Medicine & Health

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  • (2021) Huang, Wan-Chun
    Thesis
    Chronic respiratory disease (CRD), including chronic obstructive pulmonary disease (COPD), asthma, and less common respiratory diseases, is one of the four major noncommunicable diseases worldwide. Tobacco smoking is a major, avoidable risk factor for CRD. In low- and middle-income countries, there are important barriers preventing people affected by CRD from gaining access to effective, evidence-based prevention and disease management. In Vietnam, little is known about the gap between evidence-based practice and actual clinical management for CRD and cigarette smoking. This thesis aims to assess the current practice for CRD and tobacco smoking in the Vietnamese healthcare system and to evaluate the feasibility of two interventions to reduce the burden of CRD and tobacco smoking. The first part of the thesis includes two cross-sectional studies conducted at all four levels of healthcare facilities in Vietnam. In the first study, I used a syndromic approach to assess patients visiting healthcare facilities due to respiratory symptoms. The findings suggested that COPD and asthma were often misdiagnosed and more than half of patients with the diseases did not receive maintenance inhaled medicines for airways disease. In the second study, we found a high prevalence of current smoking among male patients seeking healthcare. The majority of those who attempted to quit had never used any evidence-based method to help them quit. The second part of the thesis reports pilot studies for two trials that were conducted in three rural district hospitals in Hanoi. The first trial assessed the feasibility of a novel stepped approach to treatment of patients with undifferentiated CRD (asthma and/or COPD) using inhaled budesonide-formoterol. Our data collected over 12 months follow-up period suggested that this intervention is feasible in a rural setting in Vietnam. The second trial focused on tobacco smoking and the interventions included the implementation of smoke-free hospital policy, brief advice from doctors, and follow-up counselling phone calls and text messaging. We found a high rate of self-reported smoking cessation. However, many of the participants did not consent to biochemical verification of their quit status, limiting the interpretation of the trial. Finally, I conducted a process evaluation to assess various aspects of implementing the intervention for CRD that may affect patients’ outcomes. The process evaluation shows barriers and challenges to implementing the components of the intervention, such as insufficient inhaler education from pharmacists and underutilisation of management plan by patients. The findings from this process evaluation will help to improve the implementation of interventions for COPD and asthma in Vietnam.

  • (2021) Lai, Hui-Chi
    Thesis
    Gene expression can be regulated from transcriptional initiation to RNA processing and turnover time and post translational modification of a protein. The majority of studies of gene expression have focussed on transcription. However, it is also important to understand how post-transcriptional pathways are regulated in response to inflammatory stimuli. Chapter 1 introduces background to gene expression during post transcriptional regulation and its regulation related to inflammatory diseases. The innate immune response to LPS is highly dynamic yet tightly regulated. RNA decay pathways include nonsense-mediated decay, the RNA decay exosome, P-body localised deadenylation, decapping and degradation and AU-rich element targeted decay mediated by tristetraprolin. Chapter 2, we examined the regulation of RNA degradation pathways during the lipopolysaccharide response in macrophages and these results have been published. Alternative splicing has been identified as a key process in post-transcriptional regulation of gene expression in higher eukaryotes. In the immune system, alternative splicing provides a major role in regulating gene expression and generating the diverse mRNA transcripts and protein isoforms, therefore giving rise to protein diversity.Intron retention (IR) is a form of alternative splicing where an intron is not removed during transcription coupled splicing and is considered a widely regulated process during gene expression. Chapter 3 we examined its regulation during inflammation. Also, gene expression can be regulated via nonsense-mediated decay, which can precisely control the timing and level of gene expression as well as eliminating unstable or toxic protein production. SMG1 is a member of the PIKK (phosphoinisitide 3-kinase related kinases) family and plays an important role in NMD. For Chapter 4 we investigated the role of SMG1 in the regulating in response to inflammatory stimuli. We generated a novel animal model of total SMG1 loss in macrophages to address this question. For Chapter 5, we showed how to analyse RNA-seq. of BMM from LysM+/CreSmg1fl/fl (Cre) and Smg1fl/fl (wild-type) mice treated with LPS treatment at dedicated time points by gene ontology tools to discover gene enriched clusters during an LPS treatment between LysM+/CreSmg1fl/fl (Cre) and Smg1fl/fl (wild-type) mice. A final discussion and future directions for this field of study are provided in Chapter 6.

