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Objectives This study aimed to examine the sensitivity of muscle biopsy (MB) in ANCA-associated vasculitis (AAV), identify factors predicting MB positivity and assess the prognostic value of a positive MB. Methods We conducted a single-centre retrospective study of AAV with an MB performed at diagnosis. AAV classification [granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA)] followed the European Medicines Agency algorithm. A logistic regression model was used to identify the factors associated with MB positivity. Survival curves were generated using the Kaplan–Meier method. Results Among 276 AAV patients (1995–2018), 101 had an MB. Seventy-eight patients were included: 33 with GPA, 25 with MPA and 20 with EGPA. MB samples were positive in 45 cases (58%): 17 GPA, 16 MPA and 12 EGPA. Univariate analysis focussed on GPA and MPA, revealed that the MB yield was higher in females [22/31 (71%) vs 11/27 (41%); P = 0.02] and in anti-MPO patients [25/37 (68%) vs 6/19 (32%) for anti-PR3; P = 0.01]. By multivariate analysis, three factors predicted MB positivity: anti-MPO ANCA [odds ratio (OR) 10.67 (CI 2.09, 81.68)], female sex [OR 5.3 (CI 1.16, 32.35)] and neutrophil count [OR 1.33 (CI 1.07, 1.8)]. MB positivity had no impact on relapse, death or end-stage renal disease–free survival. Conclusions MB is a safe and efficient diagnostic tool for AAV. Predictors of MB yield include ANCA type, sex and neutrophil count. MB cannot substitute for kidney biopsy when indicated, but should be considered in other cases.

Introduction Dysautonomia in Parkinson's disease (PD) has been shown to be associated with disease severity and especially with the occurrence of dementia. One proposed explanation for this finding is that phosphorylated alpha-synuclein histopathology (PASH), the characteristic pathological feature of PD is more diffuse in dysautonomia-associated PD than in disease without dysautonomia, not only in the central nervous system but also in peripheral autonomic networks. The aim of this study was therefore to determine if colonic alpha-synuclein histopathology is associated with dysautonomia in PD. Methods A total of 43 PD patients participated in this study. For each patient, two biopsies were taken in the sigmoid colon and analyzed by immunohistochemistry with antibodies against phosphorylated alpha-synuclein and PGP 9.5. All patients had a complete neuropsychological and neurological assessment along with a comprehensive evaluation of dysautonomia with questionnaires (SCOPA-Aut, NMS-Quest, Rome III constipation criteria and dry eye symptoms) and functional tests (pupillometry, Saxon and Schirmer's tests, heart rate variability, orthostatic blood pressure measure and sympathetic skin response). Results Colonic PASH was observed in 20/43 PD patients. No differences were observed in autonomic symptoms and testing between patients with and without PASH. Conclusions Although frequent in PD, autonomic dysfunction is not related to colonic PASH. In addition to the existing literature, our findings further suggest that each dysautonomic symptom in PD might not be associated with a more severe or diffuse PASH not only in the central nervous system but also in the peripheral autonomic nervous systems.

