Medicine (Northwest Academic Centre) - Theses
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ItemEndoscopic advances towards achieving safe and effective polyp removal during colonoscopy( 2023-06)Polypectomy performed via colonoscopy reduces morbidity and mortality from colorectal cancer. Colonoscopy is an invasive procedure with known associated serious adverse events. Serious adverse events in therapeutic colonoscopy include perforation or bleeding and most commonly result from the use of electrocautery to remove polyps. Cold snare polypectomy or cold EMR (endoscopic mucosal resection) to remove polyps without electrocautery is a recent evolution in the field of therapeutic endoscopy. These techniques have the potential to reduce the risks of adverse events, but evidence for effectiveness of polyp clearance and safety are lacking for medium and large-sized polyps. The use of endoscopic clips after polyp removal also has potential to reduce the risk of post-polypectomy complications, especially bleeding and perforation, but evidence of their benefit for routine use is still required. Inadequate bowel preparation reduces the ability to detect polyps and thereby reduces the effectiveness of colonoscopy in bowel cancer prevention. It also increases the risk of adverse events such as perforation during diagnostic colonoscopy due to inadequate views while advancing the colonoscope. Therefore, an improved bowel preparation that is well tolerated would be clinically beneficial and could reduce serious adverse events. This thesis reviews the literature on colonoscopic adverse events and explores novel approaches to polypectomy using cold snare techniques for medium-sized and large polyps, endoscopic clip application post-polypectomy, and bowel preparation, with the aim of enhancing safety and effectiveness of polyp removal via colonoscopy. The first major aim of this thesis was to fill the gap in the literature regarding the optimal technique for removal of medium-sized (10-19mm) non-pedunculated colonic polyps. Recent evidence cemented cold polypectomy as the preferred technique for removal of small polyps sized <10mm due to low adverse events with efficacy maintained. While logical to extend this approach to medium-sized polyps with the aim of reducing adverse events, evidence is lacking, especially regarding the effectiveness of complete polyp removal. This is an issue of concern, since polyps of this size will usually require piecemeal resection if electrocautery is absent, rather than en-bloc resection which is usually achievable with electrocautery, thereby theoretically increasing the likelihood of incomplete resection. Furthermore, safety of piecemeal cold polypectomy is expected but also unproven in this size range. Guidelines from major endoscopy societies remain uncertain in their recommendations for the optimal technique for removal of medium-sized polyps, but currently favour hot snare polypectomy as the established technique. To fulfill this aim, we conducted a large, multicentre, prospective, observational cohort study to assess the efficacy and safety of cold snare polypectomy (CSP) or cold-EMR (C-EMR) for non-pedunculated colonic polyps sized 10-19mm that are morphologically suitable for cold resection. The second major aim of this thesis was to study the role of cold snare piecemeal EMR for resection of large (greater than or equal to 2cm) non-pedunculated colorectal polyps. Conventional hot-snare EMR is the standard of care for resection of large , non-malignant non-pedunculated polyps, unless surgery or ESD is required for specific indications including morphology or location. However, conventional (hot snare) EMR is associated with adverse events including perforation (0.5-1%), clinically significant post-EMR bleeding (7%), post-polypectomy syndrome (1%) and recurrence (traditionally >15% but recently reduced to 5% with novel techniques including snare tip soft coagulation of the EMR margin). These adverse events are nearly always due to the electrocautery used in conventional EMR. Accordingly, in our endoscopy unit and some other progressive academic endoscopy units in Australia, we increasingly adopted cold EMR techniques for morphologically suitable large non-pedunculated polyps over recent years. Therefore, cold-EMR was incorporated into our practice to reduce adverse events but evidence for this practice is lacking. Recent evidence has demonstrated the benefits of cold-EMR for removal of sessile serrated lesions (SSLs), but evidence is particularly lacking for the role of cold-EMR for removal of conventional adenomas such as tubular or tubulovillous adenomas. To fulfil this aim of demonstrating efficacy and safety of cold-EMR, we conducted a retrospective, multicentre study of cold-EMR for large, non-pedunculated, colonic polyps where polyp morphology and location was suitable for cold resection. The third major aim of the thesis was to explore the role of routine prophylactic clip placement following polypectomy in reducing the risk of clinically significant post- polypectomy bleeding. Routine clip application is recommended by endoscopy society guidelines for large pedunculated polyps only. However, post-polypectomy bleeding following removal of large non-pedunculated polyps remains a clinically significant problem, particularly following removal of polyps from the right colon. Accordingly, clips post- polypectomy were increasingly used in routine clinical practice despite the lack of evidence. Therefore, we conducted a systematic review of studies of routine prophylactic clip placement following polypectomy to assess effectiveness in reducing clinically significant post-polypectomy bleeding. The fourth major aim of the thesis was to improve the quality of routine bowel preparation for all patients undergoing colonoscopy by the addition of macrogol-based osmotic laxative (Movicol) for several days prior to commencing standard bowel preparation. The purpose was to enhance views during colonoscopy to improve safety of colonoscopy and reduce the risk of missed polyps or lesions. Inadequate bowel preparation quality is a known risk factor for adverse events or missed pathology and unfortunately still affects a substantial proportion of colonoscopies (up to one-third of colonoscopies