This thesis investigates perinatal trauma and perinatal mental health, including obsessive compulsive, post-traumatic stress, panic, social phobia, agoraphobia, general anxiety, major depression and postnatal depression symptoms within attachment theory's perspective. It aims to give insight into both caregiving and caretaking experiences of mothers in the pursuit of understanding the aftermath of perinatal trauma Thus it aims to understand first of all, interrelated factors like attachment styles, social support and parental rearing experience in predicting perinatal mental health including anxiety specific symptoms. Then it examines the mediational relationship between support and attachment styles and draws attention to understanding the importance of this relationship in relation to practical implications. This thesis also aims to understand the differences and similarities in various trauma experiences. The final aim of this thesis focuses on the experience of perinatal trauma and the relationship between mothers who experienced previous perinatal trauma and the subsequent infant. The thesis employs both qualitative and quantitative design and analysis techniques.

The thesis investigates approaches to estimating productivity costs in economic evaluation, focusing on application of the friction cost approach (FCA) using low-back pain as a case study. Individual studies of validating a Single-Item Presenteeism Question (SIPQ), estimation of the friction period by occupation in the United Kingdom (UK), and comparison of sickness certification records with self-reported data are reported. Further, the thesis explores the impact of the approaches on cost-effectiveness estimates using the FCA. Results suggest SIPQ is a valid and responsive measure, and that self-reported data provides more complete data than sickness certification records. Stratified friction periods estimates were used in the FCA approach to generate absenteeism costs. This is the first time the FCA is used in a cost-effectiveness study to report productivity costs, presenteeism, compensation mechanisms and multiplier effects in UK. In this case study, consideration of full productivity costs and applying detailed friction periods did not alter interpretation of the cost-effectiveness estimates. Further testing of these approaches in the UK is required, considering growing evidence and merit for accurate estimates of productivity costs. Overall, the research contributes to methods for assessing productivity in economic evaluation, and further illustrates the feasibility of using them in the UK.

Aims: This thesis aims to design and evaluate a Patient Reported Outcome (PRO) capable of assessing change in Craniosacral Therapy (CST) users. CST is a mind-body based complementary therapy with limited evidence base partly due to lack of suitable PROs. Methods: Mixed methods including focus groups and cognitive interviews were adopted to develop and evaluate a conceptual framework and the new PRO (Warwick Holistic Health Questionnaire WHHQ). Classical Test Theory and Exploratory Factor Analysis were used for psychometric testing. Results: 1. A conceptual framework (CF) of CST outcomes was refined and approved in 3 focus groups of practitioners and CST users. 2. 73 items were generated covering domains of the CF from an existing qualitative study of CST outcomes and PRO literature. 3. Face and content validity was tested in a consensus meeting with practitioners and two round of semi-structure interviews with CST users. The WHHQ was refined accordingly (52 items). 4. The WHHQ was pre-tested in cognitive interviews. 5. Item response, construct validity and item redundancy was assessed in 142 CST users. 6. The WHHQ was refined to 25 items including representations of new concepts in healthcare evaluation. 7. Reliability, internal consistency, external validity (SF-12v2, WEMWBS and HEHIQ), repeatability and responsiveness were assessed with 105 new CST users. Conclusions: The conceptual framework of CST outcomes, the first of its kind, identifies important new domains of health and wellbeing including the development of self-awareness and the capacity to take responsibility for self. Measurement properties show the WHHQ is psychometrically sound, having good internal consistency and convergent validity with WEMWBS and HEHIQ. Test of repeatability showed mixed results: errors were bigger than the change value but comparable to WEMWBS and SF-12v2. Respondents reported improvements in health and wellbeing with small changes shown during evaluation of responsiveness. Testing in a larger sample might confirm these findings.

