ANCA-systemic vasculitic glomerulonephritides (ASV) is associated with inflammation and injury to the vascular endothelial cells. Using two different endothelial cells, human umbilical cord endothelial cells (HUVEC) and a conditionally immortalised glomerular endothelial cell line (GEnC), we investigated the role of Proteinase 3 (PR3) and human leukocyte elastase (HLE) on endothelial activation and injury. Short treatments of endothelial cells with PR3 and HLE had no effect on mitochondrial activity; endothelial detachment or intracellular ADP/ATP levels, whilst 24hour treatments induced endothelial cell apoptosis and maximal von Willebrand factor (vWf) release. Short serine protease treatments resulted in dose-dependant release of vWf from endothelial cells, which along with increased release of chemokine ligand 8 (CXCL8) and expression of P-Selectin. PR3 and HLE treatment increased neutrophil adhesion to the endothelium through interactions between P-Selectin and its ligand, P-Selectin glycoprotein ligand-1 (PSGL-1), on neutrophils, and could be inhibited by blocking antibodies directed at PSGL-1. PR3 and HLE cleaved CXCL8 for support of inflammation, perhaps inducing activation of leukocyte integrins to increase adhesion. The inhibition of CXCL8 receptors, CXCR1 and CXCR2, on neutrophils decreased the level of neutrophil adhesion. Together these results suggest a short-term activatory role for the serine proteases on the vascular endothelium.

In the UK’s National Health Service, there has been an increasing emphasis on patient and public involvement, formal measures of patient experience, and public reporting of performance measures. This, as well as the emergence of the ‘digitally engaged patient’, has shifted the traditional paternalistic doctor-patient relationship. There has also been an increase in consumers more generally using rating websites. These factors together led to the formation of online patient feedback (OPF) websites, where patients can choose a healthcare provider based on patient reviews, and give feedback about healthcare providers. Academic research has been conducted on OPF websites, especially to ascertain whether patient ratings online are associated with other measures of quality. However, very little is known about patients’ and healthcare professionals’ attitudes towards OPF websites. A multi-phase mixed method design was therefore used in this research to explore patients’ and GPs’ awareness, usage and attitudes about OPF websites as a mode to give feedback about GPs in England. In Study A, twenty GPs were interviewed to explore their awareness, usage and attitudes towards OPF. The findings highlighted GPs’ concerns about OPF, and produced recommendations for OPF website providers. In Study B, eighteen patients were interviewed to explore their awareness, usage, preferences and attitudes towards OPF websites and other methods of feedback available in general practice. The findings from this study helped develop a questionnaire, which was then validated in seven-stages. The questionnaire was then implemented nationally across England in Study C using face-to-face interviews with a nationally representative sample of members of the public (n=844). The findings from this research produced evidence both for and against OPF websites, suggesting that GPs are highly concerned about the impact of these websites on them, on their professional practice, their reputation and their patients, and are not currently using OPF for improvement. Patient usage and future intention to use OPF websites was also found to be extremely low when compared to other methods of feedback, suggesting that unlike direct methods of feedback, OPF websites currently only appeal to a very small minority of patients. However, there was evidence to suggest that OPF websites fulfil a ‘feedback gap’ for patients, and unlike other feedback methods, span age, social and regional divides. The key contribution of this research is that the majority of GPs and patients are not convinced of the value of OPF websites as a mode to leave feedback about GPs in general practice. Rather surprisingly, OPF websites cannot be used currently for patient choice in general practice, nor as a measure of quality, because OPF is biased towards negative experiences, and not representative of patient experience overall. This research provides suggestions on how this could be rectified. However, the NHS should also consider channelling its energies towards providing more direct and private methods of feedback in general practice in England.

