Obsessive-compulsive disorder (OCD), with a prevalence of 1-2 %, frequently leads a chronic course. Persons with OCD are often reluctant to seek help and, if they do, their OCD is often missed. This is unfortunate, since active treatment may substantially improve social function and quality of life. Serotonin reuptake inhibitors (SRIs) have welldocumented efficacy in OCD, but delayed response may be problematic. Methods to predict response have been lacking. Because SRIs are effective, pathophysiological research on OCD has focussed on serotonin. However, no clear aberrations of serotonin have been found, thus other mechanisms ought to be involved. Our aims were to facilitate clinical detection and assessment of OCD, to search for biochemical correlates of response and side-effects in SRI treatment of OCD and to identify any possible involvement of oxytocin in the pathophysiology of OCD. In study I, we tested in 402 psychiatric out-patients the psychometric properties of a concise rating scale, “Brief Obsessive Compulsive Scale” (BOCS). BOCS was shown to be easy to use and have excellent discriminant validity in relation to other common psychiatric diagnoses. Studies II-V were based on 36 OCD patients from a randomised controlled trial of paroxetine, clomipramine or placebo. In study II, contrary to expectation, we found that the change (decrease) of serotonin in whole blood was most pronounced in non-responders to SRI. This is likely to reflect inflammatory influence on platelet turnover rather than serotonergic processes within the central nervous system. In studies IV-V, we found relations between changes of oxytocin in plasma and the anti-obsessive response, and between oxytocin and the SRI related delay of orgasm, respectively. In both cases, the relation to central oxytocinergic mechanisms is unclear. In males, delayed orgasm predicted anti-obsessive response.

Contexte : Actuellement en France, le taux de participation au dépistage organisé du cancer colorectal (CCR) reste nettement inférieur aux recommandations européennes et ce, malgré l’implication des médecins généralistes.Objectifs : L’objectif général de ce travail de thèse était d’évaluer les pratiques des médecins généralistes en matière de dépistage organisé du CCR, de comprendre les freins au dépistage et d’évaluer les stratégies permettant d’améliorer la participation des patients à ce dépistage.Méthode : Nos travaux se sont appuyés sur les données du programme de dépistage organisé dans le Val-de-Marne. Nous avons reconstitué une cohorte historique de 157 979 patients suivis par 961 médecins généralistes, mené une recherche-action auprès de 21 médecins volontaires et réalisé un essai contrôlé randomisé en grappes incluant 144 médecins et 20 778 patients.Résultats : Une faible part de la variabilité de la probabilité de participation était attribuable à l’hétérogénéité entre médecins (coefficient de corrélation intra-classe, 5,5%). La participation au dépistage était moindre chez les hommes (odds ratio [OR], 0,79 ; IC 95%, 0,78–0,91), les jeunes (50–54 ans, OR, 0.61 ; IC 95%, 0.58–0.63 ; 55–59 ans, OR, 0.76 ; IC 95%, 0.73–0.80) ou les résidents des zones les plus défavorisées (OR, 0.82 ; IC 95%, 0.77–0.87).Nous avons identifiés 7 exigences essentielles pour l'activité de dépistage organisé du cancer colorectal par le médecin généraliste : Être proactif, Être un partenaire, Prendre en compte l’entourage, Se positionner comme expert du problème, Gérer le temps de manière efficiente, Expliquer la réalisation du test et Aider la réalisation du test. Pour chacune, nous avons pu identifier des techniques utilisables en situation de pratique clinique.Les rappels systématiques adressés par voie postale aux médecins généralistes comportant la liste mise à jour de leurs patients éligibles au dépistage n'ont pas augmenté de manière significative la participation des patients au dépistage après prise en compte de l’effet grappe (analyse multiniveau).Conclusions : Des actions ciblées vers les patients les plus jeunes, les hommes et les résidents des zones géographiques les plus défavorisées devraient être encouragées afin de réduire les disparités observées et améliorer l’efficacité globale du programme de dépistage. Des actions sur l'ensemble des médecins généralistes doivent être envisagées : mettre l'approche centrée sur le patient et la pratique réflexive au cœur du projet de formation initiale et continue, et proposer des recommandations de pratique basées sur les données issues de la pratique. / Background: Currently in France, participation rate in organised colorectal cancer (CRC) screening remains well below European guidelines, despite general practitioners involvement.Objectives: The overall objective of this thesis was to assess general practitioners practices in organized CRC screening, to understand barriers to screening participation and to assess strategies to improve patient participation to screening.Methods: Our work was based on data from the organised screening programme in the Val-de-Marne district. We conducted a retrospective cohort of 157 979 patients followed by 961 general practitioners, an action research among 21 volunteer general practitioners and a cluster-randomized controlled trial including 144 general practitioners and 20,778 patients.Results: A small part of the variability of the likelihood of participation was due to the heterogeneity among physicians (intraclass correlation coefficient, 5.5%). Screening participation was significantly lower in males (odds ratio [OR], 0.79; 95% CI, 0.78 to 0.91), the youngest age group (50-54 years, OR, 0.61; 95% CI, 0.58 -0.63; 55-59 years, OR, 0.76; 95% CI, 0.73-0.80) and patients living in socioeconomically deprived areas (OR, 0.82; 95% CI, 0.77-0.87).We have identified seven essential requirements for general practitioners when screening for CRC: Be proactive, Be partners in care, Take into consideration the patient's family and friends, Position themselves as the expert, Manage time efficiently, Explain the test procedure and Help carry out the test. We were able to identify techniques used for each requirement.Systematic reminders sent by post to general practitioners with the updated list of eligible patients for screening did not significantly improve patient participation to organised CRC screening after taking clustering into account (multilevel analysis).Conclusions: Targeted actions to improve CRC screening participation should focus on patients younger than 60 years, males, and individuals living in deprived areas. Actions to enhance the influence of general practitioners on patient participation should be directed to the overall population of general practitioners. Patient-centred care and reflective practice should be at the heart of initial and continuing medical education, and guidelines based on practice data should be proposed.