  • (2021) Rai, Robba
    Thesis
    Magnetic resonance imaging (MRI) is a key component in the oncology workflow. Radiomics analysis is a new approach that uses standard of care (SOC) magnetic resonance (MR) images to non-invasively characterise tumour heterogeneity. For radiomics to be reliable, the imaging features measured must be stable and reproducible. This thesis aims to quantify the stability and reproducibility of MRI-based radiomics in vivo and in a 3D printed phantom. Chapter 4 explores the feasibility of constructing a 3D printed phantom using an MRI visible material (‘red resin’). The study shows that the material used to construct an anthropomorphic skull phantom mimicked human cortical bone with a T2* of 411 ± 19 µs. The phantom material provided sufficient signal for tissue segmentation however was only visible with an ultrashort echo time sequence, not commonly used in SOC imaging. Chapter 5 investigates a high temperature resin (‘white resin’) where a texture object was developed for analysis. The ‘white resin’ was visible using SOC sequences. The interscanner repeatability measurements of the texture phantom demonstrated high reproducibility with 76% of texture features having an ICC > 0.9. In chapter 6, further texture and shape objects were developed and employed in a multi-centre study assessing inter and intrascanner variation of MRI-based radiomics. The phantom was stable over a period of 12 months, with a T1 and T2 of 150.7 ± 6.7 ms and 56.1 ± 3.9 ms, respectively. The study also found that histogram features were more stable (ICC > 0.8 for 67%) compared to texture (ICC > 0.8 for 58%) and shape texture (ICC > 0.8 for 0%) across the 8 scanners. In chapter 7, phantom measurements found that radiomics features were more sensitive to changes of image resolution and noise. The in vivo test-retest component of chapter 7 detected many unstable features not suitable for use in a radiomics prognostic model. In chapter 8, of the 83 features computed only 19 features had significant changes between the baseline, mid and post radiation treatment and may be informative to assess rectal cancer treatment response. When considering using radiomics analysis for SOC MRI scans, caution must be taken to ensure imaging protocols, imaging equipment including scanners and coils are consistent to improve intra and inter-institutional feature robustness. This can be achieved with regular quality assurance (QA) of imaging protocols using a suitable phantom and appropriate feature selection using phantom and in vivo datasets.

  • (2021) Kennedy, Georgina
    Thesis
    The application of machine learning models to big data has become ubiquitous, however their successful translation into clinical practice is currently mostly limited to the field of imaging. Despite much interest and promise, there are many complex and interrelated barriers that exist in clinical settings, which must be addressed systematically in advance of wide-spread adoption of these technologies. There is limited evidence of comprehensive efforts to consider not only their raw performance metrics, but also their effective deployment, particularly in terms of the ways in which they are perceived, used and accepted by clinicians. The critical care outreach team at St Vincent’s Public Hospital want to automatically prioritise their workload by predicting in-patient deterioration risk, presented as a watch-list application. This work proposes that the proactive management of in-patients at risk of serious deterioration provides a comprehensive case-study in which to understand clinician readiness to adopt deep-learning technology due to the significant known limitations of existing manual processes. Herein is described the development of a proof of concept application uses as its input the subset of real-time clinical data available in the EMR. This data set has the noteworthy challenge of not including any electronically recorded vital signs data. Despite this, the system meets or exceeds similar benchmark models for predicting in-patient death and unplanned ICU admission, using a recurrent neural network architecture, extended with a novel data-augmentation strategy. This augmentation method has been re-implemented in the public MIMIC-III data set to confirm its generalisability. The method is notable for its applicability to discrete time-series data. Furthermore, it is rooted in knowledge of how data entry is performed within the clinical record and is therefore not restricted in applicability to a single clinical domain, instead having the potential for wide-ranging impact. The system was presented to likely end-users to understand their readiness to adopt it into their workflow, using the Technology Adoption Model. In addition to confirming feasibility of predicting risk from this limited data set, this study investigates clinician readiness to adopt artificial intelligence in the critical care setting. This is done with a two-pronged strategy, addressing technical and clinically-focused research questions in parallel.

