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(2015)ThesisCurrently there is an ongoing debate and a dearth of evidence around the efficacy of facemasks and respirators. Most studies have been observational and there is a lack of trial data around use and re-use of facemasks in the healthcare setting. Due to the lack of high quality studies, I hypothesised that there would be huge variations in the policies and practices around the use of facemasks and respirators in the healthcare setting. This thesis therefore aims to examine the policies and practices around the use of these products in low resource countries. Five studies were conducted at varying administrative levels. In the first study, publicly available policies and guidelines around the use of facemasks/respirators were examined to describe areas of consistency, as well as gaps in the recommendations. In the second study, infection control stakeholders were interviewed from China, Pakistan and Vietnam to further explore the issues, which arose during the guideline review. Next, hospitals from the three countries were surveyed to examine practices around the use of facemasks/ respirators and to examine the translation of policies into practice. Samples of facemasks and respirators were also collected and tested. In the fourth study, focus groups were undertaken to examine the knowledge, attitudes and practices of Vietnamese hospital HCWs towards the use of masks/respirators. The fifth study examined the factors associated with compliance of Vietnamese HCWs with the use of various types of facemasks. In addition, the available evidence around the efficacy and use of cloth masks was reviewed. These studies provide new data around factors impacting on the use of facemasks and respirators in resource poor settings. Inconsistencies and gaps were identified in the reviewed polices, which highlight that there is a need to develop a comprehensive and uniform policy around the use of facemasks/respirators. Practices around the use of facemasks and respirators are influenced by organizational and personal factors and understanding these factors will assist with the development of strategies to improve staff compliance with respiratory protection. On the basis of these studies, recommendations have been developed around the use of facemasks and respirators in low resource settings.
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(2015)ThesisParkinson’s disease (PD) is a neurodegenerative disorder that manifests as a result of degeneration of the nigrostriatal system. While L-Dopa still remains the most effective symptomatic treatment, its benefits are limited as it is associated with the development of L-Dopa-induced dyskinesias (LIDs). Furthermore, there is currently no treatment that has proved effective in halting the nigrostriatal degeneration, thus alternative therapeutic targets are needed. To identify such targets, we first established the MPTP mouse model of PD to allow for the investigation of both pathological and behavioural outcomes. In contrast to previous studies, we demonstrated no significant effect of MPTP on motor function at 1 week and 3 months post-MPTP, despite stereological quantification showing a decrease in dopamine cells with increasing MPTP dose, suggesting the MPTP model is more appropriate for identifying effects on cell survival. A screen of novel therapeutic agents and genetic modifications in mice in the MPTP model revealed the growth factor activin A and the kainate receptor subunits GluK1 and GluK3 as the most promising neuroprotective targets. We showed activin A increased survival of dopamine neurons at 1 and 8 weeks following MPTP. Interestingly, animals receiving activin A did not have a corresponding increase in dopamine levels and striatal terminal protection. This nigral protective effect of activin A was replicated in the 6-OHDA model of PD. Animals receiving activin A also had lower numbers of astrocytes and microglia following MPTP and LPS, suggesting that activin A’s neuroprotective effects may be driven by its anti-inflammatory properties. In addition, activin A was shown to increase the efficacy of low doses of L-Dopa in 6-OHDA-lesioned mice, suggesting activin A may act as an L-DOPA-sparing agent. We also showed that blocking GluK1 or GluK3, through the use of selective antagonists or knockout animals, increased survival of dopaminergic neurons following MPTP, however there was no corresponding increase in dopamine levels and striatal terminal protection. Our results indicate that activin A, GluK1 and GluK3 are potential neuroprotective targets for PD.
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(2014)ThesisThe patient s ability to master everyday living tasks is strongly dependent on the utility of healthy functional hands. Therefore the restoration of hand function after tendon injuries is of utmost importance. Tendon injuries are common, especially lacerations in zone II. In this area flexor tendons follow a complicated anatomy and are difficult to repair. Consequently this thesis focuses on the research of tendon repairs in zone II and aims to improve repair quality and ultimately final functional outcome for the patient. To approach this topic the author of this thesis firstly analysis current concepts of tendon repair research models, secondly investigates common tendon repair techniques and improvements of these techniques and thirdly introduces new techniques for repair of deep flexor tendons in zone II. This thesis consists of ex vivo and in vivo experiments, which all build on another. Main results of these experiments are as follows: In regards to comparability to human tendons, sheep tendons are better tendon surrogates as pig tendons if used in ex vivo laboratory experiments. When focusing on gapping resistance, "locking loop" repair configurations for tendon repairs are not substantially different to "grasping loop" configurations, and only "cross-locks", as used in the Adelaide repair technique, deserve the adjective description "locking". The current gold standard of tendon repairs, the Adelaide repair, produces better repair stability if performed with larger cross locks. The author's interlocking modification of the Adelaide repair can further improve the Adelaide repair's stability. In an ex vivo setting, the author's new tendon repair concept, the knotless 3D barbed suture tendon repair, produces superior repair stability than the Adelaide repair. The turkey tendon model is the first tendon model that replicates human anatomy and tendon sizes and can be used in ex vivo as well as in vivo tendon repair experiments. In an in vivo tendon repair scenario, the use of the knotless 3D barbed suture tendon repair with resorbable barbed sutures produces inferior repair stability compared to the Adelaide repair, but improves functional outcomes. This thesis presents new insights into tendon repair research from a surgical and biomechanical point of view. The use of the novel unknotted barbed suture repair method did show superior results in ex vivo experiments but barb resorption in the in vivo experiments caused high failure rates. Nevertheless, there is a probability that with the development of more stable small barbed suturing materials in the near future it will be possible to further improve deep flexor tendon repairs using this novel repair technique.
