Contexte - Considérées comme un progrès thérapeutique notable en cancérologie, les thérapies ciblées ne sont pas sans effet secondaire, en particulier sur le plan dermatologique. Très peu de données sont actuellement disponibles quant à leurs retentissements sur la qualité de vie des patients. Le service de dermatologie de Gustave Roussy a développé un protocole de recherche prospectif (SKINTARGET) consacré à cette thématique afin de pouvoir proposer des mesures préventives et/ou curatives adaptées. Inscrite dans ces travaux, notre thèse avait pour objectif principal de décrire les changements observés du point de vue de l’état émotionnel, de l’image corporelle et des interactions sociales avec l’apparition des atteintes cutanées, en s’intéressant à la place des représentations associées au traitement dans le processus d’ajustement des patients à ces symptômes.<p>Méthode - Il s’agissait d’une étude comprenant quatre temps d’évaluation (initiation du traitement, un, deux et trois mois après), qui associait de façon concomitante deux modes d’évaluation :quantitatif (questionnaires :IPQ-R, DLQI, POMS, BDI-II, QIC) et qualitatif (entretiens semi-directifs). L’inclusion était proposée par les oncologues aux patients allant débuter un traitement par thérapie ciblée. Les analyses statistiques ont été menées à partir du logiciel SPSS version 14.0 ;les analyses des entretiens ont combiné méthode thématique et méthode par questionnement analytique, en s’appuyant sur le modèle théorique de Pedinielli. <p>Résultats - Quatre-vingt-deux patients ont donné leur accord pour la recherche biomédicale, 62 d’entre eux ont accepté de participer à l’étude psychologique. La partie quantitative a été complétée par 33 patients, pour moitié hommes (âge moyen 56 ans), soignés pour un cancer métastatique cutané, pulmonaire, rénal ou thyroïdien. L’échantillon comptait une majorité de personnes en couple, avec enfants, soit à la retraite soit en arrêt de travail. Quatre-vingt-quatorze pour cent a développé au moins un des principaux symptômes suivants :rash cutané, syndrome main-pied, alopécie ou photosensibilité. Les changements observés ont été un inconfort physique et une gêne à la réalisation des activités du quotidien. Aucun signe de perturbation de la sphère émotionnelle, de l’image du corps et des relations sociales n’a été mis en évidence au cours des trois premiers mois de traitement. Les symptômes dermatologiques ont majoritairement été rattachés par les patients à l’action du traitement, sans être interprétés comme signes de son efficacité. La représentation d’un médicament contrôlant la maladie a émergé comme un des facteurs significativement associés aux variations de l’impact des toxicités cutanées sur la qualité de vie. <p>La partie qualitative a concerné 41 patients, dont les caractéristiques médicales et socio-démographiques étaient très similaires à celles de l’échantillon quantitatif. Pour une majorité les effets secondaires dermatologiques ont été « embêtants », « gênants », quelquefois « impressionnants », voire « perturbants » lorsqu’ils entraînaient douleurs, difficultés à la mobilité ou troubles du sommeil, mais sont restés « gérables, supportables ». Les représentations associées au traitement, très positives, sont apparues comme un élément soutenant dans l’ajustement des patients. Du discours des patients en souffrance psychologique sont ressorties une défiance vis-à-vis du regard d’autrui et une impossibilité d’amorcer le travail de renoncement nécessaire à l’intégration des transformations liées au cancer et à ses traitements. L’origine de cette souffrance serait un débordement des défenses psychiques par une angoisse de mort :la difficulté pour restaurer l’état d’équilibre psychique antérieur provenant de l’activation concurrentielle de deux dynamiques, l’une surnommée « substantielle », l’autre « identitaire ».<p>Discussion - Ces résultats rejoignent les données de la littérature en concluant à un impact d’intensité faible à modérée des toxicités cutanées sur la qualité de vie pour une majorité de patients. Contrairement à ce qui était attendu, il n’a pas été observé de changement sur le plan de l’état émotionnel, de l’image corporelle et des interactions sociales. L’investissement positif du traitement, la réappréciation des valeurs, le très bon état général des patients et l’optimisme ont été évoqués pour expliquer non seulement l’absence de perturbation, mais aussi les très bas niveaux d’anxiété, de tristesse et de fatigue globalement rapportés. L’importance de l’encadrement soignant et médical a également été soulignée parce qu’il sécurise les patients en anticipant les difficultés, en informant et en proposant une prise en charge suivie.