Background: Although performed daily, intubation in intensive care units (ICU) remains a critical procedure with life-threatening adverse events. High-flow therapy by nasal cannulae (HFNC) is now widespread in the operating room and in the ICU, especially for preoxygenation before intubation in non-hypoxemic patients. However, no large randomized study has assessed its relevance in this population. Methods: The PROTRACH study is a randomized, multicenter open-labelled, controlled trial, including non-severely hypoxemic patients requiring intubation in medical or surgical ICU. Patients were randomly allocated to receive 4-minute preoxygenation delivered by HFNC or standard high-flow face mask (HFFM) before intubation. HFNC was maintained throughout the intubation procedure whereas HFFM was removed to perform laryngoscopy. The primary outcome was the lowest pulse oximetry throughout the intubation procedure. Secondary outcomes included drop in pulse oximetry, adverse events related to intubation, and outcome in the ICU. Main Findings: A total of 192 patients were randomized. In the intent-to-treat analysis, 184 patients (HFNC n = 95; HFFM n = 89), the median [IQR] lowest pulse oximetry was 100% [97;100] for HFNC and 99 % [95;100] for the HFFM group (P = 0.30). Mild desaturation below 95% was more frequent with HFFM (23%) than with HFNC (12%) (relative risk 0.51, CI 95% [0.26 to 0.99], P = 0.045). There were fewer adverse events in the HFNC group (6%) than in the HFFM group (19%) (relative risk 0.31, CI 95% [0.13 to 0.76], P = 0.007), including significantly fewer severe adverse events, respectively 6 (6%) and 14 (16%) with HFNC and HFFM (relative risk 0.38, CI 95% [0.15 to 0.95], P = 0.03). There was no difference in the outcome in the ICU with a mortality rate of 27% in both groups (P = 0.90). Interpretation: Compared with HFFM, preoxygenation with HFNC in the ICU did not improve the lowest level of pulse oximetry during intubation in the non-severely hypoxemic patients but led to a reduction in severe and moderate intubation-related adverse events. Clinical Trial Number: Clinicaltrials.gov identifier: NCT02700321, Eudra CT: 2015-A00145-44 Funding Statement: The French Ministry of Health (Interregional French Clinical Hospital Research Program grant (PHRCi 2014 - API12/N/077), a grant for research & innovation missions (University Hospital of Nantes) and by Fisher & Paykel Healthcare. Declaration of Interests: Declaration of Interest: Christelle Volteau, Gwenael Colin, Adel Maamar, Vanessa Jean Michel, Pierre Joachim Mahe, Mickael Landais, Noelle Brule, Cedric Bretonniere, Olivier Zambon and Christophe Guitton declare no conflict of interest. Stephan Ehrmann declares receiving consultancy fees from Aerogen Ltd, La Diffusion Technique Francaise and Baxter healthcare and unrestricted research support from Fisher and Paykel, Aerogen Ltd and Hamilton medical. Mickael Vourc’h declares personal fees from MSD, Pfizer, Baxter, grants from Fisher Paykel, outside the submitted work. Ethics Approval Statement: Three methods of consent were available. When possible, capable patients were included after written informed consent. Most patients were included after the written informed consent of their next-of-kin or following an emergency inclusion procedure if not available at the time of inclusion. Then, consent was obtained from all patients as soon as possible after recovery. The appropriate ethics committee (Comite de Protection des Personnes, Rennes, France) approved this study protocol in September 2015 (15/13-975).

The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN® compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.

Background Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. Methods This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). Results Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P Conclusions A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. Trial registration ClinicalTrials.gov, NCT01738360 registered 30 November 2012

Background Pain from needle-related procedures in children can alter pain perception, increase pain sensitivity, and generate inappropriate pain responses. Currently pain management includes the use of lidocaine-containing patches, which is complicated to manage in a busy medical setting such as a vaccination centre. We assessed the BuzzyⓇ device, which combines vibration and cold, to manage pain in children undergoing a needle-related procedure, compared to the standard lidocaine patch. Design Prospective, open-label, non-inferiority trial. Setting The vaccination centres of three university hospitals in France. Participants French speaking children aged 4–15 requiring a needle-related procedure (vaccination or venepuncture) were eligible. Principal exclusion criteria were allergy or sensitivity to the lidocaine patch. Methods Children were randomly allocated (1:1) to use either the BuzzyⓇ device or the lidocaine patch during the needle-related procedure. The lidocaine patch was applied to the puncture site for the hour prior to the intervention. The BuzzyⓇ device was applied to the puncture site for 30 s and then moved 5 cm along the limb during the procedure. The refrigerated wings were detached if they bothered the child. The child assessed their pain using the validated Revised Faces Pain Scale. The revised faces pain scale comprised six facial expressions from 0, normal “no pain” to 10, a screaming face “severe pain” (2 points/face). The primary endpoint was the average pain score recorded by the child. The study aimed to test the non-inferiority of BuzzyⓇ. Results Overall 219 participants were randomised. The primary outcome was assessed in 215 children: 108 in the BUZZY group (43% asked for the refrigerated wings were de to be detatched before the end of the procedure) and 107 in the PATCH group. The baseline characteristics were similar between the study groups with an average age of 9 (range: 4.08–15.81). The average needle-related pain was 2.04 in the BUZZY group and 1.42 in the PATCH group. The average difference between the children's assessments in the groups was 0.62, thus faling to demonstrate non-inferiority. Conclusions Our study failed to show that the BuzzyⓇ device was not inferior to the lidocaine patch in managing pain in children undergoing needle-related procedures. Tweetable abstract: Pain management in children undergoing a needle-related procedure vaccination: which efficacy for BuzzyⓇ device as an alternative to lidocaine patch? A prospective, randomised study.

