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(2022)ThesisIn the last 40 years there have been many strides taken towards better and more selective cancer treatment using nanoparticles. Nanoparticles can have inherent passive accumulation in tumour cells, known as the enhanced permeability and retention effect (EPR) which makes them a strong therapy candidate; however this effect is not as well defined or effective as once thought. There is a large variance of efficacy between different patients due to the heterogeneity of tumours, therefore a more targeted nanoparticle systems needs to be designed to increase selectivity and efficacy. This thesis describes the design, synthesis, and characterisation of 20 novel ellipsoidal polymersomes decorated with peptide ligands for selective targeting of medulloblastoma, a childhood brain cancer. These ligands were FSRPAFL 1 a medulloblastoma cell targeting peptide and T7 26 a transferrin targeting peptide designed to aid in crossing the blood brain barrier (BBB). A new synthetic method was designed to attach the peptide ligands post self-assembly, so the peptides were attached to the hydrophilic corona rather than the hydrophobic membrane of the polymersomes. Analysis of these polymersomes showed more ligand available for binding but this did not translate to increased cell association due to an over saturation of ligand. The ratio and density of the targeting peptide 1 and BBB peptide 26 was altered on the surface of the polymersomes and it was found that the polymersomes with 100% T7 ligand showed rapid and high cell association with two different subtypes of SHH medulloblastoma (DAOY and UW228) as well as high association with brain endothelial cells that make up the BBB (HBEC-5i) making it a promising candidate as a drug delivery system for SSH medulloblastoma. Finally, linearly conjugated dual peptides made up of both targeting peptide 1 and T7 peptide 26 sequence, were synthesised and attached to the polymersome hydrophilic corona and analysed against the non-conjugated dual-functionalised peptide polymersomes. There was no significant difference between the two ligand conjugation method analysed but further research should be conducted to confirm this. The work described in this Thesis has shed light on the multitude of nuances that make up the composition of mono and dual functionalised peptide nanoparticle systems and how these can influence biological function. Future work will allow for a better understanding of fundamental questions about targeted nanoparticles therapies and how ligand characteristics directly impact biological function, selectivity and efficacy.
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(2022)ThesisTesting for antenatal human immunodeficiency virus (HIV) and syphilis is a key component of the prevention of mother-to-child transmission (PMTCT) programs globally. While significant progress has been made over the past decade in preventing mother-to-child transmission of HIV, there were around 150,000 new HIV infections among children in 2019, which falls well short of targets for elimination. PMTCT of syphilis has not received the same amount of attention as HIV, despite syphilis affecting more children globally than HIV. Every year, there are around 180,000 infant HIV and 355,000 adverse congenital syphilis infections globally. Syphilis requires less costly and intensive interventions than HIV, making its elimination potentially more feasible. In 2004, Indonesia introduced a PMTCT program for HIV through its extensive network of antenatal care services. Despite the national expansion of the program, in 2018, only 34% of pregnant women in Indonesia were screened for HIV, and 10% were screened for syphilis. Persistently low levels of antenatal testing and treatment for HIV and syphilis remain a major challenge for Indonesia. Demand-side barriers – commonly defined as the individual, household, or community characteristics that influence the uptake of PMTCT and long-term engagement in antenatal care by patients – are well-documented. Far less is known about the supply-side factors, including those characteristics of the health system that exist beyond the control of potential health service users, such as infrastructure, drugs, equipment and human resources. The thesis explores the structural inputs and processes critical to expanding the delivery of antenatal HIV and syphilis testing and treatment in Indonesia and, in turn, critical to strengthening the quality of antenatal care more broadly. The specific objectives of this thesis are to assess the distribution of high-quality