Objectives: To explore whether a semi–structured post-traumatic amnesia (PTA) assessment interview (PTA-I) provides a practicable but equivalent estimation of PTA in patients attending the Emergency Department (ED) with head injury (HI) compared to the established Westmead PTA Scale Revised (R-WPTAS). Procedure: PTA was assessed using the R-WPTAS (includes a visual memory component) and the PTA-I (includes retrospective and verbal memory components), in patients attending an ED with (n=30) or without (n= 30) HI. Outcome measures were the Post-concussion Syndrome Checklist (PCSC) and the Glasgow Coma Scale (GCS). McNemar’s Tests and Chi-square analyses were used to determine the results. Results: The verbal memory component overestimated PTA in the control group by 24 %. Overall, the PTA-I did not discriminate between HI and control participants. However the retrospective PTA assessment embedded within the PTA-I did, with 100 % accuracy. Conclusions: The use of a verbal memory component to assess PTA in the ED is not supported by the results of this study. A retrospective PTA assessment appears to allow more accurate decision making regarding the admission criteria used in the ED and has advantages over the R-WPTAS: fewer test materials and no repeat assessments required to achieve an estimate of PTA duration.

Digital imaging has long been available in radiology in the form of computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Initially the transition to general radiography was slow and fragmented but in the last 10-15 years in particular, huge investment by the manufacturers, greater and cheaper computing power, inexpensive digital storage and high bandwidth data transfer networks have lead to an enormous increase in the number of digital radiography systems in the UK. There are a number of competing digital radiography (DR) technologies, the most common are computer radiography (CR) systems followed by indirect digital radiography (IDR) systems. To ensure and maintain diagnostic quality and effectiveness in the radiology department appropriate methods are required to evaluate and optimise the performance of DR systems. Current semi-quantitative test object based methods routinely used to examine DR performance suffer known short comings, mainly due to the subjective nature of the test results and difficulty in maintaining a constant decision threshold among observers with time. Objective image quality based measurements of noise power spectra (NPS) and modulation transfer function (MTF) are the ‘gold standard’ for assessing image quality. Advantages these metrics afford are due to their objective nature, the comprehensive noise analysis they permit and in the fact that they have been reported to be relatively more sensitive to changes in detector performance. The advent of DR systems and access to digital image data has opened up new opportunities in applying such measurements to routine quality control and this project initially focuses on obtaining NPS and MTF results for 12 IDR systems in routine clinical use. Appropriate automatic exposure control (AEC) device calibration and a reproducible measurement method are key to optimising X-ray equipment for digital radiography. The uses of various parameters to calibrate AEC devices specifically for DR were explored in the next part of the project and calibration methods recommended. Practical advice on dosemeter selection, measurement technique and phantoms were also given. A model was developed as part of the project to simulate CNR to optimise beam quality for chest radiography with an IDR system. The values were simulated for a chest phantom and adjusted to describe the performance of the system by inputting data on phosphor sensitivity, the signal transfer function (STF), the scatter removal method and the automatic exposure control (AEC) responses. The simulated values showed good agreement with empirical data measured from images of the phantom and so provide validation of the calculation methodology. It was then possible to apply the calculation technique to imaging of tissues to investigate optimisation of exposure parameters. The behaviour of a range of imaging phosphors in terms of energy response and variation in CNR with tube potential and various filtration options were investigated. Optimum exposure factors were presented in terms of kV-mAs regulation curves and the large dose savings achieved using additional metal filters were emphasised. Optimum tube potentials for imaging a simulated lesion in patient equivalent thicknesses of water ranging from 5-40 cm thick for example were: 90-110kVp for CsI (IDR); 80-100kVp for Gd2O2S (screen /film); and 65-85kVp for BaFBrI. Plots of CNR values allowed useful conclusions regarding the expected clinical operation of the various DR phosphors. For example 80-90 kVp was appropriate for maintaining image quality over an entire chest radiograph in CR whereas higher tube potentials of 100-110 kVp were indicated for the CsI IDR system. Better image quality is achievable for pelvic radiographs at lower tube potentials for the majority of detectors however, for gadolinium oxysulphide 70-80 kVp gives the best image quality. The relative phosphor sensitivity and energy response with tube potential were also calculated for a range of DR phosphors. Caesium iodide image receptors were significantly more sensitive than the other systems. The percentage relative sensitivities of the image receptors averaged over the diagnostic kV range were used to provide a method of indicating what the likely clinically operational dose levels would be, for example results suggested 1.8 µGy for CsI (IDR); 2.8 µGy for Gd2O2S (Screen/film); and 3.8 µGy for BaFBrI (CR). The efficiency of scatter reduction methods for DR using a range of grids and air gaps were also reviewed. The performance of various scatter reduction methods: 17/70; 15/80; 8/40 Pb grids and 15 cm and 20 cm air gaps were evaluated in terms of the improvement in