Acute Kidney Injury (AKI) is caused by a sudden decline in kidney function, which may be caused by numerous pathologies such as hypovolaemia or septicaemia. It has only recently been recognised that patients who develop AKI have significantly worse outcomes. The aim of this project was to develop, deploy, and evaluate a multifaceted education package aimed at improving clinician knowledge on AKI in a real life postgraduate clinical setting. We developed a web based learning resource on AKI that was recognised for its ease of use and quality in the 2013 BMJ Awards. In addition, specific AKI teaching sessions were developed, based on sound educational theory and delivered using interactive presentation software, which helped to increase audience engagement. Our findings show that it is possible for a multifaceted educational intervention to have a positive impact on clinicians’ self-reported confidence in managing AKI; as well as a trend towards better performance in knowledge based multiple choice questions. There was also a trend towards improved clinical outcomes including reduced mortality and shorter length of stay, though the significance of these findings is not clear. This thesis demonstrates the need for us to develop a better understanding about AKI prognosis, especially in the community setting. The trends shown in the mortality and length of stay data could be a consequence of factors that are currently poorly understood. The results also showed that despite increasing presence of technology in our lives, clinicians still prefer learning when it is delivered in a face-to-face setting. Much more work needs to be done in this area, so that we can better understand how to develop future postgraduate education tools that are effective and sustainable in a real world clinical setting.

Countries recovering from war increasingly use the approach of a Basic Package of Health Services (BPHS) as a means of rapidly scaling-up health care services in a coordinated way. Liberia started the implementation of a BPHS in 2007 after emerging from 14 years of civil war. The sexual and reproductive health (SRH) situation in Liberia was particularly critical (maternal mortality ratio: 990/100000 live births). No study has explored how the BPHS has influenced the provision of SRH services in Liberia or indeed globally. The aim of this study was to explore the implementation of a BPHS and its influence on the provision of SRH services in post-conflict recovery. The objectives were to (i) assess the availability of sexual and reproductive health services at facility level; (ii) explore health service providers' and policy makers' perception on how the implementation of the basic package has influenced the provision of SRH services using a health systems framework; (iii) develop recommendations for policy making regarding SRH and BPHS in postconflict recovery. The conceptual framework was based upon Lipsky's bottom-up theory on policy implementation which was then applied to a health systems framework.

Introduction: There is variation in both the incidence of renal replacement therapy (RRT) and the proportion of patients using home as opposed to hospital based treatments for their renal disease. The determinants of this variation have not been fully elucidated and this work seeks to explain this variation by looking at socio-demographic, health status, access to healthcare and renal centre practice pattern factors. Methods: The determinants of RRT incidence were examined using an ecological approach. Multilevel Poisson regression models using local health' area rate of RRT incidence per year as the outcome variable were constructed. Publically available information about the socio-demographic, health status and healthcare access of each local health area were then included in these models as explanatory variables. A national renal centre survey was purposely designed to determine the practice patterns in use in each renal centre. The contents of this survey were determined by using a two stage modified Delphi consensus generating process with a group of renal stakeholders. The survey results were then added to these models to further explain variation in RRT incidence. The determinants of home dialysis uptake were examined using individual patient level logistic regression models with the percentage of patients using home dialysis in that centre as the outcome variable and individual patient characteristics as the explanatory variables. The survey responses were then added to these models to further explain variation. Results: Population socio-demographic, health status and access to healthcare markers were all associated with RRT incidence. Renal centre capacity, rates of treatment in older persons, use of variable price contracts with private dialysis companies and the number of out-patient appointments provided were all practice patterns associated with RRT incidence. Age, distance lived from a renal unit, socio-economic deprivation score, ethnic group and primary renal disease were all associated with use of home dialysis. There were higher rates of home dialysis in centres with physician enthusiasm for the modality, home visits for education, home visits for troubleshooting problems once on home therapy and centres with a responsive access service.