in some studies). Adding additional bowel preparation to the standard split-dose preparation, which is consumed on the day prior to and day of colonoscopy, is often poorly tolerated due to the larger volume of prep consumption required. Therefore, the addition of a gentle laxative in the days leading up to commencing the formal bowel preparation has the potential to be well tolerated and effective. This approach was already being used in our endoscopy unit and many other endoscopy units without evidence of efficacy or tolerability. Therefore, we conducted a randomised trial of standard split-dose bowel preparation plus Movicol taken for 5 days prior to commencing standard bowel preparation, versus standard split-dose bowel preparation alone. We assessed the quality of the bowel preparation obtained and some additional factors including tolerance, acceptance, compliance, completion rate of colonoscopy, procedural duration, and polyp detection rates. The following conclusions were reached from the studies that comprise this thesis: (1) Cold polypectomy or cold-EMR is safe and effective for removal of morphologically suitable medium sized (10-19mm) non-pedunculated colorectal polyps. (2) Cold EMR is safe and effective for removal of large ( greater than or equal to 20mm) non-pedunculated colonic polyps, including for conventional adenomas. (3) Routine prophylactic clip closure following uncomplicated polypectomy of non- pedunculated polyps did not significantly reduce the risk of clinically significant post- polypectomy bleeding, although there was a trend towards benefit for large polyps sized 320mm. (4) Routine use of Movicol in the days prior to colonoscopy did not enhance the quality of bowel preparation in unselected patients. Its role for select patients with higher risk of inadequate bowel preparation requires further study. These studies make a clinically relevant contribution to the literature and have the potential to influence clinical endoscopy practice to achieve the goals of safe and effective polyp removal during colonoscopy.
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ItemSarcopenia in Australia and New Zealand and the importance of muscle( 2023-03)Abstract Background Sarcopenia is a condition of low muscle strength, low muscle mass and poor physical performance. Sarcopenia is highly prevalent in older adults, particularly among those with comorbidities such as frailty, or those living in residential aged care. Sarcopenia is associated with increased risk for falls, fractures, hospitalisation, institutionalisation and mortality, but remains under recognised and under treated. There is no universally accepted definition of sarcopenia which creates inconsistencies between and within regions and healthcare providers. The most recent and widely cited definitions of sarcopenia are the revised European Working Group for Sarcopenia in Older People (EWGSOP2), Sarcopenia Definitions and Outcomes Consortium (SDOC), and the revised Asian Working Group for Sarcopenia in Older People (AWGS2). The absence of a universal definition has hampered research progress and contributed to limited translation of sarcopenia knowledge to clinical practice. Additionally, the importance of low muscle mass and its contribution to negative outcomes in older people remains unclear, largely owing to disagreement around the techniques used to determine muscle quantity or quality. Furthermore, in Australia and New Zealand, there have been no regionally specific consumer-informed clinical guidelines to aid health professionals in caring for people with sarcopenia, or to guide research, which has limited knowledge translation. Aims To i) understand the impact of sarcopenia definitions on its prevalence and outcomes, ii) explore the role of an accurate measure of muscle mass on mobility and disability outcomes, and iii) establish consumer- and topic expert-informed evidence-based clinical and research sarcopenia guidelines for use in Australia and New Zealand. Methods Chapter 2 employed a narrative literature review approach to critically examine current literature and identify knowledge gaps. Chapters 3, 8 and 9 used variations of the modified Delphi method with consumer expert (Chapter 8) and topic expert (Chapters 3 and 9) participants to establish regionally specific operational definitions of sarcopenia in Australia and New Zealand, and present clinical and research sarcopenia guidelines. Chapters 4 to 7 employed either factor analysis or Classification and Regression Tree (CART) analysis to understand the prevalence of sarcopenia, and associations of muscle mass (and surrogate measures), muscle strength and physical performance with adverse outcomes in older adults. Chapter 4 applied factor analysis to the longitudinal Osteoporotic Fractures in Men Study (MrOS) to determine groupings and associations of muscle strength, physical performance, body composition and muscle mass with activities of daily living limitations and disability, and mobility disability. Chapter 5 applied CART to the MrOS study data to determine which muscle strength, physical performance, body composition and muscle mass measures predict incident mobility disability. Chapter 6 applied the CART methodology to a pooled, cross-sectional cohort of eight epidemiologic studies from Australia and New Zealand to determine optimal variables and cut points predicting slow walking speed (<0.8 m/s), and compared agreement between recent sarcopenia definitions. Chapter 7 applied the CART methodology to the Dubbo Osteoporosis Epidemiology Study (DOES2) to determine which baseline muscle strength, physical performance and body size and composition variables best predict incident mortality and falls, and prevalent slow walking speed (<0.8 m/s) in older women and men. Results Chapter 3 established consensus among topic experts that the original European Working Group for Sarcopenia in Older People (EWGSOP1) operational definition was recommended for Australia and New Zealand. Chapter 8 showed that people living with sarcopenia, their carers and healthcare consumers have different assessment and outcome priorities than sarcopenia topic experts. Chapter 9 produced 17 consensus statements on sarcopenia prevention, assessment and management in Australia