Background: Improving the sexual health of young people is a key policy focus in Scotland. As the influence of the internet has grown within a rapidly changing health information landscape, so have opportunities for both sexual health promotion, and concerns about the challenges faced by young people in navigating this online environment. This study explores young people’s sexual health literacy (SHL), primarily within this online context. Methods: Paired interviews with friendship groups and observational online activities were used to explore young people’s experiences of finding, understanding and evaluating online sexual health information. A purposive sample of 49 participants (aged 16-19), diverse in terms of gender, sexuality and religion, were recruited from across Scotland from areas that varied in terms of deprivation and urban/rural classification. Findings: Participants varied in their confidence and ability to find and identify reliable information, and typically regarded identifying and filtering reliable sources as challenging. Barriers to accessing information on websites included: inaccessible language; inappropriate or non-relatable information; and websites that were difficult to navigate or did not function correctly. Concerns about stigma and ‘being seen’ seeking sexual health information was a key barrier. Stark differences, often mediated by gender, sexuality and educational circumstances, emerged in perspectives towards accessing sexual health information and support online. Findings suggest that different social media platforms present different opportunities and challenges; for example, social content sharing services such as YouTube may be useful venues for developing critical SHL, while social networking sites such as Facebook, may be less suitable to user’s active engagement in identity construction. Dissatisfaction with school-based sexual health education appears to be a catalyst for online information-seeking, but school-based sexual health education did little to equip young people to use the online environment effectively. Conclusions: Gender, sexual identity, stigma, structural factors and social support converge and intersect around young people’s SHL. A broad range of targeted interventions are needed to improve SHL, focusing on overcoming stigma, presenting positive messages and developing interactive and critical skills. Schools could do more to develop SHL skills, including teaching the digital and critical skills to seek and appraise online information. Expanding online sexual health services may effectively complement traditional services and encourage uptake, but it is essential that research establishes a robust, comprehensive conceptualisation of SHL, and develops measurement tools specific to SHL such that interventions can be evaluated and refined.

This thesis concerns the linking together of the challenges encountered in the economic evaluation of medical devices and credible ways of performing economic evaluation in such a scenario. Although the standard methods of estimating cost-effectiveness have gained widespread acceptance, there are concerns around the methods for conducting economic evaluation in the health technology assessment of devices. Currently, the lack of appropriate comparators and evidence generation (i.e. quantity and quality of the clinical and economic evidence) have been identified as the main challenges.

Background: Malnutrition is a leading cause of childhood deaths in low- and middle-income countries and has permanent consequences for cognitive, physical and metabolic development. Globally, it is estimated that 26% and 8% children under-five years of age are stunted and wasted respectively. Approximately 90% of the world’s malnourished children live in sub-Saharan Africa and Asia. Food insecurity, which is a major driver of malnutrition, has been shown to be linked to inter-annual variability in rainfall in most of the part of sub-Saharan Africa. In general, a seasonal rainfall higher than 500 mm in sub-Saharan Africa is required to sustain healthy agriculture, with frequent droughts and periods of flooding highlighting the tenuous nature of agropastoral livelihoods in many parts of Africa. Despite the high burden of malnutrition there is limited formal investigation of its spatial epidemiology globally, especially in the most affected countries. Most of the published research has focused on the demographic, socio-economic and individual factors associated with childhood malnutrition. Little is known, however, about its geographical and contextual determinants and how policies can be formulated using the subnational distribution of these factors. Aim: The main aim of my work was to describe the space-time distribution of wasting and stunting in Somalia from 2007-2010 and determine their ecological comorbidity with Acute Respiratory Infection (ARI) and diarrhoea among children aged 6-59 months in Somalia. Methods: Data from household nutritional surveys in Somalia from 2007 to 2010 form a total of 1,066 settlements covering 73,778 children were used for the analysis throughout this thesis. Advanced Bayesian geostatistical models using stochastic partial differential equation (SPDE) in integrated nested Laplace approximations (INLA) were used for the space-time analysis. This modelling technique permits for simultaneous modelling of related issues such as risk assessment, spatial dependence, predictions and quantification of uncertainty. In the first set of analysis, the marginal effects of predictors were computed to determine their inherent spatial variability across the country (Study I). Using a novel approach, the seasonal and inter-annual variation of wasting was computed by first carrying out year-season prediction in the four main seasons in the country from 2007-2010. To then compute the effect size of each season, the survey year was used to define the temporal effect while the seasons were used separately to define the seasonality effects of wasting for the survey year (Study II). In both approaches, time-varying covariates were incorporated in the models to inform the temporal trends. The prevalence and spatial distribution of stunting between 2007 and 2010 was estimated and the role of environmental covariates in forecasting the risk of stunting was explored (Study III). Finally, a joint modelling was undertaken of wasting, stunting and underweight; and stunting, acute respiratory infection (ARI) and diarrhoea (Study IV); to concurrently determine their correlation and shared components (Study V). Results: In the period 2007-2010, the prevalence of childhood malnutrition remained very high throughout Somalia with all administrative regions reporting above acceptable levels of wasting, as defined by the WHO as above 5% prevalence. The average prevalence of wasting, stunting and mid-upper arm circumference (MUAC) < 125 mm in Somalia from 2007 to 2010 was 21%, 31% and 36%, respectively, values which meet the thresholds classified as ‘critical’ by the WHO. In addition, there was evidence of significant geographical and secular variations in the burden of malnutrition in Somalia, with South having higher levels as compared to the North in the country and clear seasonal variation was observed with a relative rise during the dry seasons and reduction during the rainy seasons. Environmental factors like rainfall and vegetation were major drivers of these variations. This study also demonstrated that wasting, stunting and underweight in children 6-59 months in Somalia shared common risk factors with evidence of correlation in space. Finally, the study showed clearly that the spatial shared component between ARI, diarrhoea and stunting was higher in the southern part of the country. Conclusion: Understanding the seasonal and annual fluctuations of different forms of malnutrition and their drivers in different regions can be used to target interventions in communities at high risk during emergency humanitarian interventions. Integrated programming and interventions focused on the common risk factors of the three indicators and specifically in regions where the co-distribution is highly prevalent may be a more effective way of reducing the burden of malnutrition in Somalia.