The study investigated the relationships between epilepsy and employment. A comprehensive and critical literature review is presented, leading to the development of a biopsychosocial framework of medical, psychosocial and occupational factors. Relationships suggested by the literature were empirically tested in three samples of employed people with epilepsy in two major UK organisations. Methods included postal questionnaires, interviews and document analysis. Empirical evidence showed two types of outcome: employment problems and career problems. These outcomes were related to different aspects of the framework. Employment problems related to seizure control aspects and psychosocial factors outside work and career problems related to characteristics of the epilepsy itself and psychosocial factors inside work. A biopsychosocial model of epilepsy in the work-place was developed from the empirical work which identifies points of intervention and is discussed in relation to the law of requisite variety (Ashby, 1964). Conclusions and future research are identified in the area of management practice. Important aspects of this study are the development of a biopsychosocial model and the conceptualisation of epilepsy as a management resource issue.

Muscles enable the skeleton to move. Muscles are attached to bones via tendons. Inappropriate stress placed upon the muscular-skeletal system, for example sporting activities for which the subject Is untrained, can result in Injuries which may occur either in the muscle, muscle-tendinous junction or the tendon tissue itself. The resultant pathology can often result in loss of strength or pain in the area. The healing processes of tendon tissue are not well understood and the difficulty In the clinical management of pathology reflects this. Current treatment of this type of Injury Is dependent upon the severity of the injury, its site of occurrence and the practitioners preference of treatment modality. The purpose of the study was to evaluate, following the application of micro-current for therapeutic purposes, the functional outcome In patients presenting with chronic pathology in the Achilles tendon in comparison with the current conservative management. A prospective comparison study was undertaken utilising a blocked randomisation method. Subjects were allocated to either group A and were exposed to current clinical management or group B the experimental micro-current regime. Classification and subsequent evaluation of pathology was assessed employing clinical assessment and tests; subjective assessment by the subject and assessment by diagnostic ultrasound. Subjects were assessed at three, six and twelve month intervals post entry into the study. Forty eight subjects, twenty four in each group completed the study. A statistical analysis was performed, calculating the differences between the two groups and between each interval assessment. Categorical variables were compared between the two groups using the Chi-squared test. The Mann-Whitney test was performed to assess changes in ordinal variables. The Spearman rank correlation test was used to test for correlation between age and changes in the variables. Statistically significant differences were found In favour of group B, the experimental group, in four out of the five clinical markers used. No difference was found between age or sex and the changes recorded. It was concluded that the appropriate application of micro-current treatment to the Achilles tendon presenting with chronic pathology can make a significant contribution to the clinical management of the condition. This has the Implication that a degenerative cycle promotes chronic pathology occurring In the Achilles tendon. In order to narrow the gap between the clinical and experimental findings an examination of in-vitro applications was undertaken with laboratory work undertaken evaluating the effect of micro-current stimulation on 3T3 mouse and human tendon fibroblast proliferation. The results showed that the cells stimulated with 40pA proliferated at a greater rate than the non-stimulated control group. Stimulating the cells with 1pA suppressed activity with a suppression in proliferation.