CNR they afford, using two different models. The first, simpler model assumed quantum noise only and a photon counting detector. The second model incorporated quantum noise and system noise for a specific CsI detector and assumed the detector was energy integrating. Both models allowed the same general conclusions and suggest improved performance for air gaps over grids for medium to low scatter factors and both models suggest the best choice of grid for digital systems is the 15/80 grid, achieving comparable or better performance than air gaps for high scatter factors. The development, analysis and discussion of AEC calibration, CNR value, phosphor energy response, and scatter reduction methods are then brought together to form a practical step by step recipe that may be followed to optimise digital technology for clinical use. Finally, CNR results suggest the addition of 0.2 mm of copper filtration will have a negligible effect on image quality in DR. A comprehensive study examining the effect of copper filtration on image quality was performed using receiver operator characteristic (ROC) methodology to include observer performance in the analysis. A total of 3,600 observations from 80 radiographs and 3 observers were analysed to provide a confidence interval of 95% in detecting differences in image quality. There was no statistical difference found when 0.2 mm copper filtration was used and the benefit of the dose saving promote it as a valuable optimisation tool.

Abstract: Background and purpose: In vivo dosimetry is one of the quality assurance tools used in radiotherapy to monitor the dose delivered to the patient. The digital image format makes electronic portal imaging devices (EPIDs) good candidates for in vivo dosimetry. Currently there is no commercial transit dosimetry module, which could facilitate routine in vivo dosimetry with the EPID. Some centres are developing their in-house packages, and they are under assessment before introduction into routine clinical usage. The main purpose of this work was to develop the EPID as an in vivo dosimetry device. Materials and methods: Knowledge of a detector’s dose-response behaviour is a prerequisite for any clinical dosimetric application, hence in the first phase of the study, the dosimetric characteristics of eleven Varian a-Si500 EPIDs that are in clinical use in our centre were investigated. The devices have been in use for varying periods and interfaced with two different acquisition control software packages, IAS2 / IDU-II or IAS3 / IDU-20. Properties investigated include: linearity, reproducibility, signal uniformity, field size and dose-rate dependence, memory effects and image profiles as a function of dose. In the second phase, an EPID was calibrated using the quadratic method to yield values for the entrance and exit doses at the phantom or patient. EPID images for a set of solid water phantoms of varying thicknesses were acquired and the data fitted onto a quadratic equation, which relates the reduction in photon beam intensity to the attenuation coefficient and material thickness at a reference condition. The quadratic model was used to convert the measured grey scale value into water equivalent path length (EPL) at each pixel for any material imaged by the detector. For any other non-reference conditions, scatter, field size and MU variation effects on the image were corrected. The 2D EPL is linked to the percentage exit-dose for different thicknesses and field sizes, thereby converting the plane pixel values at each point into a 2D dose map at the exit surface of the imaged material. The off axis ratio is corrected using envelope and boundary profiles generated from the treatment planning system (TPS). The method was extended to include conformal and enhanced dynamic wedge (EDW) fields. A method was devised for the automatic calculation of areas (to establish the appropriate scatter correction) from the EPID image that facilitated the calculation of EPL for any field, and hence exit dose. For EDW fields, the fitting coefficients were modified by utilizing the Linac manufacturer’s golden segmented treatment tables (STT) methodology. Cross plane profiles and 2D dose distributions of EPID predicted doses were compared with those calculated with the Eclipse 8.6 treatment planning system (TPS) and those measured directly with a MapCHECK 2 device. Results: The image acquisition system influenced the dosimetric characteristics with the newer version (IAS3 with IDU-20) giving better data reproducibility and linearity fit than the older version (IAS2 with IDU-II). The irradiated field areas can be accurately determined from EPID images to within ± 1% uncertainty. The EPID predicted dose maps were compared with calculated doses from TPS at the exit. The gamma index at 3% dose difference (DD) and 3mm distance to agreement (DTA) resulted in an average of 97% acceptance for the square fields of 5, 10, 15 and 20 cm thickness solid water homogeneous phantoms. More than 90% of all points passed the gamma index acceptance criteria of 3% DD and 3mm DTA, for both conformal and EDW study cases. Comparison of the 2D EPID dose maps to those from TPS and MapCHECK shows that, more than 90% of all points passed the gamma index acceptance criteria of 3% dose difference and 3mm distance to agreement, for both conformal and EDW study cases. Conclusions: The quadratic calibration can effectively predict EPL and hence exit dose. Good agreement between the EPID predicted and TPS calculated dose distributions were obtained for open fields, conformal and EDW test cases. There were noteworthy deviations between EPID, TPS and MapCHECK doses on field edges. But it should be emphasised that, for practical in vivo dosimetry, these areas of reduced accuracy at the field edges are much less important. It is concluded that the EPID Quadratic Calibration Method (QCM) is an accurate and convenient method for online in vivo dosimetry and may therefore replace existing techniques.