AimsTo map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles.MethodsMapping is based on hierarchical clustering analyses of a series of 283 CRCs. Data tabulated were histopathological patterns, immunophenotypic differentiation, RAS, RAF, CTNNB1 mutations and microsatellite instability status, tumour-infiltrating lymphocytes (TILs) and genetic setting. Beta-catenin expression in more than 10% of cell nuclei in the centre of tumour serves as a surrogate marker of significant activation of Wnt signalling pathway.ResultsNuclei beta-catenin expression was present in 95% of CRCs; 56% of them met the criteria of high level of nuclei beta-catenin expression (≥10%). Proportion of beta-catenin positive nuclei was significantly higher in younger patients, rectal and left-sided colonic carcinomas. CRCs with high level of nuclei beta-catenin expression were regrouped into three clusters: (1) microsatellite stability (MSS) CRCs with no constitutive MAPK pathway activation including 90% of low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs; (2) RAS-mutated MSS CRCs including low-grade adenocarcinoma, NOS, with intestinal differentiation and mucinous adenocarcinoma without TILs; (3) MSI-H CRCs including both BRAF-mutated CRCs evolving from serrated pathway and CTNNB1-mutated CRCs associated with Lynch syndrome.ConclusionsMSS low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs (‘crypt-like adenocarcinoma’) might be the morphological pending of canonical molecular subtype of CRC defined as displayed molecular epithelial differentiation and upregulation of WNT in consensus molecular classification of CRC.

Background The epiretinal membrane (ERM) is a degenerative condition associated with age, which can cause loss of vision and/or metamorphopsia. The treatment of symptomatic ERM involves surgical removal including a vitrectomy followed by peeling of the ERM using a microforceps. As the internal limiting membrane (ILM) is adherent to the ERM, it is sometimes removed with it (spontaneous peeling). If ILM remains in place, it can be removed to reduce ERM recurrence. However, it is important to clarify the safety of ILM peeling, while it increases surgical risks and cause histological disorganization of the retina that can lead to microscotomas, may be responsible for definitive visual discomfort. Methods PEELING is a prospective, randomized, controlled, single-blind, and multicentered trial with two parallel arms. This study investigates the benefit/risk ratio of active ILM peeling among individuals undergoing ERM surgery without spontaneous ILM peeling. Randomization is done in the operating room after ERM removal if ILM remains in place. After randomization, the two groups—“active peeling of the ILM” and “no peeling of the ILM”—are compared during a total of three follow-up visits scheduled at month 1, month 6, and month 12. Primary endpoint is the difference in microscotomas before surgery and 6 months after surgery. Patients with spontaneous peeling are not randomized and are included in the ancillary study with the same follow-up visits and the same examinations as the principal study. Relevant inclusion criteria involve individuals aged > 18 years living with idiopathic symptomatic ERM, including pseudophakic patients with transparent posterior capsule or open capsule or lensed patients with age-related cataracts. The calculated sample size corresponds to 53 randomized eyes (one eye/patient) per arm that means 106 randomized eyes (106 randomized patients) in total and a maximum of 222 included patients (116 spontaneous peeling). Discussion ILM peeling is often practiced in ERM surgery to reduce ERM recurrence. It does not impair postoperative visual acuity, but it increases the surgical risks and causes anatomical damages. If active ILM peeling is significantly associated with more microscotomas, it may contraindicate the ILM peeling during primitive idiopathic ERM surgery. Trial registration ClinicalTrials.gov, NCT02146144. Registered on 22 May 2014. Recruitment is still ongoing.

In this study, we evaluated the efficacy of a micro-immunotherapy medicine (MIM), 2LALERG, in a preclinical model of allergic respiratory disease sensitized with birch pollen extract (BPE). BALB/c mice were immunized with BPE, or saline solution, and were then challenged. Micro-immunotherapy medicine pillules were diluted in water, and 3 doses (0.75; 1.5; 3 mg/mouse) were tested and compared to vehicle control (3 mg/mouse). Treatments and vehicle were orally administered by gavage for 10 days. Micro-immunotherapy medicine (0.75 mg/mouse) reduced the number of total cells as well as the levels of interleukin (IL)-13 in bronchoalveolar lavage fluid (BALF) compared to vehicle control. Eosinophils in BALF tended to be lower compared to vehicle group, and the difference is close to significance. Histological analysis in the lungs confirms a moderate effect of MIM (0.75 mg/mice) on inflammatory infiltration and mucus production. Serum levels of IL-5 in MIM (0.75 mg/mouse)-treated mice were lower compared to vehicle; IL-4 levels tended to be lower too. Total immunoglobulin E (IgE) decreased in serum of MIM (1.5 and 0.75 mg/mouse) groups compared to vehicle control. Micro-immunotherapy medicine exerted the highest effect at the lowest dose tested. Micro-immunotherapy medicine resolved the local and systemic inflammation, even if partially, in a model of pollen-induced, IgE-mediated inflammation.

