The changes in light interaction between healthy and diseased tissues have been investigated as a potential diagnostic application. Here we attempt to differentiate between healthy and pathological gastrointestinal tissues using quantitative analysis of optical coherence tomography (OCT) data and goniophotometry. A goniophotometer was constructed and calibrated using titanium oxide and microsphere phantoms. Measurements were carried out on human gastrointestinal tissue sections collected using the methodology described below. The anisotropy factor g was extracted from the scattering curves by fitting the Henyey-Greenstein function. Measurements on human samples were in the forward scattering range with g 0.6-0.7, in agreement with the literature. Optical coherence tomography imaging was carried out on gastrointestinal tissues collected from patients undergoing elective surgery or endoscopy at St. Mary's Hospital, London. In total 146 patients were included. Data was processed using gradient analysis of signal attenuation and morphological analysis with kNN classification. Results were correlated with histological diagnoses. Gradient analysis results were statistically significant across most categories, showing particularly good differences in the gradient distributions between healthy and diseased oesophageal tissues. Morphological analysis and kNN classification produced sensitivity and specificity values for healthy oesophagus and cancer in surgical specimens reaching 100%/97.87% and 99.99%/99.91% respectively and high accuracy in detecting Barrett's oesophagus in endoscopic specimens, with sensitivity and specificity values of 99.80% and 99.02%. Results in rectal tissue where also noteworthy, with detection of dysplasia reaching a sensitivity and specificity of 99.55%/96.01%. Despite limitations in our work, we have shown that the detection of gastrointestinal pathologies using quantitative analysis of OCT data is a promising technique with good ex vivo results. Transferring the methodology to the in vivo domain holds a lot of potential as a future quick and reliable diagnostic technique.

The Ikaros family of zinc finger transcription factors is essential for B cell development, and frequently mutated in B cell malignancies. Our lab has previously identified Ikaros target genes in pre-B cells by combining Ikaros ChIP-seq binding data and gene expression profiling. To address the kinetics and mechanisms of Ikaros-mediated transcriptional regulation, I have used an inducible Ikaros system, which allows for the monitoring of cellular and molecular changes during Ikaros-mediated gene silencing at high temporal resolution. Within minutes of Ikaros induction, the Ikaros-regulated model loci Igll1 and Myc showed decreased promoter accessibility and RNA polymerase II (RNAPII) occupancy. These early events were followed by changes in nucleosome composition, including an increased histone H2B/H3 ratio, the deposition of the histone variant H2A.Z, and decreased active histone acetylation marks. Histone deacetylation was not required to initiate down-regulation of Igll1 and Myc transcription, since treatment with the histone deacetylase inhibitor Trichostatin A did not interfere with Ikaros-mediated gene silencing. I next elucidated the mechanistic relationship between the early events of decreased promoter accessibility and decreased RNAPII occupancy. Addition of Triptolide resulted in the removal of RNAPII from the Igll1 and Myc promoters, but did not affect nucleosome occupancy and its regulation mediated by Ikaros. This suggested that Ikaros regulates nucleosome positioning and occupancy directly, and not through effects on RNAPII. Consistent with this hypothesis, Ikaros-mediated gene silencing was delayed by RNAi-mediated knockdown of chromatin remodeler Mi-2β (Chd4), the ATPase subunit of the Mi-2/NuRD complex. Hence, Ikaros-initiated chromatin remodelling was identified as one of the earliest events during Ikaros-mediated gene silencing, and was required for rapid transcriptional down-regulation of Ikaros target genes.

End-stage osteoarthritis of the hip can be treated effectively with hip replacement. Many implant brands are available with multiple component options including different methods of fixation, femoral head size and articulating surface materials. The costs of these implant components vary dramatically. Surgical outcome can be assessed variously by functional and quality of life scores, risk of failure over time requiring revision surgery, post-operative mortality and complications (such as wound infections), and readmission to hospital. Patient expectation, perception of success and the satisfaction with surgery are also important metrics. Surgeon and patient characteristics may influence these outcomes. Health systems under considerable financial pressure are confronted with an aging population with increasing need for joint replacement surgery. In response, efficient, rationalised provision of services is required. The most cost-effective procedures combine the best implant survival rates (and hence the fewest revisions) and patient outcomes with the lowest mortality, complications and costs. To establish the benefits and relative performance of different hip implants, large patient numbers and long term follow-up are required, limiting the use of experimental studies. Joint registries and other large collections of data play a pivotal role in providing evidence of efficacy, although careful statistical analysis is required to ensure findings are robust. Through a series of examples, this thesis illustrates the potential of such analyses to appropriately inform patient care and explores the issues surrounding the use of these large datasets. Despite a global trend favouring cementless implants, hard bearings and larger head sizes, a cemented hip replacement with a taper slip stem, a metal-on-polyethylene bearing and a 28mm head offers equivalent or better outcomes for the vast majority of patients. Cost data from the NHS suggest these implants are also the cheapest to purchase. Young females have marginally better functional outcomes following cementless or hybrid replacement, but clinically this may not be important, and costs are higher. Standardisation of hip replacement type across all patients is likely to improve outcome, reduce error and enhance training. The posterior approach provides a marginally better functional outcome compared with the direct lateral approach. Patients with a high BMI have greater risks of complications with only slightly poorer improvement in function. Implant characteristics appear to have little or no influence on patient outcomes. Interpretation of outcome measures is complex, requiring a greater understanding of the interactions between surgical and patient factors. This thesis provides evidence to inform decision-making by surgeons, professional bodies and healthcare providers when offering hip replacement to patients with osteoarthritis.

