Epidemiological studies suggest differences in the prevalence and natural history of microvascular complications between subjects with insulin dependent (IDDM) and non-insulin dependent (NIDDM) diabetes. The haemodynamic hypothesis proposes that early functional changes in the microcirculation result in the eventual development of diabetic microangiopathy. There is now a large body of experimental evidence in support of this hypothesis in patients with IDDM, with abnormalities in blood flow, capillary pressure and permeability having been demonstrated. In contrast, there have been few studies investigating microvascular function in NIDDM; however, preliminary work has identified a profound limitation in microvascular vasodilation at an early stage, while capillary pressure does not appear to be elevated. The aim of this thesis was to further investigate functional changes in the skin microcirculation in patients with NIDDM and impaired glucose tolerance (IGT). 1. Using a sensitive plethysmographic system, no difference was found in microvascular fluid permeability between patients with NIDDM and control subjects (5.3 (3.2-9.1) x 10-3 ml.min-1.100g tissue-1.mmHg-1 vs 5.4 (3.5-8.0) x 10-3 ml.min-1. 100g tissue-1 .mmHg-1 median and range; p = 0.98, Mann-Whitney). 2. In confirmation of previous studies, reduced microvascular hyperaemia in response to local heating of the skin was found (using laser Doppler fluximetry) in NIDDM patients with large vessel disease excluded (0.82 (0.42-1.41) V vs 1.40 (0.89-2.13) V control subjects; p < 0.005). Limited vasodilation correlated with fasting plasma insulin (Rg =-0.63, p < 0.04) but not glycaemic control. Microvascular hyperaemia increased after one year of improved glycaemic control in recently diagnosed patients (1.20 (0.51-3.93) V vs 0.97 (0.22-2.17) V at baseline; p < 0.05). In hypertensive NIDDM patients, there was no further reduction in microvascular vasodilation (1.05 (0.70-1.42) V vs 1.04 (0.79-1.63) V normotensive NIDDM, p = 0.82), although there was an increase in calculated resistance to blood flow (127.2 (87.5-181.3) mmHg.V-1 vs 84.7 (61.9-123.0) mmHg.V-1 normotensive patients, p < 0.02). 3. Reduced microvascular hyperaemia was found in subjects with IGT (1.01 (0.71-1.57) V vs 1.41 (1.32-2.13) V control subjects, p < 0.001), and also insulin resistant patients with acromegaly (0.96 (0.56-1.70) V vs 1.46 (1.24-2.13) V control subjects, p < 0,05). In subjects with IGT, limited vasodilation was found to correlate with fasting plasma insulin (Rg = -0.7; p < 0.001) and insulin sensitivity (Rs = 0.52; p < 0.02), but not with β-cell function, plasma glucose or serum lipid concentrations. 4. Using iontophoresis and laser Doppler fluximetry, defective endothelium-dependent vasodilation was found in subjects with IGT (518 (410-905) AU-min-l vs 1236 (875-1588) AU.min-1 control subjects, median and range; p < 0.003). In contrast there was no significant difference in myogenic (683 (301-1175) AU.min-1 vs 898 (303-998) AU.min-1 control subjects; p = 0.5) or neurogenic vasodilation ( 61 (31-109) AU vs 46 (37-146) control subjects; p = 0.8). 5. No differences in skin capillary density were found between patients with NIDDM, subjects with IGT and control subjects under basal conditions (112 (71-144) caps.mm-2 vs 107 (76-140) caps.mm-2 vs 112 (76-138) caps.mm-2 respectively; p= 0.9, Kruskal Wallis), or after venous occlusion (122 (87-157) caps.mm-2 vs 121 (90-143) caps.mm-2 IGT vs 123 (81-147) caps.mm-2; p= 0.9). In light of the above results, a unifying hypothesis has been proposed to explain the differences in epidemiology and pathophysiology of microvascular disease between IDDM and NIDDM.