No / Objective To compare the incidence of treatment-related complications, including lymphoedema, after two programmes of shoulder mobilisation in women with invasive breast cancer when surgical treatment included axillary lymph node dissection. Design Randomised controlled trial. Setting Two secondary care National Health Service trusts. Participants One hundred and sixteen women (mean age 57 years, standard deviation 13.1 years) recruited from November 2003 to March 2006 (58 intervention group, 58 control group). Seven patients (6%) did not complete the study. Intervention Arm exercises and shoulder movement restricted to below shoulder level for the first 7 days after surgery. Controls commenced an exercise programme that incorporated exercises above shoulder level within 48 hours. Outcome measures All outcomes were recorded at baseline (pre-operatively) and at 1 year. The primary outcome was incidence of lymphoedema, defined by a limb volume difference of 200 ml or more compared with the contralateral arm. This outcome was measured using volume displacement. Secondary outcome measures included volume differences between the two limbs measured by actual volume displacement difference, wound drainage volumes, range of shoulder movement (manual goniometer), grip strength (hand-held dynamometer) and health-related quality of life (Shoulder Disability Questionnaire, Functional Assessment of Cancer Therapy – Breast). Results All statistical tests were two-sided. Data were analysed using intention-to-treat principles. The incidence of lymphoedema (200 ml or more) increased significantly in women who had undertaken a programme of early full shoulder mobilisation. Twenty-two women (19%) developed lymphoedema (200 ml or more) in their first postoperative year. There were significantly more women with lymphoedema in the early full shoulder mobilisation group (n = 16) compared with the delayed full shoulder mobilisation group (n = 6). The relative risk of developing lymphoedema after early mobilisation was 2.7 (95% confidence interval 1.1 to 6.3; P = 0.031). Limb volume differences were significantly higher in the early mobilisation group. This was apparent in differences in limb volume displacement (P = 0.004) and percentage difference between the two limbs (P = 0.007). There were no statistically significant differences in shoulder movement, grip strength or self-evaluated outcomes between the two groups at 1 year. Conclusion A programme of exercise that delays full shoulder mobilisation for 1 week is recommended after axillary node dissection for invasive breast cancer.

Yes / Abstract Objective Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22). Design A randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry. Results Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects. Conclusion Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure. / NIHR/EME Yorkshire Cancer Research (YCR)

