Approximately 102,000 individuals live with an excretory stoma in the UK. Existing research shows huge variation in how individuals experience living with a new stoma. Previous qualitative research is retrospective or explores this experience for only three months following surgery. A study exploring the experience of living with a stoma over a longer time- frame is needed to expand on existing qualitative research. This study explored individuals' experiences of living with a new stoma, examining experiences of bodily change, health care and time. An existential phenomenological methodology underpinned in-depth interviews with twelve new ostomists conducted post- surgery at three, nine and fifteen months. Individual interviews were conducted with ten healthcare professionals to provide adjunct data. Analysis using a five-staged framework facilitated iterative scrutiny of data, contributing to a universal understanding of the experience. Three themes emerged: changed body, disrupted social world and experiences of healthcare. Stoma formation changed the familiar relationship individuals had with their bodies in terms of appearance, function and sensation, undermining the unity between body and self. Disruption to participants' embodiment within their social worlds impeded social confidence. Building a new sense of embodied self and increasing social confidence were facilitated by regaining physical capacity. mastering stoma function and care and the acceptance and support of others. Exploring how time influences this experience aids understanding of the complex processes of adaptation and self-acceptance for new ostomists. Provision of responsive healthcare helps to establish self-determination, foregrounding adaptation to and acceptance of self with a stoma. This study can contribute to defining a framework of care that assists new ostomists to adapt to and accept a changed sense of embodied self in addition to highlighting to HCPs their own powerful influence in facilitating or hindering this process through their knowledge, experience and underpinning philosophy of care

Intestinal ischaemia-reperfusion (IIR) injury is a life-threatening condition affecting adults and children. Common causes include acute mesenteric ischaemia, volvulus, intussusception, necrotizing enterocolitis, sepsis and trauma. IIR triggers a cascade of inflammatory mediators, increases intestinal permeability and results in local and remote organ damage. The liver is especially prone to IIR-associated dysfunction. Adults and children respond to IIR injury in subtly different ways. This thesis reports an investigation of a rat model of IIR (90 minutes intestinal ischaemia then 60 minutes reperfusion under general anaesthetic) and describes IIR-related changes in the liver, blood composition and gut. Hepatic tissue metabolites were measured after IIR in suckling and adult rats. In both age groups ATP fell and inorganic phosphate (Pi) and alanine rose after IIR. Adult rats had higher levels of total hepatic glutathione, and hepatic glutamine fell after IIR. Hepatic lactate and succinate rose in suckling rats after IIR. Blood composition changed after IIR in adult rats - Pi rose, haematocrit rose, pH fell, and blood oxygen content rose. Systemic, but not portal, arterio-venous difference in oxygen content rose. Hepatic inflow fell with prolonged intestinal reperfusion, which was partially abrogated by whole-body hypothermia (32 0.5 C). Hypothermia also reduced IIR-related changes in blood composition and hepatic tissue metabolites, abolishing the relationship of the latter with final total hepatic inflow. IIR was associated with rises in plasma tumour necrosis factor-alpha, interleukins 6 and 10, and endotoxin. These rises were significantly reduced by hypothermia. Correlation of intestinal arterial inflow and intestinal tissue oxygenation index during IIR demonstrated a complex relationship. In conclusion, IIR perturbs hepatic metabolism, blood composition, hepatic inflow, and plasma cytokine and endotoxin levels. Some of these effects are abrogated by hypothermia. It is possible to follow intestinal tissue oxygenation during IIR with near infra-red spectroscopy. These latter observations may have clinical significance.

Aims and objectives: The aim of this thesis was to investigate the proficiency gain curve and competency in laparoscopic colorectal surgery (LCS) for specialist colorectal surgeons. The objectives were (1) to analyse the shortfalls of proficiency gain curve analysis in LCS, (2) to develop methods to describe proficiency gain and competency in LCS and (3) to analyse proficiency gain and competency within the National Training Programme (NTP). Methods: Objective 1: Two systematic reviews and a meta-analysis of current evidence were performed. Objective 2: Semi-structured interviews and a Delphi method were applied to develop proficiency and competency assessment tools and clinical cases were used for validation. A novel observational clinical human reliability analysis (OCHRA) of clinical cases was developed and evaluated. Objective 3: clinical and educational data from the National Training Programme were used for the analysis of proficiency gain and competency using advanced statistical methods. Results: Using clinical data alone is insufficient for the description of proficiency gain and competency. A generic assessment scale (GAS form) and a competency assessment tool (CAT) were developed and validated. A combination of CAT and OCHRA has been shown to be highly sensitive and specific to determine competency. Analysis of clinical and educational data revealed a shortening of the proficiency gain curve using the approach of the NTP without the risk of increased rates adverse outcomes. Conclusion: Tools for proficiency gain and competency assessment of specialist surgeons have been shown to be valid and feasible and are fully implemented in the NTP. Data suggest that a novel technique can be introduced to specialists on a National level using a structured educational approach with safe clinical outcomes.