Pain from needle-related procedures in children can alter pain perception, increase pain sensitivity, and generate inappropriate pain responses. Currently pain management includes the use of lidocaine-containing patches, which is complicated to manage in a busy medical setting such as a vaccination centre. We assessed the BuzzyProspective, open-label, non-inferiority trial.The vaccination centres of three university hospitals in France.French speaking children aged 4-15 requiring a needle-related procedure (vaccination or venepuncture) were eligible. Principal exclusion criteria were allergy or sensitivity to the lidocaine patch.Children were randomly allocated (1:1) to use either the BuzzyOverall 219 participants were randomised. The primary outcome was assessed in 215 children: 108 in the BUZZY group (43% asked for the refrigerated wings were de to be detatched before the end of the procedure) and 107 in the PATCH group. The baseline characteristics were similar between the study groups with an average age of 9 (range: 4.08-15.81). The average needle-related pain was 2.04 in the BUZZY group and 1.42 in the PATCH group. The average difference between the children's assessments in the groups was 0.62, thus faling to demonstrate non-inferiority.Our study failed to show that the Buzzy

IntroductionDepression is among the most widespread psychiatric disorders in France. Psychiatric disorders are associated with considerable social costs, amounting to €22.6 billion for treatment and psychotropic medication in 2011. Treatment as usual (TAU), mainly consisting of pharmacotherapy and psychotherapy, is effective for only a third of patients and in most cases fails to prevent treatment resistance and chronicity. Transcranial direct current stimulation (tDCS) consists in a non-invasive and painless application of low-intensity electric current to the cerebral cortex through the scalp. Having proved effective in depressed patients, it could be used in combination with TAU to great advantage. The objective is to compare, for the first time ever, the cost-utility of tDCS-TAU and of TAU alone for the treatment of a depressive episode that has been refractory to one or two drug treatments.Methods and analysisThis paper, based on the DISCO study protocol, focuses on the design of a prospective, randomised, controlled, open-label multicentre economic study to be conducted in France. It will include 214 patients with unipolar or bipolar depression, assigning them to two parallel arms: group A (tDCS-TAU) and group B (TAU alone). The primary outcome is the incremental cost-effectiveness ratio, that is, the ratio of the difference in cost between each strategy to the difference in their effects. Their effects will be expressed as numbers of quality-adjusted life-years, determined through administration of the EuroQol Five-Dimension questionnaire over a 12-month period to patients (EQ-5D-5L). Expected benefits are the reduction of treatment resistance and suicidal ideation as well as social and professional costs of depression. Should depression-related costs fall significantly, tDCS might be considered an efficient treatment for depression.Ethics and disseminationThis protocol has been approved by a French ethics committee, the CPP-–Est IV (Comité de Protection des Personnes–Strasbourg). Data are to be published in peer-reviewed medical journals.Trial registration numberRCB 2018-A00474-51;NCT03758105

Background: Thrombocytopenia is a common disorder after heart or lung transplantation. Platelet transfusion is often required to maintain haemostasis but represents a specific cause of morbidity and mortality in this setting including alloimmunisation and graft rejection. Study design and methods: As part of a health-care quality improvement project, in a single-centre before–after pilot study, the relevance of a platelet transfusion saving strategy based on romiplostim administration after transplantation was assessed in patients with platelet count 9/L. Transfusions on days 28 and 90 were compared using propensity matched score for adjustment of demographic characteristics at baseline. The primary outcome was platelet transfusion until day 28 after transplantation. Results: Ninety-three patients were analysed (73 before vs. 20 after). The median [interquartile range] number of platelet concentrate was 1 [0;4.0] before versus 0.5 [0;2.0] in the after period, mean difference 0.5 confidence interval 95% [−0.7 to 1.7], p = 0.39. On day 28, median [interquartile range] red blood cell transfusion was significantly higher in the before versus the after period, 7 [2.0;13.5] versus 6 [1.5;8.5], mean difference 3.2 CI 95% [0.4-6.0], p = 0.02. At 6 months, the rate of patients with de novo anti-human leukocyte antigen alloimmunisation was 45% before versus 53% in the after period (p = 0.56). Deep venous thrombosis was detected in nine patients (12%) before versus seven patients (35%) in the after period (p = 0.04). Conclusion: Romiplostim did not significantly reduce platelet transfusion after heart or lung transplantation. Its relevance and safety in a global transfusion strategy remains to be studied in this setting in a large randomised study.