Introduction: Brain imaging using single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to study the processes underlying neurological and psychiatric disorders. In addition, in vivo brain imaging using SPECT or PET may provide new approaches for drug target identification, pre-clinical testing and occupancy studies, and therefore improve drug discovery. The utility of in vivo brain imaging using SPECT or PET relies on the ability of different radiotracers (typically organic compounds labelled with radionuclides) to bind to a wide variety of targets, including receptors, transporters and enzymes. Therefore the development of novel radiotracers for in vivo brain imaging using SPECT of PET is of vital importance. This thesis is focused on the process of developing novel radiotracers as tools for imaging the human brain, where the radiotracer discovery and development pipeline is discussed and each step prior to clinical trials investigated. Radiotracer discovery: Previously, discovery of novel brain radiotracers has largely relied on simplistic screening tools. Improved selection methods at the early stages of radiotracer discovery and an increased understanding of the relationships between in vitro physicochemical and in vivo radiotracer properties are needed. This thesis investigated if high performance liquid chromatography (HPLC) methodologies could provide criteria for lead candidate selection by comparing HPLC measurements with radiotracer properties in humans. In this study, ten molecules, previously used as radiotracers in humans, were analysed to obtain the following measures: partition coefficient (Log P); permeability (Pm); percentage of plasma protein binding (%PPB); and membrane partition coefficient (Km). Relationships between brain entry measurements (Log P, Pm and %PPB) and in vivo brain percentage injected dose (%ID); and Km and specific binding in vivo (BPND) were investigated. Results showed that HPLC measurements of Pm, %PPB and Km were potentially useful in predicting in vivo performance and hence allow evaluation and ranking of compound libraries for the selection of lead radiotracer candidates at early stages of radiotracer discovery. The HPLC tool developed provides information on in vivo non-specific binding and binding potential that is not possible using conventional screening methods. Another important finding reported in this thesis is that Log P should not be relied on as a predictor of brain entry. The HPLC tool developed, together with competition binding assays, was used to characterise a newly synthesised library of compounds for imaging of the translocator protein (TSPO) in brain using SPECT. Results showed that compound LS 1 was the most likely to succeed within the library investigated, but the high %PPB observed for LS 1 suggested novel compounds with improved %PPB were needed. Thus, a novel library of compounds for imaging of TSPO in brain using SPECT is currently been developed for future testing using the HPLC tool developed here and competition binding assays. Pre-clinical research: radiotracers for imaging the noradrenaline transporter (NAT) in brain using SPECT. In this thesis, NKJ64, a novel iodinated analogue of reboxetine, was successfully radiolabelled via electrophilic iododestannylation and evaluated as a potential SPECT radiotracer for imaging the NAT in brain using rodents and non-human primates. Biological evaluation of the novel radiotracer, 123/125I-NKJ64, in rodents included: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. In rats, 123/125I-NKJ64 displayed saturable binding with nanomolar affinity for the NAT in cortical homogenates, regional distribution consistent with the known density of NAT in the rodent brain and high maximum brain uptake of around 2.93 % of the injected dose. The specific: non-specific ratio (locus coeruleus:caudate putamen) of 123I-NKJ64 uptake was 2.8 at 30 minutes post intravenous injection and prior administration of reboxetine significantly reduced the accumulation of 123I-NKJ64 in the locus coeruleus (> 50% reduction). Data obtained using rodents indicated that further evaluation of 123I-NKJ64 in non-human primates was needed to determine its utility as a SPECT radiotracer for imaging of NAT in brain. Consequently, in vivo kinetic