<p>Conclusion - Le développement croissant des thérapies ciblées devrait s’accompagner d’un renforcement des mesures de prévention et de prise en charge des effets secondaires dermatologiques, qui requiert formation et sensibilisation des acteurs de soin à cette problématique, en rappelant la dimension singulière du vécu de chaque patient et l’impossibilité de le réduire à l’observable médical.<p>Background - Considered as a significant therapeutic progress in cancer, targeted agents are not without side effects, particularly dermatological ones. Very little information is presently available about their consequences on patients’ quality of life. The dermatological team of Gustave Roussy has developed a prospective research (SKINTARGET) in order to provide preventive and curative adapted care. Integrated into this work, our thesis aimed to describe the psychosocial changes occurring with cutaneous toxicities and to explore the implication of treatment representations in the patient’s adjustment process.<p>Methods - The study included four phases of evaluation (treatment initiation, one, two and three months after) and used simultaneously two methods: a quantitative one (questionnaires: IPQ-R, DLQI, POMS, BDI-II, BIQ) and a qualitative one (semi-structured interviews). The inclusion was proposed by oncologists to patients who were about to start a targeted therapy. Statistical analyzes were conducted with SPSS 14.0 software; analyzes interviews combined thematic approach and analytical questioning methods and referred to the Pedinielli’s theoretical model.<p>Results - Eighty- two patients gave their consent for biomedical research, 62 of them agreed to participate to the psychological study. The quantitative part was completed by 33 patients (50% men, mean age 56 years) treated for metastatic skin, pulmonary, renal or thyroid cancer, who were mostly in a relationship with children, either retired or stopped working. Eighty- four percent developed at least one of the following main symptoms: skin rash, hand-foot syndrome, alopecia or photosensitivity. The observed changes were characterized by a physical discomfort and difficulties in the activities of daily life. No sign of disturbance was noted in emotional domain, body image or social relations during the first three months of treatment. Dermatological symptoms were mainly related by patients to treatment action, without being interpreted as an evidence of its effectiveness. The representation of a drug controlling the disease was significantly associated with a lower impact of skin problems on the quality of life.<p>The qualitative part included 41 patients. Medical and sociodemographic characteristics were very similar to those of the quantitative sample. For most people, dermatological side effects were "boring", "uncomfortable", sometimes "impressive" or "disturbing" when they were associated with pain, mobility difficulties or sleeping troubles, but remained "manageable, bearable". The very positive treatment representations appeared as a supporting element in patients’ adjustment. Psychological distress seemed appear when patients feared being stared by others and failed to engage themselves in the renouncement work which is needed to adjust oneself to the transformations related to cancer and its treatments. In such situation psychological distress was supposed to come from an overflow of the psychic defences by a fear of death; the difficulty to restore mental balance would be explained by the activation of two competitive dynamics, which struggle for the organism and the identity survival.<p>Discussion - These results are consistent with the literature data. The skin toxicities impact on quality of life is mild to moderate for a majority of patients. Contrary to our expectations, there was no evidence of change in the domains of emotions, body image and social interactions. The positive investment of treatment, a reassessment of values, the very good physical state of patients and the influence of optimism in patients state of mind have been cited to explain not only the absence of disturbance, but also the very low levels of anxiety, sadness and fatigue generally reported. The importance of the caregiving provided by health professionals was also highlighted: anticipating difficulties, giving information about side effects and effectively managing problems secure patients.<p>Conclusions - The growing development of targeted therapies implies strengthening prevention and management of dermatological side effects. Moreover, it requires to aware and to train more health professionals to this problem, recalling the singular dimension of each patient which can not being reduced to the medical observable.<p> / Doctorat en Sciences Psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished

Postoperative pain is of serious concern to patients and anesthesia providers alike. Management of a patients’ pain is a central component of anesthesia care. Ketamine as an anesthetic agent has been available for 50 years. It has been utilized as a general anesthetic and selectively as an anesthetic agent for high-risk patients. Due to dysphoric side effects associated with the dosage required to render general anesthesia, anesthesia providers may be reluctant to utilize this medication to its full potential. Recently there has been a resurgence of interest in ketamine as an analgesic agent. The researcher for this project performed a thorough literature review focusing on intravenous ketamine as an adjunct to standard opioid-based analgesia for postoperative pain. Four systematic reviews published in the last 10 years support the safety and efficacy of ketamine when administered intravenously in sub-anesthetic doses. The purpose of this project was to provide evidence-based education to anesthesia providers regarding the benefits of ketamine and follow-up to evaluate for evidence of changes in practice after the educational At a large community hospital data concerning ketamine utilization by anesthesia providers as a component of multimodal analgesia was collected for a six-month period, including three months pre- and three months post-educational intervention. Despite various methods utilized to present evidence regarding the safety and efficacy of ketamine, the results of this study demonstrated no significant change in practice. Based upon the extensive published literature the evidence is compelling that the addition of a sub-anesthetic (0.5 mg/kg) dose of ketamine to the surgical patient’s operative pain management plan would improve comfort and decrease opioid-related side effects with minimal negative impact.

Contexte. Non seulement le cancer est toujours la principale cause de décès par maladie chez les enfants, mais les deux tiers des survivants présenteront, à l’âge adulte, des séquelles liées aux traitements reçus. Tel qu’il sera décrit dans le présent mémoire, le programme VIE (Valorisation, Implication, Éducation) au Centre hospitalier universitaire Sainte-Justine propose d’implanter un programme d’interventions pour sensibiliser les patients en cours de traitement et leur famille aux bienfaits d’adopter de saines habitudes de vie et les supporter dans le changement de comportements attendus. Un volet de ce programme comprend des ateliers d’éducation culinaire et nutritionnelle. Objectifs. L’objectif principal de ce projet est de développer et de valider un curriculum d’ateliers d’éducation culinaire et nutritionnelle qui permettra de répondre aux particularités d’une clientèle en oncologie pédiatrique en cours de traitements et de prévenir les complications cardiométaboliques à long terme. Un second objectif consiste au développement d’un outil d’évaluation des ateliers. Méthode. Les thèmes, les objectifs d’apprentissages et le contenu des ateliers ont fait l’objet d’un processus de développement et de validation en huit étapes, incluant la consultation d’un comité d’experts. Les recettes en démonstration ont été développées et standardisées par deux nutritionnistes de l’équipe de recherche et leur valeur nutritive analysée à l’aide d’un logiciel d’analyse nutritionnelle. Les outils d’évaluation ont été développés en fonction des objectifs d’apprentissages des ateliers en s’inspirant d’outils de mesure existants et révisés par un expert. Résultats. Six ateliers d’éducation culinaire et nutritionnelle basés sur les données probantes et l’expérience clinique de trois nutritionnistes en oncologie pédiatrique ont été développés et validés. Douze recettes en lien avec les thèmes des ateliers, deux pour chaque atelier, ont été développées, standardisées et leur valeur nutritive validée. Six questionnaires ont été développés pour mesurer la perception de l’acquisition de connaissances, l’intention d’appliquer les apprentissages et la satisfaction des participants pour chacun des ateliers. Conclusion. À notre connaissance, il s’agit du premier programme d’éducation culinaire et nutritionnelle élaboré spécifiquement pour les familles d’une clientèle d’oncologie pédiatrique en cours de traitement. Nous pensons que ce programme répondra aux besoins spécifiques des patients en oncologie pédiatrique et de leur famille et contribuera à les sensibiliser à l’importance d’instaurer ou de maintenir de saines habitudes alimentaires pendant et après les traitements du cancer. / Context. Cancer is still the main cause of death by illness in children. Furthermore, two third of the survivors will present treatment-related late effects in adulthood. As it will be described in this thesis, the VIE program (Valorisation, Implication, Education) at the Sainte-Justine University Hospital Center aims