antenatal care, to measure readiness and availability of public and private health services to deliver PMTCT for HIV and syphilis as well as to systematically review published evidence on the costs of scaling up HIV and syphilis testing in pregnancy. The thesis shows that despite significant progress in increasing the coverage of routine antenatal care, access to high-quality antenatal care substantially varies across different socioeconomic groups and geographical areas in Indonesia (Chapter 3). The thesis also revealed widespread gaps in infrastructure, equipment, human resources, and diagnostics capacity that are essential for the delivery of the PMTCT program for both HIV and syphilis. While these gaps are evident across all providers, they were most prominent among providers in the private sector (Chapters 4 and 5). Finally, to address these gaps and achieve high levels of testing coverage for pregnant women, a sound understanding of the financial requirements is needed. The thesis concludes by showing that there is a dearth of high-quality evidence on the costs of scaling up antenatal screening for HIV and syphilis (Chapter 6). Previous existing studies point to potential economies of scale but at the same time overlook several key parameters affecting costs, including the longer-term structural changes to health system capacity and infrastructure required to fully integrate testing into routine services, especially in rural and remote areas. Overall, this thesis provides insights and practical policy recommendations on how to improve service delivery and health outcomes across the continuum of care for mothers and newborns in Indonesia (Chapter 7). It also makes recommendations on how to strengthen approaches used to measure supply-side readiness in the context of PMTCT, including the use of data linkage, and on how to generate more robust measures of the costs of scaling up, including the development of a costing checklist. It is anticipated that this research will help bring Indonesia and other low and middle-income countries closer to national and global targets for eliminating mother-to-child transmission of HIV and syphilis.
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(2022)ThesisIntroduction Poor diet is a leading cause of premature death and disability worldwide. Clear evidence about effective interventions for the prevention of diet-related ill health is mostly absent because large-scale trials that define the effects of dietary interventions on clinical outcomes and mortality are few. Novel approaches to doing trials might enable more evidence to be generated and better policies for the prevention of diet-related ill health to be implemented. Methods Excessive sodium intake and insufficient consumption of nuts are two leading dietary risks for cardiovascular diseases. A mixed methods evaluation to identify contextual factors and human behaviours influencing the successful conduct of a recently completed large-scale trial of sodium reduction was conducted. The findings were used to design and conduct a pilot study for a planned large-scale trial of nut supplementation. In addition, the validity of routinely collected health insurance claims data as a means for streamlined outcome assessment in the sodium reduction trial was quantified, while the scope and accessibility of other routinely collected health datasets in China were assessed. Results Ease of use, acceptable taste, presence of a price premium and habitual consumption of pickled food were identified as key factors affecting the long-term use of the salt reduction intervention. The pilot trial of nut supplementation demonstrated that good adherence was also possible for a simple intervention based on one or two daily sachets of walnuts provided free-of-charge, with biomarker, tolerability and safety outcomes supporting the feasibility of a future large-scale outcome trial. Health insurance claims data were showed to be a valid means for identifying cardiovascular outcomes at a lower cost than usual approaches based on face-to-face follow up, with multiple other routinely collected health databases in China potentially accessible for medical research purposes. Interpretation There is clear potential to generate increased volumes of high-quality evidence about the effects of simple dietary interventions on definitive health outcomes using novel approaches to trial conduct. Experience with the outcome data from the salt reduction study suggests that it is reasonable to expect that these data will be effective at driving changes to government policies and industry actions.
