Medicine (Northwest Academic Centre) - Theses
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ItemNitric oxide in the pathogenesis of acute decompensated heart failure( 2021)Heart failure (HF) is a heterogenous syndrome broadly defined as the inability of the heart to meet the metabolic demands of the body. HF is one of the leading causes for a hospital admission in Australia and around the world, costing the Australian health care system over $2billion per annum. Patients with HF often transition between chronic HF, where signs and symptoms are minimal and paired with a relatively stable hemodynamic profile, and acute decompensated HF (ADHF), where there is a rapid worsening of symptoms and hemodynamic profile, often requiring a hospital admission. Nitric oxide (NO) is considered one of the key regulatory molecules produced in the vasculature, playing important roles in blood pressure regulation, platelet aggregation, and endothelial cell function. Given the importance of NO within the cardiovascular system, it was thought that dysregulated NO may be a key factor in the pathogenesis of ADHF. In this thesis, NO in ADHF is the linking theme between all of the presented chapters. The first investigational chapter examined NO biology, indexed by plasma nitrite (NO2-) concentrations, in patients with chronic and acute HF with a reduced ejection fraction (HFrEF). Findings from this chapter indicate that in patients with acute HFrEF have decreased NO production and bioavailability compared to their chronically compensated counterparts. Specifically, we found higher concentrations of asymmetric dimethylarginine (ADMA) and nitrotyrosine (3-NT) in patients with acute HFrEF, in an inverse proportion to the observed plasma NO2- concentrations. Following this, a similar investigation was performed in patients with chronic and acute HF with a preserved ejection fraction (HFpEF). Results from this investigation indicated that NO production and bioavailability was decreased in patients with acute HFpEF. NO biology was then examined in patients with ADHF with a concomitant acute kidney injury, a phenomenon known as cardiorenal syndrome. This investigation yielded the somewhat surprising finding that markers of worsening renal function were associated with increased NO bioavailability. The final investigational chapter explored the role of inflammation and oxidative stress and their relationship to NO in patients with chronic HF and ADHF. Along with reduced NO bioavailability, patients with ADHF displayed proportionately increased inflammatory activation (including plasma concentrations of the biomarker myeloperoxidase) and increased oxidative stress (3-NT) compared to patients with chronic HF. The results of this chapter aided in proposing a novel paradigm of decompensation, particularly in patients with HFrEF. Finally, given the results of decreased NO bioavailability, increased inflammation, and increased oxidative stress in ADHF, a short review of the current therapeutic literature was conducted. Suggestions of therapeutic strategies are also elaborated on in the final discussion chapter. This thesis presents novel and important information surrounding the biology of NO, which may be a key determinant in patients with chronic HF decompensating into ADHF.
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ItemUnderstanding the role of vitamin D in falls and fractures prevention( 2021)Using existing data, this thesis explored the associations between serum 25(OH)D levels, physical function parameters, and incident falls in women aged 70 years and over. The linear and non-linear associations between serum 25(OH)D levels, physical function parameters and falls were explored through linear mixed, generalized linear mixed and generalized additive mixed model analyses. The results could not demonstrate a linear or non-linear relationship between serum 25(OH)D levels, physical function parameters, and incident falls in women aged 70 years and over. A systematic review of vitamin D prediction models and questionnaires was aimed to identify and compare existing prediction models and questionnaires developed to identify vitamin D deficiency or insufficiency in adults. The quality assessment of diagnostic accuracy studies (QUADAS-2) tool was used to assess the risk of bias and applicability concerns. Data were extracted on study characteristics, risk factors for vitamin D deficiency, serum 25(OH)D levels and statistical methods. Additionally, the performance measures and predictive ability of models were also extracted. A total of 12 studies were included in this systematic review. Of twelve studies, ten developed prediction models, and two studies developed questionnaires. All studies included only self-reported predictors of vitamin D status in their final models and development of scores. Sunlight exposure and related factors were important significant contributors to the predictive ability of the models and questionnaires. The sensitivity and specificity of the prediction models or questionnaires ranged from 55% to 91% and 35 to 84%, respectively. Six out of twelve studies converted final models to scores associated with vitamin D status. A systematic review laid a foundation for identifying self-reported risk factors for vitamin D and developing and validating a vitamin D prediction tool. The third study identified twelve self-reported risk factors for vitamin D deficiency in a series of univariable analyses using existing cross-sectional data from four Australian-based cohorts (individual and pooled). In the final study, self-reported risk factors were then utilised to develop and validate a vitamin D model for Australians 50 years and over. Initially, a multivariable logistic regression approach was used to develop the prediction models for defined vitamin D cut-points (<50nmol/L and <60nmol/L). The developed models were then subjected to internal validation, and their performance measures were assessed. External validation of the model was performed in another data from the Australian-based cohort. Finally, scores associated with each risk factor category and the risk of vitamin D deficiency were calculated. The essential characteristics of the vitamin D prediction model developed were, the three highest contributing factors were the winter season, female sex, and age 80 years and over, the AUC of the model 0.71, the exceptionally high specificity of 99%, and overall predictive ability of 82% after external validation. The vitamin D prediction tool may help reduce the burden of unnecessary vitamin D testing and supplementation by informing people who are not vitamin D deficient. Additionally, people with vitamin D deficiency may seek guidance from their GP for vitamin D testing or supplementation.