This thesis aimed to contribute to current understanding of ‘intervention-generated inequalities’, that is, the concern that processes in the planning or delivery of an intervention may create or exacerbate the health differences between population groups. This was done by examining the impact of secondary and tertiary preventive interventions for type 2 diabetes by socio-economic status (SES). Previous research has shown that the condition places a disproportionate burden on individuals from disadvantaged backgrounds. It addition, managing the condition involves a range of health care; all potentially exacerbating existing health inequalities. A systematic review was conducted and secondary data analyses of patient data collected by a hospital diabetes register. The Index of Multiple Deprivation 2004 was used as an indicator of patients’ SES. Multilevel models were fitted using repeated measurements, with patients nested within general practices. Interaction effects were used to determine inequalities over time and if interventions were associated with differential health outcomes by SES. The multilevel analyses showed that high SES patients were more likely to have lower blood glucose over time, but higher levels of cholesterol compared to low SES patients. In contrast, there were few differences in long-term health complications by SES over time. High SES patients were more likely to receive higher quality of care and shared care than low SES patients over time. Furthermore, there significant inequalities in health by SES were found in patients receiving the same care. There were also significant inequalities in prescriptions for treatments, conditional on other relevant covariates. The results in thesis indicate that there were intervention generated inequalities which are particularly important for practitioners. As these were either a result of interventions not being appropriately accessed and/or administered based on need or the efficacy of these interventions differed by SES. Further analyses are needed to unpick the direction of these associations.

The early diagnosis of cancer is a priority within the UK, with GPs being identified as playing a key role. The aim of this research was to look at the relationship between GP practice quality and cancer stage at diagnosis, for breast and colorectal cancer, within the North East of England. This was done by utilising existing healthcare databases, with data being obtained from the National Health Service (NHS) information centre, public health observatories and Northern and Yorkshire Cancer Registry and Information Service. Patient data was from between 2006-2008 with n = 13,610 cases of breast cancer and n = 11,606 cases of colorectal cancer. The data was combined and a range of analyses conducted to investigate the potential relationship between GP practice quality and a patient’s cancer stage at diagnosis. For breast cancer there was a significant relationship between GP practice quality and cancer stage in both multi-level and base outcome regression analyses. A range of specific variables, many of which were related to patient experience, were found to have a significant effect upon breast cancer stage. Patient age and level of income were also found to have a significant effect upon breast cancer stage. For colorectal cancer no association was found in multi-level analysis but a significant association was found between cancer stage and variables related to patient experience, such as a patient’s ability to see a doctor within two days. Patients of working age (18-64) compared to retirement age (65+), were found to be more likely to have a more advanced cancer stage at diagnosis, as were patients with low income. In summary, significant associations were found between measures of GP practice quality and patient cancer stage at diagnosis, specifically GP variables related to patient experience. This association suggests that higher quality of practice may increase the likelihood of being diagnosed with earlier stage of cancer. The limitations of this research are highlighted and directions for future research projects and healthcare policy are discussed and outlined.

Introduction: Adenoma detection rate (ADR) is an established quality marker in colonoscopy. Significant variability in ADR exists. Withdrawal time of ≥ 6 minutes; Buscopan use; position change and rectal retroflexion have been shown to improve lesion detection. We evaluated the feasibility and clinical outcome of implementing these measures, as a ‘bundle’, into routine practice to improve ADR. Factors influencing uptake were evaluated in a qualitative study. Methodology: Twelve units participated. All nominated a lead colonoscopist and nurse. Implementation combined central training, local leadership, feedback and continuous central support. The 3 months prior to implementation was compared to a 9 month period after. Colonoscopists performing ≥ 25 procedures during the baseline period were ranked in quartiles by ADR. Buscopan use was used as a surrogate marker for uptake. Changes were evaluated using a corrected Chi Squared test. For the qualitative study, units and individuals were purposively sampled to ensure a range of units were included. Semi-structured interviews were conducted until saturation was reached. Data were evaluated using thematic analysis. Results Global and quartile analyses comprised data from 118 and 68 colonoscopists performing 17, 508 and 14,193 procedures respectively. There was a significant increase in Buscopan use globally (15.8% vs. 54.4%, p<0.001) and in each quartile. The ADR also increased significantly globally (16.0% vs. 18.1%, p=0.002), with a significant reduction in variation. Interviews were conducted with 8 lead and 3 non-lead colonoscopists and 1 lead nurse. Increased emphasis on examination time, awareness of ADR as a quality marker and empowerment of endoscopy nurses to encourage the use of quality measures were positive outcomes of the intervention. Challenges included difficulty in arranging set up meetings and engaging certain speciality groups. Discussion: This evidence based educational intervention resulted in a significant change in behaviour, evidenced by increased Buscopan use. A significant increase in the global ADR and reduction in variation between quartiles was observed. Other positive outcomes included increased awareness of colonoscopy quality and empowerment of endoscopy nurses to promote quality measures. This study demonstrates that simple interventions can significantly change practice and improve quality. The timing of meetings and strategies to engage speciality groups are important.