and New Zealand, and established the EWGSOP2 sarcopenia as the preferred definition in the region. Chapters 4 and 5 demonstrated the importance of an accurate measure of muscle mass (D3Cr muscle mass) in predicting negative outcomes in older men. Chapter 4 showed that D3Cr muscle mass is strongly correlated with measures of muscle strength and physical performance, and combined these measures are associated with negative mobility and disability outcomes in older men. Chapter 5 found that D3Cr muscle mass is an important predictor of incident mobility disability in older men, in contrast to DXA-determined lean mass. Chapters 6 and 7 examined Australian and New Zealand older adults, demonstrating poor sarcopenia definition agreement (Chapter 6) and variable predictive ability of different measures of muscle strength and physical performance for mortality and falls in women and men (Chapter 7). Chapter 6 replicated the findings of the SDOC showing that hand grip strength (with body size adjustments) is the strongest predictor of prevalent slow walking speed (<0.8 m/s) and that the SDOC and EWGSOP2 sarcopenia definitions have poor agreement and produce different sarcopenia prevalence estimates. Chapter 7 found that age and walking speed adjusted for height were the most important predictors for mortality in women, and quadriceps strength (with adjustments) was the most important predictor for mortality in men. In both sexes, sit-to-stand test (with adjustments) was the most important predictor for incident falls, and timed-up-and-go test was the most important predictor for prevalent slow walking speed (<0.8 m/s). Chapter 10 critically discussed the findings, examined limitations, and outlined future directions. Conclusions This thesis demonstrated that i) different sarcopenia definitions and measures produce highly variable prevalence estimates and outcome predictions between women and men, ii) an accurate measure of muscle mass (D3Cr muscle mass) is a strong predictor of mobility and disability outcomes in older men, and iii) established consumer- and topic expert-informed sarcopenia guidelines in Australia and New Zealand. Further study is required to determine the role of the D3Cr method in clinical practice and to establish a global definition of sarcopenia.
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ItemRisk-guided strategy for reducing readmissions for acute decompensated heart failure: The Risk-HF study( 2022)Background: Congestion is the hallmark clinical manifestation of heart failure (HF) syndrome and a strong predictor of poor outcomes. Despite rapid improvements in volume status during the hospital course, about half of all patients are discharged with residual congestion, which significantly increases the risk of readmission and affects survival. Although nurse-led disease management programs (DMP) improve outcomes, patients may not be offered this level of support, often because of limited resources. Risk stratification to target DMP to high risk patients is essential; nevertheless, despite DMP and risk assessment, readmission due to re-congestion remains frequent, possibly linked to insufficient decongestion at index discharge. Thus, there is an imperative to ensure euvolemia pre-discharge and monitor post-discharge for early detection of re-congestion. To date, pre-discharge euvolemia is usually based on subjective clinical assessment, which is sometimes inaccurate. Therefore, applying sensitive congestion assessments pre-discharge may help to detect residual congestion and guide the administration of diuretic treatment before and after hospital discharge, during DMP home visits – we call this strategy “DMP-plus”. The primary focus of this thesis was guided decongestion and early detection of deterioration. Hypothesis It is hypothesised that targeting high risk patients (i.e., 33% risk or more) at an enhanced post-discharge, nurse-led DMP, comprised of ultrasound-guided decongestion and constant patient monitoring using mobile health (m-Health), will improve short-term adverse outcomes in patients admitted for ADHF. Objectives: i. To evaluate novel non-invasive congestion assessments and establish the most practical that can be applied to all patients by any health practitioner. ii. To use technological advances to: a) detect, track and eliminate congestion with a portable, non-invasive assessment and b) enhance patient monitoring with an m-Health digital HF avatar-style coach. iii. To establish the role of nurses in non-invasive congestion assessments iv. To target high risk patients (using an established risk algorithm) for non-invasive, nurse-guided community-based diuresis. Methods A randomised controlled trial was developed to test the hypothesis. Patients at high risk for 30-day readmission or mortality were randomised to receive either standard care (n=64) or a novel intervention (n=58). The latter comprised a lung ultrasound (LUS)-guided response to a congestion signal by titration of the diuretic treatment dose. With a systematic review and meta-analysis, I established that LUS assessment is the most feasible and practical approach. Nurses were trained in LUS assessment. Pre-discharge, and twice in the one-month follow-up period, patients in the intervention arm received a nurse-provided LUS assessment. A proportion (n=10) was enrolled in the m-Health HF app. Endpoints The primary outcome was composite 30-day all-cause readmission or mortality. The secondary outcomes included 90-day HF readmission. Results and conclusions This PhD project established that nurses can be ideal LUS users. Nurses detected congestion and provided independent diagnostic reports, predictive of outcomes. The incremental diuretic treatment response was correlated with the congestion signal detected by LUS assessment in a community setting. Although this enhanced DMP-plus did not reduce the primary outcome, there was a numerical 10% reduction in 90-day HF readmission rates. Whilst not statistically significant, this result warrants future investigation. M-Health using an avatar-style HF app for patient monitoring and engagement is promising but challenging to apply in a multicultural cohort. Future HF apps and patient monitoring platform designs should consider cultural and linguistic factors.