modelling studies using SPECT imaging with 123I-NKJ64 and two baboons were carried out to determine 123I-NKJ64 brain binding kinetics, brain distribution and plasma metabolism in non-human primates. Even though a high brain uptake of around 3.0% of the injected dose was determined, the high non-specific binding observed throughout the brain, a low binding potential (BPND<2) in NAT rich regions and a brain distribution that was inconsistent with the known NAT distribution in non-human primate brain precludes the translation of 123I-NKJ64 into humans. Another NAT radiotracer, 123I-INER, developed by Tamagnan and colleagues at Yale University and Institute for Degenerative Disorders, New Haven, USA, was also investigated as part of this thesis. Kinetic modelling analysis of 123I-INER in baboon brain was investigated for different models, namely invasive and reference tissue models. Bolus plus constant infusion experiments with displacement at equilibrium using six different doses of atomoxetine and four different doses of reboxetine were carried out in several baboons to obtain occupancy measurements as a function of injected dose (mg/kg) for the two NAT selective drugs. Results showed that reference tissue models were able to determine BPND values of 123I-INER in different brain regions. In addition the volume of distribution could be determined by dividing concentration in tissue by the concentration in venous blood at 3 hours post-injection. After administration of atomoxetine or reboxetine, dose-dependent occupancy was observed in brain regions known to contain high densities of NATs. Results supported the translation of 123I-INER into humans studies, despite the slow kinetics determined over the imaging period. Pharmacokinetic properties of 123I-INER described in this thesis may be used to simplify future data acquisition and image processing. Conclusion In conclusion, this thesis reported: (1) the development of novel radiotracers for brain imaging, namely NAT and TSPO; and (2) the development of a new methodology for aiding lead molecule identification at early stages of radiotracer discovery (i.e. prior to radiolabelling). In addition, an overview of radiotracer discovery and development process is provided in a single document, with a focus on brain radiotracers.

To date, there is little research into either stress reactivity or the specificity of psychological characteristics in particular forms of sleep disorder. NREM parasomnias are a relatively un-studied group of sleep disorders. The purpose of this study was to gain greater insight into how people with NREM parasomnias respond to ‘threat’ and to life situations. In particular, the aim was to investigate how their responses to a psychological stressor compared to individuals with insomnia and to good sleepers by measuring autonomic arousal, as well as subjective appraisals of stress. Baseline levels of autonomic arousal were intended to provide insight into daytime arousal levels at the trait level. Participants (N = 38) were recruited from the general population and attended the University of Glasgow Sleep Centre to take part. Autonomic arousal was measured via continuous electrocardiogram (ECG) recordings of heart rate (HR) and cardiac vagal tone (CVT) whilst participants took part in baseline, stressor (a difficult mathematical task) and recovery phases. In general, group differences were not found, however this may be partly due to the small sample size and corresponding lack of power to detect differences. The results indicated that the NREM group reacted to stress in a similar way to good sleepers. In general, it was the insomnia group but not the NREM group whose data differed from good sleepers. However, both the NREM parasomnia and Insomnia groups exhibited a relatively higher (though not statistically significant) resting baseline HR compared to the good sleeper group, suggesting a higher level of underlying sympathetic arousal. The findings of this type of study have potentially important implications for the development of treatment programmes for NREM parasomnias. However, further work needs to be done before any conclusions can be drawn. The study was intended as an exploratory study and the preliminary findings indicate that further exploration is warranted.