to implement an intervention program to raise awareness of patients ongoing cancer treatments and their family to the benefits of adopting a healthy lifestyle and to support them with expected behavior change. One component of this program consists in nutrition and cooking education workshops. Objectives. The main objective of this project is to develop and validate a nutrition and cooking education workshop curriculum which will address concerns specific to on-treatment pediatric oncology patients and help prevent cardiometabolic late effects. A second objective is to develop an evaluation tool for the workshops. Methodology. The workshops’ themes, specific objectives and content have been subject to an eight-steps development and validation process, including steering committee consultation. The recipes in demonstration have been developed and standardized by two research staff registered dietitians and their nutritional value analyzed with a nutritional analysis software. Evaluation tools have been developed in accordance with the workshops learning objectives, inspired by existing tools and reviewed by expert. Results. Six nutrition and cooking education workshops based on scientific evidence and clinical experience of three pediatric oncology registered dietitians have been developed and validated. Twelve recipes related to the workshops themes, two for each workshop, have been developed, standardized and their nutritional value validated. Six questionnaires have been developed for each workshop to measure participants’ perception of knowledge acquisition, behavioral intention and satisfaction. Conclusion. It is, to our knowledge, the first nutrition and cooking education workshop curriculum elaborated specifically for families of an on-treatment pediatric oncology population. We think that this program will address the needs specific to pediatric oncology patients and their family, while contributing to raise awareness to the importance of adopting and maintaining healthy eating habits during and after cancer treatments.

The widespread acceptance of topical formulations intended for local and/or regional activity has prompted renewed interest in developing a model to determine the bioavailability of drugs in order to establish bioequivalence as a means of evaluating formulation performance of multisource products and also for use during formulation development. Current in vivo techniques such as blister suction and skin biopsy amongst others used to determine the bioavailability and/or bioequivalence of topical formulations are either too invasive to generate appropriate concentration-time profiles or require large numbers of study subjects thereby making the study expensive and time-consuming. Moreover, there are currently no sampling techniques that can demonstrate dermal bioavailability and/or bioequivalence of topical formulations intended for local and/or regional activity. Dermal microdialysis is a relatively new application of microdialysis that permits continuous monitoring of endogenous and/or exogenous solutes in the interstitial fluid. The technique is involves the implantation of semi-permeable membranes which are perfused with an isotonic medium at extremely slow flow rates and collection of microlitre sample volumes containing diffused drugs. Tape stripping, a relatively older technique, has been extensively used in comparative bioavailability studies of various topical formulations. However, due to shortcomings arising from reproducibility and inter-subject variation amongst others, the published FDA guidance outlining the initial protocol was subsequently withdrawn. The incorporation of transepidermal water loss with tape stripping has garnered renewed interest and has been used for the determination of drug bioavailability from a number of topical formulations. Hence the primary objective of this research is to develop and evaluate microdialysis sampling and tape stripping techniques, including the incorporation of the determination of transepidermal water loss, to assess the dermal bioavailability of ketoprofen from topical gel formulations and to develop models for bioequivalence assessment. A rapid UPLC-MS/MS method with requisite sensitivity for the analysis of samples generated from dermal microdialysis was developed and validated which accommodated the microlitre sample volumes collected. An HPLC-UV method was developed and validated for the analysis of samples generated from the in vitro microdialysis and in vivo tape stripping studies. The work presented herein contributes to a growing body of scientific knowledge seeking to develop a model for the determination of bioequivalence of pharmaceutically equivalent topical formulations intended for local and/or regional activity in human subjects.