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(2022)ThesisDespite advances in critical care medicine, severe infections and sepsis-related mortality remain a pressing problem. There is considerable evidence of under- and overexposure from standard dosing regimens across numerous antimicrobial classes in critically ill patients, a result of pharmacokinetic alterations arising from unique pathophysiologic changes. Timely initiation of adequately dosed antimicrobial therapy is recognised to be paramount in improving clinical outcomes in sepsis. Therapeutic drug monitoring (TDM), a tool traditionally used to minimise toxicity of glycopeptides and aminoglycosides, is increasingly being used to increase the precision of antimicrobial dose regimens in critical illness. ‘Emerging’ candidates for which TDM is recommended include β-lactam antibiotics, linezolid, ciprofloxacin, and antifungal, antiviral and antimycobacterial drugs. Little is known about the current uptake of TDM for these agents in Australian hospitals and the barriers to TDM implementation. Performing TDM also presents a learning opportunity whereby the probability of attaining therapeutic targets using empiric dosing strategies may be (re)evaluated. Chapter 1 presents an overview of the challenges facing clinicians prescribing antimicrobials for critically ill patients and potential ways TDM data can be used to overcome these challenges. Chapter 2 explores performance, clinician attitudes and barriers to implementation of TDM for emerging antimicrobial candidates, mapping out current unmet clinical need and providing a framework for TDM data driven precision antimicrobial dosing in subsequent chapters. Chapter 3 examines concentration–toxicity relationships in critically ill patients treated with β-lactam antibiotics and defines threshold concentrations associated with neuro- and nephrotoxicity. Chapter 3 also identifies factors that contribute to underexposure of antibiotics in critically ill patients. Chapter 4 investigates the pharmacokinetics and current dosing regimens of the antifungal drug fluconazole, another emerging TDM candidate. These findings are extended in Chapter 5 with an evaluation of a novel model-based dosing strategy for fluconazole. The findings from Chapters 3 and 4 leverage TDM data to provide insights into critically ill patients at risk of under- and overexposure of antimicrobials, and the use of novel antimicrobial dosing strategies. Chapter 6 discusses the clinical implications of this work and recommendations for future research.
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(2022)ThesisBackground: The National Herpes Zoster Immunisation Program using the one-dose live-attenuated zoster vaccine commenced in Australia in November 2016 for 70-year-olds with a catch-up program for 71–79-year-olds. As surveillance data to monitor the program effects was limited, this thesis presents four studies examining aspects of program evaluation including vaccine coverage, the impact of vaccination on zoster incidence, and vaccine effectiveness. Methods: MedicineInsight consists of de-identified electronic medical records extracted from participating general practices across Australia. Vaccination data from MedicineInsight records to December 2018 was used to estimate vaccine coverage and factors associated with vaccine receipt using a logistic regression model. The additional effects of a structured older persons health assessment and co-administration of seasonal influenza vaccines on zoster vaccination uptake were analysed using generalized estimating equations. An interrupted time-series model was used to investigate the impact of the program on zoster incidence and Cox proportional hazards models were used to estimate real-world vaccine effectiveness. Results: Twenty-six months following commencement of the national program, 46.9% (25,791/55,034) of those aged 70–79 years old had received a zoster vaccine. Factors associated with vaccine receipt included female sex, area of residence, and socioeconomic status. Both the structured older persons health assessment and co-administration of seasonal influenza vaccines were associated with higher zoster vaccine uptake (adjusted OR = 3.0 for both). The program was also significantly associated with reduced zoster incidence in those aged 70–79 years old, with an estimated annual decrease of 2.3 (95% CI: 1.3–3.2) per 1000 persons in the two years after the program was launched; an estimated 7000 zoster cases were prevented through the program. In the first year of the program, vaccine effectiveness against incident zoster was 63.5% (95% CI: 47.5–74.6) but this fell to 48.2% (95% CI: 30.0–61.7) in the second year. Conclusions: This thesis uses electronic general practice records in Australia to provide estimates of zoster vaccine coverage and adds to the evidence on the impact of vaccination on zoster disease and vaccine effectiveness. I found moderate levels of coverage and a level of effectiveness and reductions in disease consistent with international data.
