Heart failure (HF) is an increasing and leading cause of cardiovascular morbidity, hospitalisation and death. Echocardiography is often used in HF patients because it provides important aetiological, diagnostic and prognostic information to assist physician management at moderate cost. This thesis has explored contemporary echocardiographic techniques for assessment of both diastolic and systolic function to ascertain their effectiveness and optimal utility. Assessment of systolic function in HF patients is optimised by the use of harmonic imaging and not enhanced with the use of transpulmonary contrast agents, whilst diastolic filling is optimised by the use of preload manipulation. When optimised in this way, echocardiography can be used to stratify HF patients in terms of risk of death and/or hospitalisation after discharge from hospital. This was confirmed in a meta-analysis of more than 6000 patients (1000 deaths) with HF or after acute myocardial infarction (AMI), where the presence of restrictive filling pattern (the most severe form of diastolic dysfunction) was associated with a four-fold increase in mortality in both patient groups. In addition, restrictive filling pattern also predicted development of HF post AMI and hospitalisation in patients with HF. This meta-analysis also evaluated the intermediate stages of diastolic dysfunction and found a stepped relationship between each grade and prognosis. The last part of this thesis explored the role of contemporary echocardiography for management of symptomatic patients in the community and found that the diagnosis of HF in the community may be optimised by using brain natriuretic peptide (BNP) as a first test to "rule-out" heart failure and then echocardiography, which was superior to BNP in patients with intermediate BNP levels to diagnose HF. Furthermore, the systolic echocardiographic parameters were important for diagnosis, whilst the diastolic parameters predicted future hospitalisation. In summary, contemporary echocardiography in HF patients should include comprehensive assessment of systolic function (using tissue harmonics imaging) and diastolic filling (utilising preload manipulation). This approach will optimise both diagnosis and prognosis and in turn may aid physician management.

The data presented and views expressed in this document are the result of multiple published and unpublished studies over the last 25 years. My over-arching goal in this research was to use modern computing power to create functionally useful diagnoses, in real time, from the monitoring systems used during routine anaesthesia and to present these diagnoses in an ergonomic manner. In addition it was intended to incorporate into the anaesthetic monitor, expert systems that help with the management of uncommon situations. The Australian and New Zealand College guidelines on monitoring during anaesthesia dictate those measurements that should be made during every anaesthetic; from these data evidence can be gathered, integrated, and presented to the clinician. Constraints in this field of research include the inability of the monitors to see, hear or understand the context of operating theatre activities, and computer processing time. Because many studies are involved the methods are detailed in the main text, and are not summarized here. Physiological 'envelopes' have been developed, in which the 'normal' variation in physiological variables, during anaesthesia, are enclosed. They have enabled the creation of intelligent alarm systems that can suggest diagnoses. A retrospective off-line study showed that it was possible to diagnose the onset of malignant hyperpyrexia, using fuzzy logic templates, about 10minutes earlier than the clinician. Some variables may be more important than others in making a diagnosis, and the strength of a diagnosis depends on the amount of supporting evidence, the amount of evidence not against the diagnosis and the amount of missing data. Decision-making (for example to transfuse or not transfuse blood) can also be mathematically modelled so that decision making is more consistent. Finally, investigation of the ways of displaying data indicates that the output can be very explicit. My overall conclusion is that real time decision support systems for the management of clinical dilemmas are possible. They can be instantly and easily accessible and can sit discretely in the background of anaesthetic monitors to be activated at will by the anaesthetist.