Background: Classification systems for use in the diagnosis of mental disorders have been developed based on a categorical model of psychopathology. Although current categorical diagnostic classification systems have been found to have good utility and reliability, studies have questioned whether these systems have adequate validity. Dimensional models of psychopathology have been examined as an alternative to categorical diagnostic classification systems and found to be more strongly related to clinical parameters, such as the severity and outcome of mental disorders. A literature review found a small evidence base on dimensional models of psychopathology experienced by adults with intellectual disabilities. However, the findings were limited by small sample sizes, biased samples and inclusion of only a limited range of items of psychopathology. Furthermore, the methods of exploratory factor analysis used do not meet established best practice guidelines. Informed by the existing literature, this thesis aimed to; 1. identify a dimensional model of psychopathology experienced by adults with intellectual disabilities 2. examine the associations of a dimensional model of psychopathology with measures of the severity and outcome of mental disorders 3. compare the predictive validity of dimensional and categorical models of psychopathology. Methods: The Psychiatric Present State- Learning Disabilities (PPS-LD) was used as a structured instrument to collect psychopathology data. Exploratory factor analysis (EFA) following best practice guidelines was used to identify dimensions of psychopathology. Continuous measures representing the dimensions of psychopathology were calculated. Meeting criteria for the diagnosis of a mental disorder from the Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities (DC-LD) was used as the variable representing the categorical model of psychopathology. Baseline data was collected on four measures of severity; the Health of the Nation Outcome Scales- Learning Disabilities (HoNOS-LD), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), and the Camberwell Assessment of Needs for Adults with Developmental and Intellectual Disabilities- Research version (CANDID-R) unmet needs. These measures were completed again at follow up 4-5 years later and change over time used as a measure of longitudinal outcome. Bivariate statistics and multivariate linear regression were used to examine the associations of the dimensions of psychopathology, and DC-LD diagnosis, with the measures of the severity of and longitudinal outcome of mental disorders. Relevant socio-clinical variables, associated with psychopathology in previous populationbased intellectual disabilities studies were included in the analyses: gender, age, living circumstances, level of intellectual disabilities, autism, Down syndrome, epilepsy, sensory impairments, mobility problems and incontinence. Key results: A model of psychopathology with four dimensions was extracted from the EFA. This model was stable in two additional EFA using random samples. There were no significant correlations between the four dimensions which were labeled depressive,organic, behaviour-affective and anxiety. Only the anxiety dimension of psychopathology was not associated with any of the measures of severity of mental disorders. The depression dimension was independently associated with severity on the HoNOS-LD (β=.413, p<.001), GAF (β=-.402, p<.001) and the CGI (β=.457, p<.001). The organic dimension was independently associated with severity on the HoNOS-LD (β=.205, p=.004), GAF(β=-.326 p<.001) and CGI (β=.266, p<.001). The behaviour-affective dimension was independently associated with severity on the HoNOS-LD (β=.332, p<.001), GAF (β=-.286, p<.001), CGI (β=.253, p<.001) and CANDID-R unmet needs (β=.178, p=.018). Level of intellectual disabilities was independently associated with severity on the HoNOS-LD and CANDID-R unmet needs. Finally, younger age (β=-.208, p=.010), living independently (β=-.599, p<.001) and not having a visual impairment (β=-.191, p=.009) were associated with greater CANDID-R unmet needs. None of the baseline measures of psychopathology were associated with longitudinal outcome on the CANDID-R unmet needs. Baseline scores on the depressive dimension were significantly associated with longitudinal outcome on the HoNOS-LD(β=.297, p=.034), GAF (β=.342, p=.002) and CGI (β=.373, p=.001). Similarly, the behaviour-affective dimension was significantly associated with longitudinal outcome on the HoNOS-LD (β=.292, p=.033), GAF (β=.244, p=.036) and CGI(β=.298, p=.009). The organic dimension was only associated with longitudinal outcome on the HoNOS-LD (β=-.382, p=.006). Individuals with mild intellectual disabilities had poorer outcomes on all four measures of longitudinal outcome. Hearing impairment was associated with poorer outcome on the GAF (β=-.483, p=.000) and CGI (β=-.331, p=.004), and poorly controlled seizures with poorer outcome on the CGI (β=-1.638, p=.004).The variable representing the categorical model of psychopathology was only independently associated with severity on the HoNOS-LD (β=.178, p=.026), and longitudinal outcome on the GAF (β=.259, p=.045) and CGI (β=.257, p=.044). However, when categorical and dimensional models were both included in the regression analyses only the dimensional model of psychopathology was retained as independently associated with these measures of severity and outcome. Conclusions: The description of a stable dimensional model demonstrates the value of using multivariate statistical methods to examine psychopathology experienced by adults with intellectual disabilities. Since the findings suggest that dimensional models have better validity than categorical models of psychopathology, the use of EFA, and other multivariate methods, could contribute to the development of valid diagnostic classification systems. The presence of affective items of psychopathology across the depressive, behaviour-affective and anxiety dimensions highlights the possible relevance of a global affective model of psychopathology. Findings reported in this thesis support the potential relevance of models of affect regulation and affective arousal to developing an understanding of psychopathology experienced by persons with intellectual disabilities. There are similarities between the dimensional model in this thesis and the tripartite model of depression and anxiety psychopathology, described in the literature- which has depressive, anxiety and general distress dimensions. Overlaps between the behaviour-affective dimension, and general distress dimension within the tripartite model, suggest that there may be an association between affective psychopathology and problem behaviours. However, it could be that this association is with affective psychopathology in the general distress dimension, rather than with depressive psychopathology, as examined in previous studies. Confirmatory factor analyses should be considered to examine the four dimension model of psychopathology. Future studies involving individuals with intellectual disabilities should examine the relevance of global affective models of psychopathology.