Background Whether they are injected peri- or intraocularly, corticosteroids are still essential tools in the therapeutic arsenal for treating inflammatory macular oedema. A few years ago, however, only triamcinolone acetonide was available to ophthalmologists. While this compound was initially developed for rheumatological or dermatological use, it has been increasingly deployed in ophthalmology, despite still being off-label. In 2011, the system for delivery of dexamethasone from a biodegradable, injectable implant into the vitreous cavity obtained approval for use in inflammatory macular oedema. While the efficacy and safety of triamcinolone in macular oedema, including inflammatory oedema, have already been studied, there are currently no publications on subconjunctival triamcinolone injections, which are simple, effective and well tolerated. To date, the dexamethasone 700 μg implant has been authorized for the treatment of noninfectious intermediate and posterior uveitis, but there have been no studies to evaluate the efficacy and safety of the different peri- and intraocular strategies, including the treatment of inflammatory macular oedema. Methods This protocol is therefore designed to compare the efficacy and safety of peri- and intraocular corticosteroid injections in the treatment of inflammatory macular oedema. In this ongoing study, 142 patients will be included, and the oedematous eye will be randomised to treatment with either subconjunctival triamcinolone injection or an intravitreal implant containing 700 μg dexamethasone. Follow-up is planned for 6 months with monthly visits. Each visit will include visual acuity measurement, a slit lamp examination, fundoscopy, intraocular pressure measurement, laser flare measurement (if available) and spectral domain optical coherence tomography. Discussion The results of this trial will have a real impact on public health if it is shown that a Kenacort retard® (i.e. triamcinolone) injection costing just €2.84 and performed in the physician’s office (with no additional overhead costs) is at least as effective as the dexamethasone 700 μg implant (Ozurdex®; costing approximately €960 with the injection performed in a dedicated room), with no increased side effects. Trial registration ClinicalTrials.gov, NCT02556424. Registered on 22 September 2015.

Endoscopic submucosal dissection is currently regarded as the method of choice for the resection of superficial tumours. The objective of our study was to evaluate prospectively the efficiency of an endoscopic submucosal dissection training course using live anaesthetised pigs.Fourteen novice endoscopists participated in three gastric endoscopic submucosal dissection training courses on anaesthetised pigs. Each trainee resected five 'fake' antral lesions. Resected specimen sizes, endoscopic submucosal dissection speeds and the complication rate were evaluated prospectively.Among the 70 procedures performed, 58 could be analysed. There was a strong increase in endoscopic submucosal dissection speed (from 9.7 mmThere is a clear benefit from endoscopic submucosal dissection training courses on animal models. Improved endoscopist capability is evident from the third endoscopic submucosal dissection. These data validate the indispensable nature of dedicated training courses and echo the European Society of Gastrointestinal Endoscopy proposition for multistep learning, beginning on animal models.

Objective The primary objective of this study was to compare the efficacy of local injection of a local anesthetic with a glucocorticoid versus a local anesthetic with saline to treat low back pain due to lumbosacral transitional vertebras (LSTV) with a pseudoarticulation. Methods A randomized placebo-controlled double-blind study was conducted in patients with unilateral low back pain ascribed clinically to LSTV. Patients were randomized to lidocaine plus saline (LS group) or lidocaine plus cortivazol (LC group) injected locally under computed tomography guidance. The primary outcome measure was the 24-hour mean visual analog scale (VAS) score for low back pain 4 weeks after the injection. Results Of 16 randomized patients, 15 were included in the analysis, 8 in the LS group and 7 in the LC group. The mean VAS pain score at week 4 was not significantly different between the two groups. In the two groups pooled, the mean VAS pain score decreased significantly from baseline to week 4, from 5.52 ± 0.99 to 3.86 ± 2.55 (P ≤ 0.05). The difference remained significant at week 12. Significant improvements occurred in the EIFEL disability index and items of the Dallas Pain Questionnaire. No adverse events were recorded. Conclusion In patients with chronic low back pain consistent with a symptomatic LSTV type II or IV in the Castellvi classification, a local injection of lidocaine with or without cortivazol may provide sustained improvements in pain and function. The underlying mechanism is unclear.

Resume Objectif L’objectif principal de cette etude etait de comparer l’efficacite des infiltrations anesthesie locale et corticoides versus anesthesie locale et serum physiologique dans le traitement des anomalies transitionnelles de la charniere lombosacree (ATLS). Methodes Les patients presentant une lombalgie unilaterale cliniquement liee a une ATLS ont ete randomises pour infiltration en double insu lidocaine et serum physiologique (LSP) versus lidocaine et cortivazole (LC) sous scanner. Le critere principal etudie etait l’evolution de l’EVA moyenne des 24 dernieres heures a 4 semaines. Resultats Seuls 16 patients ont ete randomises et 15 etudies (8 LSP et 7 LC). Il n’existait pas de difference significative entre les 2 groupes sur l’EVA moyenne a S4. Par contre si on regardait l’evolution de l’ensemble des patients, on notait une amelioration significative de l’EVA a S4 par rapport au baseline : EVA 5,52 ± 0,99 a S0 et 3,86 ± 2,55 a S4 ( p = Conclusion Dans les douleurs chroniques evoquant une origine ATLS avec neoarticulation de type II ou IV de la classification de Castellvi une infiltration peut etre proposee car elle peut ameliorer la douleur et la fonction durablement sans prejuger du mecanisme de l’amelioration.

