Medicine & Health

Publication Search Results

Now showing 1 - 10 of 121
  • (2022) Ma, Trevor
    Thesis
    The aim of this study was to estimate the prevalence and identify potential determinants of cardiometabolic disease (CMD) in people with psychotic disorders in secure settings and compare these to people with psychotic disorders in the community. A systematic review of the literature was undertaken to determine existing rates of CMD indicators in people with psychotic disorders in secure settings. Data from a comprehensive health and wellbeing survey, the Forensic Mental Health Patient Survey (FMHPS), were obtained to determine the prevalence and determinants of CMD indicators in a sample of forensic patients. Findings were directly compared to a sample of people with psychotic disorders living in the community using data from the second Australian National Survey of High Impact Psychosis (SHIP). The weighted pooled prevalence rates from the reviewed studies were hypertension 25.0% (N=857, 95% CI 22.1-27.9), dyslipidaemia 29.2% (N=1,135, 95% CI 26.6-31.9), diabetes 11.2% (N=2,582, 95% CI 9.9-12.4), being overweight or obese 72.4% (N=840, 95% CI 69.4-75.5), cardiovascular disease 15.6% (N=1,047, 95% CI 13.4-17.8) and metabolic syndrome 23.5% (N=1,390, 95% CI 21.3-25.7). The prevalence of CMD indicators in the reviewed studies were predominantly higher compared to the general population. When directly compared, the forensic patient sample were older, more likely to be male, and more likely to be of Aboriginal and/or Torres Strait Islander background, than the community-based psychosis sample. The former also had higher rates of polypharmacy, clozapine prescribing, physical activity, and food consumption. However, on multivariate analysis, the forensic patients had a lower prevalence of hypertension (OR 0.36, 95% CI 0.23-0.57) and metabolic syndrome (OR 0.41, 95% CI 0.25-0.67) compared to the community-based psychosis sample. There are clearly important differences in the sociodemographic characteristics, treatment needs and lifestyle practices of forensic patients in secure settings and there may be aspects of secure care that actually reduce CMD risk, however the resultant impact on CMD prevalence is complex. Forensic patients in secure settings require early detection and assertive treatment of CMD indicators and further research to assess the feasibility and effectiveness of these interventions in secure settings is required.

  • (2022) Patterson, Kate
    Thesis
    3D computer generated biomedical animations can help audiences understand and contextualise scientific information that can be challenging to communicate due to resolution and complexity. Biomedical animators bring together multiple sources of authentic scientific data, to translate abstract information into a visual form through storytelling and visualisation. The field of biomedical animation has emerged from a long history of science visualisation and science-art endeavours, and despite there being rich discourse in the fields of data visualisation and science communication, the academic literature in the field of biomedical animation is limited, and focussed on the technical methods for visualisation, or the role these animations play in scientific research, rather than the processes through which they are created. However, as the field matures, there is a need for a deeper understanding of the creative process, and the field is now poised to expose and characterise these aspects, particularly from the perspective of the practitioner. This practice-based research project aims to expose and characterise both the visible and invisible factors that influence my personal process of creating a biomedical animation, and the tacit dimensions that influence orchestrated design choices. This research project employs a multi-method and reflective practice approach with disciplined capture and documentation of critical moments of self-reflection, that ultimately comprise the data for analysis. Thematic analysis was then used to analyse the data, and to identify themes that could contribute to frameworks that represent my personal process(es) in creating 3D biomedical animations. This has allowed me to identify and contextualise my creative process both in terms of my personal and professional position as well as within the field more broadly. I am now able to better advocate for the intangible and often undervalued aspects of my creative practice, and can articulate how a hierarchical decision matrix that considers multiple inputs contributes to my creative process. These insights will also be relevant to others in the field of biomedical animation and in the field of design more broadly, who may gain a deeper insight into their own processes of working and ways of exploring creative practice.

  • (2022) Phan, Kevin
    Thesis
    Background: Anterior lumbar interbody fusion (ALIF) remains one of the mainstay surgical approaches in treating painful degenerative disc disease with or without segmental instability in the lower spine. The risk factors and complication profile for ALIF differs significantly from other established fusion techniques. Objectives: The goal of the first part of this thesis is to establish the factors associated with long-term clinical outcome (Chapter 2) and short-term perioperative outcomes (Chapter 3) following ALIF. Chapter 4 focuses on the long-term radiographic evidence for biomaterial alternatives for ALIF implants, namely titanium (Ti)-coated PEEK integrated cages. Methods and Results: From a prospective cohort analysis of 147 patients undergoing ALIF, elderly age (≥64 years old) was associated with an increased rate of subsidence but does not affect clinical outcomes. Obesity was not associated with postoperative complications or follow-up patient-reported outcomes. Failed fusion was significantly higher for smokers, and they were significantly more likely than non-smokers to experience postoperative complications such as pseudoarthrosis. To assess risk factors for perioperative complications and readmissions after ALIF, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analysed. ALIF was associated with prolonged length of stay and higher rate of return to operating theatre compared to posterior lumbar fusion. Obesity and alcohol intake increased the risk of 30-day readmissions. Discharge to non-home destination following ALIF was independently associated with wound complications and venous thromboembolism. Finally, a prospective follow-up study was performed to determine the long-term radiographic outcome following ALIF using Ti-coated PEEK cages with allograft and INFUSE. Effective fusion was achieved at up to 24-month follow-up for various indications including degenerative spine/disc disease, low grade lumbar isthmic spondylolisthesis, spondylotic radiculopathy and discogenic low back pain. Conclusions: Collectively, this thesis highlights the importance of personalising the care of an ALIF surgery patient, through identification and optimization of individual risk factors for short-term and long-term outcomes, as well as through choice of implant biomaterial and design.

  • (2022) Forest, Chelsea
    Thesis
    In 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.

  • (2022) Adawiyah, Rabiah Al
    Thesis
    Testing 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.

  • (2022) Liu, Yishu
    Thesis
    Introduction 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.

  • (2022) Sandaradura, Indy
    Thesis
    Despite 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.

  • (2022) Lin, Jialing
    Thesis
    Background: 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.

  • (2022) So, Sean
    Thesis
    Though 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.

  • (2022) Biswas, Raaj Kishore
    Thesis
    Rear-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.