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Mesenchymal stromal cell (MSC) apoptosis is required for in vivo immunosuppression. However, the induction of apoptosis is heavily dependent on the recipient’s immune system. In graft-versus-host disease (GvHD), patients who fail to respond to MSCs are in fact those whose immune cells are unable to induce MSC apoptosis ex vivo. The information is critical to explain why responses in clinical trials vary even though the same sources of MSC products are infused. More importantly, it highlights the need for an alternative MSC treatment for the nonresponders. By using a mouse model of ovalbumin (OVA)-induced allergic inflammation, we demonstrated that we could generate apoptotic MSCs (ApoMSCs) in vitro and use them to successfully reduce allergic airway inflammation. In order to address the logistics of their potential future clinical application, we have shown that ApoMSCs could be cryopreserved without impairing efficacy compared to freshly generated ApoMSCs. We have also highlighted that MSCs need to undergo complete apoptosis before cryopreservation to retain their immunosuppressive activity. The cryopreserved ApoMSCs could serve as a potential future off-the-shelf cellular product, in particular for patients who suffer from inflammatory conditions yet do not harbor the immune capacity to induce MSC apoptosis in vivo. Our data provide proof-of-concept that under laboratory conditions, ApoMSCs can be successfully frozen and thawed without affecting their anti-inflammatory activity, as tested in a murine model of allergic inflammation.

Purpose: Qualitative research (QR) take advantage of a wide range of methods and theoretical frameworks to explore people’s beliefs, perspectives, experiences, and behaviours and has been applied to many areas of healthcare. The aim of this review was to explore how QR has contributed to the field of perioperative anesthesiology. Source: We performed a systematic scoping review of published QR studies pertaining to the field of perioperative anesthesiology in three databases (CINAHL, Pubmed, and Embase), published between January 2000 and June 2018. We extracted data regarding publication and researchers’ characteristics, main study objectives, and methodological details. Descriptive statistics were generated for each data extraction category. Principal findings: A total of 107 articles fulfilled our inclusion criteria. We identified 13 main research topics addressed by the included studies. Topics such as “patient safety,” “barriers to evidence-base medicine,” “patient experiences under local/regional anesthesia,” “training in practice,” “experiences of care,” and “implementation of changes in clinical practice” were commonly tackled. Others, such as “interprofessional communication”, “work environment,” and “patients’/healthcare professionals’ interactions” were less common. Qualitative research was often poorly reported and methodological details were frequently missing. Conclusion: Qualitative research has been used to explore an array of issues in perioperative anesthesiology. Some areas may benefit from further primary research, such as interprofessional communication or patient-centred care, while other areas may deserve a detailed systematic knowledge synthesis. We identified suboptimal reporting of qualitative methods and their link to study findings. Increased attention to quality criteria and reporting standards in QR is called for.

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and is associated with significant morbidity and mortality. Among PH, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare and life-threatening diseases evolving to right ventricular failure and death in absence of treatment. Development of PAH specific therapies contributed to improve prognosis of patients. Medication adherence (MA) of PH patients is poorly described while it is well recognized that high levels of MA are correlated to better clinical and economical outcomes in cardiovascular diseases.

Le dysfonctionnement tubaire (DT) obstructif peut être à l’origine de complications otologiques à l’origine d’un choléstéatome et requiert une prise en charge spécifique. Un lien de causalité entre l’existence d’une rhinosinusite chronique (RSC) et la survenue d’un DT obstructif a précédemment été suggéré. La tubomanométrie (TMM) est un outil diagnostique récent permettant l’objectivation et la compréhension d’un DT. Son utilisation a largement été décrite dans la pathologie otitique chronique pure mais jamais dans l’étude des conséquences tubaires d’une RSC. L’objectif de ce travail était d’obtenir les résultats tubomanométriques d’une population de patients souffrant d’une RSC et symptomatiques d’un DT obstructif.