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ItemSessile Serrated Adenoma/Polyps: a new target for effective colon cancer prevention( 2022)This work pertains to a Master of Medicine thesis entitled: “Sessile Serrated Adenomas: a new target for effective colon cancer screening”. Colorectal cancer screening and surveillance programs aim to detect and remove adenomatous polyps, on the basis that the adenoma-carcinoma sequence results in the development of colorectal cancers from pre-existing adenomatous polyps. However, other molecular pathways for colorectal cancer development have recently been recognised. The serrated neoplasia pathway accounts for 15-30% of all colorectal cancers and sessile serrated adenoma/polyps (SSA/P) are the principal serrated precursors of colorectal cancer. Recently, a recommended SSA detection rate during colonoscopy of at least 4% has been proposed for all practising Australian colonoscopists by the Australian Colonoscopy recertification committee. Furthermore, updated Australian colonoscopic surveillance guidelines published in 2018 have now included SSA/P as a separate entity to conventional adenomas, in their recommendations. SSA/P are often difficult to detect on colonoscopy and have unique endoscopic features. Evidence suggests that SSA/P recognition during colonoscopy and their optimal resection using colonoscopic polypectomy techniques is an acquired skill that may be separate to conventional adenomatous polyp detection. This project comprises three separate studies. The first aims to evaluate SSA/P detection rates over a 4-year audit period, for a single colonoscopist, in comparison to their adenoma detection rate (ADR). This study demonstrated a statistically significant increase in SSADR over time with learning and experience, with a relatively stable but adequate conventional ADR. The second study documented existing ADR and SSADR for a broad group of colonoscopy practitioners at Western Health during Jul-Dec 2015, to identify groups of practitioners who may benefit from targeted education to improve their SSADR. This study demonstrated variable detection rates for different categories of colonoscopy practitioners and identified non-interventional gastroenterologists and colorectal surgeons as the categories that may benefit from further education to improve their SSADR. The third and main component of this project aimed to improve SSADR for these practitioners by a targeted educational intervention, including comparing their ADR, SSADR and PSLDR (proximal serrated lesion detection rate) before and after the educational intervention. This consisted of a multimedia presentation and reinforcing posters in the endoscopy suites across Western Health. Overall, there were no statistically significant increases in ADR or SSADR following the educational intervention. However, a significant increase in ADR and a trend towards improved SSADR was seen for non-interventional gastroenterologists. Furthermore, when compared to the original control cohort from 2015, both ADR and SSADR demonstrated a statistically significant increase, suggesting that improvement in SSADR likely occurs with experience and exposure to these lesions over time, similar to results from the first study. Large multicentre longitudinal cohort studies are required to investigate whether improvements in SSADR translate to reduced mortality from colorectal cancer. However, SSA/P are now firmly established as a new target, in addition to conventional adenomatous polyps, for removal via colonoscopy, to achieve effective colon cancer prevention. Further studies are required to evaluate more effective but practical ways to improve the SSADR for Australian colonoscopists, as the results from this project suggest that there is room for further improvement.
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ItemIdentification of compounds to inhibit the stress transcription factor, Heat Shock Factor 1, as novel anti-cancer agents( 2022)Heat Shock Factor 1 (HSF1) is the master stress transcription factor which enables cells to overcome and survive otherwise lethal stresses, including but not limited to heat, acidosis, hypoxia, genomic aberrations and oxidative stress. HSF1 orchestrates these survival processes primarily through activation of the heat shock response (HSR) pathway, which enables cells to upregulate the expression of heat shock proteins (HSPs) and other pro-survival targets. While central to several pathophysiological conditions, in cancer cells, HSF1 is intimately linked with cancer initiation, progression and metastasis. As cancer cells must overcome numerous stress insults and exhibit elevated biosynthetic demands when compared to non-cancer cells, HSF1 has been identified as an essential factor for the survival of advanced cancer cells. Consequently, HSF1 has emerged as a major therapeutic target, which has motivated numerous research groups to undertake programmes that seek to develop small molecule-based HSF1 inhibitors. To this end, these have been largely unsuccessful, as a compound capable of direct and selective HSF1 inhibition remains to be fully validated. While various compounds which can modulate the HSF1 pathway have been identified, these have been shown to impact the HSF1 pathway only in an indirect manner or via an uncharacterised mechanism of action. In this thesis, an alternative approach to targeting HSF1 has been taken through the development of rationally designed peptide inhibitors which mimic the protein-protein interactions that are essential for HSF1 functionality. Using biophysical approaches, six rationally designed novel peptide sequences were characterised for their ability to inhibit the activation and functionality of HSF1. Through this work, a lead peptide inhibitor (HiPe4) was shown to interact with HSF1 in a pulldown assay and disrupt HSF1 binding to HSE-DNA oligonucleotides (IC50 60.1 uM). Through trial and incorporation of protein transduction domains/cell permeability sequences, it was also demonstrated that HiPe4 blocks HSF1 activity in cells by reducing levels of HSF1 regulated HSPs. Further experiments also elucidated that HiPe4 impairs activation of the HSR in three cell lines and reduces the viability of cancer cells. In contrast, the viability of a non-oncogenic cell line model was shown to be unaffected following treatment with HiPe4, suggesting that cancer cells exhibiting elevated expression and activation of HSF1 face increased susceptibility to HiPe4 toxicity. HiPe4 was demonstrated to significantly deplete levels of HSF1 in three cancer cell lines, pointing to a novel joint mechanism of action not previously demonstrated by peptides. In summary, the findings of this study present a significant turning point in the search for HSF1 inhibitors for use as a cancer treatment strategy. It is the first study demonstrating inhibition of HSF1 functionality and activity using biophysical, biochemical and molecular approaches. Furthermore, it is one of only two inhibitory compounds which have been shown to inhibit HSF1 activity without activation of the HSR. Therefore, this work is likely to provide a viable starting point for the development of a therapeutic HSF1 inhibitor, while also providing significant insight into the design approaches which should be taken when targeting other ‘undruggable’ molecular targets in the future.