This thesis addresses itself to the challenges of health technology assessment (HTA) to inform healthcare policy decision making in the presence of missing or sparse data. HTA advocates the use of evidence synthesis methods. Such an approach involves the analysis of clinical trial data through to the collation, and synthesis, of all relevant information pertaining to the decision question. Motivated by an example in overactive bladder syndrome (OAB), methodological developments together with practical applications are explored throughout the evidence synthesis process. This thesis begins with a novel application of Bayesian methodology to evaluate a large randomised controlled trial (RCT) of repeat treatment in patients with interval-censored data. Performance of Bayesian prediction models were assessed for varying proportions of missing data, and misspecification of distributional form, through a series of simulation studies. Following this, all RCTs evaluating interventions for OAB were identified in a systematic review, and critically appraised. In the current literature, all cross-modality treatment comparisons were performed using pairwise meta-analyses. In this thesis, a cross-modality treatment comparisons was performed using network meta-analysis (NMA) methods in order to obtain treatment effect estimates in terms of efficacy, safety, and tolerability. Network meta-regression techniques were employed to investigate the impact of potential treatment effect modifiers including baseline effects. Building on the general NMA framework, this model was extended to account for similarities between the same interventions with different methods of administration, making use of a natural treatment hierarchy, and where appropriate, incorporating dose-response constraints. Use of hierarchical NMA models increased the precision of treatment effect estimates used for decision-making. The hierarchical NMA model was further extended to incorporate a multivariate approach. This approach borrowed information across outcomes, increasing the precision in the treatment effect estimates. Multivariate hierarchical NMA allowed for the comparison of all interventions across all outcome measures, ameliorating the impact of outcome reporting bias, and thus increasing the ability to make decisions for healthcare policy. In doing so, sacral nerve stimulation (SNS) appeared to be the most promising intervention for the management of OAB.

People access health services to preserve or improve their health status. In some situations, accessing health services can lead individuals to pay relatively high proportions of their available income, which can push many households into poverty. Universal health coverage is a means to provide health coverage to everyone in terms of effective access to required health services with financial protection against catastrophic spending. In Thailand, the Universal Coverage Scheme (UCS) is the largest public insurance scheme. Launched in 2001, it covers 76% (48 million) of Thais. Its members are households mainly in the informal sector, lower socioeconomic groups, the elderly, the disabled, and all children under 12. In 2008, 7 years after its launch, the UCS introduced the renal replacement therapy (RRT) benefit intended to increase access to health services and reduce bottlenecks of treatment for end‐stage renal disease (ESRD). Although the UCS exists, there is inadequate health care infrastructure resulting in accumulated patients waiting for many kinds of treatments including RRT. To manage this problem, the UCS has introduced various socalled disease management programmes intended to increase access to highcost health services. The purpose of this study is to explore the introduction and functioning of a high‐cost health benefit programme of the UCS using the RRT programme as a tracer and assess how a disease management approach facilitated the inclusion of RRT in the benefit package. Its methods involve both qualitative and quantitative techniques to explore different aspects of high‐cost conditions and a disease management approach. They are 1) qualitative approaches of document review, semi‐structured interview, focus group discussion, and structured observation to explore the rationale of the RRT programme, also how the disease management approach works in administering and arranging the RRT programme; 2) age‐period‐cohort analysis based on administrative patient data of the National Health Security Office (NHSO) to assess the changing patterns of access to RRT and all‐cause mortality of ESED patients; and 3) cost modelling and time‐series projection of RRT patient numbers to estimate the long term financial consequences of the RRT programme. 4 This study found that the RRT programme was the outcome of lobbying by various stakeholders responding to concerns of the burden of ESRD on households and inequitable access to high‐cost treatment. Components of disease management, such as evidence‐based guidelines and collaborative practice, were crucial to organise the RRT programme and rapidly scale up access to care. The family played an important role in patients’ decision making to enroll in the RRT programme. Without family support, patients were likely to not take up the RRT benefit. Introduction of the RRT programme has resulted in a significant increase in access to care and decrease in the rising all‐cause mortality rate of ESRD patients. The RRT programme’s long term implications involve an increasing number of ESRD patients and growing budget needs for providing care. This study suggests strengthening involvement of various stakeholders, particularly community participation in health care in order to create efficient services that are responsive to the local needs. Locally made medications and budget optimisation and allocation should be put in place to manage the programme’s costs.

Urinary incontinence is not a topic that is openly discussed in any society. Rather it remains a subject that attracts social stigma, isolation and embarrassment that inevitably restricts individuals seeking health care. Previous research conducted in this area provides useful information about the causes, complications, contributing factors, management options and outcomes. However, this research has predominantly been conducted in the White female population. Little is known about the effects of urinary incontinence within specific ethnic groups. Even less is known about the impact of UI in religiously motivated groups, such as the Muslim communities. This study helps to explore these insights, and aims to explore the religious and cultural influences on help-seeking behaviour and decision-making within South Asian Muslim women and the 'meaning' of urinary incontinence. This is a hermeneutic phenomenological study. Forty-one South Asian Muslim women living in the Northwest of England were interviewed using an open-ended interviewing technique. All interviews were tape recorded, and took between 1 to 2 hours to complete, as the data was allowed to unfold naturally and took a conversational style. Twenty-six interviews were translated into English from the original language of Urdu and Punjabi, the remaining fifteen were conducted in English. Transcribed and analysed data was then interpreted using the philosophical underpinning of phenomenology. The search for meaning in the text, and interpretation of the data resulted in the development of six major themes; 'it's the norm'; 'it's like a hush hush thing'; 'me, my family and I'; 'my religion my identity'; 'it's not cancer'; and 'get myself checked out'. Within each of the major themes sub-themes emerged. Clearly articulated was a balancing act; on one end of the scale was the participant and their health, and on the other was the family - which included cultural traits and religious beliefs, practices and views. In order to understand what these women are describing I draw upon Antonovsky's 'salutogensis' model and the 'five-fold medical knowledge' concept by Young, both of which gear towards the subjective interpretations that individuals apply to health, illness and wellness. A number of recommendations are made and suggestions for future research are also included as a result of the findings from this study.