The traditional approach to medical education is changing and simulation is increasingly being incorporated into the curriculum, particularly in the context of emergency care. Simulation takes many forms, but this thesis refers only to whole patient simulators, where a computerised mannikin placed in a clinically appropriate environment is used to recreate a realistic clinical encounter. The focus of this work is the management of medical emergencies. Aim The overall aim of this body of work is to evaluate the effectiveness of simulationbased education across a range of different learners, and to investigate the properties of simulation-based assessment. In particular: To review the literature on the effectiveness of simulation, and its use in assessment. To evaluate the current status and effectiveness of CME interventions and the relative usefulness of simulation courses in this context. To determine if simulation-based courses in crisis management can lead to changes in physician behaviour. iii To evaluate student perceptions of learning in a simulator environment. To assess students' ability to manage simulated emergencies, and their opinion of simulation-based assessment. To define the psychometric properties and feasibility of simulation-based assessment in anaesthesia, the accuracy of self-assessment and the impact on learning. Methods and Results A number of different methods were used, which will be described in detail in the subsequent chapters. Overall, the results provide evidence for the effectiveness of simulation across a range of applications. Simulation-based assessment is acceptable, likely to have a positive impact on learning, and evidence support aspects of validity. Reliable scores can be generated but large numbers of cases are required. Conclusions There is sufficient evidence to recommend incorporating simulation-based courses into the acute care curriculum of medical undergraduates. Simulation is effective in CME in the context of anaesthesia crisis management and this is likely to apply to other acute care specialties. Like other clinically based assessments, extended testing time is required to generate reliable scores, limiting the feasibility of large scale, simulation-based exit examinations.

Heart failure (HF) is an increasing and leading cause of cardiovascular morbidity, hospitalisation and death. Echocardiography is often used in HF patients because it provides important aetiological, diagnostic and prognostic information to assist physician management at moderate cost. This thesis has explored contemporary echocardiographic techniques for assessment of both diastolic and systolic function to ascertain their effectiveness and optimal utility. Assessment of systolic function in HF patients is optimised by the use of harmonic imaging and not enhanced with the use of transpulmonary contrast agents, whilst diastolic filling is optimised by the use of preload manipulation. When optimised in this way, echocardiography can be used to stratify HF patients in terms of risk of death and/or hospitalisation after discharge from hospital. This was confirmed in a meta-analysis of more than 6000 patients (1000 deaths) with HF or after acute myocardial infarction (AMI), where the presence of restrictive filling pattern (the most severe form of diastolic dysfunction) was associated with a four-fold increase in mortality in both patient groups. In addition, restrictive filling pattern also predicted development of HF post AMI and hospitalisation in patients with HF. This meta-analysis also evaluated the intermediate stages of diastolic dysfunction and found a stepped relationship between each grade and prognosis. The last part of this thesis explored the role of contemporary echocardiography for management of symptomatic patients in the community and found that the diagnosis of HF in the community may be optimised by using brain natriuretic peptide (BNP) as a first test to "rule-out" heart failure and then echocardiography, which was superior to BNP in patients with intermediate BNP levels to diagnose HF. Furthermore, the systolic echocardiographic parameters were important for diagnosis, whilst the diastolic parameters predicted future hospitalisation. In summary, contemporary echocardiography in HF patients should include comprehensive assessment of systolic function (using tissue harmonics imaging) and diastolic filling (utilising preload manipulation). This approach will optimise both diagnosis and prognosis and in turn may aid physician management.

The data presented and views expressed in this document are the result of multiple published and unpublished studies over the last 25 years. My over-arching goal in this research was to use modern computing power to create functionally useful diagnoses, in real time, from the monitoring systems used during routine anaesthesia and to present these diagnoses in an ergonomic manner. In addition it was intended to incorporate into the anaesthetic monitor, expert systems that help with the management of uncommon situations. The Australian and New Zealand College guidelines on monitoring during anaesthesia dictate those measurements that should be made during every anaesthetic; from these data evidence can be gathered, integrated, and presented to the clinician. Constraints in this field of research include the inability of the monitors to see, hear or understand the context of operating theatre activities, and computer processing time. Because many studies are involved the methods are detailed in the main text, and are not summarized here. Physiological 'envelopes' have been developed, in which the 'normal' variation in physiological variables, during anaesthesia, are enclosed. They have enabled the creation of intelligent alarm systems that can suggest diagnoses. A retrospective off-line study showed that it was possible to diagnose the onset of malignant hyperpyrexia, using fuzzy logic templates, about 10minutes earlier than the clinician. Some variables may be more important than others in making a diagnosis, and the strength of a diagnosis depends on the amount of supporting evidence, the amount of evidence not against the diagnosis and the amount of missing data. Decision-making (for example to transfuse or not transfuse blood) can also be mathematically modelled so that decision making is more consistent. Finally, investigation of the ways of displaying data indicates that the output can be very explicit. My overall conclusion is that real time decision support systems for the management of clinical dilemmas are possible. They can be instantly and easily accessible and can sit discretely in the background of anaesthetic monitors to be activated at will by the anaesthetist.