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ItemEvaluation of pathologic mechanisms in patients with coronary microcirculatory dysfunction and novel therapy and systems of care in acute coronary syndromes( 2022)Myocardial ischaemia is the result of perturbations in coronary perfusion occurring at the epicardial and/or microcirculatory level of the coronary arterial system. Ischaemic heart disease due to stable and acute coronary syndromes carry significant morbidity and mortality burden globally. There have been significant efforts to further improve therapies for acute myocardial infarction and to investigate coronary microcirculation as the final common pathway and mechanism of myocardial ischaemia, however, with limited results. Furthermore, the outcomes of cardiogenic shock, a grave complication of myocardial ischaemia, remain poor over the decades despite improvements in timely coronary reperfusion and vasoactive pharmacotherapies. This thesis aims to explore the mechanisms of myocardial ischaemia secondary to epicardial coronary artery disease and microcirculatory dysfunction across different clinical presentations including acute coronary syndromes and cardiogenic shock. Coronary reperfusion is the only intervention that has been proven to reliably reduce myocardial infarct size. However, there are concerns that reperfusion itself is linked to deleterious effects by potentiating myocyte necrosis of cells that were viable before or at the time of reperfusion through a well-described process of ischaemia-reperfusion injury. Therefore, optimising successful reperfusion using adjunctive pharmacotherapy aimed at reducing the adverse effects of reperfusion injury could further reduce infarct size and ameliorate the consequent adverse left ventricular remodelling as well as improve clinical outcomes. We conducted and report on the results of the SALVAGE MI trial, a randomised, double-blind, placebo-controlled trial evaluating the effect of doxycycline (a powerful matrix-metalloproteinase inhibitor and reactive oxygen species scavenger) administered prior to primary percutaneous coronary intervention and continued for 7 days thereafter on myocardial infarct size and left ventricular remodelling among patients presenting with acute myocardial infarction. Patients treated with doxycycline had a paradoxical trend for larger 6-month infarct size adjusted for the area-at-risk, larger absolute final infarct size at 6 months, but similar acute infarct size compared to placebo as assessed using cardiac magnetic resonance imaging. Doxycycline did not ameliorate adverse left ventricular remodelling and was independently associated with larger final infarct size. Thus, these data raise safety concerns regarding doxycycline use in ST-elevation myocardial infarction for infarct modulation and healing. Coronary microvascular dysfunction has gained increased recognition as the cause of myocardial injury or ischaemia among patients with non-obstructive epicardial coronary artery disease. The evaluation of coronary microcirculatory dysfunction has become feasible with validation of invasive measures of coronary blood flow and microcirculatory resistance. Mechanistic insights into myocardial ischaemia development and myocardial metabolic adaptations in microcirculatory dysfunction remain to be elucidated. We report the results of a mechanistic, invasive haemodynamic study investigating changes in microcirculatory resistance and metabolic profiles in patients presenting with clinical coronary microvascular dysfunction. Patients with documented ischaemia or myocardial injury and non-obstructive epicardial coronary artery disease underwent thermodilution-derived microcirculatory resistance assessment as well as transcardiac blood sampling during graded exercise with adenosine-mediated hyperaemia. These patients were found to exhibit distinctive coronary microcirculatory resistive and myocardial metabolic profiles at rest and in response to exercise based on their resting microcirculatory resistance. These findings have significant implications for the design of future randomised controlled trials evaluating tailored therapies in these patients based on their resting microcirculatory phenotypes. Cardiogenic Shock is the leading cause of mortality in patients presenting with acute coronary syndromes despite timely reperfusion and contemporary systems of care. We report the results of 2 large cohort studies using data from 2 of the largest percutaneous coronary intervention registries in Victoria, Australia. In the first study we assessed the outcomes of cardiogenic shock complicating acute coronary syndromes among 13,184 all-comers patients undergoing percutaneous coronary intervention enrolled prospectively in a large multicentre Australian registry, the Melbourne Interventional Group, from 2005 to 2013. Compared to the non-cardiogenic shock group (n=13,184), patients who were in cardiogenic shock (n=636) had higher rates of in-hospital (40% versus 1.2%), 30-day (41% versus 1.7%) and long-term mortality (51% versus 14%), all p<0.01. Trends of in-hospital, and 30-day mortality rates of cardiogenic shock complicating acute coronary syndromes were relatively stable at around 40% from 2005 to 2013. We concluded that over time, the rates of cardiogenic shock-related mortality complicating acute coronary