The aim of this study was to interrogate the heterogeneity of colorectal mucinous adenocarcinomas. This study is based on hierarchical clustering approach combining clinicopathological and molecular patterns known to be relevant to oncogenesis and therapeutic management of patients with colorectal carcinoma, ie, microsatellite instability, O6-methylguanine-DNA methyltransferase (MGMT) status, KRAS, and BRAF mutations and wnt signaling pathway activation. Comparison of the study group of 60 mucinous adenocarcinomas defined according to World Health Organization classification with control group of 136 colorectal adenocarcinomas successively removed shows higher frequency of BRAF and KRAS mutations and microsatellite instability-high status and lower frequency of wnt signaling pathway activation in mucinous adenocarcinomas. Hierarchical clustering isolated three relevant clusters: (i) cluster of microsatellite stable mucinous adenocarcinomas (54%) with KRAS mutation, and frequent MGMT changes, more frequently located in the left colon, often associated with contiguous precursor adenoma; (ii) cluster of BRAF-mutated mucinous adenocarcinomas (28%) with either microsatellite instability-high or microsatellite stable status, occurring in elderly female patients, nearly all located in the right colon, having the signature of serrated pathway of carcinomas; and (iii) a heterogeneous cluster of microsatellite instability-high mucinous carcinomas (18%), including inherited colorectal carcinomas, displaying a high-grade histological pattern. Age, TNM stage, and BRAF mutation had prognostic value. Hierarchical clustering analysis led to the identification of several clinicopathological entities of colorectal mucinous adenocarcinomas with epidemiologic, prognostic, and therapy relevance. Both KRAS and BRAF mutations appear as drivers in the alternate oncogenetic pathways governing the development of sporadic colorectal mucinous adenocarcinomas.

Background The benefits of single-use ultrasonic scissors in thyroid surgery are still debated. Although this device has been shown to reduce operating time compared with conventional haemostasis, its cost-effectiveness has never been demonstrated. The aim of this study was to evaluate the efficacy, cost-effectiveness and safety of ultrasonic scissors for total thyroidectomy. Methods This was a prospective, randomized, multicentre trial conducted at 13 hospital sites. The primary endpoint was the percentage of patients with hypocalcaemia (serum calcium level below 2 mmol/l) on day 2. Secondary endpoints included postoperative complications and costs, with calculation of incremental cost differences and cost-effectiveness ratios. Results In total, 1329 patients who underwent total thyroidectomy were included in the analysis: 670 were randomized to treatment with ultrasonic scissors and 659 to conventional haemostasis. There was no difference between groups in the rate of complications, including hypocalcaemia on day 2 (19.7 per cent in ultrasonic scissors group versus 20.3 per cent in conventional haemostasis group; P = 0·743). Median operating times were significantly shorter with ultrasonic scissors (90 versus 100 min with conventional haemostasis; P

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and -kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open-label, randomized, monocentric, 5-year follow-up study, a tacrolimus- and a sirolimus-based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti-thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval -4.61% to 4.61%) and 6% (90% confidence interval -6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty-four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).

International audience; We previously demonstrated that HLA-E/β2m overexpression by tumor cells in colorectal cancers is associated with an unfavorable prognosis. However, the expression of its specific receptor CD94/NKG2 by intraepithelial tumor-infiltrating lymphocytes, their exact phenotype and function, as well as the relation with the molecular status of colorectal cancer and prognosis remain unknown. Based on a retrospective cohort of 234 colorectal cancer patients, we assessed the expression of HLA-E, β2m, CD94, CD8, and NKp46 by immunohistochemistry on tissue microarray. The expression profile of HLA-E/ β2m on tumor cells and the density of tumor-infiltrating lymphocytes were correlated to the clinicopathological and molecular features (Microsatellite status, BRAF and RAS mutations). Then, from the primary tumors of 27 prospective colorectal cancers, we characterized by multiparameter flow cytometry the nature (T and/or NK cells) and the co-expression of the inhibitory NKG2A or activating NKG2C chain of ex vivo isolated CD94 + tumor-infiltrating lymphocytes. Their biological function was determined using an in vitro redirected cytolytic activity assay. Our results showed that HLA-E/β2m was preferentially overexpressed in microsatellite instable tumors compared with microsatellite stable ones (45% vs. 19%, respectively, p = 0.0001), irrespective of the RAS or BRAF mutational status. However, HLA-E/β2m + colorectal cancers were significantly enriched in CD94 + intraepithelial tumor-infiltrating lymphocytes in microsatellite instable as well as in microsatellite stable tumors. Those CD94 + tumor-infiltrating lymphocytes mostly corresponded to CD8 + αβ T cells, and to a lesser extent to NK cells, and mainly co-expressed a functional inhibitory NKG2A chain. Finally, a high number of CD94 + intraepithelial tumor-infiltrating lymphocytes in close contact with tumor cells was independently associated with a worse overall survival. In conclusion, these findings strongly suggest that HLA-E/β2m-CD94/NKG2A represents a new druggable inhibitory immune checkpoint, preferentially expressed in microsatellite instable tumors, but also in a subgroup of microsatellite stable tumors, leading to a new opportunity in colorectal cancer immunotherapies.

