Medicine (St Vincent's) - Theses
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ItemPredicting response to anti-TNF therapy in Crohn's disease: clinical and metabolic studiesDing, Nik Sheng ( 2018)Crohn’s disease is a chronic, disabling inflammatory condition that affects the gastrointestinal tract that is associated with significant morbidity. Up to 80 percent of patients require surgery at some point in their lives. A third of patients require surgery within five year of diagnosis even in the era of biologic therapy. Ant- Tumour Necrosis Factor alpha (Anti-TNF) therapies form the backbone of drug therapy in patients with moderate to severe Crohn’s disease and remain the most effective biologic drugs available. There are currently three classes of biological drugs available on the Pharmaceutical Benefits Scheme (PBS) for Australians with many more under development. Up to thirty percent of patients fail to have an adequate response to anti-TNF therapy and loss of response occurs at a rate of ten percent per year. There are at present no highly sensitive biomarkers of response to anti-TNF therapies. Without biomarkers to assist with selecting the most effective biologic for a particular patient, there is a risk of exposing patients to ineffective drug therapies with unnecessary side-effects and costs. This thesis comprises a range of clinical and scientific studies that seek to identify predictors of loss of response to anti-TNF therapies in Crohn’s disease. Two types of loss of response have been identified: Primary nonresponse (PNR), is defined as a lack of response to the initial drug therapy as determined at 12 weeks post induction, and Secondary Loss of Response (SLOR) is defined as the loss of response after the patient has had an initial response to the drug. Based on the clinical observation that patients with altered body composition and those with strictures have a variable to response to anti-TNF therapy, we sought to identify whether there were specific clinical, endoscopic, histologic and biochemical parameters that correlated with response to anti-TNF therapy amongst patients from whom longitudinal body composition and endoscopic data had been collected. A prospective cohort study of patients who had been newly started on anti-TNF therapies was also undertaken. In this cohort samples of urine, blood and faeces were taken prior to anti-TNF therapy delivery (baseline) and then at 3 monthly intervals thereafter. A combination of bioinformatic analyses and novel techniques evaluating the metabolome were applied to the cohort, in order to find clinical factors and biomarkers that might correlate with therapeutic response to anti-TNF therapy. This series of studies presented in this thesis on clinical and metabolic predictors of outcomes in patients receiving anti-TNF therapy for Crohn’s disease reveals new insights into the pathophysiology of Crohn’s disease and has identified biomarkers for the prediction of therapeutic response – thereby helping to come a step closer towards the ultimate goal of precision medicine.
ItemIntegration of advanced echocardiographic metrics and biomarkers to the fields of heart failure and exercise physiology in the era of precision medicineMoneghetti, Kegan James ( 2018)Exercise testing is widely used for risk stratification of ischaemic heart disease, however, its application in other cardiovascular conditions, specifically heart failure and other disease states is less defined. Heart failure is a leading cause of mortality and morbidity. Despite advances in medical therapy, its prevalence is expected to increase. Recent developments in cardiac echocardiography, exercise testing and reducing costs of biomarker assays provides the opportunity to improve identification and prognostication of the heart failure syndrome. These principles may also prove useful in the discrimination of other disease states, in which a diagnostic biomarker is lacking. The principle aim of this thesis was to identify novel echocardiographic and non-invasive cardiopulmonary parameters during exercise that provide incremental prognostic value to established risk markers in heart failure. An exploratory sub aim was to investigate the ability of a personalised exercise test to discriminated disease states outside the cardiovascular system. Cohorts of heart failure patients undergoing assessment with echocardiography and cardiopulmonary exercise testing were selected to assess the incremental value of novel parameters. Recently, deformation imaging, also known as strain and quantitative measures of the right heart have shown prognostic value in patients with heart failure. These measures have rarely been analysed with cardiopulmonary exercise testing, therefore, their prognostic value in outcome models and contemporary risk scores were assessed. Dynamic changes in selected parameters were evaluated with regard to risk stratification potential. Finally, as biomarker assays are becoming increasingly used to identify the heart failure syndrome, their contribution to discrimination of disease and risk modeling when performed in conjunction with an exercise test was evaluated. In summary the main findings of this thesis were: 1. Echocardiographic contractile reserve and cardiopulmonary exercise testing parameters provide complementary information, therefore, in combination provide an opportunity to improve prognostication in heart failure. 