Mineral bone disturbances are common in chronic kidney disease (CKD), and associated with significant risk of mortality and morbidity in patients on renal replacement therapy (RRT). Surrogate biomarkers of bone turnover such as parathyroid hormone (PTH), phosphate, calcium and Vitamin D are used to diagnose, evaluate, and guide treatment. This thesis examines the effect of RRT on mineral bone disturbances, it's association with bone morbidity, and management strategies for phosphate control. Initially the incidence of radiologically proven bone fracture by site, in prevalent RRT groups is quantified and the relationship to associated risk factors studied. In this multicentre observational study of 2096 patients over a 3-year period the risk of fracture is higher in haemodialysis (HD) patients than in transplant patients even when controlling for other risk factors. Exposure to lanthanum and Vitamin D is apparently a protective factor in the HD group. I then examine a thrice-weekly nocturnal in-centre dialysis model in which we attain normal phosphate levels without dietary restriction or supplementation by altering the dialysis prescription and time. This observational trial over a 2-year period with over 2000 sessions of dialysis in 14 patients is associated with reduction of blood pressure medications. Subsequently I investigate the relationship of phosphate to FGF23 in a group of peritoneal dialysis patients. Finally, I study the effect of dialysis on clearances of FGF23 and expand on the knowledge of FGF-23 during a session of dialysis.

Pharmacovigilance plays an important role in monitoring adverse drug reactions (ADRs) resulting from an intervention related to medicinal products. Due to the frequencies and potentially serious consequences, ADRs pose a considerable economic and clinical burden. Patients with an underlying risk factor or established cardiovascular disease (CVD) are usually on long-term treatment, thus it is important to monitor the efficacy and safety of drugs prescribed. Modern antihypertensive drugs have been showed to effectively reduce high blood pressure (BP) hence prevents the development or complications of CVD in high-risk patients. However, there is evidence from clinical trials and observational studies suggesting the association between antihypertensive drugs and risk of cancer. Furthermore, these observations are inconsistent and the majority of clinical trials were directed towards cardiovascular outcomes. The thesis is divided into five main result chapters (4 to 8) based on the antihypertensive drug classes evaluated for risk of cancer in the systematic review and meta-analyses. Altogether, 90 randomised controlled trials (RCTs) enrolling 390,750 participants with an average follow-up of 3.5 years were included for qualitative and quantitative analysis. Angiotensin-converting enzyme inhibitor (ACEI) and risk of cancer: ACEI lowers BP through preventing the conversion of angiotensin 1 to angiotensin II by ACE in the renin-angiotensin system (RAS) pathway. In the present study, no significant association between ACEI and risk of cancer incidence or cancer-related death is reported. Factors such as tissue binding capacity, comparator used, clinical settings, age, and study duration do not affect the risk of cancer overall. Angiotensin receptor blockers (ARB) and risk of cancer: In the RAS pathway, ARB acts directly on the angiotensin type 1 (AT1) receptor to inhibit downstream signalling which results in downregulation of sympathetic activity and lowering of BP. The present meta-analysis has reported no association between ARB use and risk of cancer incidents or cancer-related mortality. Subgroup assessment indicates that valsartan has a cancer-protective effect, particularly against lung cancer. Patients' clinical settings, age, and study duration do not influence the risk of cancer in relation to ARB overall. Calcium channel blockers (CCB) and risk of cancer: As a class, CCBs are potent vasodilators and are recommended for use as first or second-line drugs in treating hypertension. This study has reported a marginally increased risk of cancer incidents (P=0.06) but not cancer-related death overall in relation to CCB use. DHP-CCB is associated with a 9% increased risk for cancer compared to controls (P=0.05). A positive relationship is also observed with older patients and in patients with longer exposure to CCB. Therefore, a properly designed further research into the risk of a specific type of cancer with use of DHP CCB is warranted to detect a safety signal. Beta-blockers (BB) and risk of cancer: Inhibition of stress mediators from activating beta-adrenoceptors has been proposed to be the underlying mechanism by which BB lower the risk of cancer. This study has found no evidence of an association between BB and the risk of cancer or cancer-related death. Factors such as cardioselectivity, treatment indication, age and study duration do not have an impact on cancer risk altogether. Thiazide diuretics (TZ) and risk of cancer: TZ induces diuresis at the distal convoluted tubule and a great number of studies had attempted to link TZ and risk of renal cancer. No evidence of an association between TZ and the risk of cancer or cancer mortality is reported in the present study. Chemical structure differences, clinical settings, age, and study duration does not significantly influence the risk of cancer in relation to TZ use. Strengths and limitation: The strengths of the systematic review and meta-analyses conducted in this thesis include; only RCTs were included, a comprehensive search strategy spanning over 60 years with no language restrictions, and a sufficiently large sample size of over 390,000 trial participants from various clinical settings with an average 3.5 years follow-up duration. Lack of individual-level data and non-standard reporting of cancer in RCTs are the main limitations. Future recommendations: All RCT evaluating drug intervention should pre-identify cancer as one of the study outcomes as part of drug safety monitoring.