Occupational therapists believe that identity is shaped by engagement in occupations but this relationship has yet to be fully understood. This thesis is an account of a study which aimed to investigate how narratives told about occupations contribute to the construction of identity. Narratives, extracted from interviews with 17 leisure enthusiasts, were subject to systematic analysis of content, form and interactive elements. This was based on an understanding that identity is expressed in the meanings attributed to the events told in a narrative. The meanings were used to construct a framework which provides a basis for conceptualising the ‘occupied self’. The framework is organised around three dimensions. The dimension of the ‘active self’ enables people to present themselves in terms of morality, competence and agency. The ‘located self’ enables them to present a sense of location in time, place, society and the body. The ‘changing self’ enables the individual to present the self as changing in itself and in relation to occupation. These facets of the self are manifested and foregrounded differently by each individual. Based on a narrative perspective, the framework provides a unique and useful theoretical development, structuring and enhancing what is currently understood about the relationship between occupation and identity. The findings of the research contribute to the debate about how occupation is defined and how the meanings of occupations are understood. Other implications are also explored in the thesis. The framework offers practitioners a structured way of understanding the ways in which occupation can contribute therapeutically in the reconstruction of damaged identities. The method of analysing narratives used in this study has much to offer in understanding occupational engagement. Further research is needed to understand the various manifestations of the parts of the framework, and to explore its potential for use as a practice tool.

The subject of this thesis is the lived experience of training in non-orthodox health care professions1 or CAM (complementary and alternative medicine) as it is commonly known. The thesis focuses both on the nature of the knowledge and skills acquired during training (knowledge of the body) and the changing embodiment of the students (embodying knowledge). It is based on ethnographic research, conducted over one academic year, at two case-study sites: the anonymized Colleges of Homeopathy and Osteopathy. The data presented in this thesis offers four distinct contributions. Methodologically, it offers insights into the embodied experience of conducting sociological research and the deep impact that this experience has on the researcher, further supporting the argument that reflexivity is a vital component of valid and reliable research. Empirically, it contributes to our understanding of an under-researched area, the ?Tactice of CAM therapies generally, and the training of practitioners particularly. Theoretically, the explicit focus of both the participants in the study .and myself, as researcher, on 'bodies' makes it a worthwhile topic of study to contribute to the growing discipline of embodied sociology. Finally, from a social policy perspective, the explosion of interest in CAM in recent years, and particularly the growing pressure on practitioners to regulate their professions, makes research into the nature of professional knowledge and practice very timely. The thesis concludes that it is of critical importance to consider embodiment in any understanding of healthcare knowledge or practice. In particular, an embodied sociological perspective permits recognition of the depth and nature of the knowledge and skills that healthcare practitioners learn to deploy on a day-to-day basis.