This thesis describes a quantitative experimental investigation into instantaneous colour constancy in humans. Colour constancy may be defined as the ability of the visual system to maintain a constant colour percept of a surface despite varying conditions of illumination. Instantaneous, in this context, refers to effects which happen very rapidly with the change of illumination, rather than those which may be due to long term adaptation of the photoreceptors. The results of experiments are discussed in the context of current computational models of colour constancy. Experiments on subjects with damage to the cerebral cortex are described. These highlight the different uses of chromatic signals within the cerebral cortex and provide evidence for location of the neural substrates which mediate instantaneous colour constancy. The introductory chapter describes briefly the visual system, in the first section, with particular reference to the processing of colour. The second section discusses the psychophysics of human colour vision and the third presents a summary of computational models of colour constancy described in the literature. Chapter two describes the dynamic colour matching technique developed for this investigation. This technique has the advantage of quantifying the level of constancy achieved, whilst maintaining a constant state of adaptation. The C index is defined as a measure of constancy, with 0 representing no constancy and 1 perfect constancy. Calibration procedures for the computer monitor and the necessary transformations to accurately simulate illuminant reflectance combinations are also described. Light scattered within the eye and its effect on colour constancy are discussed. Chapter three is concerned with the effects of altering the illuminant conditions on instantaneous colour constancy. The size of the illuminant shift is varied. Artificial illuminants are compared with those of the Plankian locus. The effects of overall illuminance and the luminance contrast between target and surround are investigated. Chapter four considers the spatial structure of the visual scene. Simple uniform surrounds are compared with those which have a more complex spatiochromatic structure (Mondrians). The effects of varying the test target size and shape are investigated. The decrease in constancy as a black border is placed between test target and surround is measured. Chapter five describes experiments on four subjects with damage to the cerebral cortex. Chromatic discrimination thresholds are investigated for three subjects with achromatopsia as are the contribution of both sighted and blind hemifields to constancy for a subject with hemianopia. Contrary to the predictions of many of the current computational models, using unnatural illuminants has no substantial effect on the C index, nor does the size of the illuminant shift or the luminance contrast between experimental target and surround. The complexity of the surrounding field does not effect constancy. These findings are similar to those from chromatic induction experiments reported in the literature. However, the effect of a black annulus is found to have different spatial parameters that those reported from experiments on chromatic induction, suggesting that a different mechanism may be involved. The three achromatopsics can be shown to exhibit instantaneous colour constancy. However the blind hemifield of the hemianope does not contribute. This suggests that the fusiform gyrus is not the human homologue of V4 and that the primary visual cortex is necessary for instantaneous colour constancy.

This thesis is about the development and evaluation of an intervention incorporating structured sensory stimulation. It was designed for use with adults with learning disabilities who were not yet intentional communicators. The intervention was termed an 'Individualised Sensory Environment' (I.S.E.). The main objective was to reduce the levels of non-purposeful engagement and to increase the levels of purposeful interaction. Appropriate opportunities for adaptive responding were organised by the provision of sensory stimulation that was identified as personally motivating to the individual. The reinforcing sensory experience was contingent on the participant's responses. The focal sensory domains of the intervention were the tactile and vestibular systems for input, and the proprioceptive for participant response feedback. An alternating treatments design was used to evaluate the effects of the intervention (I.S.E.) on engagement levels of participants. An attention placebo condition was also used. The participants attended a social service's Day Centre and formed therapy groups whose membership ranged from two to four, based on their location within the service's structure. Groupings were then randomly assigned to two experimental groups, the order of interventions for one being the reverse of the other. Data was collected by systematic observation of participant's engagements in the natural environment: at baseline, after each phase of therapy and at two follow-up points. Analysis of variance was the main method of statistical interpretation. The results showed that high levels of non-purposeful behaviour were emitted at baseline when compared with the construct purposeful interaction. When the intervention (I.S.E.) was introduced, a significant decline in the level of non-purposeful behaviour was observed, which maintained its new lower level up to one month after the termination of therapy. The placebo condition also effected a similar change initially. However, a significant increase in purposeful interactions was only observed after a phase of the 'Individualised Sensory Environment'. Some limitations of the study are discussed and recommendations for future work are indicated.