syndromes have remained very high and steady over nearly a decade despite progress in acute coronary syndrome systems of care, timely reperfusion, percutaneous coronary intervention techniques and medical therapy. In the second study, we assessed the association between the availability of on-site cardiac surgery and percutaneous coronary intervention volume with clinical outcomes of cardiogenic shock complicating acute coronary syndromes in consecutive patients undergoing percutaneous coronary intervention for cardiogenic shock who were prospectively enrolled in the Victorian Cardiac Outcomes Registry across 26 hospitals in Victoria, Australia. We compared patients treated at cardiac surgical centres against non-cardiac surgical centres as well as the annual cardiogenic shock percutaneous coronary intervention volume (stratified into tiers of <10, 10-25, >25 cases per year) for in-hospital outcomes and long-term mortality. We observed no difference among patients treated at non-cardiac surgical centres compared to cardiac surgical centres for in-hospital (42% versus 42%) and long-term mortality (51% versus 50%), both p>0.05. Similarly, there was no association between tiers of annual cardiogenic shock percutaneous coronary intervention volume with in-hospital (44% for tier 1 versus 41% for tier 2 versus 41% for tier 3) and long-term mortality (55% for tier 1 versus 48% for tier 2 versus 49% for tier 3), both p>0.05. These findings underscore that emergent treatment of these gravely ill patients at their presenting coronary intervention-capable hospital is warranted prior to considering subsequent transfer if required to a cardiac surgical centre.
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ItemInflammatory Bowel Disease-associated Osteosarcopenia: identification of mechanisms and therapeutic targets( 2022)Chronic inflammatory disorders such as inflammatory bowel disease (IBD) of the intestine cause an appreciable risk of musculoskeletal disorders, mainly affecting children and youth. Osteosarcopenia in IBD patients develops with generalized muscle weakness, reduced muscle mass (60%), sarcopenia (42%), osteopenia (77%) and osteoporosis (42%). Osteosarcopenia remains silent until it manifests by physical disability due to fatigue, falls and fractures, increased hospital admissions, and substantially reduced quality of life. Multifactorial etiologies comprise direct effects of underlying inflammatory disease processes, nutritional deficits, and therapeutic effects. Understanding the complex interplay between various factors that lead to IBD-induced osteosarcopenia is a formidable challenge. Murine models are widely used to explore gut-bone-muscle interactions because of the challenges and limitations inherent to human studies. Studies investigating bone and muscle status have been mainly conducted in the acute models of TNBS or DSS-induced colitis. These models enriched our understanding of bone and muscle pathology in colitis. However, the chemical damage to the gut epithelium in these models results in self-limiting inflammation in these models rather than replicating specific chronic immunopathology present in inflamed colons of IBD patients. Therefore, the association between long-term chronic inflammation and musculoskeletal health status cannot be studied in these models. Winnie mice model of colitis with single point missense mutations in the mucin gene show both innate and adaptive immune response. Colitis in Winnie mice exacerbates with age, similar to inflammation progression in IBD patients. The epithelial mucosal dysfunction, colon morphology, motility and faecal microbial and metabolomic profiles in Winnie mice are also analogous to UC patients. The objectives of our study are to define whether there are musculoskeletal alterations in Winnie mice with the onset and progression of chronic colitis, to resolve whether GDS levels are associated with underlying changes and to elucidate associated molecular mechanisms. We analyzed the phenotypic, cellular, and functional characteristics of cortical and trabecular bone in Winnie mice from prior (6 weeks old, w.o.) and during the development of inflammation (14w.o. and 24 w.o.) and these changes were compared to age and sex-matched control C57BL/6 mice. We observed skeletal deterioration with advancing age starting from the onset of colitis symptoms after 6 weeks, and gradually increasing from 14 weeks (progressive) to 24 weeks (severe colitis). Our results indicate significant and reproducible defects in bone structure, formation, and mechanical properties. Winnie mice showed deteriorated bone microstructure leading to fewer, thinner, and more separated trabeculae, and reduced cortical thickness. Paradoxically, we observed loss of some bone parameters in Winnie mice at 6w.o. without any clinical symptoms of colitis. Winnie mice at 14w.o. and 24w.o. were more susceptible to bone loss. This was evidenced by a more significant difference in deterioration of some bone parameters (trabecular thickness, elastic modulus) in Winnie mice at 14w.o. and 24w.o.. In this study, we also attempted to deduce mechanisms associated with bone loss, mediated by gut-derived serotonin (GDS) in our model. GDS levels progressively increase in Winnie mice, starting from 6w.o. to drastically higher levels at 14w.o.. The degree of bone deterioration