  • (2021) Collins, Scott
    Thesis
    Chronic liver diseases including cirrhosis and primary liver cancer are a significant health burden worldwide. Liver cirrhosis is end stage liver injury resulting in a progressive fibrosis phenotype, in which the hepatic architecture is distorted. The most common cause of cirrhosis is chronic liver injury caused by hepatitis B, alcohol related liver disease, hepatitis C or non-alcoholic steatohepatitis. Primary liver cancer is a leading cause of cancer mortality globally and is commonly observed as a progression of liver cirrhosis. Liver injury usually occurs because of immune-mediated or direct injury to the hepatocytes and involves multiple cellular subsets; including hepatic stellate cells, liver adipocytes, liver resident macrophages kupffer cells, endothelial cells and infiltrating immune cells. Injury to these cells result in the release of reactive oxygen species, proinflammatory signals, proliferation-associated cytokines, and the activation of repair pathways. A chronic activation of these signals can result in dysregulation of the normal repair response and generation of a pathogenic fibrotic response. A broadly canonical response, chronic inflammation drives fibrosis and cirrhosis irrespective of liver injury aetiology. The burden of liver disease provides the impetus to pursue the use of representative in vitro models of liver function and responses to injury. Improved 2D and 3D in vitro disease models would enhance our understanding of the causes of liver injury and the development of cirrhosis and primary liver cancer while increasing the efficacy of preclinical drug discovery. Current 2D in vitro assays based on cell lines such as HepG2 that have reduced metabolic capacities compared to primary hepatocytes ex vivo, and the use of primary human hepatocytes suffers from high donor-to-donor variation and only retain in vivo characteristics for a short time ex vivo. The shortcomings of 2D cell culture models have driven the development of 3D cell culture techniques. The advantages of 3D models include replicating the complex attributes of the liver beyond liver specific metabolism, such as increased cell density, organisation, and cell-cell signalling, O2 zonation, as well as the anatomy of the liver lobule and the circulatory system. After a comprehensive review of all the current in vitro models of the liver we hypothesised that a liver organoid cell culture model co-cultured with myofibroblast like hepatic stellate cells can model liver injury. An organoid cell culture is defined as a collection of cells culturing several cell types that develop from stem cells or organ progenitors and self-organise through cell sorting and spatially restricted lineage commitment, similar to organogenesis in vivo. Liver organoids have demonstrated many advantages over conventional in vitro models such as long-term genetic stability, 2D in vivo-like organisation, and maintaining the necessary cellular cross talk and behavioural characteristics of their primary corresponding cells. The focus of this thesis is the application of 3D liver organoids to model and analyse the molecular and cellular effects of liver injury. We established a 3D liver organoid cell culture model from primary mouse tissue and characterised the capacity of these organoids to model liver characteristics in vitro and used this model to define the interactions between organoid hepatocytes and hepatic stellate cells in a co-culture trans-well system. The impact of inflammatory cytokines tumour necrosis factor-α and transformation growth factor-β on this model, as well as other variables such as hypoxia and the anti-fibrosis drug Halofuginone were assessed. Hepatic stellate cell dependent decreases in organoid viability and organoid dependent increases in hepatic stellate cell viability were observed, as well as Halofuginone dependent decreases in hepatic stellate cell viability were also observed. Markers characteristic of liver injury and fibrosis, such as Actn1 and Lamb3 were upregulated in hepatic stellate cells, although collagen expression was downregulated in these cells. Transcriptional profiling revealed a tumour necrosis factor-α mediated apoptotic response in organoids and an inflammatory response in both the organoids and hepatic stellate cells. We concluded that while liver organoids and hepatic stellate cells responded to experimental variables, there were limitations when it came to the cross talk between the cultures in the trans-well system. While apoptotic bodies from the organoids may have stimulated proliferation of hepatic stellate cells, many key genes responsible for liver injury were either not upregulated or were downregulated in co-culture. Electron microscopy analysis of liver organoids showed important ultrastructural changes compared to a whole liver section. Our findings of secreted exosomes, microvilli within the lumen of the organoids, and many ultrastructural features found within liver cells in vivo confirm that our 3D liver organoids closely resemble the liver. We also demonstrated how the use of high-resolution field emission scanning electron microscopy with automated scan resolution can generate a high-resolution ultrastructure map of the whole organoid. This method can also be combined with correlative light electron microscopy for immunofluorescent labelling of proteins of interest using quantum dot nanoparticles. Overall, our 3D organoid model of liver injury had encouraging results and furthering our understanding of pathogenesis of liver fibrogenesis in vitro and the study of novel anti-fibrotic therapeutic agents.