Chronic kidney disease (CKD) is a major public health issue, which is associated with significant cardiovascular risk. Increased arterial stiffness is believed to be a key pathway leading to this excessive cardiovascular burden. In this thesis, the use of allopurinol, a xanthine oxidase inhibitor, was found to be associated with lower arterial stiffness amongst a cohort of high-risk, CKD patients. A systematic review and meta-analysis of the cardiovascular effects of mineralocorticoid receptor antagonists demonstrated a consistent blood pressure lowering effect but highlighted the risk of hyperkalaemia and shortage of conclusive evidence of their use on other cardiovascular outcomes in patients with CKD. A pilot randomised controlled trial was conducted aiming to examine the effect of a low-dose mineralocorticoid receptor antagonist, spironolactone, on arterial stiffness in patients with stage 3 CKD in primary care. The study was terminated early due to low recruitment rate. Qualitative studies embedded within the trial found that patients with CKD in the community were generally unaware of their diagnosis and had misconceptions and negative views on the disease terminology. Perceiving that the research topic was relevant to patients’ personal health was identified as a significant prerequisite for their participation in CKD research in primary care.

This study examines social constructions of infertility in Malawi. The literature on infertility consists of epidemiological studies, describing patterns of infertility in terms of its incidence, causes and health seeking behaviour; studies of the psychological correlates of infertility; and ethnographic studies which describe experiences, perceptions and management of infertility within specific socio-cultural contexts. In addition, some studies discuss social aspects of medical practice in relation to infertility. Overall, studies of infertility in developing countries emphasize its many serious psychological and social consequences, usually attributed to cultural norms mandating parenthood. There appear to be several lacunae in the literature: men with fertility problems are rarely included, an in-depth examination of practitioners’ views is missing, and no qualitative study has been conducted on infertility in Malawi, which has a considerable secondary infertility rate. Furthermore, although ethnographic studies highlight the interpersonal (related to others’ judgements), normative (related to ideas about what ‘ought’ to be) and moral (related to ideas about what is good or bad) issues involved in infertility, no study has investigated how these issues are managed in situ, in verbal interactions. However, it has been argued that ‘talk’ is a prime site for the management of issues such as blaming and deflecting responsibility. Hence, this study addresses several gaps in the literature. It focuses on Malawi, and includes a wide range of participants: women and men with a fertility problem, significant others, indigenous and (Malawian and expatriate) biomedical practitioners. Semi-structured interviews with 63 participants were recorded and transcribed, and translations were obtained of interviews in which interpreters were used. For the analysis, I used discourse analysis (DA), informed by conversation analysis (CA). This analytic approach, novel in infertility studies, examines the interpersonal functions of statements in interactions, such as blaming or justifying. Use of DA and CA has led to novel insights into how respondents construct infertility, its causes, solutions (sought and offered), and consequences, and how they thereby manage interpersonal, normative, and moral issues, revolving around accountability, blame and justification, and attribution of (problematic) identity categories. For instance, I have shown how respondents construct childbearing as a cultural, normative requirement, and how this can be used to justify practices like extramarital affairs, or polygamy, as necessary solutions. In addition, identifying causes appears to be problematic for people with a fertility problem due to certain interpersonal and interactional issues, such as the idea that they are not entitled to medical knowledge. Practitioners can be seen to work up and bolster an identity of professional, competent expert in constructions of causes of infertility, and by attributing problems in helping infertility clients to external factors, including patients’ intelligence. This study has several theoretical, practical, and methodological implications, although I discuss some thorny methodological issues, especially those concerning the use of translations and the transferability of the analytic findings. A first contribution pertains to methodological debates and developments in conversation analysis, and in studies of infertility and other health issues which rely upon people’s self-reports. Second, my study contributes to theoretical developments in health psychology and health promotion. My analysis points to the relevance of social and normative considerations for engagement in ‘risky’ behaviours, such as extramarital affairs. This challenges cognition models which treat health behaviour as the outcome of individualistic decision-making processes, and see providing information as the main way of changing people’s behaviour. Therefore, a third set of implications is of a practical nature: some of the findings can contribute to health promotion, as well as to improvement of health services. For example, practitioners’ attribution of failures and (communication) problems to their patients, may prevent them from reflecting critically on, and addressing, their own contributions to problems. Overall, this thesis shows that when one wants to ‘give voice’ to people who are suffering from infertility, it is valuable to examine what they say in detail, within its interactional context, and the concerns they themselves make relevant, in their own terms.