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(2022)ThesisThough G protein-coupled receptors (GPCRs) are the target of 30% of the clinically-approved drug market, these drugs target just ~25% of the non-olfactory GPCR superfamily (108). Almost half of the remaining untargeted GPCRs are “orphans” with no known endogenous ligand(s), representing a rich and underutilised source of pharmacotherapeutic targets. To facilitate ligand identification, the Kufareva and Smith research groups previously developed GPCR-Contact-Informed Neighbouring Pocket (GPCR-CoINPocket). It is a metric of pharmacological similarity between Class A GPCRs, incorporating sequence similarity and structurally-observed ligand interaction patterns derived from liganded GPCRs in the Pocketome, an annotated encyclopaedia of liganded protein structures. In this thesis, I re-evaluate previous GPCR-CoINPocket predictions and develop an upgraded and improved version of GPCR-CoINPocket. In Chapter 2, I re-investigated the pharmacology of the orphan receptor, GPR37L1. In the previous iteration of GPCR-CoINPocket, GPR37L1 was used as a prototypical orphan for the prospective validation of the metric. However, previous retractions from our lab meant that clear evidence was once again lacking for the signalling pathways and activity of GPCR-CoINPocket-predicted ligands at GPR37L1. In the present study, I found no evidence of ligand-dependent or constitutive Gαi- or GαS-directed agonism in HEK293 or CHO-K1 cells, leaving the pharmacological toolbox of GPR37L1 once again empty. In Chapter 3, I developed a method for quantifying the similarity of ligand sets and generated a benchmark of pharmacologically similar and dissimilar Class A GPCRs for the assessment of updates and upgrades to GPCR-CoINPocket. My method formalises the intuitive concept of pharmacological similarity by deriving receptor similarity scores from high quality ChEMBL-annotated receptor:ligand binding data via an approximation of the number of shared unique chemotypes. In Chapter 4, I used my benchmarking set to evaluate four areas of potential improvement for GPCR-CoINPocket: the orthosteric contact fingerprints defining receptor pockets, the inclusion (or exclusion) of ECL2 fingerprints, the logic of score aggregation, and the amino acid similarity matrix used to score sequence similarity. The evaluation of these upgrades led to the development of GPCR-CoINPocket v2, which outperformed transmembrane similarity and GPCRdb-defined orthosteric pocket similarity in the discrimination of pharmacologically similar from dissimilar Class A GPCRs. The primary upgrade responsible for this improvement was the replacement of the Gonnet amino acid similarity matrix with a chemically-informed matrix developed in this thesis that directly (and solely) reflected structurally-observed ligand binding pattern similarities between amino acids. In Chapter 5, I prospectively validated GPCR-CoINPocket v2 using the human β2-adrenoceptor as the prototypical target. I identified 4 compounds typically binding to the OT, MCH1, and SST2 receptors with nanomolar affinity/potency that unexpectedly had affinity for the β2-adrenoceptor in competitive radioligand binding assays. The key output of this thesis is GPCR-CoINPocket v2, a direct upgrade to the original orthosteric pocket-based metric of pharmacological similarity between Class A GPCRs. I have validated it both retrospectively and prospectively, illustrating one use of the method that allows it to complement virtual and physical high-throughput screening technologies. Further applications and limitations are discussed in Chapter 6, but it is hoped that the methods and tools I have developed here can be easily adopted and aid in elucidating orphan GPCR physiology and pharmacology.
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(2022)ThesisRear-end crashes are a major part of road injury burden, accounting for one-third of all vehicle-to-vehicle crashes in New South Wales, Australia. Close following or driving with short headways is a key cause, yet the role of driver behaviour in rear-end crash risk is not well researched. The primary aim of this research was to develop a better understanding of rear-end crashes by assessing headways on Australian roads and investigating driver behaviour and performance associated with close following in crash and non-crash scenarios. Two systematic reviews of headway were conducted. First, a review of research on headway identified the need for a consistent and accurate definition of headway, so the thesis puts forward an improved definition. The second review identified the range of external factors that increase the risk of short headway and increase crash risk including speed, task engagement, lead vehicle type, traffic conditions, road characteristics, weather/visibility, drug use, driving fatigue, innovative lane markings, and various warning systems. These factors were then explored in New South Wales data on rear-end casualty and multiple vehicle crashes. The modelling of these associated factors were confirmed as contributing factors in rear-end crashes, congruent with the review of headway. Higher speed, free flowing traffic, volitional task engagement, low cue environments, and collision warning lead to longer headway. Despite lower fatalities, higher odds of injury were observed for rear-end crashes than other crash types. Rear-end crashes were more likely to lead to multiple vehicle crashes, which had a higher chance of fatality than other types of crashes. Finally, naturalistic driving study data was used to investigate headway during normal driving, exploring close following at different speeds and classifying potential risky driving at various headways. In 64 hrs accumulated across 2101 trips, short headways of under 1 s occurred in around 15% of driving. Common manoeuvres to avoid rear-end crashes when close following were changing lanes, or braking, almost always by the following driver. Headway was associated with both driver speed and posted speed limits, decreasing as posted speed limits increased. Over-the-speed-limit driving was observed in all headway scenarios, but especially in higher speed zones. The findings challenge the notion that rear-end crashes are less severe with low injuries. Road users should be made aware of how frequently safe headways are violated and severity of injury outcomes. Driver education, community engagement, application of driver assistance technology consistent with driver behaviour and safety campaigns need to focus on safer speed and headway management to reduce rear-end crash risk.