In an effort to identify further published, unpublished and ongoing studies, conference proceedings and trials registers were searched, reference lists of relevant articles were scanned and researchers and authors in the field were contacted. Selection criteria: Studies were included if the focus was on; study participants as a provider of care to a stroke survivor living in the community, had no restrictions on admissible participants, had no restrictions on type of stroke patient, depression was measured using standard criteria and measures of occurrence of depression presented in a binary format (i.e., depressed/ not depressed). Types of epidemiologic study eligible included: cohort studies, case-control studies, including prevalent case-control studies and cross sectional studies, including prevalence studies. Data collection and analysis: Two review authors selected studies for inclusion, independently extracted data and assessed methodological quality. Estimates of pooled prevalence were calculated using inverse variance methods. Results: 19 studies were identified. 12 studies used a single cohort design and six studies used a cross sectional design. One study is ongoing and awaiting assessment. No cohort studies included a referent or comparator group of people who were unexposed to providing informal care. Data on prevalence of depression were available from 16 studies (1848 participants). No studies were identified that collected data on incidence of depression. No investigators reported including participants to cohort studies that were free of depression at the initial observation. The estimates of prevalence of depression are based on the number of people who scored above a clinical cut point on a self-report dimensional rating scale for depression. The overall pooled prevalence estimate calculated using the inverse variance method using a random effects model was slightly lower (28%, 95% CI 23%, 33%) than when the analysis was restricted to studies with an ideal design (30%, 95% CI 25%, 34%). The majority of studies lack a description of important characteristics that define the informal caregiver population. Lack of a clear and unambiguous operational definition of informal care is common across studies. Conclusions: Estimates of prevalence of depression in people who provide care to informal stroke survivors are similar to those observed in community studies of the prevalence of depression. There is currently insufficient evidence from epidemiological studies to suggest and association between the provision of informal care and the development of depression. Chapter 5 Non-pharmacological interventions for informal carers of stroke survivors. Synopsis of chapter 5. Chapter 5 focuses on the analysis and evaluation of the existing literature on the effects of non pharmacological interventions targeted towards people who provide informal care to stroke survivors. For presentation purposes, this chapter is divided into several sections. Section A describes the background and rationale for the systematic review. Section B describes the methods of the review including the types of participants, types of interventions, types of outcome and types of study, searching for studies, selecting studies and collecting data, assessing risk of bias in included studies, methods for analysing data and undertaking meta-analysis. Section C presents the meta-analysis of the relevant studies. The results are presented and discussed. Abstract. Background: A substantial component of care is provided to stroke survivors by informal caregivers. However, providing such care is often a new and challenging experience and has been linked to a number of adverse outcomes. A range of interventions targeted towards stroke survivors and their family or other informal caregivers have been tested in randomised controlled trials (RCTs). Objectives: To evaluate the effect of interventions targeted towards informal caregivers of stroke survivors or targeted towards informal caregivers and the care recipient (the stroke survivor). Search methods: The Cochrane Stroke Group Trials Register (last searched March 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2010); MEDLINE (1950 to August 2010), EMBASE (1980 to December 2010), CINAHL; (1982 to August 2010), AMED (1985 to August 2010), PsycINFO (1967 to August 2010) Science Citation Index (1992 to August 2010) and six other electronic databases were searched. In an effort to identify further published, unpublished and ongoing studies, conference proceedings and trials registers were searched, reference lists of relevant articles were scanned and researchers and authors in the field were contacted. Selection criteria RCTs were included if they evaluated the effect of non-pharmacological interventions (compared with no care or routine care) on informal caregivers of stroke survivors. Trials of interventions were included if they delivered to stroke survivors and informal caregivers only if the stroke survivor and informal caregiver were randomised as a dyad. Studies which included stroke survivors and caregivers were excluded if the stroke survivors were the primary target of the intervention. Data collection and analysis: Two review authors selected studies for inclusion, independently extracted data and assessed methodological quality. Original data was sought from trialists. Interventions were categorised into three groups: support and information, teaching procedural knowledge/vocational training type interventions, and psycho-educational type interventions. The primary outcome was caregivers' stress or strain. Disagreements were resolved by consensus. Results: Eight studies, including a total of 1007 participants, met the inclusion criteria. The results of all the studies were not pooled because of substantial methodological, statistical and clinical heterogeneity. For caregivers' stress or strain no significant results were found within categories of intervention, with the exception of one single-centre study examining the effects of a 'vocational training' type intervention which found a mean difference between the intervention and comparator group at the end of scheduled follow-up of -8.67 (95% confidence interval -11.30 to -6.04, P < 0.001) in favour of the 'teaching procedural knowledge' type intervention group Conclusions: It was not possible to carry out a meta-analysis of the evidence from RCTs because of methodological, clinical and statistical heterogeneity. One limitation across all studies was the lack of a description of important characteristics that define the informal caregiver population. However, 'vocational educational' type interventions delivered to caregivers prior to the stroke survivor's discharge from hospital appear to be the most promising intervention. However, this is based on the results from one, small, single-centre study. Chapter 6 Conclusions. Synopsis of Chapter 6. This chapter, after outlining the findings of the individual studies included in this thesis and how they fit into the broader literature, makes observations about the approach that has been taken and lessons learned, some with the benefit of hindsight, in order to inform future research work on informal carers. This chapter also examines the structure, purpose, limitations, use and misuse of the informal care epidemiological literature. The chapter finishes with recommendations for future research, clinical practice and policy.