  • (2021) Xu, James
    Thesis
    The role of coronary microvascular dysfunction (CMD) in the pathogenesis of ischaemic heart disease and in determining long-term prognosis is increasingly recognised. Coronary microvascular dysfunction has therefore emerged as an important therapeutic target in the contemporary management across the clinical spectrum of ischaemic heart disease. However, due to a lack of a reliable traditional ‘gold-standard’ test for CMD, optimal treatment remains undefined. Currently, there is still paucity of data on targeted therapies for CMD and their implications on long-term clinical outcomes, particularly in the setting of non-ST elevation acute coronary syndromes (NSTEACS). Recent technical advancements, such as the invasively derived index of microcirculatory resistance (IMR), may provide novel insights into the assessment and treatment of CMD. Endothelial dysfunction is understood to be a systemic process and is also independently predictive of adverse prognosis. Abnormal endothelial function has been confirmed on peripheral tissue biopsies in patients with CMD. Peripheral endothelial function is most commonly assessed using the non-invasive brachial reactivity or brachial artery flow-mediated vasodilation (FMD) technique, which has been shown to have a close relationship with coronary endothelial function. However, the relationship between brachial artery FMD and invasive measures of CMD, such as the IMR, has not been studied. The overall aims of this thesis were to evaluate acute and longitudinal changes in coronary microvascular function and peripheral endothelial function, their relationship, and their responses to contemporary therapies in patients with NSTEACS. In particular, the effects of antiplatelet agents (ticagrelor versus clopidogrel), percutaneous coronary intervention, smoking cessation, and statin treatment were examined. The studies in this thesis provided unique insights into the assessment and treatment of CMD and peripheral endothelial dysfunction in patients with NSTEACS.

  • (2021) Jeon, Megan
    Thesis
    Aim. Sleep disturbance (SD) is a common symptom in cancer patients and their caregivers, contributing to increased morbidity, poor quality of life, and poor prognosis. Yet, understanding SD and options for management have been overlooked in both neuro-oncology care and research. This thesis aimed to build an evidence-base for the prevalence and severity of SD in adults with malignant brain tumours (BT) and their caregivers. Methods. Three research studies are presented in this thesis. The first study used a cross-sectional, mixed-methods approach to explore the prevalence, types and risk factors of SD in ambulant BT patients and caregivers using self-reported outcome assessments (Chapter 4); and semi-structured interviews in a sub-sample (Chapter 5). The second study utilised a longitudinal, national clinical dataset prospectively collected in routine care at palliative care centres (Chapter 6). A multi-level analysis was conducted to identify patterns of change in severity and determine clinical indicators for SD throughout palliative care. The final study was a survey (Chapter 7), complemented by a sub-study of semi-structured interviews (Chapter 8), of healthcare professionals (HCPs) to explore their perception and current management of SD in neuro-oncology care. Results. All three studies indicate a high prevalence of SD in both BT patients and caregivers. SD varies both in the type and severity of SD along the BT trajectory; from insomnia post-diagnosis and during initial treatment to hypersomnolence in advanced BT. SD is linked to several other symptoms, such as fatigue in patients and anxiety in caregivers, indicating distress and functional impairment. HCPs perceive SD as a secondary, complex issue which takes low priority in current neuro-oncology care. HCPs report the lack of knowledge and resources for SD screening and management. Implications. Risks and aetiology of SD in BT patients and their caregivers are multifactorial and not necessarily aligned with the current clinical opinion that views corticosteroids as a major causal factor. Findings indicate inadequate recognition and management of SD. An improved approach to detecting sleep issues in routine practice is warranted, to more effectively involve HCPs in proactive management and deliver improved outcomes for patients and caregivers. This body of research provides important groundwork to inform future studies to design, evaluate, and implement optimal sleep assessments, interventions and to plan care in neuro-oncology clinics.