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

Cette thèse s'intéresse au contenu calculatoire des preuves classiques, et plus spécifiquement aux preuves avec effets de bord et à la réalisabilité classique de Krivine. Le manuscrit est divisé en trois parties, dont la première consiste en une introduction étendue des concepts utilisés par la suite. La seconde partie porte sur l’interprétation calculatoire de l’axiome du choix dépendant en logique classique. Ce travail s'inscrit dans la continuité du système dPAω d'Hugo Herbelin, qui permet d’adapter la preuve constructive de l’axiome du choix en théorie des types de Martin-Löf pour en faire une preuve constructive de l’axiome du choix dépendant dans un cadre compatible avec la logique classique. L'objectif principal de cette partie est de démontrer la propriété de normalisation pour dPAω, sur laquelle repose la cohérence du système. La difficulté d'une telle preuve est liée à la présence simultanée de types dépendants (pour la partie constructive du choix), d'opérateurs de contrôle (pour la logique classique), d'objets co-inductifs (pour "encoder" les fonctions de type N → A par des streams (a₀,a₁,...)) et d'évaluation paresseuse avec partage (pour ces objets co-inductifs). Ces difficultés sont étudiées séparément dans un premier temps. En particulier, on montre la normalisation du call-by-need classique (présenté comme une extension du λµµ̃-calcul avec des environnements partagé), en utilisant notamment des techniques de réalisabilité à la Krivine. On développe ensuite un calcul des séquents classique avec types dépendants, définie comme une adaptation du λµµ̃-calcul, dont la correction est prouvée à l'aide d'une traduction CPS tenant compte des dépendances. Enfin, une variante en calcul des séquents du système dPAω est introduite, combinant les deux points précédents, dont la normalisation est finalement prouvée à l'aide de techniques de réalisabilité. La dernière partie, d'avantage orientée vers la sémantique, porte sur l’étude de la dualité entre l’appel par nom (call-by-name) et l’appel par valeur (call-by-value) dans un cadre purement algébrique inspiré par les travaux autour de la réalisabilité classique (et notamment les algèbres de réalisabilité de Krivine). Ce travail se base sur une notion d'algèbres implicatives développée par Alexandre Miquel, une structure algébrique très simple généralisant à la fois les algèbres de Boole complètes et les algèbres de réalisabilité de Krivine, de manière à exprimer dans un même cadre la théorie du forcing (au sens de Cohen) et la théorie de la réalisabilité classique (au sens de Krivine). Le principal défaut de cette structure est qu’elle est très orientée vers le λ-calcul, et ne permet d’interpréter fidèlement que les langages en appel par nom. Pour remédier à cette situation, on introduit deux variantes des algèbres implicatives les algèbres disjonctives, centrées sur le “par” de la logique linéaire (mais dans un cadre non linéaire) et naturellement adaptées aux langages en appel par nom, et les algèbres conjonctives, centrées sur le “tenseur” de la logique linéaire et adaptées aux langages en appel par valeur. On prouve en particulier que les algèbres disjonctives ne sont que des cas particuliers d'algèbres implicatives et que l'on peut obtenir une algèbre conjonctive à partir d'une algèbre disjonctive (par renversement de l’ordre sous-jacent). De plus, on montre comment interpréter dans ces cadres les fragments du système L de Guillaume Munch-Maccagnoni en appel par valeur (dans les algèbres conjonctives) et en appel par nom (dans les algèbres disjonctives). / This thesis focuses on the computational content of classical proofs, and specifically on proofs with side-effects and Krivine classical realizability. The manuscript is divided in three parts, the first of which consists of a detailed introduction to the concepts used in the sequel.The second part deals with the computational content of the axiom of dependent choice in classical logic. This works is in the continuity of the system dPAω developed Hugo Herbelin. This calculus allows us to adapt the constructive proof of the axiom of choice in Martin-Löf's type theory in order to turn it into a constructive proof of the axiom of dependent choice in a setting compatible with classical logic. The principal goal of this part is to prove the property of normalization for dPAω, on which relies the consistency of the system. Such a proof is hard to obtain, due to the simultaneous presence of dependent types (for the constructive part of the choice), of control operators (for classical logic), of co-inductive objects (in order to "encode" functions