This PhD project developed the femoral 3-in-1 nerve block to provide safe, effective regional analgesia to the 60,000 patients admitted annually to UK hospitals with a fractured neck of femur. The hospital mortality for patients with a fractured hip in a large UK study was 14.3% with cardiac aetiologies predominating in the first 2 days (Bottle & Aylin 2006). In contrast to the marked improvements in mortality for elective surgery, the overall mortality from emergency surgery and in particular surgery for fractured neck of femur patients has remained unchanged (Roberts & Goldacre 2003). Development of the femoral 3-in-1 nerve block for fractured neck of femur patients will provide analgesia but may also improve outcome. A relationship between effective pain analgesia and improved cardiac morbidity and reduced mortality in patients with a fractured neck of femur was demonstrated by Matot et al using epidural analgesia in 2001 but this is not the current clinical standard in the UK (Matot et al. 2003). The femoral 3-in-1 nerve block (also called the fascia iliacus block or anterior psoas compartment block) offered a viable solution to provide analgesia to patients with a fractured neck of femur prior to surgical fixation. The femoral 3-in-1 nerve block is technically undemanding and requires a minimum of extra training and resources. In contrast to epidural analgesia which requires extensive training of practitioners and continuous cardio-respiratory monitoring of patients and an increased level of nursing care, ultrasound guided nerve blocks have been associated with an increased success rate, need less local anaesthetic and have shorter onset times than traditional techniques (Marhofer et al. 1997;Marhofer et al. 1998). Ultrasound guidance may increase the nerve block success rate and lower complication rates but it is associated with the extra cost of the ultrasound machine, disposables and staff training. In contrast, needle guidance using loss of resistance for a femoral 3-in-1 block is technically simple and cheap but is potentially inaccurate and, as a result, may be less effective. Anaesthetists currently utilise the femoral 3-in-1 nerve block to provide effective pain after surgical fixation of the femur but these techniques use large doses of local anaesthetic. Further information on dosing based on efficacy and duration of action will allow a reduction in dose and hence an improvement in safety of the femoral 3-in-1 nerve block. The information needed to develop the femoral 3-in-1 nerve block to provide analgesia for patients with a fractured neck of femur was provided by undertaking one prospective observer-blinded muticentre randomised controlled study, a clinical trial of an investigational medicinal product and a cadaveric dissection study. A multicentre randomised controlled study compared the efficacy of using ultrasound, nerve stimulator and loss of resistance techniques to guide the needle for a femoral 3-in-1 nerve block in elective primary total hip arthroplasty patients. This initial study recruited patients scheduled for a similar operation to fracture neck of femur patients (elective primary total hip arthroplasty) as it was impossible to recruit and assess a large number (>100) elderly, frail emergency patients. The use