  • (2021) Yap, Su-Jen
    Thesis
    Background: Knowledge of perioperative risk and context are important as year-on-year the global volume of surgery is increasing. Despite decades of policy responses to surgical demand, national registries and local evidence report that a distinct cohort of surgical patients have a higher-than-average risk of complications with added costs to quality of life and service sustainability. The research aim was to examine the impact of context on how in practice the perioperative workforce (comprising clinicians and managers) understand risk, and how this knowledge influences their work practices and use of resources. Three questions were investigated: what has been the impact of health policy on the organisation and practice of perioperative care; how is perioperative work practice organised around low, intermediate and high-risk patients; and what do individuals, teams and organisations require to implement appropriate models of perioperative care for the high-risk patient? Methods: Mixed methods study. The research setting was four university adult general hospitals (113, 360, 440, 547 bed capacity) in a health district in NSW, Australia. Institutional ethics approved a mixed methods study – site observation (187 hours), secondary documents (223 documents: paper and electronic), survey (113 completed) and interviews (143 conducted). Purposive sampling targeted 129 participants in 167 roles, including multidisciplinary clinicians (nurses, doctors and allied health) in senior and junior roles, and managers. Data collection (September 2017 – June 2019) and analysis was conducted using a parallel convergent design through triangulation with descriptive statistics and thematic analysis. Results: National and state health policies that focused on access and efficiency successfully addressed high volume surgical demand for low and intermediate risk patients in predictable, reliable and linear perioperative business process models (BPMs). However, the policies are now three decades old, have resulted in unintended consequences and not addressed the clinical and organisational complexity evident in the three larger hospitals today. The high-risk complex care surgical patient traversed parallel BPMs that were not linear but rather, unpredictable complex adaptive systems. High-risk patients had more invasive surgery and the challenges of chronic multisystem disease and ageing. Complications were more common and cumulative with increased utilisation of hospital resources across multiple fragments of perioperative care; increasing specialty specific expertise were co-opted from multiple clinical disciplines, multiple ‘one-off’ teams were deployed for rescue, resuscitation, and critical care. Complications were associated with months-long hospital stays, discharge to a care level higher than home and readmissions. For high-risk patients the impact of context on the perioperative workforce caring for them could be synthesised as a wicked complexity in perioperative context (WCPC). Wicked complexity is a complexity that was unintended, unwarranted and promulgated by the behaviours of the practice environment. Three research arcs were identified. In the policy arc, at the intersections of the three themes of compression of time and space, fragmentation of care and clinical complexity, there was a wicked complexity in competing priorities and demands (WCCPD) arising from the pressure on clinicians and managers to deal with the ‘here and now’ and not delay care processes downstream. In the risk and practice arc, at the intersections of the three themes of multiple incomplete understandings of high-risk, work practice organisation and an unclear patient outcome measure, there was a wicked complexity in gaps in fully comprehending high-risk (WCGFCHR). In the interprofessional arc, at the intersections of the three themes of professional immersion, multiple formations of perioperative teams and using technology, there was a wicked complexity in gaps in perspective (WCGP). Service sustainability in the perioperative system evolved to encompass WCPC. WCPC was the outcome and rendered solutions clinicians, managers and the organisation derived by continually adjusting elements of care to address current challenges. Wicked complexity in perioperative context is represented by the equation: WCPC = WCCPD +WCGFCHR + WCGP Discussion: Continually adjusting elements of perioperative care to address current challenges is supported by frontline clinicians and the initiatives of local and