Falsified medicines are a global health and pharmaceutical sector issue which affect supply chains in low, middle and high-income countries. There are many methods to identify substandard and falsified medicines. However, the European Union has introduced the Falsified Medicines Directive (FMD) to combat this problem. This directive requires the majority of all prescription-only medicines to be serialised, risk-based verified at wholesaler level and decommissioned at the end of the supply chain at a healthcare facility; using digital medicine screening technology (DMST) often referred to as medicines authentication technology. This thesis implemented a DMST into a live hospital environment for use by healthcare professionals. This thesis looked at the technical and operational effectiveness of the proposed digital solution in a hospital, gained user consensus on the strengths and limitations of the hospital DMST and implemented technological change to understand if the proposed changes demonstrated a quantitative or qualitative benefit. This thesis explains how the health information technology (HIT) intervention was perceived by the users and draws on literature to explain the observed results. This thesis involved the development and testing of a mobile app based DMST which could be used by public for the verification of medicines. This thesis involved a sample of social media users to gain an understanding of the consumer-based medicine verification concept, its limitations, and its opportunities from a convenience sample cohort. A DMST in a hospital environment can work effectively in practice. However, some factors such as DMST offline instances, poor compliance to the DMST alerts and poor staff engagement remain a risk for this solution. It is established that ‘active’ alerts, such as an audio alert can improve adherence to policy (detection rates) and that staff-led technology improvements have a positive impact on technology compliance. There is also a consumer appetite for a mobile DMST app, and although some consumers are happy to share their data, this cohort would prefer if a hospital or University controlled the data generated by the app due to concerns relating to data management. This thesis has generated evidence to support the development of DMST systems for hospitals and mobile phone users.

Ovarian cancer is a complex disease characterized by low incidence, accounting for about 4% of cancer diagnoses in women, but with rapid progression and higher mortality rate than any other gynecological malignancy. Approximately 70 % of the cases are diagnosed late in the course of the disease due to unawareness of subtle symptoms and failure of screening methods for detecting the disease at early-stage. Although most patients respond well to standard treatment, which involves surgery followed by platinum/taxane combination therapy, relapse seems unavoidable and the majority of patients presented with chemoresistant disease, which is considered as the main obstacle to successful treatment. Reduced susceptibility to apoptosis is one of the major causes for the development of resistance to chemotherapy, one cause of it is overexpression of pro-survival members of Bcl-2 family. Advances in understanding of the molecular mechanisms of the involvement of pro-survival proteins in the emergence of resistance to chemotherapy has made them attractive targets for the development of new therapies to treat ovarian cancer. BH3 mimetics are agents that antagonize the apoptosis inhibitors of Bcl-2 family, and have been shown to potentiate the activity of carboplatin against a panel of ovarian cancer cell lines. However, in clinical trials, agents that antagonize Bcl-XL were associated with life-threatening thrombocytopenia. To avoid this venetoclax was developed to selectively inhibit Bcl-2 and avoid inhibition of Bcl-XL. Unfortunately, Bcl-XL appears to be more frequently deregulated than Bcl-2 in ovarian cancer. In this study, the ability of venetoclax, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin were assessed in ovarian cancer cell lines. In addition to the genes encoding the Bcl-2 family of proteins, a number of other genes have shown to be overexpressed in drug resistant ovarian cancer. These are potential targets for the development of new therapeutic agents to overcome drug resistance. Work from our group previously reported an RNAi screen to assess whether knockdown of some of these genes increases the sensitivity to carboplatin or paclitaxel. In the present study, some of these hits were validated and branched-chain amino acid dehydrogenase kinase emerged as a potential new target for developing chemosensitizing agents.