Introduction: There is an increasing need for economic evaluation of public health interventions to ensure efficient allocation of resources. Outcomes of such interventions often consists of health and non-health and do not fit in the conventional economic evaluation of quality-adjusted life year (QALY) framework. A cost-benefit analysis (CBA) could be appropriate but has concerns of assigning monetary values to health outcomes. Questions remain on how to consider the broad outcomes of a public health intervention in an economic evaluation. Objective: This thesis aimed to develop an integrated approach for an economic evaluation of a public health intervention that combines the standard cost-utility analysis (CUA) for health outcomes with the stated preference discrete choice experiment (SPDCE) approach for non-health outcomes on a single monetary metric. Methods: A natural experiment of the Woods In and Around Towns (WIAT) study in Scotland was used for empirical analysis. Costs were assessed using a top-down approach based on resources used. A difference-in-differences (DiD) approach was used to establish the impact. A CUA valued the health outcomes in terms of QALYs while a previously developed conceptual model of the WIAT was used to identify the SPDCE attributes and levels for the non-health outcomes. The WIAT study questionnaire was mapped to the SPDCE which generated relative willingness to pay (WTP) values from a general Scottish population. The WTP estimates were applied to the changes or improvements in the attributes and levels resulting from the intervention. A net monetary benefit (NMB) framework was then used to combine the CUA with the SPDCE on the same monetary scale, effectively deriving a CBA. Results: The WIAT interventions were of low cost despite the base case DiD analysis showing a statistically insignificant effect for interventions. The incremental cost-effective ratios (ICERs) for the interventions revealed that they were cost-effective. The probabilistic sensitivity analysis (PSA) showed that the physical intervention was 73% likely to be cost-effective at WTP of £20,000 and £30,000. The combined physical and social interventions had 74% and 75% likelihood of being cost-effective at WTP of £20,00 and £30,000, respectively. There was a great deal of uncertainty around QALY results. Overall, the integrated approach revealed that the WIAT interventions were cost-beneficial in terms of both health and non-health outcomes. Conclusion: This thesis has proposed and demonstrated the integrated approach that combines the conventional QALY framework with the SPDCE on a single monetary scale, hence a broader economic evaluative space particularly suitable for an economic evaluation of a public health intervention.

The experience of living with a chronic illness can impact on both the person receiving a diagnosis and those close to them. Experiences of diagnosis and any subsequent treatment are important as it allows individual, lived experiences to be better understood. Through exploring these experiences, it is hoped that services, treatment and support could be developed and improved. This paper consists of three chapters. Chapter one focuses on the experiences of partners of men with prostate cancer. A review of the literature identified twenty-two papers that are reviewed and synthesised into four overarching themes. Changes to the relationship and the unmet needs of partners are explored. Further ways in which services and professionals can support partners are identified. Chapter two involves a qualitative study exploring the experiences of seven men living with a diagnosis of Bipolar Disorder. Interpretative Phenomenological Analysis is utilised to understand men’s lived experiences. One theme identifies the battles men experience internally and externally in relation to vulnerability, masculinity, medication and stigma. Clinical implications and research directions are identified. Chapter three is a reflective account of the overall research process. It spans from the development of the research proposal through to conducting and reflecting on the research undertaken. Consideration is given to the role of a Clinical Psychologist in the research process.

