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.

  • (2020) Do, Viet
    Thesis
    Background: Randomised clinical trials describe the benefit of chemotherapy (CT) for cancer patients with selected patient and disease characteristics. The overall survival (OS) benefits for the whole population of cancer patients in Australia, if evidence-based guidelines for CT were implemented, are unknown. The purpose of this thesis was to estimate the absolute improvements in overall survival that might result from systematically applying evidence‐based guidelines about the optimal use of a first course of chemotherapy to the whole population of people with cancer in Australia. Methods and Materials: Decision trees with evidence-based indications for CT have been previously defined. Each branch of the tree corresponds to a specific cohort who have, or do not have, defined indication for curative and palliative CT. CT OS benefit was defined as the absolute incremental OS of first-course CT over best supportive care for palliative indications or over radiotherapy or surgery with or without radiotherapy in curative indications. Multiple electronic citation databases were systematically queried, including Medline and Cochrane library. In cases where there were multiple sources of the same level of evidence, then hierarchical meta-analysis was performed. A literature search was updated with a cut-off of December 2017. The OS benefits of CT were estimated for one year, five years and ten years. To assess the robustness of our estimates, sensitivity analyses were performed. Results: The estimated one-year, five-year, ten-year absolute population-based OS benefits of optimally-used first-course CT for cancer were 5.9% (95% Confidence Interval, CI 4.8%-7.0%), 4.5% (95% CI, 4.4%-4.5%) and 3.3% (95% CI, 3.3%-3.4%) respectively. The additional benefit of CT over other modality for five-year OS ranged from 0% (malignant pleural mesothelioma) to 26.7% (testes). Sixty one percent of OS benefit was attributed to first-course palliative CT at one year, and 24% at five years. Conclusion: This is the first comprehensive study, using robust modelling methodologies, to estimate the population-based overall survival benefits from first-course CT for all cancers in Australia. The model can be adapted for other jurisdictions readily. First-course CT offers vital benefits to the cancer population. The population survival benefit can serve as an evidenced-based benchmark as part of the consensus quality standard in the treatment of cancer in Australia. Consequently, it can further aid decision making for cancer treatment. As a result, future studies may utilise this approach to estimate the population benefits for surgery and other endpoints. This model is flexible, enabling the consideration of any future changes to the population benefits of CT in the management of cancer within Australia or can be altered to address other jurisdictions where differing prevalence and stage data may exist.

  • (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.

  • (2020) Pham, Trang
    Thesis
    Prediction of chemoradiotherapy (CRT) response in rectal cancer would enable stratification of management whereby responders could undergo ‘watch-and-wait’ to avoid surgical morbidity, and non-responders could have early treatment intensification to improve therapeutic outcomes. Functional MRI can assess tumour function and heterogeneity, and may improve therapeutic response prediction. The aims of this PhD were to (i) prospectively evaluate multi-parametric MRI at 3.0 tesla in vivo combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for prediction of CRT response and 2 year disease-free survival (DFS), and (ii) examine diffusion tensor imaging (DTI) MRI biomarkers of rectal cancer extent and heterogeneity at ultra-high field 11.7 tesla ex vivo in order to establish a pipeline for MRI biomarker discovery from ultra-high field to clinical field. Patients with locally advanced rectal cancer undergoing CRT followed by surgery underwent multi-parametric MRI before, during, and after CRT. A whole tumour voxelwise histogram analysis of apparent diffusion co-efficient (ADC) and Ktrans heterogeneity was performed and correlated with histopathology tumour regression grade. After CRT (before surgery) ADC 75th and 90th quantiles were significantly higher in responders than non-responders. Patients with higher Ktrans values after CRT or greater increase in Ktrans values from before to after CRT had a significantly higher risk of distant metastases, and lower 2 year DFS. Biobank tissue from patients with rectal cancer were examined at 11.7 tesla and DTI-MRI results correlated with histopathology. This work established a discovery framework for screening Biobank cancer tissue for novel MRI biomarkers of tumour extent and heterogeneity, and resulted in good preservation of tissue integrity and MRI-histopathology alignment. DTI-MRI derived fractional anisotropy (FA) was able to differentiate between tumour and desmoplasia, fibrous tissue, and muscularis propria, allowing for more accurate delineation of rectal cancer tumour extent and stromal heterogeneity ex vivo. In conclusion, DWI-MRI was predictive of CRT response, DCE-MRI was predictive of 2 year DFS, and DTI-MRI was able to more accurately define tumour extent and heterogeneity in rectal cancer. These findings could be useful for stratification of patients for individualised treatment based on accurate assessment of tumour extent and therapeutic response prediction.