Accurate estimation of geometric musculoskeletal parameters from medical imaging has a number of applications in healthcare analysis and modelling. In vivo measurement of key morphological parameters of an individual’s upper limb opens up a new era for the construction of subject-specific models of the shoulder and arm. These models could be used to aid diagnosis of musculoskeletal problems, predict the effects of interventions and assist in the design and development of medical devices. However, these parameters are difficult to evaluate in vivo due to the complicated and inaccessible nature of structures such as muscles and tendons. Ultrasound, as a non-invasive and low-cost imaging technique, has been used in the manual evaluation of parameters such as muscle fibre length, cross sectional area and tendon length. However, the evaluation of ultrasound images depends heavily on the expertise of the operator and is time-consuming. Basing parameter estimation on the properties of the image itself and reducing the reliance on the skill of the operator would allow for automation of the process, speeding up parameter estimation and reducing bias in the final outcome. Key barriers to automation are the presence of speckle noise in the images and low image contrast. This hinders the effectiveness of traditional edge detection and segmentation methods necessary for parameter estimation. Therefore, addressing these limitations is considered pivotal to progress in this area. The aims of this thesis were therefore to develop new methods for the automatic evaluation of these geometric parameters of the upper extremity, and to compare these with manual evaluations. This was done by addressing all stages of the image processing pipeline, and introducing new methods based on artificial intelligence. Speckle noise of musculoskeletal ultrasound images was reduced by successfully applying local adaptive median filtering and anisotropic diffusion filtering. Furthermore, low contrast of the ultrasound image and video was enhanced by developing a new method based on local fuzzy contrast enhancement. Both steps contributed to improving the quality of musculoskeletal ultrasound images to improve the effectiveness of edge detection methods. Subsequently, a new edge detection method based on the fuzzy inference system was developed to outline the necessary details of the musculoskeletal ultrasound images after image enhancement. This step allowed automated segmentation to be used to estimate the morphological parameters of muscles and tendons in the upper extremity. Finally, the automatically estimated geometric parameters, including the thickness and pennation angle of triceps muscle and the cross-sectional area and circumference of the flexor pollicis longus tendon were compared with manually taken measurements from the same ultrasound images. The results show successful performance of the novel methods in the sample population for the muscles and tendons chosen. A larger dataset would help to make the developed methods more robust and more widely applicable. Future work should concentrate on using the developed methods of this thesis to evaluate other geometric parameters of the upper and lower extremities such as automatic evaluation of the muscle fascicle length.

Breast cancer is the most common malignant tumour among females world-wide. The complexity of the pathogenesis of the disease and its heterogeneous clinical presentation, with an increasing incidence of the development of chemotherapeutic resistant cases, make its treatment challenging. This report describes the analysis of the role of the catalytic subunit of PP4 (PP4c) in controlling survival and death of breast cancer cells. These investigations suggested that PP4c regulates both apoptosis and proliferation in human breast cancer cells and have shown that the level of PP4c has a strong influence on the cell cycle and on the anchorage-dependent growth of these cells. This wide variety in the functions of PP4 enzyme is likely to be related to its interacting proteins which determine the location and the functions of the PP4 holoenzyme. This work has identified the effects of modulating the expression level of some of the PP4c-regulatory subunits on the function of PP4c in breast cancer cells. This study has also highlighted a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. This study has showed that modulation in the endogenous expression level of PP4c changes the phosphorylation status of important proteins in the Akt-mTOR signalling pathway. Most of these proteins are implicated in the regulation of a variety of cellular functions including cell survival, proliferation, apoptosis and protein translation. Furthermore, this study has revealed important differences between hormone positive and triple negative breast cancer cells in the term of changes in phosphorylation status of some of downstream proteins in the Akt-mTOR pathway as a result of modulating endogenous expression of PP4c. These differences may partly explain the different behaviour of these cell lines and require further investigation in the future which may open up new opportunities for developing therapeutic approaches to breast cancer.