No / The European RHAPSODY project sought to develop and test an online information and support programme for caregivers of individuals diagnosed with young onset dementia. The objectives were to assess user acceptability and satisfaction with the programme and to test outcome measures for a larger effectiveness study. DESIGN: A pilot randomised controlled trial in England, France, and Germany was conducted with 61 caregivers for adults with young onset Alzheimer's disease or frontotemporal degeneration. Evaluations at baseline, week 6, and week 12 assessed user acceptability and satisfaction. Use of the programme was measured from online back-end data. Qualitative feedback on user experiences was collected via semi-structured interviews. Measures of caregiver well-being (self-efficacy, stress, burden, frequency of patient symptoms, and caregiver reactions) were explored for use in a subsequent trial. RESULTS: Participants logged in online on average once a week over a 6-week period, consulting approximately 31% of programme content. Seventy percent of participants described the programme as useful and easy to use. Eighty-five percent expressed intent to use the resource in the future. Reductions in reported levels of stress and caregivers' negative reactions to memory symptoms were observed following use of the programme. CONCLUSIONS: Results indicated that the RHAPSODY programme was acceptable and useful to caregivers. The programme may be complementary to existing services in responding to the specific needs of families affected by young onset dementia. Distribution of the programme is underway in England, France, Germany, and Portugal.

Many Low and Middle Income Countries (LAMICs) still lack sufficient health research capacity to build a local evidence-base with which to inform policy and improve population health. Recognising this, The 2013 World Health Report called for all nations to be producers of health research. To achieve this, new strategies that can develop sustainable locally-led capacity are required. Among the health research capacities needed, ability to conduct clinical trials is important. However, there is no evidence-informed guidance on the best ways to develop locally-led trial capacity. This thesis aims to fill this gap. Three cases-studies using qualitative methods to explore the barriers and enablers to locally-led trial conduct were conducted in Ethiopia, Cameroon and Sri Lanka. Current and potential local trial researchers and health research system stakeholders were recruited. A synthesis of the health research capacity development literature was conducted to compare the case-studies’ findings with wider published perspectives. These data permit an examination of the key issues facing the development of locally-led trial capacity in LAMICs. Barriers and enablers to locally-led trial conduct were found at macro, institutional and individual levels. Although different country research systems, and institutions and individuals within them, were variably successful at conducting trials, the key issues and mechanisms influencing successful trial undertaking were largely similar. Agreement among the case-studies and with the diverse literature suggests that many of the findings will be transferable to other LAMICs, and are also of relevance to other health research methods. A conceptual framework explaining the antecedents and consequences of locally-led trial undertaking in LAMICS is presented. This identifies the following factors as important for supporting locally-led trial undertaking: awareness and appreciation for health research and clinical trials; motivation to conduct clinical trials; availability of human resources with trial knowledge and technical skills; research leadership capabilities; ability to form collaborations, effective teams and acquire resources; trial management dedicated to sustainable capacity development and producing useful research; and system-wide prioritisation of health research. The theories of change presented within this framework are used to develop practical recommendations for development of locally-led trial capacity in LAMICs. These recommendations have four inter-related goals: fostering pro-research cultures in stakeholder institutions; developing trial leaders and staff; providing a facilitative operational environment for trials; and ensuring trial research has an impact. However, to create the will to enact change, advocacy from research champions and conducting trials in a way that benefits local institutions and population health is needed.

I performed two randomised controlled trials (RCTs) to determine the best treatments for enteric fever in Kathmandu, Nepal, an area with a high proportion of nalidixic acid resistant S. Typhi and S. Paratyphi A isolates. I recruited 844 patients with suspected enteric fever to compare chloramphenicol versus gatifloxacin. 352 patients were culture confirmed. 14/175 patients treated with chloramphenicol and 12/177 patients treated with gatifloxacin experienced treatment failure (HR=0.86 (95% CI 0.40 to 1.86), p=0.70). The median times to fever clearance were 3.95 and 3.90 days, respectively (HR=1.06 [CI 0.86 to 1.32], p=0.59). The second RCT compared ofloxacin versus gatifloxacin and recruited 627 patients. Of the 170 patients infected with nalidixic acid resistant strains, the number of patients with treatment failure was 6/83 in the ofloxacin group and 5/87 in the gatifloxacin group (Hazard Ratio, HR=0.81, 95% CI 0.25 to 2.65; p=0.73); the median times to fever clearance were 4.7 and 3.3 days respectively (HR=1.59 [CI 1.16 to 2.18], p=0.004). I compared conventional blood culture against an electricity free culture approach. 66 of 304 patients with suspected enteric fever were positive for S. Typhi or S. Paratyphi A, 55 (85%) isolates were identified by the conventional blood culture and 60 (92%) isolates were identified by the experimental method. The percentages of positive and negative agreement for diagnosis of enteric fever were 90.9% and 96.0%, respectively. This electricity free blood culture system may have utility in resource-limited settings or potentially in disaster relief and refugee camps. I performed a literature review of RCTs of enteric fever which showed that trial design varied greatly. I was interested in the perspective of patients and what they regarded as cure. 1,481 patients were interviewed at the start of treatment, 860 (58%) reported that the resolution of fever would mean cure to them. At the completion of treatment, 877/1,448 (60.6%) reported that they felt cured when fever was completely gone. We suggest that fever clearance time is the best surrogate for clinical cure in patients with enteric fever and should be used as the primary outcome in future RCTs for the treatment of enteric fever.