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(2022)ThesisBackground: Ocular surface characteristics in children have not been as well investigated as in adults. Children’s digital device usage is rapidly increasing, and smartphones are the most commonly used device. The ocular surface impacts are unknown in children. In adults, use of digital devices induces ocular symptoms, adversely impacts blinking, and disrupts ocular surface homeostasis. Although blinking is integral to a healthy ocular surface, this is yet to be characterised in children, including the effects of digital devices. This thesis aims to characterise the ocular surface of children including blinking and to examine the impact of smartphone use on ocular surface homeostasis in children. Methods: The literature on ocular surface (symptoms, clinical indices, tear film function, blinking) of healthy children was reviewed and a meta-analysis of tear film stability and tear secretion was conducted. Cross-sectional studies of healthy school-aged children were conducted to examine the utility of commonly used adult-validated dry eye symptom questionnaires (SANDE, OSDI, NRS, OCI, DEQ-5, IOSS), and to characterise ocular surface clinical indices. This included blinking which was measured in situ using a novel eye tracking headset (Pupil Labs GmbH, Germany). The impact of one hour smartphone gaming on the ocular surface (including symptoms and blink parameters) of this paediatric population was examined with an intervention study. Blinking was also examined in situ under different conditions and tasks (reading from hard copy and on digital devices, conversation, walking) using the eye tracking headset in healthy adults. Repeatability of blink measurements (blink rate and interblink interval) in adults using the eye tracking headset was determined. Results: Ocular symptoms, tear film function and blinking were sparsely reported in children. The pooled mean by tear stability measurement methods in the meta-analysis were higher than previously reported in healthy adults while the pooled mean for tear secretion by methods were within the expected normal range for adults. Six existing dry eye questionnaires could be successfully used in paediatric eye care, and their repeatability was mostly comparable to that reported previously in adults. More time and assistance were at times required for younger children and specific terms such as ‘gritty’ and ‘foreign body sensation’ were not always well understood by younger children. The DEQ-5 and IOSS are recommended for use in younger age children. Blinking was associated with greater tear volume and worse meibomian gland expressibility but not digital device use, age, sex, or symptoms in children. One hour smartphone gaming led to increased symptoms of dryness, discomfort, and tiredness but did not impact tear film function. Blinking was rapidly reduced by a third within the first minute of gaming and this effect remained unchanged throughout one hour of gaming (p<0.001). Blink rate was consistently slower during all reading tasks compared to conversation (p≤0.002) and walking (p≤0.03), irrespective of task complexity, screen brightness, working distance or device used. Blinking could be reliably measured using a wearable eye tracking headset; the coefficient of repeatability for blink rate was ±12.4 blinks/min. Conclusions: This study established that existing dry eye questionnaires can be reliably used in children to examine the impact of challenges such as digital device use. An eye tracking headset reliably measured blink rate in situ in adults and detected differences in blinking during various real-life tasks. It was successfully used in children to measure blinking in situ showing an immediate and sustained slowing of blinking, evident after up to one hour of smartphone gaming. An hour of smartphone gaming worsened ocular comfort in children but did not appear to disturb the tear film. Given the ubiquitous use of smartphones by children, future work should examine whether effects reported herein persist or get worse over the longer term, potentially causing cumulative damage to the ocular surface. Blink amplitude and relationships with ocular surface clinical indices and digital device use may be explored using the methods established in this study.
