Acute Respiratory Distress Syndrome is a late cause of morbidity and mortality following hemorrhagic shock and resuscitation. Previous work in our laboratory showed that alveolar macrophages were primed for increased responsiveness to lipopolysaccharides, as evidenced by augmented inflammatory cytokine production. Recent studies have shown that macrophages can be polarized into two phenotypes, namely pro-inflammatory M1 and anti-inflammatory M2 macrophages, in response to various environmental cues. The major hypothesis to be tested in this thesis is that HS/R shifts the M1/M2 polarization of alveolar macrophages to favour a pro-inflammatory milieu in the lung. A biphasic shift in the phenotype of alveolar macrophages in response to HS/R characterized by an early reduction of M2 cells followed by a late up-regulation of M1 macrophages was observed. The administration of M2- polarizing PPARγ agonists prior to HS/R restored the M1/M2 balance of alveolar macrophages and reduced lung injury.

Acute Respiratory Distress Syndrome is a late cause of morbidity and mortality following hemorrhagic shock and resuscitation. Previous work in our laboratory showed that alveolar macrophages were primed for increased responsiveness to lipopolysaccharides, as evidenced by augmented inflammatory cytokine production. Recent studies have shown that macrophages can be polarized into two phenotypes, namely pro-inflammatory M1 and anti-inflammatory M2 macrophages, in response to various environmental cues. The major hypothesis to be tested in this thesis is that HS/R shifts the M1/M2 polarization of alveolar macrophages to favour a pro-inflammatory milieu in the lung. A biphasic shift in the phenotype of alveolar macrophages in response to HS/R characterized by an early reduction of M2 cells followed by a late up-regulation of M1 macrophages was observed. The administration of M2- polarizing PPARγ agonists prior to HS/R restored the M1/M2 balance of alveolar macrophages and reduced lung injury.

Aim: To develop an outcome measure to identify “responders” for patients who had a clinically important improvement in lupus disease activity with treatment. Methods: The outcome measure derived was based on the commonly used disease activity measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose. SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months. Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30 days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50 Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months. Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial, ≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent outcome measure of improvement in patients with SLE.

Aim: To develop an outcome measure to identify “responders” for patients who had a clinically important improvement in lupus disease activity with treatment. Methods: The outcome measure derived was based on the commonly used disease activity measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose. SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months. Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30 days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50 Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months. Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial, ≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent outcome measure of improvement in patients with SLE.

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.