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ItemTranslation of established and advanced echocardiographic imaging techniques and novel imaging protocols to enhance diagnostic value and appropriate use in the new cardiovascular epidemic( 2021)Despite improved strategies leading to a significant decline in the rate of myocardial infarctions, there is an emerging cardiovascular epidemic comprising of heart failure, aortic stenosis, and atrial fibrillation. This is driven by the rise in life expectancy and other comorbidities and cardiovascular risk factors, including hypertension, smoking, diabetes, obesity, and physical inactivity. These diseases carry a high rate of morbidity and mortality, and they also place a tremendous burden on our health system. Cardiovascular disease represents 15 % of the total burden of diseases in Australia which is only second to cancer. Continued gains in maintaining the quality of life and preventing acute decompensation in these illnesses will be assisted by the effective translation of emerging technologies in cardiac imaging into earlier clinical decision-making to prevent disease progression. These applications will not only be dependent on imaging at baseline, but also on follow-up. This presents clinical challenges in terms of the quality control of imaging, as well as its growth - in Australia, cardiac imaging continues to grow at approximately 10% per year. In view of the preceding background, the themes and research questions for this thesis will focus on the application and utilization of the latest advances in echocardiography: Theme A: testing new echo tools to improve early diagnosis and clinical decision making. Theme B: patient selection for diagnostic echocardiography to reduce inappropriate testing. Theme C: peer review of image interpretation and quality control through online-based training. This thesis consists of a number of studies. The first study is based on results from a randomized trial which was conducted in a single tertiary centre in Melbourne. As part of the NIL-CHF trial cardiac inpatients aged greater than 45 years were screened for study eligibility including any cardiovascular diagnosis excluding HF. After baseline history and Charlson Comorbidity Index were assessed, a transthoracic echocardiogram was performed, and LV strain analysis was performed offline. Extended follow-up was organised via data linkage, and analyses included: 1. Evaluation of a novel imaging LV strain as a predictor of heart failure in a cohort of stage A and B heart failure? 2. Evaluation of a novel imaging LV strain as a predictor of heart failure in coronary artery disease? We also conducted three prospective trials based on appropriate patient selection for echocardiography and image interpretation (quality control studies): 3. Evaluation of a new handheld ultrasound protocol to address the issue of inappropriate echocardiography. 4. Evaluation of web-enabled teaching to address interobserver variability in the assessment of aortic stenosis. 5. Evaluation of web-enabled teaching to address interobserver variability in the assessment of left atrial function.