Objectifs: Observer l’évolution de la stomatite prothétique dans le temps quant à la fréquence et la sévérité ainsi que son association avec de potentiels facteurs de risque au cours d’un suivi longitudinal de 2 ans. Matériels et méthodes : Cent trente-cinq patients âgés complètement édentés et en bonne santé ont été sélectionnés pour participer à cette étude et ont été divisés de façon randomisée en deux groupes. Ils ont tous reçu une prothèse dentaire amovible totale conventionnelle au maxillaire supérieur. La moitié d’entre eux a reçu une prothèse totale mandibulaire implanto-portée retenue par deux attachements boule et l’autre moitié une prothèse conventionnelle. Ils ont été suivis sur une période de deux ans. Les données sociodémographiques, d’habitudes de vie, d’hygiène et de satisfaction des prothèses ont été amassées à l’aide de questionnaires. Les patients ont aussi subi un examen oral complet lors duquel une évaluation de la stomatite prothétique, basée sur la classification de Newton, a été effectuée ainsi qu’un prélèvement de la plaque prothétique. Les analyses microbiologiques pertinentes afin de détecter la présence de Candida ont ensuite été effectuées. Des tests Chi-carré de Pearson et McNemar ont été utilisés pour analyser la fréquence de la stomatite, son association avec de possibles facteurs de risque ainsi que son évolution dans le temps. Des rapports de cotes (odds ratio) et leurs intervalles de confiance (95%) ont été effectués afin de déterminer la force d’association entre les facteurs de risque et la stomatite prothétique. Résultats : La prévalence de la stomatite a augmenté entre la première (63,6%) et la deuxième année de suivi (88,7%) avec une incidence de 78,8%. Les patients souffrant d’une stomatite de type 2 ou 3 et qui brossent leur palais ont environ 6 fois plus de chance de voir la sévérité de leur stomatite diminuer [p = 0,04 OR 5,88 CI (1,1-32,2)]. Il n’y a pas d’association statistiquement significative entre la fréquence de la stomatite et les facteurs de risque investigués. La prévalence de la candidose est demeurée stable dans le temps (45,8% et 49,2% à la première et deuxième année de suivi respectivement, p > 0,05). Il n’y a pas d’association entre la présence d’une candidose orale, la stomatite prothétique et les facteurs de risque étudiés. Conclusion : Les résultats de cette étude suggèrent que la stomatite prothétique progresse dans le temps indépendamment de la présence d’une candidose. Le brossage du palais pourrait être une approche simple à conseiller aux patients souffrant d’une stomatite prothétique de type 2 ou 3. / Objectives: To assess the evolution of denture stomatitis in term of frequency and severity and its association with potential risk factors over a two-year period. Methods: One hundred thirty five healthy edentulous elders who were randomly rehabilitated with a maxillary complete denture opposed by a conventional denture or an implant-supported overdenture retained by two ball attachments were followed over two years. Demographic and clinical data concerning oral and general health, smoking, denture status and hygienic habits were obtained from oral examination and standard questionnaires. Denture stomatitis was evaluated according to Newton’s classification. Microbiological analyses consist of detection of Candida species in denture plaque and inoculation in selective growth medium. Pearson Chi-square and McNemar tests were used to analyse the frequency of denture stomatitis, its association with potential risk factors and it’s evolution over time. Odds ratios and their 95% confidence intervals were calculated to determine the strength of association between risk factors and denture stomatitis. Results: The prevalence of denture stomatitis increased between the first (63.6%) and second year follow-up (88.7%) with an incidence rate of 78.8%. Those individuals suffering from type 2 or type 3 denture stomatitis and who brushed their palate had approximately 6 times more chance of observing a decrease in the severity of their condition [p=0.04 OR 5.88 CI (1.1-32.2)]. There was no statistically significant association between the frequency of denture stomatitis and classical risk factors at both follow-ups. The carriage rate of Candida species remained stable over time (45.8% and 49.2% first and second year of follow-up consecutively, p > 0.05). There was no association between the presence of oral candidiosis and denture stomatitis or its potential risk factors. Conclusion: The results of this study suggest that denture stomatitis progresses overtime independent of Candida carriage. Palatal brushing could be a preventive approach to minimise the inflammation in individuals suffering from type 2 or type 3 denture stomatitis.