The traditional approach to medical education is changing and simulation is increasingly being incorporated into the curriculum, particularly in the context of emergency care. Simulation takes many forms, but this thesis refers only to whole patient simulators, where a computerised mannikin placed in a clinically appropriate environment is used to recreate a realistic clinical encounter. The focus of this work is the management of medical emergencies. Aim The overall aim of this body of work is to evaluate the effectiveness of simulationbased education across a range of different learners, and to investigate the properties of simulation-based assessment. In particular: To review the literature on the effectiveness of simulation, and its use in assessment. To evaluate the current status and effectiveness of CME interventions and the relative usefulness of simulation courses in this context. To determine if simulation-based courses in crisis management can lead to changes in physician behaviour. iii To evaluate student perceptions of learning in a simulator environment. To assess students' ability to manage simulated emergencies, and their opinion of simulation-based assessment. To define the psychometric properties and feasibility of simulation-based assessment in anaesthesia, the accuracy of self-assessment and the impact on learning. Methods and Results A number of different methods were used, which will be described in detail in the subsequent chapters. Overall, the results provide evidence for the effectiveness of simulation across a range of applications. Simulation-based assessment is acceptable, likely to have a positive impact on learning, and evidence support aspects of validity. Reliable scores can be generated but large numbers of cases are required. Conclusions There is sufficient evidence to recommend incorporating simulation-based courses into the acute care curriculum of medical undergraduates. Simulation is effective in CME in the context of anaesthesia crisis management and this is likely to apply to other acute care specialties. Like other clinically based assessments, extended testing time is required to generate reliable scores, limiting the feasibility of large scale, simulation-based exit examinations.

Heart failure (HF) is an increasing and leading cause of cardiovascular morbidity, hospitalisation and death. Echocardiography is often used in HF patients because it provides important aetiological, diagnostic and prognostic information to assist physician management at moderate cost. This thesis has explored contemporary echocardiographic techniques for assessment of both diastolic and systolic function to ascertain their effectiveness and optimal utility. Assessment of systolic function in HF patients is optimised by the use of harmonic imaging and not enhanced with the use of transpulmonary contrast agents, whilst diastolic filling is optimised by the use of preload manipulation. When optimised in this way, echocardiography can be used to stratify HF patients in terms of risk of death and/or hospitalisation after discharge from hospital. This was confirmed in a meta-analysis of more than 6000 patients (1000 deaths) with HF or after acute myocardial infarction (AMI), where the presence of restrictive filling pattern (the most severe form of diastolic dysfunction) was associated with a four-fold increase in mortality in both patient groups. In addition, restrictive filling pattern also predicted development of HF post AMI and hospitalisation in patients with HF. This meta-analysis also evaluated the intermediate stages of diastolic dysfunction and found a stepped relationship between each grade and prognosis. The last part of this thesis explored the role of contemporary echocardiography for management of symptomatic patients in the community and found that the diagnosis of HF in the community may be optimised by using brain natriuretic peptide (BNP) as a first test to "rule-out" heart failure and then echocardiography, which was superior to BNP in patients with intermediate BNP levels to diagnose HF. Furthermore, the systolic echocardiographic parameters were important for diagnosis, whilst the diastolic parameters predicted future hospitalisation. In summary, contemporary echocardiography in HF patients should include comprehensive assessment of systolic function (using tissue harmonics imaging) and diastolic filling (utilising preload manipulation). This approach will optimise both diagnosis and prognosis and in turn may aid physician management.