observed in our model goes in parallel with increasing GDS levels with age. Simultaneous with increasing GDS levels, the molecular regulators FOXO1 and ATF4 genes were augmented in Winnie mice at 14w.o. compared with 6w.o.. Our data showed disease severity–dependent alteration of bone microarchitecture in Winnie mice model of colitis. Furthermore, analysis of the cellular mechanisms of bone loss revealed that the number of osteoblasts was reduced at all ages, with a concomitant elevation in osteoclasts. Chronic colitis associates with increased GDS availability, which could negatively impact osteoblastogenesis in this model. Our earlier study in Winnie mice reported that GDS is at the maximum high level after 14 weeks and ceases to rise after 24 weeks. To pin-point mechanisms potentially responsible for bone loss in colitis, we observed association of high GDS levels and FOXO1 molecular partners to regulate bone metabolism. Our study reports a high level of GDS in Winnie mice, which is paralleled with increased transcriptional activity of FOXO1. Our immunohistochemical analysis revealed dissociation of FOXO1-CREB complex in bone marrow derived mesenchymal stromal cells (BM-MSCs) of 14 weeks Winnie mice. This releases the inhibiting effect of CREB on FOXO1, leading to suppression of proliferation of osteoblasts. In contrast, no significant changes in association/dissociation of complexes with FOXO1 were observed at 6 w.o. Winnie mice compared with age-matched controls. This is in agreement with no differences in the levels of 5-HTR1B expression at 6 w.o. Winnie mice and age- matched controls. These findings may have implications for FOXO1 as the molecular node of intricate transcriptional machinery that may be associated with inhibition of bone formation. There is a possibility that in the presence of high GDS levels, most of the 5-HTR1B on bone is bound by GDS, which upregulates the expression of 5-HTR1B and FOXO1. Concomitantly, there is a shift in FOXO1 target genes from CREB to ATF4- dependent responses. Our findings suggest that the interaction of FOXO1 with ATF4 or CREB can shift to ATF4-dependent responses in the Winnie mice. In conclusion, our findings support the hypothesis that changes in GDS signaling might be one of the contributing factors to the bone loss associated with colitis. Immune cells have GDS receptors on them; therefore, we cannot exclude the role of systemic inflammation in IBD-induced osteopenia/osteoporosis. For muscle phenotype study, experimental mice were obtained from heterozygote breeders (Winnie+/-) to obtain Winnie-/- and control mice from the same breeding pair. Winnie-/- mice were compared with littermate controls (Winnie+/-). Our previous studies showed that Winnie mice develop mild spontaneous inflammation in the colorectum after they are 6w.o. in pathogen-free conditions; it progresses over time and results in severe colitis by 12 to 16w.o.. Therefore, we chose pre- and post-inflammatory stages: 6w.o. (no colitis) and 14w.o. (progressive colitis) to study colitis induced skeletal muscle phenotype alterations. We studied physiological and functional properties of muscles located in the hind limbs (TA and soleus) of Winnie mice compared to controls as declining muscle mass in the lower extremities is most significant in age-related sarcopenia. The mouse soleus has been reported to express the closest molecular resemblance to several human skeletal muscles. Human soleus muscle mediate interaction between its fascicle and tendon to generate force and mechanical work during walking and running. In this study, we tried to elucidate the phenotypic effects on skeletal muscle in Winnie mouse model of spontaneous chronic colitis. Physical parameters, namely, body weight, muscle wet weights, muscle fibre size, grip strength and voluntary locomotion and running were assessed to demonstrate functional deficits of sarcopenia. Mitochondrial oxidative activity was also assayed in muscle tissue to evaluate the possible role of oxidative stress in the development of the sarcopenic state. In fact, the explicit loss of both type 1 and 2 fibers as shown by ATPase staining demonstrated the sarcopenic state of our mouse model. Our results indicate significant and reproducible defects in muscle mass, size, oxidative capacity, and physical performance at inflammatory 14w.o. Winnies compared to age- and sex-matched controls. Therefore, Winnie mouse model of spontaneous chronic colitis can be used as a robust model to study phenotypic and functional alterations of muscle in IBD. To validate the systemic impact of colitis on muscle, we initially confirmed decreased muscle weights in Winnie mice. The most frequent phenotype in IBD patients was reduced muscle mass and weight loss. Colitis induced decreased body and muscle mass at 14w.o. Winnies undergoing colitis compared to controls. Following normalization with body weight, female and male Winnie mice displayed significantly decreased muscle (both TA and soleus) wet weights at 14w.o. vs age and sex-matched controls. This suggests that the deleterious effects of intestinal inflammation on muscle mass in Winnie mice are not solely attributable to impairment in general body weight gain. Our results are in accordance to previous studies which showed colitis associated decrease in muscle mass. However, there was no decline in