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ItemMaximising Recovery of Health-Related Quality of Life Following Major Osteoporotic Fracture: A Focus on Health Care Pathways( 2021)Fragility fractures are the most severe clinical outcome of osteoporosis and lead to limitations in physical functioning, increased risk of mortality, and reduced health-related quality of life (HRQoL). Post-fracture health care pathways have been developed to improve the care of older patients following a fracture by guiding healthcare professionals with evidence-based treatment recommendations in accordance with clinical guidelines. Previous studies report consistent benefits of post-fracture care pathways for older people including elevated treatment rates, decreases in subsequent fractures, and decreased rates in long-term mortality. However, the benefits on patient-reported outcomes such as HRQoL is not well established, particularly for non-hip fracture sites. The overarching aim of this thesis is to enhance the evidence-base of post-fracture care pathways for the optimal recovery of HRQoL. This thesis includes five interrelated research components: 1) a meta-analysis to investigate the effect of existing post-fracture care pathways on HRQoL and physical function compared to usual care; 2) a before and after study to evaluate the effect of an electronic care pathway on patient outcomes compared to a traditional paper-based care pathway; 3) a series of analyses using data from a multinational observational study – the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS) – to identify distinct, multidisciplinary care pathways associated with recovery of HRQoL post-fracture; 4) a micro-costing study to estimate the cost per patient of each post-fracture care pathway identified; and 5) a data linkage study to investigate the association between HRQoL recovery 12-months post-fracture and 5-year mortality using data from the Australian arm of ICUROS (the AusICUROS study). The main findings of these studies are presented below. Existing post-fracture care pathways have short and long-term improvements for both HRQoL and physical function in hip fracture patients, however there is an insufficient number of non-hip fracture studies to establish the same conclusions. Implementation of an electronic care pathway can reduce the total number of delays to surgery in hip fracture patients, an important mediating variable for lower risk of mortality and improved HRQoL, compared to a traditional paper-based care pathway. The latent class analyses identified several multifaceted care pathways (i.e. common combinations of health services used by older adults post-fracture) associated with improved HRQoL recovery 12-months post-fracture across individual fracture sites (hip, wrist, vertebrae, humerus) at a lower cost per patient. Recovery of HRQoL was also determined to be associated with improved 5-year survival in older adults post-fracture, providing indirect evidence that these care pathways may have the potential to reduce mortality post-fracture. Together, the findings of this thesis present significant new knowledge about the understanding, development, and evaluation of post-fracture health care pathways. The multidisciplinary care pathways identified can be utilised by clinicians worldwide to achieve benefits in HRQoL post-fracture at a considerably lower cost to the patient and healthcare system. However, further clinical trials are required to develop evidence-based post-fracture care pathways that will increase the diagnosis of osteoporosis, improve initiation and adherence to osteoporosis treatment and fracture prevention strategies, and improve patient outcomes following fragility fracture.
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ItemThe biological characterization of circulating osteoprogenitor cells and their role in geriatric musculoskeletal disease( 2021)Circulating Osteoprogenitor (COP) cells are a relatively newly identified population of musculoskeletal precursor cells in the peripheral circulation. While some evidence has shown their capacity for osteogenic differentiation, there is little else known. Additionally, there is contradiction between studies regarding their origin – whether from the mesenchymal, or hematopoietic lineages. Research into COP cells, particularly the hematopoietic lineage, has been slowed by the lack of ability for isolation and expansion in culture – limiting understanding of their potential for use clinically. In this thesis, a model for the isolation, and expansion of COP cells is designed and validated. COP cells expressing CD45, CD34, and alkaline phosphatase can be isolated through flow cytometric cell sorting and proliferate in culture. They are also able to form bone in vitro. This is followed by a detailed -omics scale characterization of the cells, utilizing transcriptomic and proteomic approaches. This analysis found that they are a distinct cell population, with characteristics of both mesenchymal progenitors and immune cells. They show significant transcriptomic and proteomic overlap with mesenchymal stem cells and adipose-derived stem cells, expressing a range of genes and proteins associated with differentiation and proliferation. They also show several changes associated with aging, such as decreased protein translation, vesicular transport and cell cycle regulation, and increased proteins associated with ion homeostasis and transport. While regulated in aging, there were no changes in COP cell physiology with sex difference, at the genetic or proteomic level. Finally, to aid clinical translation in the management of chronic musculoskeletal disease, two clinical studies are described. One, a cross-sectional analysis, identifies correlations with important musculoskeletal parameters such as bone mineral density and content and evaluates their value as a biomarker of osteoporosis. It shows that COP cells are strongly associated with bone mineral density, particularly of the neck of the femur. COP cells are also associated with male sex and appendicular lean mass. Importantly, the percentage of COP cells in the circulation shows good performance as a biomarker of osteoporosis of the neck of the femur and total body. The second study, an interventional study examines the effect of vitamin D supplementation on COP cell numbers. It shows that supplementation with vitamin D leads to an increase in the percentage of COP cells in the circulation.