2. Right heart metrics specifically, right atrial volume and exercise performance add value to previously validated heart failure risk scores in dilated cardiomyopathy. 3. The combination of exercise performance, left ventricular strain and left atrial volume presents a simple model for predicting heart failure outcomes in hypertrophic cardiomyopathy. 4. Percent predicted values of maximal oxygen consumption derived from the Fitness Registry and the Importance of Exercise National Database (FRIEND) registry equation appear to accurately predict heart failure outcomes. 5. Cytokine profiling post exercise appears to have greater discriminatory power than at rest when used to identify patients with myalgic encephalomyelitis / chronic fatigue syndrome; Echocardiographic parameters, have limited value. 6. The integration of cardiac biomarkers, cytokine profiling, exercise performance and cardiac imaging in a personalised exercise test is achievable and has the potential to improve risk profiling. In conclusion, this thesis demonstrated the opportunity to further refine risk stratification in heart failure using novel images techniques, specifically deformation imaging, right heart metrics and exercise performance. The use of serum samples post a bout of exercise may provide an opportunity to further refine diagnostics in the field. Future studies should address biological variability of serum biomarkers and investigate their value when integrated with established markers of risk.
ItemIdentification of structural heart disease in a high risk, asymptomatic community cohort - the SCREEN-HF StudyColler, Jennifer ( 2015)The development of symptomatic heart failure portends a poor prognosis, even in the current era where many effective heart failure therapies are available. Identification of subjects at particularly elevated risk of heart failure, including those with classic heart failure risk factors or underlying structural heart disease, could facilitate a more preventative approach to this condition. However, effective risk stratification tools have not yet been developed and the potential role of screening tools such as clinical risk prediction models and cardiac biomarkers requires further evaluation. The SCReening Evaluation for the Evolution of New Heart Failure (SCREEN-HF) study was designed to determine whether serum N-terminal B-type natriuretic peptide (NT-proBNP), a cardiac biomarker associated with increases in myocardial wall stress, could be used as an effective risk stratification tool in an older, asymptomatic community cohort selected by heart failure risk factors. The initial cross-sectional component of the study, with which this thesis is concerned, was developed to assess the ability of serum NT-proBNP to predict the presence of significant structural heart disease associated with an elevated risk of incident heart failure. However, longitudinal follow up in of the SCREEN-HF cohort will later assess whether serum NT-proBNP levels are effective in predicting the onset of symptomatic heart failure and other cardiovascular events. Structural heart disease was found to be common within the high risk SCREEN-HF cohort, with significant echocardiographic abnormalities detected in approximately one in four subjects. Serum NT-proBNP quintile was associated with structural heart disease, particularly left ventricular systolic dysfunction with a reduced ejection fraction. However the poor test performance characteristics of serum NT-proBNP, even at optimized cut-points, suggest that it would be an inadequate tool for detecting structural heart disease in this population, resulting in an unacceptably high number of missed cases of structural heart disease. The poor predictive capacity of serum NT-proBNP for structural heart disease in the SCREEN-HF cohort may relate to an increased noise-to-signal ratio in the setting of low absolute serum NT-proBNP values, and also to the narrower spectrum of cardiovascular risk in a population selected by heart failure risk factors. In contrast, transthoracic echocardiography was able to detect clinically significant structural heart disease in a quarter of subjects in this selected population. The high prevalence of echocardiographic abnormalities, associated with an increased risk of incident heart failure, suggests that echocardiographic screening, though more expensive and resource-intensive than measurement of serum NT-proBNP levels, may be justified in a similarly selected, high-risk population.