Chimeric Antigen Receptor (CAR)-T cells have proven highly successful in the treatment of some haemopoietic neoplasms. However, in several cases the treatment fails and disease does not respond and/or relapses. Amongst the different factors impacting on a negative clinical outcome, an unfavourable immunosuppressive microenvironment has been proposed as playing a critical role, particularly in the context of acute myeloid leukemia. We hypothesised that bone marrow mesenchymal stromal cells (BM-MSC) acquire immunosuppressive properties after exposure to the by-stander effects of activated CAR-T cells against leukemic cells. We used a CAR-T cell consisting of a CD33 binder and CD28z-OX40 costimulatory moiety. BM-MSC were exposed to the CAR following in vitro activation on CD33-coated plates for 24 hours. To model the different ways by which stromal cells can license their immunosuppressive activity, BM-MSC were exposed to the supernatant harvested from the cultures of activated CARs or in direct contact with the activated CARs themselves. In the first case, after incubation with the CAR-conditioned medium (CAR-cm), BM-MSCs were investigated for their transcriptome by RNASeq. Gene ontology analysis of the transcriptome revealed a strong NF-κB and STAT1 signature in BM-MSC exposed to the CAR-cm compared to those which were not exposed. Amongst the most upregulated molecules, we identified several chemokines (CXCL10, CCL8, CXCL8, and CXCL9), PDL1 and CECAM1, IL-6, indoleamine-2,3 dyoxigenase (IDO), and most prominently PTGES and PTGS2. We then interrogated the immune functional profile by incubating by CAR-cm licensed BM-MSC with fresh CD33-activated CAR-T cells. We observed that CAR proliferation, cytotoxicity and cytokine production was significantly inhibited. CAR function was restored if Rel-A - a REL-associated protein critically involved in NF-κB heterodimer formation, nuclear translocation and activation - was inhibited in BM-MSC by shRNA before exposure to CAR-cm. We previously described that BM-MSC undergo apoptosis when in contact with activated cytotoxic T cells and that this also triggers their immunosuppressive capability. Therefore, we evaluated the impact of cell contact dependent mechanisms on BM-MSC licensing. CD33-activated CAR-T cells were incubated with BM-MSC and the proportion of annexin-V positive BM-MSC were assessed after 4 hours. We observed that a large fraction of BM-MSC underwent apoptosis and that this was dependent on caspase activation, but not RIP kinase 3, and the release of cytolytic granules in a contact-dependent fashion. The supernatant of apoptotic BM-MSC but not the terminally apoptotic and neither the live cells exhibited a strong inhibitory activity on CAR-T cell proliferation, cytotoxicity and effector cytokine production. Similarly to what described with the CAR-cm induced profile, BM-MSC immunosuppression required NF-κB and was effected via the COX2 pathway. We finally tested the impact of apoMSC in vivo in a xenograft model of AML (Fig. 1). CD33-positive KG1 cells were injected in NSG mice and 2 weeks later, CD33-specific CAR-T were administered with or without (controls) apoMSC. Peripheral blood samples were collected 7, 14, and 21 days after. We observed an inhibitory effect of apoMSc on the in vivo expansion of CAR-T cells which was accompanied by disease progression. Accordingly, the survival of the mice treated with apoMSC was markedly reduced compared to those receiving CAR-T cells only.

(Int J Obstet Anesth. 2020;41:83–103)Both epidural (EP) and combined spinal-epidural (CSE) techniques are used to establish effective labor analgesia. Over time, the latter has gained popularity due to faster onset of pain relief and superior sacral nerve coverage. The addition of opioids in neuraxial labor analgesia allows for lower concentrations of local anesthetic and a longer duration of the analgesic effect. However, opioids also impart risk for additional side effects including pruritus, sedation, nausea, vomiting, hypotension, and fetal heart rate pattern disturbances. This study was designed to analyze how individual and combined routes of neuraxial opioid administration impact the incidence of maternal and fetal side effects.

Traditionnellement, ces interventions visent à corriger les décalages à responsabilité mandibulaire par une avancée de la portion dentée de la mandibule après ostéotomie mandibulaire. Au cours de la mise en place des plaques d’ostéosynthèses se décide la position des condyles, déjà plus reculés de par la position allongée et l’atonie musculaire du patient curarisé. Toutes les études montrent que la chirurgie « d’avancée mandibulaire » entraîne un mouvement latéral et un recul des condyles, ainsi qu’un mouvement de torque, tous préjudiciables aux condyles. Les facteurs prédisposant aux atteintes dégénératives sont « le patient » : femme (entre 15 et 40 ans) hyperdivergente ayant des antécédents de dysfonctionnement de l’appareil manducateur (DAM) et le geste chirurgical de par la surcharge appliquée aux condyles. Quelles sont les solutions possibles pour éviter les échecs ? Bien préparer le patient avant la chirurgie et effectuer une simulation (sur articulateur), maîtriser la position du condyle pendant la chirurgie, travailler avec les chirurgiens à la réalisation de système de stabilisation de la portion condylienne (avec l’aide de la CAO), mettre en place rapidement une mobilisation de la mandibule par kinésithérapie.