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ItemThe management of acute decompensated heart failure in a geriatric population: evaluation of novel strategies in a contemporary hospital setting( 2020)Heart failure is a heterogeneous complex disease, with increasing prevalence in the elderly. It is a morbid disease characterized by high mortality and frequent hospital re-admissions, responsible for a significant burden to the patient and to healthcare services. This thesis will examine unique approaches to the hospital system care of acute decompensated elderly heart failure patients by two main projects. Project one is an evaluation of Western Health’s implementation of a ‘cardio-geriatric ’unit and its effect on length of stay and readmission compared to previous routine practice. This found that the intervention did not change length of stay or readmission, however uniquely described a complex group and explores reasons why it may be difficult to achieve these outcomes. Project two explores the significance of anemia and iron deficiency, and the effect on treatment of iron deficiency, a significant comorbidity in heart failure in an elderly population. It demonstrates the prevalence and patterns of iron use in this group of patients. This thesis adds to the literature an exploration of the care provided to elderly comorbid heart failure patients in the hospital setting. It demonstrates the medical complexity of this group of patients and the difficulty in curbing outcomes in this group of patients. It allows for future research to develop alternative models of care or intervention or perhaps induce a paradigm change in the approach to care for the elderly comorbid heart failure patients.
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ItemPragmatic research in elderly multimorbid populations: A case study of community-acquired pneumonia( 2020)This thesis explores pragmatic research methodologies that can be embedded into routine clinical practice to simultaneously implement and evaluate health-system interventions. It is centred around the design and implementation of the IMPROVing Evidence-based GAPs and outcomes in community-acquired pneumonia (IMPROVE-GAP) project, which evaluated the effectiveness of a multidisciplinary care bundle for treatment of Australia’s most common illness requiring hospitalisation. This project addressed three key barriers restricting generalisability of experimental results to routine clinical practice for hospitalised multimorbid populations: i) limited representativeness of participants, setting or intervention delivery, ii) failure to utilise randomisation and minimise potential for confounding and bias, and iii) failure to select outcomes that measure the value of interventions to end users. IMPROVE-GAP’s novelty lay in the way it facilitated clinical practice and evaluation operating in tandem, eliminating costly parallel data and outcome collection. It represents a vital precedent for conducting robust clinical trials in the hospitalised elderly, and provides a template for future high-quality, low-cost health-services research.
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ItemAn Examination of Heart Failure Rehospitalisation in a Western Metropolitan Melbourne Population( 2020)Heart failure is a complex clinical syndrome, associated with a significant burden of morbidity and mortality, including a high rate of rehospitalisation. Reducing the burden of rehospitalisation among patients with heart failure is a recognised priority for healthcare systems. However, in order to optimize outcomes, contemporary studies have emphasized the need for better understanding of the clinical heterogeneity of heart failure populations. Extending beyond the understanding of pathophysiological heterogeneity, the elucidation of sociodemographic factors may also reveal greater opportunities for targeted optimisation. Moreover, utilising new methods by which rehospitalisation is assessed may lead greater insights than would otherwise be captured by conventional means. This project aims to expand the understanding of rehospitalisation burden in evolving heart failure populations. It evaluates the adverse impact of cultural and linguistic diversity on rehospitalisation outcomes in patients with heart failure. A discussion of important methodological concepts into researching culturally and linguistically diverse (CALD) patient groups is carried out. In doing so, a novel operational approach to defining CALD patients is presented. This thesis also explores the measures of which rehospitalisation is evaluated in heart failure patients. It described the added value of analysing all recurrent hospital admissions (events), an approach which is very seldom performed in heart failure research. An assessment of several modelling techniques for evaluating rehospitalisation burden is performed, specifically in relation to heart failure type (i.e. heart failure with preserved vs reduced ejection fraction). In doing so, demonstrate the analysis of recurrent hospitalisations, compared to traditionally utilised first-event statistical approaches, may be a more informative and clinically relevant measure when evaluating the burden of heart failure rehospitalisation. As the prevalence of heart failure is rising and patients are becoming more diverse and complex, there is an increasing need to better characterise and understand these evolving heart failure populations. Further elucidating the heterogeneity of heart failure populations will help guide improvements to existing management approaches, as well as the direct the development of new targeted approaches.