Best available research evidence is essential but not the only type of evidence needed in public health decision making. Decisions are also influenced and must take into account factors other than research evidence. This approach in public health is called evidence-informed public health (EIPH). A fundamental concept of EIPH is to take into account realities of a specific real-world environment when translating research evidence into policy and practice. Therefore approaches to co-creation of best available evidence for decision making - evidence that is informed by best available research evidence but that also incorporates other types of information to address decision makers’ needs - are necessary for knowledge translation in public health. This thesis includes published works which report findings on 1) the use of research and other types of evidence and barriers and facilitators of its use and 2) KT approaches facilitating co-creation of best available evidence in public health policy making and practice. The eight publications included in this thesis studied factors associated with evidence use and present examples of co-creating evidence. The published works on evidence use (Publications 1 and 2) were undertaken using qualitative methods, specifically, content analysis of policy documents and interviews with decision makers within physical activity policy-making. Examples of co-creating evidence to address barriers identified in Publication 2 (such as relevance of research, lack of resources, lack of applicability of research etc.) used the Delphi technique, Population Impact Measure and Coverage with Evidence Development methodologies. They were applied to inform public health policy and practice in areas which include SARS and SARS-like diseases (Publications 3 and 4), rare diseases (Publication 5), cardiovascular diseases, strokes, cancers (Publication 6) and Dupuytren’s disease (Publication 7 and 8). It is essential that approaches supporting the use of research and other types of evidence in public health continue to be developed and documented, and this thesis represents such an endeavour. Usefulness and effectiveness of different KT approaches facilitating evidence use and reduce its barriers must also be continuously evaluated as they are adopted or modified to deal with different issues in different settings. Effective interventions along with strategies facilitating their delivery and implementation can then be utilised by public health professionals and policy makers who wish to promote EIPH.

This study aims to make a sociological contribution to understanding the experience of medical students from graduate-entry medicine degree programmes. In this study, I asked the research question ‘what are the challenges experienced by graduate-entry medicine degree programme students during their transition through medical school training?’ Medical students from the University of Warwick Medical School graduate-entry medicine degree programme were invited to take part in this interview-based study. A volunteer sample of 21 medical students took part in a stage one semi-structured one-to-one interview. Fourteen of 21 medical students took part in a follow-up stage two interview between four to thirteen months later. Their interview transcripts were transcribed verbatim and analysed using thematic analysis. Results showed there were three key transition periods within the University of Warwick Medical School’s graduate-entry medicine degree programme. Medical students encountered a range of challenging issues throughout their medical school journey that could be categorised under three conceptual themes: challenges associated with the curriculum, challenges associated with their social role and generic life challenges. Learning, professional identity development and managing coping strategies were the three key challenging issues dominating their transition experience. These challenging issues were in keeping with my findings from literature review on the medical school experience of undergraduate-entry and graduate-entry students. This study has made one original sociological contribution to understanding the professionalism issue about how medical students manage health advice requests from their family and friends. The findings from this study could be useful to educators and medical schools in enhancing their student support services. It could also be useful to prospective and existing medical students in understanding the realities of undertaking a graduate-entry medicine degree programme.

Internationally, there is an emerging interest in the inadvertent harm caused to patients by the provision of healthcare services. Since the publication of the Institute of Medicine’s report, To Err is Human, in 1999, research and policy directives have predominantly focused on patient safety in hospital settings. More recently, the World Health Organization has highlighted 2-3% of primary care encounters result in a patient safety incident. Given around 330 million general practice consultations occur in the UK each year, unsafe primary care is a poorly understood, major threat to public health. In 2003, a major investment was made in the National Reporting and Learning System to better understand patient safety incidents occurring in England and Wales. Over 40,000 incident reports have arisen from general practice. These have never been systematically analysed, and a key challenge to exploiting these data has been to generate learning from the largely unstructured, free-text descriptions of incidents. My thesis describes the empirical development and application of methods to classify (structure) incident report data. This includes the development of coding frameworks specific to primary care, aligned to the WHO International Classification for Patient Safety, to describe the incident, contributory factors and incident outcomes. I have developed a mixed-methods approach which combines a structured process for coding reports and an exploratory data analysis with subsequent thematic analysis. Analyses of reports can generate hypotheses about priorities for systems improvement in primary care at a local and national level. Existing interventions or initiatives to minimise or mitigate patient safety risks can be identified through scoping reviews. Future research and quality improvement activities should deepen understanding about the risks to patients, and generate knowledge about how interventions made in practice can improve safety.