ECG signals were recorded from isolated, Langendorff-perfused rabbit hearts to establish the relationship between dominant frequency and myocardial perfusion during ventricular fibrillation. Lower perfusion rates produced faster rates of dominant frequency decline, to lower steady state values. Optically mapping the anterior epicardial surface demonstrated heterogeneity of dominant frequency in ventricular fibrillation. During low-flow ischaemia, the dominant frequency reduction was restricted to the left ventricle. Application of individual ischaemic components during ventricular fibrillation demonstrated that raised [K+]EC, but not hypoxia or acidic pHEC, reproduced the ischaemic reduction of dominant frequency in the ECG, pseudoECG and over the left ventricular epicardial surface. In contrast, minimum defibrillation energies were increased by hypoxia and acidic pHEC, and not by raised [K+]EC. The dominant frequency heterogeneity during ventricular fibrillation in low-flow ischaemia and raised [K+]EC was not due to differential prolongation of repolarisation or post-repolarisation refractoriness in the left ventricle. Monophasic action potential studies showed that APD90 was reduced to similar degrees in each ventricle by low-flow ischaemia and raised [K+]EC. Effective refractory period was not altered in either ventricle by either condition. Low-flow ischaemia decreased conduction velocity in the left, but not the right ventricle. Conduction velocities were unaltered by raised [K+]EC in either ventricle. The activation threshold of the left ventricle was increased in low-flow ischaemia and raised [K+]EC, whilst the threshold of the right ventricle was unchanged. The increased activation threshold was associated with decreased upstroke velocity and diastolic depolarisation.

Background: Health related quality of life (HRQL) measures are becoming increasingly used in the evaluation of health care interventions. They allow us to better understand the impact of disease on a patient's life as a whole and to incorporate the patient's perspective in clinical decision making and in the evaluation of health care. A number of studies have explored the HRQL of people with stroke. Still, due to a number of conceptual and methodological issues, there is no clear understanding of the HRQL of a stroke subgroup: people with aphasia. Aims: The broad aim of this research was to explore the HRQL of people with chronic aphasia following stroke in a way that could be replicated in clinical practice. Thus, a single stroke-specific scale (the SS-QOL) was chosen for the assessment of HRQL. The specific research questions that were addressed were: A) Can an acceptable, reliable and valid version of the SS-QOL be developed for people with chronic aphasia? This involved: i) development of an aphasia-adapted version of the SS-QOL and ii) evaluation of its psychometric properties. B) What are the predictors of HRQL in people with chronic aphasia, as measured by the aphasia adapted version of the SS-QOL? Methods: The development of an aphasia-adapted version of the SS-QOL involved consultation with professionals with experience in measure development, language and aphasia, and pilot testing for the modification of the instrument, and a pre-test of the adapted version with 18 people with aphasia. This process resulted in the Stroke and Aphasia Quality of Life Scale (SAQOL). A cross-sectional interview-based survey study was undertaken to evaluate the psychometric properties (acceptability, reliability and validity) of the SAQOL and to determine the predictors of HRQL as measured by the SAQOL. Convenience sampling was used in the pilot and pre-test studies and cluster sampling in the survey study. Measures: HRQL was measured with the SAQOL. In the construct validation of the SAQOL, the following measures were used: for emotional distress the GHQ-12, for cognition the RCPM, for activities the FAI, for social support the SSS and for language the FAST and the ASHA-FACS. Potential predictors of HRQL included demographic, stroke-related variables and variables implicated in previous research or of theoretical interest measured with the following instruments: the GHQ-12, the FAI, the SSS, the ASHA-FACS, the RCPh1 and the PSI (patients' satisfaction with stroke care). Results A) i) Development of an aphasia-adaptedv ersion of the SS-QOL resulted in the SAQOL, an interview administered self-report measure. People with moderate or mild receptive aphasia (as determined by a score of >_ 7 in the receptive domains of the FAST) found the SAQOL acceptable and were able to self-report to it. A) ii) Psychometric evaluation: 83 out of 95 participants self-reported on the SAQOL. The results supported the reliability and the validity of the overall SAQOL, but not of its subdomains' structure. A shorter 39-item version was derived through factor analysis (SAQOL-39). This instrument had a stable, conceptually clear 4-factor structure (physical, psychosocial, communication and energy) and high acceptability, internal consistency [scale(a= .93) and subdomains' (a=. 74-. 94)], test-retest reliability [scale (ICC=. 98) and subdomains' (ICC=. 89-. 98)] and construct validity [corrected domain-total correlations (r=. 38-. 58), subdomains' convergent (r=. 55-. 67) and discriminant (r=. 02-. 27), and scale's discriminant (r=. 19-. 31) and correlated measures (r=. 45-. 58)]. B) Predictors of HRQL: High emotional distress, reduced involvement in home and outdoors activities, high communication disability and >_2 comorbid conditions predicted poorer HRQL (adjusted R2=. 52). Stroke type (infarct vs haemorrhage) and demographic variables (age, gender, ethnicity, marital status, employment status and socioeconomic status) were not significant predictors of HRQL in these participants. Conclusions:The SAQOL-39 is an acceptable, reliable and valid measure for the assessment of HRQL in people with chronic aphasia. Further testing is needed to establish the usability of this measure in evaluative research and routine clinical practice. Poor HRQL is predicted by distress, reduced involvement in activities, communication disability and comorbidity. Service providers need to take these factors into account when designing intervention programmes.