of type N → A as streams (a₀,a₁,...)) and of lazy evaluation with sharing (for this co-inductive objects). These difficulties are first studied separately. In particular, we prove the normalization of classical call-by-need (presented as an extension of the λµ̃µ-calculus with shared environments) by means of realizability techniques. Next, we develop a classical sequent calculus with dependent types, defined again as an adaptation of the λµ̃µ-calculus, whose soundness is proved thanks to a CPS translation which takes the dependencies into account. Last, a sequent-calculus variant of dPAω is introduced, combining the two previous systems. Its normalization is finally proved using realizability techniques. The last part, more oriented towards semantics, studies the duality between the call-by-name and the call-by-value evaluation strategies in a purely algebraic setting, inspired from several works around classical realizability (and in particular Krivine realizability algebras). This work relies on the notion of implicative algebras developed by Alexandre Miquel, a very simple algebraic structure generalizing at the same time complete Boolean algebras and Krivine realizability algebras, in such a way that it allows us to express in a same setting the theory of forcing (in the sense of Cohen) and the theory of classical realizability (in the sense of Krivine). The main default of these structures is that they are deeply oriented towards the λ-calculus, and that they only allows to faithfully interpret languages in call-by-name. To remediate the situation, we introduce two variants of implicative algebras: disjunctive algebras, centered on the "par" connective of linear logic (but in a non-linear framework) and naturally adapted to languages in call-by-name; and conjunctives algebras, centered on the "tensor" connective of linear logic and adapted to languages in call-by-value. Amongst other things, we prove that disjunctive algebras are particular cases of implicative algebras and that conjunctive algebras can be obtained from disjunctive algebras (by reversing the underlying order). Moreover, we show how to interpret in these frameworks the fragments of Guillaume Munch-Maccagnoni's system L corresponding to a call-by-value calculus (within conjunctive algebras) and to a call-by-name calculus (within disjunctive algebras).

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

Background: Improved clinical effectiveness and therefore positive modification of multiple sclerosis (MS) with basic therapy can be achieved by long-term regular intake of drugs as prescribed but investigations have shown that a high percentage of patients do not take their medications as prescribed. Objectives: We assessed the satisfaction and adherence of patients with MS with their current disease-modifying treatment under clinical practice conditions. We compared different facets of satisfaction as well as their internal relationship and identified predictors in an exploratory manner. Methods: Therapy satisfaction in patients with relapsing–remitting multiple sclerosis (THEPAMS) was a noninterventional, prospective cross-sectional study performed throughout Germany in 2013 and 2014, and included patients with clinically isolated syndrome or relapsing–remitting MS. We applied a standardized approach to document satisfaction and adherence by patient-reported outcomes (Treatment Satisfaction Questionnaire for Medication) as well as by physician ratings. Results: Of 3312 patients with a mean age of 43.7 years, 73.3% were women and the mean level of disability according to the Expanded Disability Status Scale was 2.29; 13.3% did not receive any medication at the time of documentation, 21.3% received interferon β1a intramuscularly, 20.7% had interferon β1a subcutaneously, 17.0% had interferon β1b subcutaneously and 23.7% had glatiramer acetate. Adherence rates varied between 60% (lifetime) and 96.5% (current medication). Differences between current medications were found for side effects and convenience scores but not for effectiveness, satisfaction and adherence. Higher global satisfaction and effectiveness were associated with fewer relapses, longer duration of medication, lower disability score and the absence of several side effects. Conclusion: In a connected model of patient satisfaction, effectiveness, side effects, convenience and adherence, patients’ individual needs and concerns have to be addressed. Most differences were found with respect to side effects and convenience of treatment. Therefore, an improvement in these two domains seems to be the most promising proximate approach to elevate adherence levels.