of the nerve stimulator is the current gold standard for elective femoral 3-in-1 nerve blocks but if used on patients with a fractured neck of femur it will cause unnecessary discomfort in a limb with an unfixed fracture. In order to determine the comparative efficacy of ultrasound, nerve stimulator and loss of resistance techniques, we performed femoral 3-in-1 nerve blocks on 180 patients scheduled for elective primary total hip arthroplasty. The efficacy of these three techniques was measured by assessing femoral nerve sensory and motor response at 30 minutes after the femoral 3-in-1 nerve block. The use of ultrasound and nerve stimulator (US+NS) for the femoral 3-in-1 femoral nerve block for elective total hip replacement was statistically significantly more effective than loss of resistance (LOR-59.5%, US+NS-80.3%, p=0.0159 (p≤0.025)) with a number needed to treat of 5. There was no statistically significant difference in the effectiveness of using the nerve stimulator(NS) and ultrasound(US) to guide the insertion of a femoral 3-in-1 nerve block (NS-77.5, US-83.1%, p=0.527 (p≤0.025)). Since the use of nerve stimulator would result in significant unnecessary discomfort in patients with an unfixed fracture it was concluded that ultrasound was the optimal technique to guide femoral 3-in-1 nerve blocks for analgesia in patients with a fractured neck of femur. The dosing and safety of the femoral 3-in-1 nerve block was determined in patients with a fractured neck of femur. Levobupivacaine dosing was estimated by a Dixon’s up/down sequential methodology. Femoral 3-in-1 nerve blocks were performed and the concentration of levobupivacaine was increased or decreased (using a fixed volume) for an ineffective or effective nerve block respectively, as a result the concentration tended towards the EC50 (effective concentration in 50% of patients). The EC50 and the EC95 (effective concentration in 95% of patients) for 30 ml of levobupivacaine was estimated using a binary probit regression model; in which the probability of an effective nerve block was modelled against the concentration of levobupivacaine. The second part of this clinical trial assessed the pharmacokinetics (to ensure that serum levels were within the safe range) and pharmacodynamics (to assess duration of analgesia). The estimated EC95 concentration of levobupivacaine for the femoral 3-in-1 nerve block was 30mls of 0.036% with 95% confidence interval of 0.0332% to 0.0383%. The EC95 concentration of levobupivacaine gave a mean duration of analgesia of 166 minutes with a standard error of the mean of 35 minutes and peak median plasma level of 52 ng/ml 30 minutes after the femoral 3-in-1 nerve block. The measured plasma levobupivacaine concentrations were below the threshold (2100ng/ml) associated with toxicity. The clinical anatomy of the femoral 3-in-1 nerve block was determined by dissection. We investigated the distribution of 30 ml of black 10% latex injected lateral to the femoral nerve under the fascia iliacus membrane in two unembalmed adult cadavers. In all four dissections the lateral cutaneous and femoral nerves were stained at the inguinal ligament and the latex travelled distally in the adductor canal into the popliteal fossa to stain the sciatic nerve and its terminal branches.