Poor sleep and pain conditions present a major public health challenge due to their pervasive impact on well-being. Using a mix of experimental and observational methodologies, this thesis assesses sleep disruptions and its potential associations with the experience of pain. Chapter 4 comprises two experimental studies in healthy young adults (n = 57; n = 118) revealing that impairment in central pain inhibitory processes (conditioned pain modulation response) may be associated with self- reported sleep disruptions. The studies also support the validity of the conditioned pain modulation response as a physiological marker of pain inhibition. Chapter 5 presented a quasi-experimental study comparing chronic pain groups (Fibromyalgia n = 9; Chronic Back Pain n = 8) with healthy controls (n = 9) across range of self-reported and objective sleep and pain-related parameters. Findings revealed differences in patterns of self-reported sleep but not objective sleep between the two chronic pain conditions compared with healthy controls. The study also provided some extension of the findings from Chapter 4 by exploring the associations of objective sleep disturbance with less efficient pain inhibitory processes. To expand on these findings, the thesis adopted an epidemiological approach to explore the long-term interrelationship between sleep and pain-related outcomes in the general population. A systematic literature review (Chapter 6) of 16 longitudinal studies involving 61,000 participants consolidated evidence that changes in sleep are associated with several dimensions of the pain experience (risk of developing a pain condition, elevations in levels of inflammatory markers, and a decline in self-reported physical health status). Finally, Chapter 7 presents an analysis of a sample of the UK population and revealed the association between four-year changes in different insomnia symptom (sleep onset latency, awakenings, and daytime sleepiness) and perceived physical and psychological well-being in the general population (n = 30,594) and a subgroup with arthritis (n = 4,300). Overall, the findings from this thesis provide support for the associations of sleep disturbances with the processes underlying and shaping the experience of pain. The thesis highlights future research and beneficial interventions aimed at improving sleep and addressing associated pain-related health outcomes.

Gastroenteritis, causing vomiting and diarrhoea, is very common all over the world. Viral causes, such as norovirus and rotavirus, are the most frequent, although some bacteria, parasites and fungi can also lead to gastroenteritis. Many countries operate surveillance systems of diseases, including gastroenteritis or specific gastroenteritis causing pathogens. Typically, statistical methods are used to analyse surveillance data and alert public health authorities of unexpectedly high levels of illness. These methods use historical data to predict the expected value of current data. In this thesis, we address some of the challenges that remain when analysing gastroenteritis surveillance data, with a particular focus on syndromic surveillance data. We work with both mechanistic and statistical modelling approaches in an attempt to bridge the gap between the statistical methods that are used in practice for syndromic surveillance and mechanistic models that are used to model infectious diseases. In particular, we address three challenges. In chapter 2 we present a flexible framework for deriving approximations of stochastic mechanistic models of epidemics for fast inference. In chapter 3 we investigate day of the week and public holiday effects in syndromic indicators of gastroenteritis from syndromic surveillance systems operated by Public Health England in order to improve existing surveillance methodologies. In chapter 4 we identify and analyse additional online datasets for gastroenteritis, and in particular norovirus, surveillance.

Evidence of inadvertent patient harm due to healthcare staff errors - both within the NHS and in other healthcare providers worldwide - prompted regulator-led changes to eliminate such distressing incidents to patients and medical staff alike. Surgical disciplines, including orthopaedic surgery, became a focus of attention given the scale of the problem within operating theatres. Orthopaedic theatres are an example of a complex working environment that has been likened to an airplane cockpit whereby the delivery of unsafe and low quality service can lead to highly significant consequences. Around 32.6% of all surgical patient safety incidents reported by the NPSA are related to orthopaedics. Evidence suggests that harm incidents are influenced by the surgical team’s non-­‐technical skills, and can occur through an unpredicted combination of small, seemingly innocuous everyday events. It is also suggested that non-technical factors including the non-technical skills of the operating team can influence the technical tasks during surgery. In elective orthopaedic surgery, one important technical task during TKA surgery is achieving a neutral limb alignment making it a suitable surrogate for technical success and quality indicator for intra-operative performance. The impact of malalignment on patient outcomes is not fully understood. A systematic review of the literature demonstrated that although malalignment appears to associate with poor procedure outcomes however, the evidence in the literature to support this conclusion is subject to several limitations. There is also variability in the assessment methods qualities and a checklist to assess the radiological assessment methods is presented. Malalignment on the coronal plane is regarded as the most significant in determining long term implant survival. A novel X-­‐ray method using custom made jig and trigonometry principles designed during this thesis has demonstrated higher agreement with CT scan than the commonly used conventional short leg X-­‐rays in assessing coronal malalignment; (95% Limits of agreement = -­‐3.616867 to 3.616867 for novel technique versus -­‐6.333201 to 5.754254 for conventional short leg X-­‐rays). In order to explore the relationship between non-­‐technical factors and technical success, successive TKAs were observed to collect data on surgical team’s non-­‐ technical performance and the number of unwanted events. 3D malalignment was assessed using a low dose CT. Parson’s correlation and regression analysis showed that better overall limb alignment following TKA correlates significantly with better intra-­‐operative non-­‐technical skills measured using the Oxford NOTECHS II score (r=-­‐ 0.407, p=0.01), and not with eventless procedures (measured by the glitch count). The surgical teams’ non-­‐technical skills play a significant role in the team’s ability to carry out technical tasks. If we are to provide optimal patient care we need to invest in improving non-­‐technical skills in the theatre.