Les thérapies ciblées orales sont une classe de médicaments anti-tumoraux en pleine expansion. À l’issue d’essais cliniques menés sur des populations sélectionnées, ces molécules sont approuvées le plus souvent selon une posologie unique. Pourtant, elles présentent une grande variabilité pharmacocinétique inter et intra-individuelle, et un index thérapeutique étroit qui peuvent rendre leur prescription à risque chez les individus non sélectionnés de la pratique clinique quotidienne. La multiplication des thérapies ciblées à notre disposition doit conduire à prendre en compte de nouveaux enjeux qui concernent notamment la prescription chez les patients hors-norme, et les modalités d’adaptation posologique pour tenir compte des facteurs de vulnérabilité de ces individus, et parvenir à une prescription sécurisée et individualisée. D’autre part, nombre de ces thérapies sont métabolisées par le CYP 3A4, en faisant des traitements à risque élevé d’interactions médicamenteuses, non seulement avec les produits de la pharmacopée traditionnelle mais aussi avec les médecines alternatives et complémentaires, elles aussi en pleine expansion, mais souvent mal connues de l’oncologue. Enfin, la voie orale soulève la question de l’observance, dont l’évaluation doit désormais s’intégrer à la prise en charge.

Objective: To compare otologic outcomes in patients with cleft palate who underwent 2 different surgical protocols.Design: Monocentric retrospective analysis of medical reports.Patients, Participants: All consecutively treated patients affected by a cleft palate, born between January 1998 and December 2002 (group 1) and between January 2007 and December 2010 (group 2).Interventions: Patients in group 1 underwent Veau-Wardill-Kilner palatoplasty at 10 months and had ventilation tubes inserted in case of otitis media with effusion (OME) during surgery. Patients in group 2 underwent Sommerlad intravelar veloplasty at 5 months. Ventilation tubes were inserted only in case of persistent OME.Main Outcome Measure(s): The need for a second set of ventilation tubes to be inserted in case of persistent OME, the presence of OME at the age of 2 years, and tympanic abnormalities at the age of 5 years were analyzed.Results: There was no statistically significant difference either for the presence of OME at the age of 2 years (27 [45%] vs 32 [57.14%], respectively, in groups 1 and 2; P= .191) or for tympanic abnormalities at the age of 5 years (20 [33.33%] vs 15 [26.79%]; P= .433). Statistically significant difference was found for the need to insert a second set of ventilation tubes in case of persistent OME (29 [48.33%] vs 12 [21.42%], respectively; P= .02).Conclusion: Early Sommerlad intravelar veloplasty may reduce persistent OME and consequently the need for ventilation tubes insertion, compared to later Veau-Wardill-Kilner palatoplasty.

Les traumatismes cervico-faciaux par corps étrangers transfixiants sont rares et associés à un risque important de lésions vasculo-nerveuses. Ils nécessitent une prise en charge chirurgicale pluridisciplinaire.

La simulation est une méthode d’enseignement active permettant la mise en pratique de connaissances théoriques. Cet article se veut une mise au point sur l’intérêt des mannequins simulateurs largement utilisés en anesthésie-réanimation. Les séances de simulation utilisant des mannequins permettent de travailler à la fois les compétences techniques et non techniques. Le débriefing qui suit le scénario permet une pratique réflexive de l’apprenant favorisant ainsi l’acquisition, le renforcement et le développement de compétences. Il est l’élément principal de la séance de simulation et nécessite des compétences particulières de la part du formateur pour garantir un apprentissage optimal. Plusieurs travaux confirment que ce type de simulation est efficace dans l’apprentissage de gestes et procédures à risque, ainsi que des principes de gestion des situations critiques en anesthésie-réanimation. Cependant, pour développer tout son potentiel cette méthode doit être intégrée dans un curriculum global. Les défis principaux dans cette mise en place sont la mise à disposition du temps nécessaire aux formateurs et aux apprenants pour y participer, ainsi que la formation adéquate des formateurs.