international medical colleges and societies However, the consequences of continuing this strategy alone without acknowledging and addressing WCPC, include: the potential practical inability of the majority of clinicians and clinician managers to be involved with new initiatives as they continue to struggle with competing priorities and demands in day-to day practice, the organisational gaps in fully comprehending high-risk and the cultural gaps in perspective. The research shows that what is critically needed is a commonly agreed and complete definition of perioperative high-risk that considers the impact of context and culture. The impact of context on the perioperative workforce and their patients can be clearly analysed and articulated. Addressing WCPC systematically enables the charting of an evolving course to equip clinicians and managers to: deal with the impact of context, face economic challenges to service sustainability and address the needs of the high-risk complex care perioperative patient. It is necessary and time to revisit a policy strategy that was successful short-term, a workforce generation ago when surgical services were first re-engineered. Namely, an investment in leadership for the future, capable of generating the solutions to optimising care for the high-risk surgical patient, both clinically and contextually. This may only be achieved through interprofessional education and collaboration at all levels of policy enactment, across all professions. The health services research perspective that enabled defining WCPC could work to simultaneously address clinical complexity, context and culture.

  • (2021) Ghandourh, Wsam
    Thesis
    Stereotactic ablative body radiotherapy (SABR) is the current standard of care for inoperable early-stage non-small cell lung carcinoma (NSCLC). It is a curative treatment option that offers excellent survival rates through non-invasive out-patient visits. SABR can be offered to frail, elderly patients and those with comorbidities or poor performance status, who may be ineligible for surgery or radical radiotherapy and would otherwise be referred to palliative treatments or (sometimes) left untreated. While strong evidence from randomised trials have supported SABR use for peripherally located tumours (>2cm from the proximal bronchial tree (PBT), treatment of central tumours with SABR remains controversial due to increased risks of severe toxicities. Determining the total demand for lung SABR, also known as the optimal rate of utilisation, is an important step in ensuring adequate and efficient provision of radiotherapy services. Once established, it can used as a benchmark against which actual SABR utilisation rates can be compared and any shortfalls in service provision identified. This optimal SABR utilisation rate can be calculated using an evidence-based approach involving first identifying all indications/clinical situations for which lung SABR is a guideline-recommended treatment, then obtaining data on the proportion of each indication within the lung cancer population. This, however, has so far been hindered by lack of published data on the proportions of peripheral versus centrally located lung tumours. The difficulty in determining the distribution of central and peripheral tumours is related to how these tumours are distinguished in clinical practice; based on clinicians’ manual delineations (i.e. contours) of the PBT. Manual contouring is a well-known source of uncertainty caused by inter- and intra-observer variabilities. Such uncertainties preclude relying on retrospective records of patients (assessed by multiple clinicians) to establish reliable estimates of the proportions of central and peripheral tumours. To overcome this, a novel, fully automatic tool for PBT contouring and measuring distance to the tumour was developed as part of this thesis. The tool relies on an intensity-based algorithm that detects bronchus airways based on pre-determined Hounsfield Unit thresholds. Manual PBT contours generated by different clinicians were used to assess inter-observer variabilities11 and to assess the accuracy of automatically generated contours. Results from this investigation have validated the tool’s ability to generate contours within the accuracy experts-generated ones without the need for manual intervention. Subsequently, this tool was applied on a retrospective dataset (N=234) of Stage I and II NSCLC patients treated with radiotherapy at Liverpool and Macarthur Cancer Therapy Centre in Sydney, Australia. This allowed for