Death receptor 3 (DR3) is a member of the TNFRSF and has one confirmed TNFSF ligand - TNF-like protein 1A (TL1A). Recent studies have suggested a role for DR3/TL1A in osteoclast (OC) and osteoblast (OB) biology. However, the mechanism through which they acted and the consequences in diseases characterised by adverse bone pathology were not investigated. This thesis investigated the role of DR3/TL1A in OC formation and resorptive function (murine and human), diseases characterised by OC hyper-activity and homeostatic OB differentiation and function (murine) using cell culture and molecular biology techniques. DR3/TL1A were demonstrated for the first time to have a direct effect on in vitro OC formation and resorptive function in both murine and human models. DR3 was revealed to be critical for OC resorptive function (murine) while TL1A dose-dependently increased osteoclastogenesis and resorptive function in the human system. Studies into the mechanism identified that DR3/TL1A regulated expression of the chemokines CCL2 and CCL3 as well as the activation of MMP-9. In rheumatoid arthritis patient serum TL1A was significantly increased, with levels linked to the presence of rheumatoid factor and erosive disease. Intriguingly, DR3/TL1A were shown to have no direct significant role in the increased OC activity associated with post-menopausal osteoporosis; DR3 was not detected on patient-derived OC precursors and serum levels of TL1A were not elevated. Analysis of murine osteoprogenitors and OB revealed expression of DR3 and TL1A and suggested a novel autocrine role in OB differentiation. This was supported by the OB mineralisation assay results which demonstrated reduced differentiation, MMP-2 and MMP-9 activation and mineral deposition in DR3ko cultures. The results presented in this thesis identify a novel, complex and multi-factorial role for DR3/TL1A in controlling OC and OB differentiation and function; imbalances in which can lead to the pathogenesis of adverse bone pathology.

Allergic bronchopulmonary aspergillosis (ABPA) is an inflammatory lung disease characterised by a local immunological reaction to the intra-luminal antigen of aspergillus fumigatus (A. fumigatus) that has colonised the airway, with a prevalence of 2 to 15 % had been reported in patients with cystic fibrosis (CF). The difficulties of diagnosing ABPA in the context of CF are because of overlapping clinical, radiographic, microbiologic and immunological features. Untreated ABPA may lead to lung damage, including proximal bronchiectasis and segmental , lobar or whole lung collapse. This thesis describes a cross-sectional study on prevalence of ABPA, atopy as a risk factor in the development of ABPA and reveals a prevalence of 21% of ABPA in our cohort of adult patients with CF, a 1 in 4 risk of developing ABPA in patients who have serum sensitisation >3 common aeroallergens. A longitudinal study on the impact of ABPA shows a significant decline of spirometric lung function for at least 2.8 years before the diagnosis, treatment of ABPA is associated with a significant improvement of lung function that sustained for at least 6 months. A longitudinal study on the impact of aspergillus sensitisation confirms the rate of decline of spirometric lung function became significantly faster after the development of aspergillus sensitisation. The cross sectional study on exhaled nitric oxide (NO) level shows a significantly decreased level of exhaled NO in patients with high risk of developing ABPA. The prospective study reveals a specific pattern of specific IgG and subclass antibodies to water soluble somatic hyphal (WSSH) antigen with increase IgG, IgG1, IgG2 and IgG4 antibodies levels in patents with ABPA. Patients with asthma and 4 Nelson criteria may have a similar pattern of specific IgG and subclass antibodies. On studying correlation between the specific IgG and subclass antibodies , spirometric lung function and Nelson criteria; The combination of total IgE level above 500 KU/L or a recent (within 4 months) doubling level to 200-500 KU/L and specific IgE to A. fumigatus RAST score >3 would confirm ABPA in adult CF patients and warrants treatment. An increase of specific IgG, IgG1, IgG2 and IgG4 antibodies levels would confirm ABPA. In particular, an increase of specific IgG and IgG4 antibodies levels (89 % and 9 EU respectively) would warrant ABPA treatment. It is known that the soluble aspergillus antigens are responsible for the development of ABPA. Soluble enzymes such as manganese superoxide dismutase and soluble glycoproteins from hyphae with certain antigenic fractions have shown to have increase activities and reacted with sera of ABPA patients. The advantages of WSSH A. fumigatus antigen are being a multivalent purified soluble antigen, untreated with alcohol, a cytoplasmic antigen from the mycelium, previous animal and CF studies have shown to be specific in the diagnosis of ABPA.