skeletal muscle mass (soleus and TA) from 6w.o. to 14w.o. unlike decreased muscle masses shown from 7w.o. to 14w.o. in pathogenic bacteria infested gene-deficient interleukin 10 (IL-10-/-) mice. Consistently, decreased muscle mass of hind limb muscles (e.g. quadriceps and gastrocnemius) was noticed in DSS-model of colitis. However, longissimus and soleus muscles were only slightly affected in DSS-treated mice. It has also been shown that skeletal muscle mass and proteins were reduced in murine models of TNBS-induced colitis, suggesting the linkage between IBD and muscle wasting. CD patients show lower muscle mass due to poor nutritional status whereas the incidence of nutrient deficiencies is less significant in patients with UC, because CD can affect any part of the gastrointestinal tract, mainly, the small bowel. To investigate the influence of impaired mucin in goblet cells on the morphology of skeletal muscles, we observed muscle phenotype to ascertain muscle fiber sizes in Winnie mouse model of colitis. At non-inflammatory 6w.o. females and males Winnies, it was found that Muc2 knock outs didn’t affect TA fiber size. Our previous results showed that Winnie mice at 6w.o. had no lipocalin-2 (an inflammatory marker) expression, thereby, no disease activity detected at non-inflammatory 6w.o. Winnies. Consistently, we observed no muscle phenotype alterations at 6w.o. Winnies vs age and sex-matched controls. Evidently, there is chronic progression of skeletal muscle phenotypic alterations. Concomitant to reduced whole muscle mass, average TA and soleus muscles’ fibre sizes were significantly decreased at 14w.o. female and male Winnies undergoing colitis compared to age- and sex-matched controls. Male Winnie mice at 14w.o. showed more reduced muscle fiber size in TA and soleus muscle compared to age- and sex-matched controls. In summary, advanced inflammation in Winnie mice at 14w.o. induced loss of muscle mass and muscle individual fibres atrophy in both slow-twitch (soleus) and fast-twitch (TA) muscles. Muscle fibre frequency distribution showed that colitis in female Winnies at 14w.o. shifted the TA and soleus muscle fiber sizes towards more number (or increased frequency) of small-sized muscle fibers while lesser number (or decreased frequency) of large-sized fibers. Muscle fibre frequency distribution showed that colitis in male Winnies at 14w.o. shifted the TA and soleus muscle fiber sizes towards more number of smaller fibers but particularly towards lesser number of large-sized fibers. This implies atrophic signaling pathways induce large individual fibres to smaller fibres in Winnies at 14w.o. compared to controls. A delicate balance between oxidative and anti-oxidant enzymes activity get disturbed in chronic inflammation to generate mitochondrial-derived oxidative stress. We tested for SDH enzyme activity, which a common marker of mitochondrial oxidative metabolism. TA muscles showed decrease mitochondrial oxidative activity in both female and male Winnies at 14w.o. compared to age- and sex-matched controls. Oxidative and metabolic stress act as a compensatory anti-inflammatory response to re-establish homeostasis. Male Winnies showed reduced oxidative activity in soleus muscle at 14w.o. compared to age- and sex-matched controls. TA muscles in male Winnies showed more oxidative damage (51%) than female Winnies (47%). Particularly, TA muscle is more prone to the detrimental effects exerted by the enhanced oxidative stress than soleus muscle. It has been evidenced that soleus remain more oxidative than the TA and expressed higher levels of markers of mitochondrial biogenesis. Female Winnies did not show reduced oxidative activity in soleus muscle at 14w.o. compared to age- and sex-matched controls. From physical activity data, we concluded notable effect of on physical activity, particularly voluntary wheel running performance by 14w.o. Winnie mice with inflammation. A relative lack of physical activity also explains a reduction in muscle mass. Even individuals with quiescent CD have reduced physical activity. Low skeletal muscle mass, decreased oxidative capacity of TA muscle in inflammatory Winnies at 14w.o. is linked to muscle fatigue, which may be associated/causative for low voluntary wheel running activity. Short-term muscle inactivity severely reduces muscle mass and strength even in young individuals. It is reasonable to assume that exercise could be more arduous for Winnies with advanced inflammation. Skeletal muscle atrophy in inflamed Winnie mice with colitis is characterized by low muscle mass and size. We propose that in response to elevations in systemic inflammation and physical inactivity, lead to the onset of muscle atrophic responses in Winnie mice with colitis. Noticeably, Winnie mice showed reduced muscle mass/size without fiber attrition. We can conclude that Winnie mice is at the ‘sarcopenia’ stage, which is characterized by low muscle mass and size, plus low physical performance. As Winnies do not show low muscle strength, Winnies do no exhibit phenotype of ‘severe sarcopenia’. Further studies are warranted to decipher whether sarcopenia is because of impaired muscle protein synthesis and/or suppressed inhibition of muscle protein breakdown or both.
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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.