This study aimed to assess patient investigational medication knowledge and to identify factors associated with medication understanding by adult outpatients included in clinical trials. A cross-sectional prospectively designed survey was conducted on consecutive volunteers at 21 university teaching hospitals (in France) from February to December 2014. Investigational medication understanding was assessed at the time of the first dispensing using a structured interviewer-administered questionnaire based on information obtained from the literature that provided an 8-point score. Demographic and other baseline data were collected using structured interviews. Of the 236 participants, 139 (58.9%) of the respondents were male, and the median age was 54.9 years (range: 18-83 years). The mean understanding score was 6.24 and 72.5% of the patients had a score of 6 or higher. In univariate analysis, the medication understanding score was negatively correlated with age (r = -0.15, p = 0.0247) and positively correlated with the level of education (r = 0.25, p = 0.0002). In multivariate analysis, prognostic factors of a higher medication understanding score were: graduation from high school or a higher level of education; HIV infection; phase II/III/IV studies; mention of the drug on the prescription form, and the dispensing of a single investigational medication. Only a quarter of the adult outpatients included in clinical trials had a maximum possible investigational medication understanding score. Being old and having a low level of education were found to be important risk factors for inadequate medication understanding. This and other data suggest that sponsors should encourage initiatives aimed at improving investigational medication understanding in adults enrolled in clinical trials.

IntroductionManagement of out-of-hospital cardiac arrests (OHCAs) in France is performed by a particular prehospital system based on medicalisation of mobile intensive care units composed of an emergency physician and a nurse with all the required devices for advanced care. It follows the European recommendations which advocate for the use of early point-of-care focused echocardiography (EPOCE) in the prehospital setting. An ability of EPOCE may be to predict the absence of return of spontaneous circulation (ROSC) in cases of absence of cardiac motion. We thus intended to investigate this predictive value with a prospective multicentre study. This paper describes the study protocol, while the first patients were recruited in December 2018.MethodsACE is a prospective multicentre (n=8) prognostic study. Briefly, as soon as OHCA is diagnosed and advanced life support (ALS) is initiated, EPOCE will be performed during the automated external defibrillator’ analysis period. The physician will assess detectable motion within the heart and reversible causes of OHCA. However, as the prognostic value of absence of cardiac motion is not currently validated, the results of EPOCE will not be used to withdraw ALS, and the decision to withdraw life support will be done following the European Resuscitation Council recommendations during our study.AnalysisThe primary endpoint is the positive predictive value of absence of cardiac motion for the absence of final ROSC. The secondary endpoints are predictive characteristics of EPOCE asystole on morbimortality 30 days after OHCA, description of reversible cause and analysis of the EPOCE technique.Ethics and disseminationACE was approved by an ethical committee (2018-AO1491-54). While ACE is adapted to the French prehospital system, its results will be translatable to other organisations if inter-rater variability is not found.Trial registration numberNCT03494153.

The aim of this Letter to the Editor was to respond to a comment highlighting potential statistical biases in an analysis of our recently published article. We therefore specified the method for selecting the model variables in order to limit overfitting, then we used the Firth method to control the sparse data bias, and finally for checking internal validity we used bootstrapping methods. In total, the conclusions of our model were not changed by these new analyses.