Pulmonary hypertension (PH), a disease state affecting the pulmonary circulation, was first recognised in the 1950s. Obliteration of pulmonary capillary beds and vasoconstriction lead to elevated pulmonary vascular resistance (PVR) and increased right ventricular afterload. The direct consequence is impaired cardiac output (CO) response to exercise, resulting in progressive exercise limitation, and ultimately premature death from right heart failure. Despite the considerable expansion in pulmonary vasodilatory therapy in recent years, PH remains an incurable disease associated with high morbidity and mortality. Exercise CO is an important outcome measure in PH as it is directly linked to the consequences of disease. Cardiac output is conventionally measured at right heart catheterisation (RHC). The invasive nature of this procedure does not permit serial measurements to be made readily during follow-up to assess disease progression or treatment response. As a result, six-minute walk distance (6MWD), a simple measure of submaximal exercise capacity, has been used as a surrogate of exercise CO and the primary end-point in most randomised controlled trials of pulmonary vasodilatory agents to date. However, there are recognised limitations to the ability of 6MWD to predict outcome, and this necessitates the development of alternative outcome measures which are non-invasive, reproducible and responsive to change. Measurement of CO using the inert gas rebreathing method (IGR) may be such an alternative to 6MWD. It is a direct measure of right heart function and hence disease-specific. It can be combined with submaximal constant-load exercise to provide an objective assessment independent of patient effort. This form of exercise would also allow isotime comparison of metabolic variables which were shown to be more sensitive than variables measured at peak exercise in demonstrating improved exercise capacity from therapeutic interventions in chronic obstructive pulmonary disease (COPD). Another potential alternative outcome measure is end-tidal carbon dioxide partial pressure (PETCO2). It is a marker of ventilatory inefficiency and was shown to correlate with disease severity in PH. Accurate prognostication is central to PH management as it would inform treatment planning and patient counselling. Different strategies could be adopted to optimise the performance of existing prognostic factors. The predictive value of 6MWD may be improved by using % predicted 6MWD which adjusts for age, gender and anthropometric factors, and hence would give a more accurate representation of disease severity. A composite scoring system, combining key prognostic variables, would be more discriminatory than individual variables in predicting survival. Such prognostic equations have been derived from contemporary PH cohorts in France and the United States. Validation data published so far support their predictive value, but these equations may not perform as well in the United Kingdom (UK) as a locally derived risk score, due to differences in patient demographics and healthcare systems. The aims of this thesis were to investigate the use of novel non-invasive exercise variables and prognostic algorithms as outcome measures in PH. 1. The first two studies evaluate the ability of IGR haemodynamic measurements and isotime metabolic variables during submaximal constant-load exercise, and PETCO2 during the six-minute walk test (6MWT) to predict treatment response. 2. The last two studies explore the prognostic value of % predicted 6MWD and a novel UK-based composite risk score. The reproducibility and clinical correlates of IGR pulmonary blood flow (PBF) and stroke volume (SV) were determined. Changes in IGR PBF and SV and isotime metabolic variables, at rest and during submaximal constant-load exercise, were assessed after three months of new or modified disease-targeted therapy in patients with precapillary PH. IGR measurements were found to have good intersession reproducibility and correlate with conventional outcome measures including World Health Organisation functional class (WHO FC), 6MWD, N-terminal pro-brain natriuretic peptide (NT-proBNP) and Cambridge Pulmonary Hypertension Outcome Review (CAMHPOR) score. Resting and submaximal exercise IGR PBF and SV were able to detect treatment response, and may be more sensitive than 6MWD in detecting the effects of therapy in fitter patients. In comparison, isotime metabolic variables were less useful in detecting a treatment effect. The metabolic response during the 6MWT was determined and changes in PETCO2 were assessed after 3 months of new or modified disease-targeted therapy. Therapy-induced changes in the nadir of PETCO2 (PETCO2 nadir) correlated with changes in 6MWD, but resting, end-of-walk or PETCO2 nadir did not improve significantly at follow-up. Post-hoc analysis demonstrated that the study was under-powered to detect a change in PETCO2 with therapy. The prognostic performance of % predicted 6MWD, calculated using four different published reference equations, was compared with that of absolute 6MWD, at baseline and on treatment. Despite adjusting for physiological inter-subject variance, % predicted 6MWD is not superior to absolute 6MWD in predicting all-cause mortality. This may be related to limitations of existing reference equations or the use of all-cause rather than disease-specific mortality as the end-point. Baseline mortality predictors were identified from a Scottish cohort of incident and treatment-naive PH patients, and used to derive a simple scoring system for survival prediction over time. When validated in an independent UK PH cohort, the Scottish Composite Score (SCS) was predictive of survival and able to provide further risk stratification in WHO FC III patients. It may perform better in UK populations than other published equations derived from PH cohorts in France and the United States. In conclusion, IGR haemodynamic measurements may be useful as alternative outcome measures to 6MWD, and the SCS shows promise as the first UK-based composite risk score in PH. Further studies in larger cohorts are warranted to confirm their clinical utility.