Lung cancer is the most common cause of cancer death in the UK. In suitable cases, the best chance of cure is surgical resection. Due to high levels of co-morbidity seen in this population, lung resection is associated with high cardio-respiratory complication rates. One such complication is the development of Acute Lung Injury / Acute Respiratory Distress Syndrome (ALI/ARDS). ALI/ARDS is reported to occur in four to 11% of patients undergoing lung resection and is the major cause of hospital mortality following lung resection. ALI/ARDS occurring following lung resection is widely interpreted to be a variant of ALI/ARDS and follows an identical clinical and pathophysiological course to that seen in the wider critical care environment. The pathophysiology of lung injury following lung resection is complex and can be broadly conceptualised as occurring secondary to insults specific to both the ipsilateral (surgical) lung, the contralateral (anaesthetic) lung in addition to those insults common to both lungs. Increased recognition of the role of ventilator induced lung injury, and peri-operative fluid prescribing in the pathogenesis of lung injury in this population has brought the prevention of lung injury to the attention of the thoracic anaesthetist. Though high quality evidence is lacking, expert opinion widely favours the adoption of lung protective ventilatory strategies and restriction of peri-operative fluids in patients undergoing lung resection. This thesis presents the rationale, methodology and results of four discrete studies concerning the development of lung injury in the thoracic surgical population undergoing resection of primary lung cancer. Investigation I is a survey of contemporary UK thoracic anaesthetic practice when anaesthetising for thoracic surgery and lung resection, with specific reference to strategies designed to prevent lung injury. Though implementation of the techniques described is far from universal, the survey results suggest that aspects of lung protective ventilation are widespread within UK thoracic anaesthetic practice. Investigation II seeks to examine the impact of increased adoption of such strategies over time. A random effects meta-analysis and meta-regression analysis was performed to examine the trends in the incidence of and mortality from ALI and/or ARDS over time. The main findings of this study are that whilst there is no evidence to suggest the incidence of ALI and/or ARDS post-lung resection is falling, mortality due to ARDS (but not ALI) does appear to be falling over time. Investigations III and IV examine the utility of two clinical monitoring methodologies which have potential to provide bedside clinical monitoring of lung injury development in the thoracic surgical population in order to guide clinical decision making, monitor patient progress and serve as a surrogate end point in future clinical studies. Investigation III examines the utility of a single lung injury biomarker (long chain Pentraxin 3 – PTX3) and a panel of multiple lung injury biomarkers in the early post-operative period following lung resection. The properties of the ‘ideal’ lung injury biomarker are defined, against which PTX3 and the multiple biomarker panel are compared. PTX3 compared favourably to properties of the ‘ideal’ lung injury biomarker and appeared to identify a population of patients with elevated post-operative Lung Injury Score with high sensitivity. Conversely there is no evidence from the results presented that a ‘risk of lung injury score’ derived from a panel of 7 candidate lung injury biomarkers (as previously defined in a cohort of critically ill patients with ALI/ARDS) has any utility in the lung resection population. Investigation IV tests the reproducibility and construct validity of transpulmonary thermodilution derived measurements of extravascular lung water and pulmonary vascular permeability index in patients undergoing lung resection. The study’s findings are largely supportive of the reproducibility and construct validity of extravascular lung water measurement and pulmonary vascular permeability measurements after lung resection. In combination, it is hoped that the studies presented provide greater insight into the syndrome of post lung resection lung injury. More accurate definition of standard anaesthetic practice and the incidence of and mortality from ALI/ARDS following lung resection should serve to inform future clinical studies seeking to prevent, treat, or better understand this important clinical syndrome. The biomarker PTX3 and transpulmonary thermodilution derived measurement of extravascular lung water and pulmonary vascular permeability index are presented as surrogate endpoints suitable for use in such studies.