Background: Complex interventions, those that incorporate multiple interacting components, are difficult to define, measure and implement. The aim of this research was to develop and evaluate the complex intervention, very early mobilisation (VEM) in acute stroke care. The clinical effectiveness and cost-effectiveness of VEM were evaluated whilst simultaneously considering the implications for future implementation. Methods: A mixed methods approach was used: systematic review, predictive modelling, observational study design, individual patient data meta-analysis, qualitative methods and economic evaluation. Statistical models to accurately predict mobility post-stroke were developed. A multicentre observational study was conducted to establish pre-implementation activity levels of acute stroke patients. Data from two completed and comparable feasibility trials were used to estimate the clinical and economic impact of VEM. A qualitative process evaluation was conducted to identify the barriers and facilitators to implementing VEM, if shown to be effective. Results: Two predictive models were developed with age and stroke type common factors to both. Pre-implementation activity levels were low. Patients who underwent VEM were 3-times more likely to be independent at 3 months than were standard care (SC) patients. The incremental cost-effectiveness ratio associated with VEM in comparison to SC indicated VEM to be potentially cost-effective from a societal perspective. Barriers and facilitators identified for each stage of the stroke pathway and a set of HCPs’ beliefs towards VEM were formulated. Conclusions: This research has adhered to current guidance provided by the Medical Research Council to develop and evaluate VEM. The clinical effectiveness and cost-effectiveness of VEM were estimated. The ongoing A Very Early Rehabilitation Trial phase III will provide definitive evidence for the effectiveness of VEM and the wider consequences for stroke care. This research has provided the support and the foundations for the development of a clear implementation strategy for VEM.

Background: In the UK specialty trainees are a major source of clinical teaching for junior doctors. Medical education and teaching skills are core competencies included in the generic curriculum for specialist training. Hence, there is a need for a validated assessment instrument that can measure the attributes of specialty trainees as effective teachers, leading to the research question; Is it possible to devise an instrument to measure the teaching ability of specialty trainee doctors? Methods: The study was conducted in two phases. In the first phase, the content of the instrument was generated from the literature and tested using the Delphi technique. This was followed by pilot testing the instrument. In the second phase, the instrument was field tested for validity and reliability by conducting factor analysis, Cronbach alpha and Generalizability coefficient. The instrument was also tested for feasibility by calculating the time taken to complete the instrument. Acceptability and educational impact were determined by qualitative analysis of written feedback from participants. The attributes of specialty trainees were assessed by clinical supervisors, peers and students. Results: The Delphi study produced a consensus on 15 statements for the final draft of the instrument. This draft was piloted and finalised using feedback from that pilot. The instrument was field tested. In the field study a total of 340 instruments were completed. The instrument exhibited internal consistency (Cronbach’s alpha 0.90) and the Generalizability coefficient was 0.92. Factor analysis demonstrated a three factor solution (learning-teaching milieu, teaching skills and learner-orientated). The mean time to complete the instrument was five minutes. Feedback from participants indicated that it was an acceptable method of assessment, and trainees also found it useful for improving their teaching performance. Discussion: Findings from the present study suggest that this instrument demonstrates robust validity and reliability. It is feasible to use it in a busy clinical setting. It is acceptable by stakeholders which indicate that it can be used for assessment of teaching in clinical settings. Further specialty trainees found it useful, thereby indicating a positive educational impact. Conclusion: This new instrument, specifically designed to test the teaching attributes of doctors-intraining, can be useful for providing formative and summative assessment of clinical teaching.

The report as a whole presents a collection of academic papers that make a significant contribution to the field of demand and capacity management in healthcare. The report is divided into six main sections. In this section the context of the challenges faced by healthcare organisations is explained, the objectives of the research are outlined, and the research methodologies employed are described. Section 2 summarises the key contributions to theory contained within the submitted papers. Section 3 provides a justification and explanation of the theoretical perspectives employed in this research. Section 4 provides a summary of each of the submitted papers together with a commentary on the contribution that the paper makes. The work is presented in a sequence that best explains the conceptual logic rather than a chronological overview. Section 5 discusses and evaluates these papers with a critical perspective. The final section contains concluding comments and presents a framework of demand and capacity management in healthcare.