Suboptimal airway management is an ongoing cause of serious adverse events in anaesthesia. Education and training is thus of paramount importance but faces several challenges. Therefore the acquisition and maintenance of competences in airway management require sound teaching and learning strategies. The aim of this review is to provide important educational principles based on published evidence in order to guide the conception and the implementation of such training programs. The desired content of an airway course is discussed as well as the importance of technical and non-technical skills. A special focus is given to the contribution of non-clinical training modalities such as models, task-trainers and simulators to efficient training in complement to clinical practice.

La sindrome dell’apnea ostruttiva del sonno è frequente nel bambino e interessa tutte le fasce d’età. Essa è, il più delle volte, dovuta a un’ipertrofia delle tonsille e delle vegetazioni adenoidee. La presentazione clinica è diversa da quella dell’adulto. La gestione si basa generalmente su un’adenotonsillectomia in prima intenzione. La polisonnografia è l’esame di riferimento per la diagnosi, ma le indicazioni devono essere riservate a certi casi particolari. Le norme di interpretazione sono specifiche della pediatria. La ventilazione non invasiva assume un ruolo sempre più importante e permette, in numerosi casi, di evitare di dover ricorrere a una tracheotomia.

To carry out a systematic review of scientific evidence available about necrotizing otitis externa, emphasizing epidemiologic data, diagnosis criteria, treatment protocols, follow-up criteria, prognosis factors, and chronologic evolution.

Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase Cζ (PKCζ) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia. Up to 5 months, sparse microglia/macrophages were detected in the subretinal space, together with numerous pores in retinal pigment epithelial (RPE) cells, allowing inflammatory cell traffic between the retina and choroid. Intercellular adhesion molecule–1 (ICAM-1), caveolin-1 (CAV-1), and PKCζ were identified at the pore border. At 12 months of hyperglycemia, the significant reduction of pores density in RPE cell layer was associated with microglia/macrophages accumulation in the subretinal space together with vacuolization of RPE cells and disorganization of photoreceptors outer segments. The intraocular injection of a PKCζ inhibitor at 12 months reduced iNOS expression in microglia/macrophages and inhibited their migration through the retina, preventing their subretinal accumulation. We show here that a physiological transcellular pathway takes place through RPE cells and contributes to microglia/macrophages retinal trafficking. Chronic hyperglycemia causes alteration of this pathway and subsequent subretinal accumulation of activated microglia/macrophages.

Femtosecond laser surgery in the volume of corneal tissue is typically performed wavelengths of about 1 m, which gives excellent results on transparent corneas. However, the outcome is much worse in the case of oedematous or pathological corneas as the laser beam propagation is disturbed by optical scattering. Our studies suggest that this phenomenon can be greatly reduced by using a better suited laser wavelength. Best results are obtained at 1.65 m. Currently, no compact femtosecond laser at this wavelength is commercially available. We have developed a new simple, compact and stable laser source consisting of a non linear crystal pumped by a compact commercial solid-state laser emitting at 1.03 m in a configuration of an Optical Parametric Generation (OPG). The output wavelength of this system can be tuned in the spectral range of 1.45 - 1.8 m. A series of ex vivo penetrating incisions using energies of the order of a few microjoules on corneal tissues have been performed while varying the wavelengths from 1.45 m to 1.7 m. The results have been compared to experiments performed at 0.8 m and 1 m. The use of longer infrared wavelengths around 1.65 m for femtosecond laser keratoplasty significantly improves the quality and the penetration depth of incision in case of pathological tissues, without inducing any additional side effects.

(Eur J Anaesthesiol. 2019;36:575–582)Pain management within the first 36 hours after cesarean section can have significant impact on postoperative maternal health and satisfaction. Inadequate pain relief may be associated with delayed breastfeeding and increased risk of postoperative complications. In addition, persistent pain at the 2-week postpartum mark is a risk factor for ongoing pain at 3 months postpartum as well as postpartum depression. Anesthesiologists often administer intrathecal morphine (ITM) during spinal anesthesia to manage postcesarean pain, but this approach often results in side effects such as postoperative nausea and vomiting (PONV) and pruritus; these adverse effects can considerably reduce maternal satisfaction. The current investigators conducted this study to determine if a transversus abdominis plane (TAP) block that included both local anesthetic and clonidine was a better pain management treatment compared with ITM in terms of PONV occurrence, other adverse effects, analgesic efficacy, and postoperative recovery quality.