<b>Background:</b> Defined by their mechanisms, social and psychological interventions are those interventions that work through mental processes and social phenomena. They are often complex and challenging to evaluate, so understanding randomised controlled trials (RCTs) of these interventions requires detailed reports of the interventions tested and the methods used to assess them. However, reports of these RCTs often omit important information. Poor reporting hinders critical appraisal and synthesis of RCTs in systematic reviews, thereby impeding the effective transfer of research evidence to policy and practice. The Consolidated Standards for Reporting Trials (CONSORT) Statement is a reporting guideline that has contributed to improvements in the quality of RCT manuscripts in journals publishing medical research. However, studies have shown persistent deficiencies in the reporting quality of social and psychological intervention trials. A new CONSORT extension for these interventions may be needed given their distinct and complex features. This DPhil thesis reports on a project to develop and disseminate an official CONSORT Extension for Social and Psychological Interventions: CONSORT-SPI. <b>Structure:</b> Following a preface, this DPhil thesis includes eight chapters. Chapter 1 provides an overview of the conceptual rationale that prompted the CONSORT-SPI project. Chapter 2 details the project protocol, which consists of a five-phase methodology that follows current best practices for reporting guideline development and dissemination. Chapter 3 discusses systematic literature reviews to assess reporting guidelines for and the reporting quality of publications of social and psychological intervention RCTs. Chapter 4 discusses an online, international Delphi process to generate a prioritised list of possible items to include in the CONSORT-SPI extension. Chapter 5 discusses a formal consensus meeting to select reporting items to add to or modify for the CONSORT-SPI Extension checklist. Chapter 6 involves drafts of the CONSORT-SPI checklist as well as a template for the Explanation and Elaboration (E&E) document providing detailed advice and examples of good reporting for each checklist item. These drafts have not yet been circulated to co-authors or other members of the project team; their purpose in this thesis is to give an indication of how previous project phases have led into initial prototypes of the checklist and E&E, which will undergo further development and revision by the project team before publication. Chapter 7 proposes a coordinated dissemination and implementation strategy informed by theoretical frameworks and tools used to guide the implementation of clinical guidelines and empirically-supported interventions. The final chapter summarises the information gained from the CONSORT-SPI project to date, assesses strengths and limitations of the project methodology, and discusses implications for future research. <b>Conclusion:</b> A CONSORT-SPI Extension could improve the reporting quality of social and psychological intervention RCTs. This extension could also facilitate better critical appraisal of this body of research and its use in evidence-based decision-making. With successful dissemination and implementation, the guideline will hopefully contribute to the improvement of intervention evaluations—as well as the methodology underpinning these studies—within the social and behavioural sciences.

Evidence-based practice is an integral part of multi-disciplinary healthcare, but its routine clinical implementation remains a challenge internationally. Written asthma action plans are an example of sub-optimal evidence-based practice because, despite being recommended, these plans are under-issued by health professionals and under-used by patients/carers. This thesis is a critical analysis of the generation and implementation of evidence in this area and provides fresh insight into this specific theory/practice gap. This submission brings together, in five published papers, a body of work conducted by the candidate. Findings report that known barriers to action plan use (such as a lack of practitioner time) are symptomatic of deeper and more complex underlying factors. In particular, over-reliance on knowledge derived from randomised controlled trials and their systematic review, as the primary and sole source of evidence for healthcare practice, hindered the implementation of these plans. A lack of evidence reflecting the personal experience of using these plans in the real world, rather than in trial settings, contributed to a mismatch between what patients/carers want from asthma action plans and what they are currently being provided with by professionals. This submission illustrates the benefits of utilising a broader range of knowledge as a basis for clinical practice. The presented papers report how new and innovative research methodologies (including meta-ethnography and cross-study synthesis) can be used to synthesise individual studies reporting the personal experiences of patients and professionals and how such findings can then be used to better understand why interventions can be implemented in trial settings rather than everyday practice. Whilst these emerging approaches have great potential to contribute to evidence-based practice by, for example, strengthening the ‘weight’ of experiential knowledge, there are methodological challenges which, whilst acknowledged, have yet to be fully addressed.