Background There are national UK general practitioner (GP) shortages, particularly in deprived areas, and an insufficient number of medical students intend to become GPs. Medical students currently have limited exposure to settings which provide care for deprived communities. This research investigates student learning during the Difficult and Deprived Areas Programme (DDAP), an innovative pilot programme which places fourth year students in general practice and community placements in under-served, post-industrial, deprived areas for 14 weeks. Method A systematic review investigating the efficacy of undergraduate community placements in under-served areas was completed. A qualitative approach was used collecting data from: DDAP students (n=9) before, during, and end of placement; GP supervisors (n=14), and patients (n=12). Comparison data was collected from peers taking alternative placements to the DDAP (n=16) and students taking an established rural programme (n=6). Semi-structured interviews were conducted to collect data. Data were analysed using framework analysis and the Experience Based Learning theory. Findings In total, 85 interviews were conducted over a two and a half year period. The DDAP experience enhanced student knowledge about psychosocial determinants of health, developed compassion, and reinforced clinical skills. Learning was facilitated through independent time with patients, which promoted deeper learning about the role of the doctor. The integrated and immersive DDAP structure gave students an understanding of delivering healthcare for patients with complex deprivation issues. Comparative placement experiences highlighted the importance of having a nurturing supportive supervisor and having an active role delivering healthcare within a community team. Conclusions There is increasing evidence on the value and importance of clinical placements in rural and remote communities, but little in regard to other under-served, deprived areas. This research explored medical student learning during an innovative placement in such a setting. The thesis provides evidence of the value of these placements and puts forward a model explaining why these placements are effective, and why they may help to create better doctors for the future.

A mixed-methods non-participant evaluation of an integrated care pathway for adult inflammatory bowel disease patients in a North East of England health economy was undertaken utilising a realist evaluation framework. The evaluation commenced at an early stage in the pathway’s life in October 2009 and closed two and a half years later in March 2012. The evaluation identified internal and external enablers and inhibitors to the pathway, primarily in the design and implementation phases as opposed to the operational phase. Inferences were made to contemporaneous evaluations of integrated care projects which served to validate this evaluation and identify the additional value of the evaluation to the health services research field. Contextual enabling and inhibiting factors were identified along with their associated mechanisms and actual or potential outcomes. An additional pilot project identified the scope for, and potential nature of, a role for community pharmacy in the management of adult IBD patients.

This thesis is focused on identifying current practices in the management of large non pedunculated colorectal polyps (LNPCPs) and the development of a structured management framework to improve outcomes. The methodology used includes a systematic review to ascertain current knowledge and retrospective quantitative analysis to identify current LNPCP management outcomes. The English Bowel Cancer Screening Programme (BCSP) which has a high volume of recorded LNPCP data was used to facilitate the latter process. In addition, qualitative analysis using consensus methodology to create best practice guidelines, key performance indicators (KPIs) to audit LNPCP outcomes and a complex polyp multidisciplinary team process was undertaken. The main outcomes of this thesis were: 1. Confirmation of variation in LNPCP management practices leading to variable outcomes 2. Formulation of evidence based and expert consensus LNPCP management guidelines 3. Identification of KPIs to allow audit of LNPCP management and outcomes 4. Identification of pertinent research questions to improve evidence LNPCP base 5. Development and pilot of regional complex polyp multidisciplinary team meeting.

Background Decommodification is the extent to which living standard is independent of market position. In recent decades, some states have embarked on a process of recommodification, restricting the alternatives to participating in the market. This study has investigated how recommodification of unemployment healthcare and pensions are correlated with health inequalities. Methods Using Health Survey for England and the Swedish Living Conditions Survey, this study computes the magnitude of health inequalities in Sweden and England and correlates the magnitude of inequalities with measures of recommodification. In stage 1, the odds ratio of Not good health/having visited a doctor was computed using logistic regression for each year, using the employed and the high educated as the reference categories. In stage 2, the log (odds ratios) of poor health or doctor visits computed in stage 1 were correlated with the net replacement rate/price of primary care using linear regression. Results Health inequalities between the employed and the unemployed were significantly higher in both England and Sweden in 2011 than in 1991, a period during which unemployment benefit was recommodified in both countries. The association between health inequality and net replacement rate was much stronger in Sweden. Health inequalities increased slightly among English pensioners, while those of the Swedish sample remained steady. This is not what we would expect from the development of recommodification in the two countries: Sweden recommodified while England did not. 3 For groups with similar needs, the higher educated are more likely to seek healthcare. There were no trends in inequality in access to healthcare in Sweden. Conclusion This study has shown that recommodification is associated with health inequalities, especially in Sweden, and that inequalities in replacement rates are associated with health. However, the links between recommodification and health are context-dependent.