Background: Up to 55% of patients administered ketamine, experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury. While genetics accounts for about 50% of severe adverse drug reactions, no studies have investigated genetic association of ketamine-induced EP in healthy patients. Ketamine is metabolized by CYP 2B6 enzymes and CYP 2B^8^ allele significantly alter ketamine metabolism. In addition, ketamine exerts most of its effects by inhibiting the N-methyl-D-aspartate receptor (NMADR), and NMDAR genes (GRIN2B) are associated with learning and memory impairment and schizophrenia. Purpose: To investigate the relationship between CYP2B6*6 and GRIN2B single nucleotide polymorphisms (SNPs) and ketamine-induced emergence phenomena (EP). Methods: This cross-sectional pharmacogenetic study recruited 75 patients having minor orthopedic, hand, foot, anorectal surgeries from two outpatient surgical centers. EP was measured with the Clinician Administered Dissociative State Scale (CADSS). DNA was genotyped using standard Taqman assays and protocols. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 & rs1806191) SNPs and ketamine induced EP occurrence and severity were tested using multivariate logistic and linear regression, adjusting for age, ketamine dose, duration of anesthesia, and time since ketamine administration. Results: Forty-seven patients (63%) received ketamine and were genotyped. Nineteen EP cases were identified (CADSS > 4), leaving 28 non-EP controls. For our population, CADSS has an internal consistency reliability Cronbach’s alpha of 0.82, and could reliably distinguish ketamine from non-ketamine cases. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p > 0.1). Models removing genotype and containing age, ketamine dose, duration of v anesthesia, and time since ketamine administration significantly predicted EP occurrence (p = 0.001) and severity (p = 0.007). Presence and severity of EP did not affect patient satisfaction with care. Discussion: Younger age, higher dose and longer duration of anesthesia significantly predicted EP occurrence and severity among our sample. This study provides effect size estimates useful for the design of adequately powered future genetic association studies. The feasibility of recruitment from patients undergoing elective, outpatient surgeries and ease of post-operative EP assessment with CADSS supports our approach. However, the small sample size may have limited about ability to determine significant differences. Conclusion: Fully powered studies are needed to investigate this important phenomena. Determining factors for anesthesia-related EP symptoms may reduce risks and costs associated with this adverse medication effect.

Indiana University-Purdue University Indianapolis (IUPUI) / Choroidal neovascularization (CNV) is the vision-threatening characteristic of wet age-related macular degeneration (AMD), a major cause of blindness affecting almost 2 million elderly Americans. The current approved treatments target the dominant angiogenic mediator, vascular endothelial growth factor (VEGF). However, repeated injections of anti-VEGF drugs can cause ocular and systemic side effects, and about 30% of wet AMD patients are non-responsive. There is thus an unmet need to develop VEGF-independent antiangiogenic molecules to complement or combine with existing medications. I studied SH-11037, a novel homoisoflavonoid with potent and selective antiangiogenic activity against human retinal endothelial cells. Intravitreal SH- 11037 dose-dependently suppressed angiogenesis in the laser-induced CNV (LCNV) mouse model. These effects were prominent as early as 7 days post-laser treatment as measured by a novel ellipsoid quantification method of optical coherence tomography images in vivo. A supratherapeutic dose of 100 μM SH- 11037 was not associated with signs of murine ocular toxicity, and did not interfere with pre-existing retinal vasculature or retinal function. SH-11037 synergized with anti-VEGF therapy in vitro and in vivo, suggesting a VEGFindependent mechanism. By photoaffinity pulldown, I identified soluble epoxide hydrolase (sEH) as an SH-11037-binding target. sEH is a key enzyme in ω-3 and ω-6 fatty acid metabolism. sEH levels were dramatically upregulated in retinal sections from L-CNV mice and a specific sEH inhibitor, t-AUCB, significantly suppressed L-CNV lesion volume. Additionally, SH-11037 inhibited sEH enzymatic activity in vitro and in vivo in L-CNV mice. Given the role of sEH in the metabolism of docosahexaenoic acids (DHA), inhibition of sEH using small molecules like SH-11037 would enhance ocular DHA levels, with beneficial antiangiogenic and anti-inflammatory effects. SH-11037 is thus a novel sEH inhibitor, which could make it an alternative or additive therapy to existing anti- VEGF drugs for treatment of neovascular diseases in the eye and other tissues.