Antibiotic resistance is an increasing global public health problem. Resistance is increasing sharply in gram-negative organisms, including Escherichia coli (E. coli), the main causative organism for community-acquired urinary tract infection (UTI). Antimicrobial stewardship strategies in primary care to help contain antibiotic resistance include supporting general practitioners (GPs) in deciding whether to prescribe an antibiotic for UTI and selecting the most appropriate antibiotic. In this thesis, I aim to describe the management of uncomplicated UTI in primary care and evaluate potential point of care tests (POCT) to assist the diagnosis and/or appropriate prescribing of antibiotics for uncomplicated UTI. The program of work includes: 1. Laboratory evaluation of a culture-based test that allows the quantification, identification and susceptibility profile of infecting bacteria from urine (FlexicultTM). 2. Evaluation of a novel chromatic sensing technique to identify bacterially infected urine compared to visual assessment of urine turbidity and urinalysis dipsticks. 3. Systematic review and analysis of data (descriptive and multi-level modelling) from an international primary care based observational study to describe UTI management. I identified unwarranted variation in clinical management of UTI between countries and between general practices within countries. Empirical antibiotic prescribing for UTI in Europe is high and treatment is generally prescribed for longer than guidelines recommend. FlexicultTM identifying bacterial UTI. The use of FlexicultTM in practice may support GPs in screening out negative samples reducing the proportion of patients that are prescribed antibiotics empirically. Chromatic sensing and visually assessing turbidity were equally useful at identifying negative urine samples and both improved the analytic performance of urinalysis dipsticks. The chromatic sensing system requires development prior to further evaluation.

Over three decades ago, W.H.O. declared infertility as a public health issue; due to its impact on millions of people worldwide. While cases of infertility could be multifactorial (affecting both male and female), 50% of cases are due to male factor infertility and this is mostly characterised by reduced sperm motility (asthenozoospermia). Assisted Reproduction Technology (ART) is the only treatment option available for this condition. Over 20 years ago, non-selective phosphodiesterase inhibitors (PDEi), such as pentoxifylline, were shown to enhance motility of human spermatozoa; however, contradictory results and stimulation of premature acrosome reaction has precluded their clinical use. Advancement in our knowledge have now made it clear that human sperm express several different PDEs and these are compartmentalised at different regions of the cells. By using type-specific phosphodiesterase inhibitors, differential modulation of sperm motility can be achieved without affecting other sperm function such as acrosome reaction. Additionally, by enhancing sperm function through PDE inhibition, there is a possibility of increasing IVF rates. The objective of this thesis is to: (1) examine the effect of phosphodiesterase inhibitors on spermatozoa in order to identify compounds that have clinically relevant enhancement of human sperm motility; (2) identify the signalling pathway(s) involved in the motility enhancing effects of identified compounds by targeting the modulator and mediator of cyclic nucleotides; (3) develop an animal IVF model to assess effects of Ibudilast on fertilization; and (4) optimise high performance liquid chromatography (HPLC) techniques for routine detection of cyclic nucleotides in sperm cells. A two phase drug screening approach was used to systematically and comprehensively screen series of compounds in order to identify those that have clinically relevant enhancement of human sperm motility. In phase 1, 6 compounds (out of 43 compounds) were found to have strong effects on poor motility samples, with magnitude of response ≥60% increase in percentage total motility. Additionally, these compounds significantly enhanced sperm penetration into cervical mucus substitute (p≤0.05), and they did not affect sperm acrosomal integrity nor cause externalisation of phosphatidylserine (p=0.6 respectively). 63% of IVF samples treated with compounds #26, #37 and #38 had significant increase in percentage total motility. For ICSI samples, compounds #26, #37 and #38 were the most effective. In respect to total motility, 88%, 81% and 79% of samples treated with these compounds showed significant increases in total motility, and 94%, 93% and 81% of samples showed significant increases in percentage of progressive cells, respectively. Analysis of the signalling pathways, using PKA, sGC and PKG inhibitors, showed that chosen PDE inhibitors were working predominantly through PKA signalling pathways. Additionally, this study revealed that this pathway is needed for the maintenance of basal progressive motility and hyperactivation in human sperm. Animal IVF studies showed that addition of Ibudilast (compound #26) during sperm-oocyte incubation leads to higher IVF rates. Lastly, this study used an HPLC system to detect cAMP in boar sperm. This was done to explore if HPLC system can be used for high throughput detection of cyclic nucleotides in mammalian sperm.