  • (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.

  • (2020) Kumar, Shivani
    Thesis
    Magnetic resonance imaging (MRI) is increasingly being incorporated in radiotherapy (RT) planning due to superior soft tissue contrast compared to CT, however its use for lung cancer RT has been limited. This thesis addresses the feasibility and potential benefit of MRI for lung cancer RT. A literature review on the feasibility of MRI in lung RT identified that a combination of T2 and T1 weighted images can demonstrate tumour infiltration and mediastinal nodal involvement. Using this information, a free-breathing protocol was developed to aid target volume delineation and overcome challenges with breath-hold non-compliance. An assessment of a radiologist-led workshop on inter-observer variability in volume delineation showed no significant improvement. To assess the potential benefit of MRI for lung RT, a prospective clinical trial was conducted. Inter-observer variability on target volume delineation for T2 MRI and CT was assessed. Volumes delineated on CT and T2 datasets showed significant differences in overlap measures (p<0.01). However inter-observer variability within each imaging modality demonstrated good agreement between observers (dice similarity coefficient ≥0.7), indicating that replacement of CT with T2 MRI did not have a negative impact on interobserver variability. Assessment of motion between 4DCT and cine MRI was investigated. Tumour motion between 4DCT and 2D cine MRI was shown to be similar, however cine MRI showed larger variation in superior inferior motion for individual patients. Cine MRI can potentially be used as a complementary imaging tool to 4DCT for motion definition. Potential application of MRI for adaptive RT (ART) was investigated by evaluating tumour changes on sequential imaging. Volumes delineated on cone beam CT and MRI were significantly different. Rate of primary tumour regression was shown to be similar, but nodal regression was greater on MRI. While further work is necessary to demonstrate the benefit of MRI to CBCT and CT, the results of this study provide initial data for incorporation of MRI for ART. This thesis suggests that MRI has the potential to enhance lung cancer RT. However the differences demonstrated between MRI and current imaging modalities needs further investigation prior to any clinical implementation.

  • (2020) Burgess, Sonya
    Thesis
    This thesis examines the impact of incomplete revascularization in ST-elevation myocardial infarction (STEMI) patients. The research presented in this thesis employs consecutive observational study methodology to ascertain the associations between incomplete revascularization in STEMI and hard clinical outcomes such as cardiac death and myocardial infarction. These publications study long term outcomes in unselected STEMI cohorts, and compare outcomes between genders, between diabetic and non-diabetic patients and between those with a high burden of residual disease to those with complete or near complete revascularization. The papers contributing to this thesis examine the associations between incomplete revascularization and hard clinical outcomes for STEMI patients, using the residual SYNTAX score and the presence of multivessel disease. These studies validate the use of the residual SYNTAX Score (rSS) to quantify incomplete revascularization in STEMI, define appropriate cutoffs for STEMI patients, and examine the relationship between incomplete revascularization and prognosis for high risk cohorts. These studies found incomplete revascularization, female gender, and diabetes were all independently associated with adverse outcomes including cardiac death and myocardial infarction post STEMI. For women and for patients with diabetes outcome differences were primarily evident in patients with a high burden of incomplete revascularization (rSS>8). Suggesting future research targeting those with a rSS>8 may most successfully minimize outcome differences. This thesis demonstrates the importance of objective evaluation of the residual burden of disease in STEMI.

  • (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.