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(2014)ThesisSex hormones may influence symptoms and signs of dry eye. This thesis aims to identify relationships between circulating sex hormones and dry eye symptoms and signs and to investigate the effects of transdermal sex hormones treatment on these variables. Method development was undertaken for ocular surface sensitivity and the Cochet-Bonnet aesthesiometer was selected above a pneumatic instrument based on validation and repeatability data. A cross-sectional study of 76 normal-to-mild dry eye subjects demonstrated inverse relationships between circulating androgens, their precursors or metabolites and symptoms (r = -0.34, p = 0.003) and tear osmolarity (r = -0.30,p = 0.03) and positive associations with corneal sensitivity (r = 0.28, p = 0.02) and tear volume (r = 0.35, p = 0.002). In contrast, oestradiol was positively associated with symptoms (r = 0.31, p = 0.03) in women only. However, when potential confounding was considered, neither androgen nor oestradiol were able to predict symptoms in regression analysis. A similar analysis in 45 postmenopausal women with dry eye, showed that oestradiol was positively associated with corneal staining (r = 0.56, p = 0.001), but there were no relationships between symptoms and hormone levels in either univariate or multivariable analysis. A double-masked randomised placebo-controlled 8 week pilot intervention study was conducted on 40 postmenopausal women with dry eye using transdermal testosterone, oestradiol or their combination. Key findings included a significant improvement in ocular symptoms in the testosterone, combination and placebo groups (p < 0.1) and increased in tear volume in the combination group (p < 0.05). While dry eye signs and symptoms in a mild dry eye population show associations with hormones, specifically an improvement with androgen and the reverse with oestradiol, these relationships were not evident in multivariable analyses. Corneal staining was associated with oestradiol in postmenopausal women with dry eye and an intervention study suggested that a combination of testosterone and oestradiol improved both the signs and symptoms of dry eye in this group. This thesis describes a series of studies to establish the influence of hormones on dry eye signs and symptoms in males, menstruating and postmenopausal women. Such relationships are likely to vary with hormone levels, the combination of key hormones and dry eye status. The inferior conjunctival sensitivity was among the significant predictors of symptoms, revealing the importance of ocular surface sensitivity as an important dry eye clinical indicator. The corneal sensitivity measurement may be affected by the androgen level especially in males.
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(2018)ThesisCardiovascular disease affects about 1.4 million Australians and was responsible for more than 45000 deaths in 2011. Compelling evidence from human population studies has shown a positive correlation between elevated plasma high density lipoprotein cholesterol (HDL-C) levels and a reduced risk of major cardiovascular events. HDLs have several potential cardioprotective functions, the most extensively studied of which is their ability to remove excess cholesterol from macrophages. They also have anti-inflammatory properties, enhance endothelial repair and improve endothelial function. HDLs also have anti-oxidant, anti-apoptotic, anti-thrombotic and anti-diabetic functions. Therapies that increase HDL-C levels reduce atherosclerotic lesion development in animals. These observations have led to the hypothesis that increasing HDL-C levels will reduce cardiovascular events in humans. Although CETP inhibitors have been shown to markedly increase HDL-C levels and reduce major cardiovascular events in a recent clinical outcome trial, there remains doubt about the effects of CETP inhibition on the cardioprotective properties of HDLs. The work in this thesis examines the effects of inhibiting CETP on the cardioprotective functions of HDLs. The studies investigate the effects of a novel CETP inhibitor, AMG-899, on HDL composition, size and several of their cardioprotective properties. Subjects were treated with placebo or AMG-899 (2.5 mg/day or 10 mg/day) over 12 weeks. HDLs were isolated from subjects before and after treatment. AMG-899 treatment increased plasma HDL-C levels and decreased LDL-C levels (Chapter 3). Treatment with AMG-899 also changed the composition of HDLs, increased HDL size (Chapter 3) and increased HDL-mediated ABCA1- and ABCG1-specific cholesterol efflux (Chapter 4). Treatment with 10 mg/day AMG-899 also improved the anti-inflammatory properties of HDLs (Chapter 5), while HDLs isolated from subjects after treatment with 2.5 mg/day and 10 mg/day AMG-899 were equally effective at increasing endothelial proliferation and migration relative to HDLs isolated prior to treatment (Chapter 6). These studies establish that inhibiting CETP activity with AMG-899 does not impair, and in some cases, improves the potentially cardioprotective functions of HDLs. In conclusion, as AMG-899 treatment increases HDL-C levels more effectively than other CETP inhibitors, and does not impair the major cardioprotective functions of HDLs, it is a potential candidate for future clinical development.