We investigated the relationships between intragastric food maldistribution and antral dysmotility in functional dyspepsia, and whether these abnormalities relate to meal-induced symptoms. Intragastric distribution of food throughout gastric emptying was determined in patients (n= 24) and controls (n= 38) after a liquid nutrient meal labeled with 99mtechnetium phytate. Antral contractility was also periodically assessed by dynamic scintigraphy and postprandial symptoms were monitored with visual analog scales. Residence of food in the proximal stomach was decreased in 8 (33%) and antral contractility was increased in 9 (37.5%) and decreased in 2 (8%) patients. Proximal and distal stomach motor abnormalities were neither significantly correlated nor associated. Increased antral contractility was significantly correlated (Rs = 0.54; P< .01) with postprandial nausea. We conclude that diminished residence of food in the proximal stomach and disturbed antral contractility occur independently in different subsets of functional dyspepsia patients. Increased antral contractility seems to play a role in postprandial nausea in functional dyspepsia.We investigated the relationships between intragastric food maldistribution and antral dysmotility in functional dyspepsia, and whether these abnormalities relate to meal-induced symptoms. Intragastric distribution of food throughout gastric emptying was determined in patients (n= 24) and controls (n= 38) after a liquid nutrient meal labeled with 99mtechnetium phytate. Antral contractility was also periodically assessed by dynamic scintigraphy and postprandial symptoms were monitored with visual analog scales. Residence of food in the proximal stomach was decreased in 8 (33%) and antral contractility was increased in 9 (37.5%) and decreased in 2 (8%) patients. Proximal and distal stomach motor abnormalities were neither significantly correlated nor associated. Increased antral contractility was significantly correlated (Rs = 0.54; P< .01) with postprandial nausea. We conclude that diminished residence of food in the proximal stomach and disturbed antral contractility occur independently in different subsets of functional dyspepsia patients. Increased antral contractility seems to play a role in postprandial nausea in functional dyspepsia.

Objectif: Les barriéres à la formation fondée sur la simulation en enseignement universitaire supérieur et en formation continue pour les anesthésiologistes ne sont pas bien connues. Nous avons émis ľhypothése que le niveau de formation pouvait influencer ľattitude face à ce type de formation et avoir un effet sur ľutilisation de la simulation. Notre étude a été réalisée à ľuniversité de Toronto qui posséde deux sites équipés de simulateurs de haute fidélité. Méthode: Un questionnaire de 40 questions sur les expériences, les perceptions, les motivations et les barriéres perçues de la formation par simulation a été distribué à 154 anesthésiologistes en réunion départementale. Les données ont été analysées par des statistiques descriptives et les liens entre les réponses par le test chi-deux ou une analyse simple de la variance. Résultats: Le taux de réponses a été de 58 %. Les résidents avaient plus ďexpérience de la simulation (96 %) que les spécialistes (58 %) et les boursiers (36 %), (P &lt; 0,001 respectivement). Les résidents avaient aussi assisté à plus de sessions de simulation que les spécialistes et les boursiers (moyenne de 2,8 vs 1,05 et 1,04, P &lt; 0,001 respectivement). Les résidents et les boursiers ont trouvé la simulation plus pertinente que les anesthésiologistes (88 % vs 65 %, P &lt; 0,05). Parmi les répondants, 81 % ont reconnu au moins une barriére importante qui empêche ou limite la participation à des sessions de simulation. Les spécialistes ont perçu de multiples barriéres significatives dont le «temps» et «les questions financiéres». Conclusion: Le niveau de formation des anesthésiologistes influence ľattitude face à la simulation et leurs perceptions de la formation par simulation. Les limites à un plus grand usage de la simulation, reconnues dans ľenquête, pourraient servir à des interventions ciblées comme ľorganisation ďun cours, des incitatifs et des stratégies ďinformations pour améliorer ľaccés à la simulation et son usage futur.