Background There has been an explosion of interest in medical professionalism over the past decade but at present there are no evidence based guidelines on how to effectively develop medical professionalism in future doctors (Passi et al. 2010). Role modelling has been highlighted as an important method to help develop professionalism but there is no current theory regarding the process of role modelling (Passi et al. 2013). Therefore, the aim of this PhD was to investigate how positive doctor role modelling influences the development of professionalism in future doctors. Methods A qualitative methodology using the grounded theory inquiry approach of Strauss and Corbin (2008) was used to generate a general explanation (a theory) of the process of role modelling shaped by the views of the participants. The study involved focus groups with final year medical students, semi structured interviews with consultants and semi structured interviews with consultants and final year medical students immediately after outpatient clinics. This systematic approach used involved open coding, axial coding and selective coding to reveal the processes involved in role modelling, which is illustrated in a coding paradigm diagram. Results The results revealed a new theory of doctor role modelling which is described as follows – Doctor role modelling is an important process in medical education that involves conscious and subconscious elements. It consists of an Exposure Phase followed by an Evolution Phase. The exposure phase involves demonstration of professional attributes by the doctor role models (clinical expertise; relationships with patients, students and colleagues; personality and inspirational characteristics). The evolution phase begins with observation of the role model by the modellee, following which the modellee makes a judgement whether or not to trial the observed behaviours of the role model. When the decision to trial is reached, this then leads to the Model Trialling Cycle which involves 5 stages of assembly, emulation, experimentation, adaptation and assimilation. The outcome is the evolution of a professional doctor who has developed their unique professional identity and career aspirations. Conclusion This detailed qualitative study has provided a new theory of doctor role modelling in medical education. The impact of role modelling is in the development of medical professionalism professional identity and the influence of career choice. The theory can now be incorporated in medical curriculums worldwide to enhance the development of medical professionalism. Detailed recommendations for clinical practice and future research are described.

Background: Restless legs Syndrome is a sensorimotor disorder characterised by unpleasant sensations in the legs when at rest and only relieved by movement. RLS is associated with deterioration in quality of life and depression is a common comorbid problem. Methods: The present study aimed to establish whether RLS is a risk factor for depressive symptoms by comparing 3 groups - RLS patients (RLS), a primary insomnia group (PI), and non-restless good sleeper controls (NRC). Fifteen participants were recruited to each group. To elucidate the mechanisms of the observed comorbidity between RLS and Depression, measures of mood/affect prior to, during and immediately following a Suggested Immobilization Test (SIT) were employed. The BDI-II measured depressive symptoms retrospectively over the previous two-week period. A mood visual analogue scale (VAS) was rated by participants during the SIT at 5-minute intervals. The Positive and Negative Affect Schedule (PANAS) retrospectively measured affect experienced by participants during the SIT. In addition, new actigraphy techniques were utilised to measure Periodic Leg Movements during Sleep (PLMS) over 3 nights at home – an objective measure of RLS severity. Results: The groups did not differ on demographic data except for age which was added as a covariate to further analyses. The RLS group had higher levels of negative affect following the SIT than the PI and NRC groups (both p<.05). The RLS group also had higher levels of positive affect than the PI and NRC groups (both p<.05). The level of sensory discomfort felt in the legs during the SIT was strongly associated with negative affect in the RLS group (r=.853, p<.001). PLMS were not found to be associated with BDI-II scores. Conclusions: It appears that sleep quality and depressive symptoms as measured by the BDI-II were similar in the RLS and PI groups. There were some limitations of the study but tentative conclusions were made. The role of emotional arousal in RLS, shown by the high correlation between sensory discomfort and negative affect, potentially demonstrates a qualitative difference in the restlessness experienced by this group and further studies are required.