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(2022)ThesisFrom a child interrupting a conversation between her parents to ask "What's for dinner?" to a nurse interrupting a physician in the middle of a complex procedure with an urgent message, interruptions are an inevitable part of our daily lives no matter who we are, where we live, or what we do. Interruptions can have a variety of affects on people's performance and behavior. While interruptions may sometimes facilitate performance, often interruptions have negative consequences. For example, interruptions may result in people making more errors or forgetting to complete a prior task altogether. This thesis examines existing strategies to help mitigate interruption costs and explores the effects of interruptions within different decision environments. Chapter I introduces the topic by discussing a few theoretical frameworks of interruptions and reviewing prior research on what makes interruptions disruptive. One strategy to minimize interruption costs is to use what is called an interruption lag, which can be thought of as taking time to prepare for a pending interruption. Chapter II presents a novel experiment to systematically explore the potential benefits of interruptions lags and an alternative intervention (i.e. providing feedback) when interruption lags are not possible. Chapters III and IV discuss the results from three experiments and a final replication study that all focus on how interruptions affect people's decision making in unique environments. The environments consist of easy problems (i.e. basic arithmetic problems) and trick problems, designed in such a way to lead the reader down an incorrect path. Results from these studies were mixed. While there was some evidence that interruptions may make people more susceptible to falling for the trick answer, this finding was inconsistent across all the experiments. Chapter V applies the findings from the previous chapters to a medical context. This chapter presents novel medical cases that were developed with the help of a medical expert. These cases consisted of easy, hard, and trick cases designed for medical students. The goals of this chapter were to validate the cases and to investigate the effects of interruptions within the different case types. The final chapter (Chapter VI) concludes with a general discussion of the experimental findings, the theoretical implications of the results, and the broader implications of this research for the field of medicine.
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(2022)ThesisWellbeing, a key aspect of mental health, is defined as a state of positive subjective experience and optimal psychological functioning. This thesis presents a series of studies devised to comprehensively explore phenotypic, genetic, and neural correlates of wellbeing. The first study (Chapter 2) aimed to compare the heritability and stability of different wellbeing measures in the TWIN-E dataset (N~1600) to discern the most suitable approach for measuring wellbeing for subsequent gene discovery efforts. This twin-based study concluded that multi-item measures of wellbeing such as the COMPAS-W scale, were more heritable and stable than single-item measures. Wellbeing-associated variants were identified via genome-wide association studies (GWAS) and highlighted the need for larger sample size. The subsequent studies were conducted using population-scale data from the UK Biobank comprising ~130,000 participants with phenotypic and genetic data. Thus, in Chapter 3, I constructed a multi-item “wellbeing index” measure using UK Biobank data to investigate its relationship phenotypically and genetically (using GWAS, polygenic scores and LD score regression) with negative mental health indicators (e.g., neuroticism and loneliness), childhood maltreatment and psychiatric illness. I confirmed that SNP-heritability of wellbeing index was higher than both single-item measures and estimates previously reported (SNP-h2 = 8.6%). Moreover, I provide an overview of phenotypic and genetic correlations between wellbeing index and negative mental health indicators. In addition, childhood maltreatment and psychiatric illnesses were associated with reduced wellbeing, with evidence that genetic factors may influence their correlations. In Chapter 4, I investigated the genetic and phenotypic associations between wellbeing index and brain structure, using magnetic resonance image-derived phenotypes from the UK Biobank. This study found associations between wellbeing and volumes of brainstem, cerebellum and subcortical regions, and structural morphology of various cortical regions. Thus, wellbeing is associated with complex structural variations, each with a small effect. Together, this thesis explores the multifaceted nature of wellbeing, elucidating its phenotypic and genetic relationships with related phenotypes, childhood maltreatment, and psychiatric outcomes, and provides novel insights into the associations between wellbeing, its genetic signatures and brain structure.