Diabetes mellitus (DM) is a very common chronic disease, as well as being a major public health issue internationally. Hyperglycaemia is the most important clinical manifestation of diabetes. It develops through a multifactorial aetiology which includes genetic, environmental, and behavioural factors. It is estimated that 171 million people in the world currently have diabetes mellitus. This figure is expected to increase to 366 million by the year 2030. The distribution of DM varies around the world. The country with the greatest number of people with DM is India, with 31.7 million in 2000 and estimated to increase to 79.4 by 2030, though this is a low prevalence rate of 3% of the population. The USA has 18.8 million cases in 2011, representing 8% of the population, and this figure is estimated to rise to 30.3 million cases by 2030. The UK has 2.8 million cases in 2010, representing 4.2% of the population, and estimated to reach 4 million cases by 2025. The prevalence of DM has reached epidemic status in Saudi Arabia, where it affected 8.3 million people, or 23.7% of the population, in 2007. It is clear from these figures that there is variance in rates of diabetes prevalence in different countries. Moreover, researchers reported that this high rate of diabetes occur at lower average adiposity levels in some ethnic groups, such as South Asians, than in European populations, suggesting that South Asians are more susceptible to the effects of obesity. Several studies have investigated these differences in specific ethnic populations, but other populations, such as Saudi Arabs, have received less attention in these studies. The impending global pandemic of obesity, type 2 diabetes and vascular disease suggests an urgent need for both prevention strategies and effective treatment, which need to account for these ethnic differences. Physical activity has been shown to improve glucose metabolism and insulin sensitivity in men and women of all ages and ethnicities. Diabetes UK and the American College of Sport Medicine (ACSM) recommend that adults take at least 30 minutes of moderately intense physical activity on most days. They also recommend walking 10,000 steps most days. This is supported by the work of Tudor-Locke, Bassett, Le Massurier et al. (2007). These recommendations are aimed at European and American populations. However, to date there has been no study of the benefits of accumulation of 10,000 steps daily on glycaemic control or insulin sensitivity. Despite the benefits of physical activity being well-known, previous findings have reported that more than 43% of Saudis do not take any moderately intense physical activity. Moreover, the current evidence emphasises the importance of creating a programme to increase physical activity, encompassing multiple levels of the social environment. The aims of this thesis are to investigate if a walking programme can be conducted successfully among Saudi Arabian and, if so, whether it can deliver improved glycaemic control. In addition, the second study evaluated the efficacy of a social ecological intervention to increase walking among sedentary Saudi men. First Study: The first study was a 12-week randomised controlled trial. It recruited 39 overweight men with a family history of type 2 diabetes. After two weeks of baseline activity, participants were randomised into two groups: control and active. The control group (n = 17, 45±9 yr) was instructed to continue with their baseline activity for 12 weeks. The active group (n = 22, 47±7 yr) was instructed to walk at least 10,000 steps per day, 5 or more days per week, for 12 weeks. Steps were measured using a Yamax SW-200 pedometer. All subjects participated in a pre-test and a post-test. Each session consisted of a metabolic and anthropometric test. The baseline physical activity was not significantly different in the active and control groups (3781 ± 344 and 3298± 516 steps/day; P = 0.57). Subjects in both groups significantly increased physical activity during the intervention phase of the study. The active group increased to 9199 ± 1084 steps per day (P = 0.002) and the control group increased to 4863 ± 787 (P = 0.03). In the active group, glucose concentration reduced from 6.33 ± 0.4 at pre-test to 5.73 ± 0.3 at post-test (P = 0.008), which was a significant decrease. Fasting insulin reduced from 14.0 ± 2.5 to 13.4 ± 2.3 (P =0.046). Body mass also significantly decreased in the active group (P = 0.01). There was no significant change in these figures in the control group. Second Study In the second study, overweight male volunteers were recruited. They were randomised into two groups: a social ecology group (SE) of 35 volunteers and a self-monitoring group (SM) of 28 volunteers completed the study. Both groups monitored their steps/day during a one-week control period and over the 10-week study. In addition, the men in the active group attended four weekly sessions designed to target intrapersonal (self-efficacy, and self-regulation), and interpersonal (social support functions: attachment, social integration, reassurance of worth, reliable alliance, guidance and opportunity of nurturance) levels of the social environment. During the study period, data was collected at three time points: pre-test (baseline), post-test (at 4 weeks), and follow-up (at 11 weeks). Steps were measured using a Yamax SW-200 pedometer. Both groups significantly increased their steps/day at each time point (P < 0.001). This increase was significantly greater in the SE group (baseline 3321 ± 950 to post-test 7294 ± 338 to follow-up 5514 ± 394) compared to the SM comparison (baseline 3305 ± 720 to post-test 4865 ± 263 to follow-up 3540 ± 217). The intervention had a significant impact on self-regulatory self-efficacy, task self efficacy, self regulation for walking and some of the social support functions (attachment, reassurance of worth and reliable alliance) in SE participants only. In conclusion, the results presented in this thesis are the first to show that it is feasible to conduct a 10,000 step/day walking programme for overweight men. In addition, this programme was effective in producing statistically significant improvements in glycaemic control. The thesis also describes the first social ecology study to be conducted with overweight men. Such comparatively simple methods as social support and advice also significantly increased physical activity. In this pilot project, the use of pedometers has proved to be an effective tool for promoting healthy lifestyle changes that include daily physical activity and self-monitoring of therapeutic goals.