Acute myocardial infarction (AMI) remains a common and serious manifestation of coronary artery disease. The development of heart failure (HF) and/or evidence of left ventricular systolic dysfunction (LVSD) following AMI increases both in-hospital and longer-term mortality. A series of structural and functional changes occur within the heart in general and within the left ventricle (LV) in particular following AMI, initially providing a stabilising mechanism to maintain the cardiac output but over time becoming maladaptive and leading to progressive ventricular dilatation, dysfunction, HF and premature death. This process is termed remodelling. It is now understood that a complex series of mechanical, genetic and neurohormonal factors, including the mineralocorticoid hormone aldosterone, are implicated in its pathogenesis. Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with advanced chronic HF and survivors of large AMI who develop HF and/or are diabetic. These benefits could, at least in part, be due to an anti-remodelling action, although this was uncertain at the time I began my research project. The work contained in this thesis examines cardiac remodelling, and the effects of the mineralocorticoid receptor antagonist eplerenone, in a cohort of 100 patients admitted with AMI, with depressed LV ejection fraction (LVEF) but without HF or diabetes mellitus, using a gold standard modality for LV functional assessment and infarct imaging: late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR). Patients were treated with (double-blinded) eplerenone or placebo for 24 weeks, and underwent serial LGE-CMR scanning and measurement of haematological, urinary and genetic markers thought to be of pathophysiological importance in post-infarction remodelling. There was, by chance, a significant imbalance in LV function at baseline between the randomised groups. After pre-specified covariate-adjustment, however, I found a significant effect of eplerenone on LV remodelling. Moreover I found that the use of eplerenone in addition to an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was well-tolerated. I also found an effect of eplerenone on two matrix metalloproteinases (MMPs) considered key enzymes in extracellular matrix turnover. Specifically, eplerenone decreased MMP-2 and attenuated the drop in MMP-9 seen in the placebo group, changes that are protective against remodelling. These findings suggest a potential anti-remodelling effect of eplerenone in ‘asymptomatic’ LVSD after AMI, i.e. patients in whom eplerenone is not currently indicated. Patients with limited functional recovery early after AMI resulting in a persistently reduced LVEF require stringent monitoring and may qualify for an implantable cardioverter defibrillator. The use of predictive biomarkers to identify such patients is gaining popularity. I found that two biomarkers, tissue plasminogen activator (tPA) antigen and tissue inhibitor of metalloproteinase-4 (TIMP-4), measured in a blood sample taken a mean of 3 days after AMI, were independent predictors of adverse remodelling. These findings are novel, provide further pathophysiological insights into the inter-related biological systems that underlie remodelling, and may inform future trials aimed at modulating these pathways in order to attenuate remodelling. LGE-CMR affords detailed characterisation of myocardium. In keeping with previous studies, infarct volume, endocardial extent and transmurality predicted LV remodelling. In addition I also found that the presence of microcirculatory dysfunction, defined as persistent microvascular obstruction (MVO) within the infarcted region on baseline LGE-CMR, divided my study population into two distinct groups with opposite remodelling outcomes. Patients with late MVO progressively remodelled, while those without reverse remodelled over 24 weeks. From these results, I propose that late MVO be used as an indicator of adverse ventricular remodelling. This may enhance the risk-stratification of survivors of AMI. Aldosterone has a number of detrimental effects on the cardiovascular system and is strongly implicated in the pathogenesis of remodelling. I observed direct correlations between aldosterone sampled at baseline and CMR parameters of remodelling. Analysis by treatment group revealed an association between change in aldosterone over time and parameters of remodelling in placebo- but not eplerenone-treated patients, despite higher circulating aldosterone concentrations in the latter group. We propose that the cardiac effects of aldosterone display a temporal variation after AMI, specifically that circulating aldosterone in the first few days after infarction is key in selecting a remodelling pathway but that over the following weeks and months circulating aldosterone is less influential in potentiating the remodelling process. I also found a novel relationship between aldosterone and infarct volume, which merits further investigation as the role of aldosterone in the pathophysiology of remodelling is further described. My trial design afforded the opportunity to examine the relationships of certain novel biomarkers with LV function and other established biomarkers after AMI. I demonstrated that circulating concentrations of the peptide apelin were reduced over 24 weeks after AMI compared to healthy controls but bore no relationship to LV function. Separately, I showed that concentrations of the soluble interleukin-1 receptor family member ST2 fell significantly over time after AMI and correlated with early and medium-term LV function and infarct volume. I detected a novel relationship between ST2 and aldosterone, which may suggest a pathophysiological role for ST2 in post-infarction remodelling and merits further investigation. These studies provide further insights into the roles of aldosterone and of selective mineralocorticoid receptor antagonism in cardiac remodelling in a relatively under-studied population: survivors of AMI with ‘asymptomatic’ LVSD. The primary results may inform clinical trials powered to detect a mortality benefit in this patient group. The data provided on the use of established and recently-discovered biomarkers in the prediction of medium-term LV function after AMI represents a highly topical area for further studies. Finally, pre-discharge CMR was safe in AMI patients, and facilitated the detection of additional findings that positively influenced the management of almost one-quarter of the trial cohort. These findings may lead to greater uptake of this increasingly-available modality, to enhance the early management and risk stratification of survivors of large AMI.