama
    Thesis
    Memory B cells (Bmem) provide a unique layer of defence against pathogens and are an essential component of the immunological memory acquired by vaccination and infection. Long-lived Bmem are generated upon antigen encounter in the primary immune response. Following the resolution of primary response, a subpopulation of Bmem is retained in the lymph node draining the site of vaccine injection or pathogen entry. In this draining lymph node, resting Bmem occupy the subcapsular sinus (SCS) niche where they scan SCS macrophages for antigen. Booster immunisation reactivates Bmem to become either short-lived plasma cells (PC) or re-enter secondary germinal centers (GC) to increase their B cell receptor affinity and diversity to the immunising antigen. However, it is unclear whether Bmem retained in the draining lymph node after primary immunisation have different cellular phenotypes, transcriptional states, and cell fate potential compared to recirculating Bmem found in the non-draining lymph node. Here, the established SWHEL mouse model was used to track and characterise antigen-specific Bmem in the draining and non-draining lymph nodes. Using intravital two-photon microscopy to probe the cellular dynamics of Bmem under homeostatic conditions in vivo, this study found that recirculating Bmem in the non-draining lymph node have distinct localisation, dynamic, and behaviour compared to Bmem residing in the draining lymph node. Importantly, boosting in the draining lymph node reactivates Bmems that preferentially re-enter the GC, facilitating affinity maturation of the secondary antibody response. In contrast, boosting in the non-draining lymph node preferentially recalls the PC response. These differential memory recall responses are not dependent on persisting primary GC or memory CD4 T cells but can be altered by disrupting the SCS macrophages. Furthermore, transcriptomic profiling by single-cell RNA sequencing revealed that Bmem in the draining and non-draining lymph nodes occupy distinct cell states, suggesting their cell fate potentials may also be molecularly imprinted. This thesis thus highlights an additional layer of control over Bmem fate through their geographical positioning and suggests that the site of booster vaccinations can affect the Bmem cell fate choice and, thereby, the quality and quantity of the resulting secondary antibody response.

  • (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.

  • (2022) Pang, Bairen
    Thesis
    Prostate cancer (PCa) is the most common cancer in men worldwide with higher prevalence in the developed countries. Current screening and diagnostic approaches cannot accurately detect PCa in the early stage and stratify the risk groups to guide clinicians for the best treatment option. Extracellular vesicles (EVs) secreted from all kinds of cells contain proteins, nucleic acids and metabolites and play an important role in intercellular communication. EVs hold promise for PCa early diagnosis and progression monitoring. The goals of my PhD study were to: 1) evaluate the EVs isolated from PCa cell lines with immunoaffinity and aldehyde magnetic beads capturing, and investigate the performance of self-conjugated ApoB beads for lipoprotein quantification; 2) investigate the characteristics of plasma-derived EVs with commercial isolation kits combined with magnetic beads for clinical assignment; 3) discover novel biomarkers in a panel of PCa cell lines, and then validate these identified potential markers in plasma and urine of PCa patients for predicting the presence of “clinically significant cancer” and the prognostic risk groups. My findings indicate that magnetic beads can pull down EVs easily and immunoaffinity beads approach, based on biochemical composition by using common EV markers, is obviously better than the aldehyde beads for EV isolation and quantification with flow cytometry. Furthermore, the study of combination of three commercial kits with magnetic beads capturing established a systematic assessment of the EV quality, demonstrating that beads combining with size exclusion chromatography are superior to that combining with precipitation kit for EV isolation. Moreover, my proteomics analysis of PCa cell lines identified a total of 20 new EV protein biomarkers such as Kindlin3, LAMB1, Histone H4 et al. These EV markers are associated with cancer invasion, migration, regulation, tumour microenvironment and metastasis. My validation results show the unique expression patterns of these markers, in EVs of plasma and urine samples from different stages of PCa patients, are promising and demonstrate the potential value for PCa diagnosis and prognosis. In summary, my PhD studies have established unique EV isolation methods for clinical EV application and discovered a panel of novel EV biomarkers for PCa diagnosis and stage stratification, holding promise for personalised medicine.