patients’ tumour centrality to be assessed efficiently and, more importantly, with less influence from observer variabilities. The tool successfully generated PBT contours and measured the minimum distance to the tumour for all patients within the obtained dataset. Patients were then stratified based on the tumour proximity to the PBT, allowing the distribution of peripheral and central tumours to be determined. Previous studies reporting this distribution have relied on manual PBT contours, which are largely affected by observer variabilities as shown in this work. To calculate the total demand for lung SABR, epidemiological data on the proportions of all clinical attributes where SABR is recommended (including the proportion of peripheral versus central tumours) were incorporated into an evidence-based optimal utilisation model developed as part of this work. Based on most recent evidence and guidelines, it was estimated that a total of 6% of all new patients diagnosed with lung cancer in Australia will require SABR at least once during the course of their illness. In those with early-stage NSCLC, this rate was estimated to be at 24%. This is the first report of evidence-based optimal rates of lung SABR utilisation. The utilisation model can be easily modified and updated with new data to ensure accurate and up-to-date estimates of lung SABR demands within the population. Finally, this work also provided an investigation into the potential impact of upcoming technologies on future demands for lung SABR. Magnetic resonance imaging (MRI) guidance, for example, promises to significantly improve treatment accuracy and transform how radiotherapy is delivered. A planning study was conducted to simulate the dosimetric gains expected by such technologies, in particular, the potential reductions in planning safety margins. Results from this study indicated the potential for such technologies to extend SABR treatments to a substantial proportion of patients currently deemed too high-risk to receive it. As such, it is expected that the demand for lung SABR may increase in the near future as such technologies become more widely available

  • (2021) Etaher, Aisha
    Thesis
    This thesis evaluated and characterised patients presenting to emergency departments (ED) with symptoms suggestive of acute coronary syndromes (ACS) and having troponin testing. Characteristic rises and /or falls in troponin levels in an appropriate clinical context are required for the diagnosis of myocardial infarction (MI). However, elevated troponin levels can occur in conditions other than an acute coronary thrombotic event (called type-1 MI), due to either type-2 MI or myocardial injury; such elevations can be associated with significant morbidity and mortality. Four studies were conducted among patients presenting to EDs with suspected ACS, examining associations between troponin levels, diagnoses and late mortality. In Chapter 3, 18-month mortality rates were determined in the 4388 patient Australia and New Zealand 2012 SNAPSHOT ACS study, who were classified in 5 diagnostic groups. Among the 837 non-ACS patients, mortality was 12.8% and among 2356 ACS patients was 12.6%; adjusted hazard ratio for those with troponin elevations, 1.03 [95% CIs 0.98-1.07]; p=0.333. Three studies were undertaken on a 2773 patient cohort presenting to Liverpool Hospital ED with suspected ACS, over 4 months in 2014. The overall rates of type-1 MI were 3.5%, type-2 MI and acute myocardial injury 6.2%, and chronic myocardial injury 27% and the respective 4-year mortality rates were 14%, 44% and 33%; relative to type-1 MI, respective adjusted mortality hazard ratios were 1.95 [95% CIs 1.06-3.57]; p=0.032 and 1.14 [95% CIs 0.64- 2.02]; p=0.66. Of 545 patients aged ≥80 years [median 85 years], 85% with elevated baseline high sensitivity troponin-T (HsTnT) levels, there were associations between increasing HsTnT levels, and late mortality irrespective of diagnoses (5 groups). Also, associations were studied between HsTnT levels, sex, age and adjudicated diagnoses and early and late outcomes. Some attenuation of associations between late mortality, and increasing HsTnT levels occurred with increased age. In summary these studies show that among patients presenting to EDs with symptoms suggestive of an ACS, an elevated HsTnT level has adverse prognostic implications irrespective of the diagnosis. Those with type-2 MI or chronic myocardial injury have higher risk characteristics than those with type-1 MI largely accounting for their higher late mortality.