The data presented and views expressed in this document are the result of multiple published and unpublished studies over the last 25 years. My over-arching goal in this research was to use modern computing power to create functionally useful diagnoses, in real time, from the monitoring systems used during routine anaesthesia and to present these diagnoses in an ergonomic manner. In addition it was intended to incorporate into the anaesthetic monitor, expert systems that help with the management of uncommon situations. The Australian and New Zealand College guidelines on monitoring during anaesthesia dictate those measurements that should be made during every anaesthetic; from these data evidence can be gathered, integrated, and presented to the clinician. Constraints in this field of research include the inability of the monitors to see, hear or understand the context of operating theatre activities, and computer processing time. Because many studies are involved the methods are detailed in the main text, and are not summarized here. Physiological 'envelopes' have been developed, in which the 'normal' variation in physiological variables, during anaesthesia, are enclosed. They have enabled the creation of intelligent alarm systems that can suggest diagnoses. A retrospective off-line study showed that it was possible to diagnose the onset of malignant hyperpyrexia, using fuzzy logic templates, about 10minutes earlier than the clinician. Some variables may be more important than others in making a diagnosis, and the strength of a diagnosis depends on the amount of supporting evidence, the amount of evidence not against the diagnosis and the amount of missing data. Decision-making (for example to transfuse or not transfuse blood) can also be mathematically modelled so that decision making is more consistent. Finally, investigation of the ways of displaying data indicates that the output can be very explicit. My overall conclusion is that real time decision support systems for the management of clinical dilemmas are possible. They can be instantly and easily accessible and can sit discretely in the background of anaesthetic monitors to be activated at will by the anaesthetist.

Colorectal cancer (CRC) is common in Ontario. This study described the processes of care following CRC resection, and identified CRC relapse from administrative data. Methods: CRC patients aged 18-80 from 1996-2001 with a colorectal resection were identified from the Ontario Cancer Registry. Linked discharge abstracts and physician billings were examined for physician visits, body imaging and endoscopy over the 5 year follow-up period. Administrative codes suggesting disease relapse were compared with patient charts. Results: Overall, 12,804 patients were identified and 8,804 had no evidence of relapse. Most (96.2%) patients had general practitioner follow-up, while 49.3% had medical oncology and 80.4% had general surgery follow-up. Greater than 90% of patients received endoscopy, while only 68.7% of patients received body imaging. Detecting disease relapse was 87.5% sensitive and 93.0% specific. Conclusions: There is potential for improving post-resectional follow-up in CRC patients. It is possible to detect relapse through administrative databases.

Endothelial progenitor cells (EPCs) have reduced neovascularization capacity in the context of coronary artery disease (CAD) or cardiac risk factors (RFs). Since, endothelial NO synthase (eNOS) is critical to normal EPC function, we hypothesized that bone marrow cells (BMCs) from rats with RFs and EPCs from humans with CAD and/or RFs show dramatically reduced neovascularization capacity in vitro and in vivo, which can be reversed by eNOS overexpression. BMCs were isolated from rat models of type II diabetes and the metabolic syndrome, and we showed a significant reduction in their ability to stimulate neovascularization in vitro and in vivo. In humans, we isolated circulating ‘early EPCs’ from healthy subjects and patients with CAD and RFs, and transduced them using lentiviral vectors containing either eNOS or GFP (sham). EPCs from patients had reduced in vitro migration in response to SDF-1 or VEGF, which was reversed by eNOS-transduction. In co-culture with human umbilical vein endothelial cells (HUVECs) on Matrigel, eNOS-transduced EPCs contributed to increased and more complex angiogenic tube formation compared to sham-transduced cells. Human EPCs from patients were ineffective in enhancing ischemic hind limb neovascularization and perfusion in a nude mouse, whereas eNOS-transduced EPCs resulted in a significant improvement compared to sham-transduced cells. In a swine model of acute myocardial infarction (MI), eNOS- and non-transfected BMCs both increased left ventricular function compared to sham. However, there was no benefit to eNOS overexpression in this model. Various differences in the models and procedures may explain the incongruous results obtained. Taken together, these results show that eNOS overexpression significantly improves the neovascularization capacity of EPCs of human subjects with CAD and RFs and could represent an effective adjunctive approach for the improvement of autologous cell therapies for cardiovascular disease.