Les mutations du gène codant pour la protéine XIAP (X-Linked Inhibitor of Apoptosis Protein) sont à l’origine du syndrome lymphoprolifératif lié à l’X de type 2 (XLP-2). Il s’agit d’un déficit immunitaire rare caractérisé par une susceptibilité anormale à l’infection par le virus d’Epstein Barr (EBV). De plus, certains patients déficients en XIAP peuvent souffrir d’une pathologie intestinale parfois sévère. XIAP est molécule anti-apoptique qui a aussi été impliquée dans la signalisation et les fonctions de récepteurs de l’immunité innée, les récepteurs NOD1 et NOD2. Mon travail de thèse a eu pour objectif de caractériser cette pathologie intestinale et ses mécanismes physiopathologiques. Pour cela, nous avons étudié une cohorte de patients déficients en XIAP présentant une pathologie inflammatoire intestinale. Nous avons également recherché des mutations de XIAP dans une cohorte d’enfants ayant présenté comme unique signe clinique une pathologie intestinale précoce. Sur 83 patients testés, 3 patients porteurs de mutations de XIAP ont été identifiés. Nous avons ensuite montré que cette pathologie intestinale est très proche sur les plans clinique et histologique de la maladie de Crohn, qui est une des principales affections inflammatoires de l’intestin chez l’adulte. La maladie de Crohn est associée à des facteurs environnementaux et une susceptibilité génétique, dont les polymorphismes dans le gène NOD2 qui représentent le facteur plus important identifié à ce jour. Nous avons ensuite montré que les monocytes des patients déficients en XIAP ont un défaut de production d’IL-8, de MCP-1 et d’IL-10 en réponse à la stimulation de la voie NOD2. Par contre, nous n’avons pas mis en évidence d’excès d’apoptose des cellules épithéliales digestives chez les patients. En revanche, ils présentaient un nombre diminué de leur lymphocytes T innés circulants, Enfin, au cours de cette étude, nous avons identifié pour la première fois des femmes vectrices d’une mutation de XIAP à l’état hétérozygote, ayant développé des manifestations inflammatoires intestinales. Chez ces patientes, l’inactivation du chromosome X, qui normalement est biaisée en faveur de l’allèle sain chez les vectrices asymptomatiques, est de façon inhabituelle biaisée vers l’allèle muté contribuant à une diminution de l’expression de XIAP dans les monocytes et une altération de la voie NOD2. Ce travail a permis de montrer que le déficit en XIAP est responsable d’une forme monogénique de la maladie de Crohn. Nos résultats suggèrent que le défaut d’activation des monocytes par NOD2 est un mécanisme important de la pathogénèse de la maladie. Sur le plan thérapeutique, la greffe de moelle osseuse semble indiquée dans les formes sévères, puisque le principal défaut identifié est une anomalie du compartiment hématopoïétique, et chez deux de nos patients, elle a permis en effet une amélioration franche de la pathologie digestive qui était très sévère. / Mutations in the gene encoding for XIAP (X-Linked Inhibitor of Apoptosis Protein) are causing the X-linked lymphoproliferative syndrome type 2 (XLP-2). It is a rare immunodeficiency characterized by an abnormal susceptibility to infection with Epstein Barr virus (EBV). In addition, some XIAP-deficient patients may suffer from an intestinal disease that can be severe. XIAP is an anti-apoptotic molecule which has also been involved in the signaling and the functions of receptors of the innate immunity, NOD1 and NOD2. My thesis work aimed to characterize this intestinal pathology and its pathophysiology. For this, we studied a cohort of known XIAP-deficient patients with inflammatory bowel disease. We also looked for mutations of XIAP in a cohort of children who presented as the only clinical sign an early intestinal pathology. In 83 patients tested, three were identified as carrier of a XIAP mutation. We then showed that this intestinal pathology is clinically and histologically very close to Crohn’s disease, which is a major inflammatory bowel disease in adults. Crohn's disease is associated with environmental factors and genetic susceptibility, including polymorphisms in the NOD2 gene that represent the most important factor identified to date. We then showed that the monocytes from XIAP-deficient patients have a defect in production of IL-8, MCP-1 and IL-10 in response to stimulation of the NOD2 pathway. However, we did not reveal any excess of apoptosis in intestinal epithelial cells from XIAP-deficient patients. On the other hand, they showed a decreased number of their circulating innate T cells. Finally, during this study, we identified for the first time, female carriers of a mutation of XIAP in the heterozygous state, who developed intestinal inflammatory manifestations. In these patients, the inactivation of the X chromosome, which is normally biased toward the healthy allele in asymptomatic vectors, is biased to the unusually mutated allele contributing to a decrease of the expression of XIAP in monocytes and an alteration of the NOD2 pathway. This work showed that XIAP deficiency is responsible for a monogenic form of Crohn's disease. Our results suggest that the lack of monocyte activation by NOD2 is an important mechanism in the pathogenesis of the disease. Therapeutically, the bone marrow transplant seems indicated in severe cases, since the main identified defect is an abnormality of the hematopoietic compartment and in two of our patients, it allowed a clear improvement of the digestive pathology that was very severe.