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(2017)ThesisMuch is still unknown about sensory and perceptual changes in the cortex associated with complex regional pain syndrome (CRPS). This PhD aimed to investigate cortical integration of tactile sensation of the hand specifically the fingers, and how this might be altered in CRPS. A match-paired cross-sectional design was used in a series of neuroimaging and psychophysical studies on patients with unilateral upper limb CRPS (n=21). Clinical characteristics were described and compared with age, gender and hand dominance matched controls (Chapter 2). Methodological improvements for fine-grained fingertip mapping in the primary somatosensory cortex were piloted (n=1) in two separate experiments (Chapter 3). Single fingertip stimulation versus bilateral simultaneous fingertip stimulation was compared using phase encoded functional magnetic resonance imaging (fMRI). Fine-grained fMRI maps of the fingertips in S1 in CRPS were described. Structural morphometry measures underlying the functional S1 fingertip maps including cortical thickness were analysed with step-wise mixed modelling with a priori hypothesised effects including hand dominance and medication. Patient characteristics including pain- related measures were correlated with morphometry measures (Chapter 4). A new finger illusion experiment was applied for the first time in patients with CRPS (Chapter 5). The pilot found that bilateral tactile stimulus was most suitable for use in CRPS and had superior time efficiency. Disordered S1 functional fingertip maps in CRPS with no distinct pattern were found using this stimulus, when compared to the orderly homogenous map pattern in healthy controls. These functional imaging observations were strengthened by the key finding that increased cortical thickness underlying these maps together with hand dominance predicted group (CRPS versus healthy controls) membership. An abnormal finger illusion response in CRPS compared to controls, also suggests a disruption to normal efficiencies of bimanual hand representation cortically, not previously reported. In conclusion, disruption to cortical integration of tactile sensation in CRPS is suggested from the results. These changes also suggest cortical representation of differences in hand dominance rather than CRPS-sided-differences predicted those with CRPS in this study. Future directions to test these suggested cortically mediated changes in CRPS were explored.
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(2016)ThesisHLA-B27 is a Class I Major Histocompatability Molecule that is highly prevalent in patients with Acute Anterior Uveitis (AAU) and Seronegative Arthritis (SNA). Despite over 40 years of research, the pathogenic mechanism of HLA-B27-related disease remains elusive. The bacterium Chlamydia trachomatis has been implicated in disease pathogenesis, whereby molecular mimicry results in an antigen derived from the microorganism to cross-react with a molecule in the host, triggering an inflammatory response. Lumican is an extracellular molecule that is found in both the eye and joint and has important structural, functional and immunological functions. This study showed that lumican was present in the aqueous humor of eyes in patients with AAU. Furthermore, immunohistochemical studies did show it is present in the iris and associated blood vessels, the site of inflammation of AAU. Additionally it was found that lumican has sequence homology with the cell wall component of C. trachomatis. Given these properties of lumican, this study aimed to examine cellular responses to peptide antigens derived from C. trachomatis and lumican in the peripheral blood of patients with AAU and SNA and to compare the prevalence of positive serology to Chlamydia in patients who are HLA-B27-positive to those who are HLA-B27-negative. It was shown that HLA-B27-positive patients with both AAU and SNA were more likely to display positive IgG serology to Chlamydia compared to healthy controls, suggesting that past exposure to Chlamydia is important in disease pathogenesis. ELISPOT assays were employed to measure cellular responses to antigens. They showed that HLA-B27 patients had a higher percentage of responders to groups of peptides derived from C. trachomatis, lumican and other extracellular matrix components than both HLA-B27 negative patients and healthy controls. Using flow cytometric methods CD4+ and CD8+ T cell responses were measured which indicated that patients with HLA-B27-related disease responded more to some antigens, and these reached statistical significance when CD8+ T cell responses to some antigens were measured. In summary, this study does suggest that cross-reactivity between a bacterial trigger and a self-protein may be important in disease pathogenesis, lending weight to the hypothesis that there exists an arthritogenic or uveitogenic peptide.