We previously demonstrated that HLA-E/β2m overexpression by tumor cells in colorectal cancers is associated with an unfavorable prognosis. However, the expression of its specific receptor CD94/NKG2 by intraepithelial tumor-infiltrating lymphocytes, their exact phenotype and function, as well as the relation with the molecular status of colorectal cancer and prognosis remain unknown. Based on a retrospective cohort of 234 colorectal cancer patients, we assessed the expression of HLA-E, β2m, CD94, CD8, and NKp46 by immunohistochemistry on tissue microarray. The expression profile of HLA-E/β2m on tumor cells and the density of tumor-infiltrating lymphocytes were correlated to the clinicopathological and molecular features (Microsatellite status, BRAF and RAS mutations). Then, from the primary tumors of 27 prospective colorectal cancers, we characterized by multiparameter flow cytometry the nature (T and/or NK cells) and the co-expression of the inhibitory NKG2A or activating NKG2C chain of ex vivo isolated CD94

Background Many studies have demonstrated a link between pelvic floor myofascial syndromes and chronic pelvic pain. Botulinum toxin has been extensively used for several years in the field of pain, especially due to its action on muscle spasm. However, the efficacy of botulinum toxin in the context of chronic pelvic pain remains controversial. Objectives This multicentre, randomized, controlled, double-blind study was designed to compare the efficacy of botulinum toxin and local anaesthetic (LA) injection versus LA injection alone for pelvic floor myofascial syndrome and chronic pelvic pain. Methods According to the number of painful trigger points detected on physical examination, patients received from 1 to 4 injections of botulinum toxin with LA (BTX) or LA alone. The primary endpoint was Patient Global Impression of Improvement (PGI-I) score on day 60 after infiltration. Secondary endpoints were pain intensity, number of painful trigger points on palpation, analgesic drug consumption and quality of life. Results We included 80 patients, 40 in each group. This study failed to demonstrate a significant difference between the 2 groups on day 60 in the primary endpoint or secondary endpoints (PGI-I score ≤ 2 = 20% [LA] versus 27.5% [BTX], P = 0.43). However, both groups showed significant alleviation of global pain. Conclusion This study does not justify the use of botulinum toxin in the context of chronic pelvic pain with myofascial syndrome but does justify muscle injections with LA alone. ClinicalTrials.gov: NCT01967524 .

International audience; OBJECTIVE: To determine whether high-flow oxygen therapy by nasal cannulae (HFNC) is more effective than a high-flow face mask (HFFM) in severe hypoxemia. DESIGN: Randomized, single-center, open-labeled, controlled trial. SETTING: University Hospital of Nantes, France. PARTICIPANTS: Cardiac surgery patients presenting oxygen saturation

Background The impact of obesity on total thyroidectomy (TT) morbidity (recurrent laryngeal nerve palsy and hypocalcaemia) remains largely unknown. Methods In a prospective study (NCT01551914), patients were divided into five groups according to their body mass index (BMI): underweight, normal weight, overweight, obese, and severely obese. Preoperative and postoperative serum calcium was measured. Recurrent laryngeal nerve (RLN) function was evaluated before discharge, and if abnormal, at 6 months. Results In total 1310 patients were included. Baseline characteristics were similar across BMI groups except for age and sex. Postoperative hypocalcaemia was more frequent in underweight compared to obese patients but the difference was not statistically significant in multivariate analysis. There was no difference between groups in terms of definitive hypocalcaemia, transient and definitive RLN palsy, and postoperative pain. Conclusion Obesity does not increase intraoperative and postoperative morbidity of TT, despite a longer duration of the procedure.

It is well known that total thyroidectomy is feasible on elderly patients but is linked to complications because of their underlying comorbidities. In this study we analyzed the specific risks linked to surgery, hypoparathyroidism and recurrent nerve palsy.materials-methods:Prospective, multicentre trial conducted at 13 hospital sites. The primary endpoint was the percentage of patients with postoperative hypocalcaemia (albumin-corrected serum calcium level2 mmol/L at day 2). Secondary endpoints included recurrent nerve palsy rate at day 2, the percentage of patients with hypocalcaemia (serum calcium level2 mmol/L) and recurrent nerve palsy at month 6, operating durations and postoperative pain. Patients were separated in two groups:70 years and ≥70 years old.In total, 1329 patients who underwent total thyroidectomy were included (median age 51.17 years [18.10; 80.90], 80% women, and hyperthyroidism in 20%, 101 ≥ 70 years old). Rates of hypocalcaemia at day 2 and month 6 were 20.02% and 1.98% respectively. Nasofibroscopy showed postoperative abnormal vocal cord motility in 9.92% cases (hypo-motility 5.76% - immobility 4.16%) and 0.95% at month 6 (hypo-motility 0.48%, immobility 0.48%). Patients ≥70 years had a lower (but non-significant) postoperative and definitive hypocalcaemia rate than patients 70 years: 14.85% vs 20.44% at day 2 (p = 0.1773) and 0% vs 2.15% at month 6 respectively (p = 0.2557). Abnormal vocal cord motility rate was 12.00% in patients ≥70 years vs 9.75% in patients70 years at day 2 (p = 0.4702), and 2.06% in patients ≥70 years vs 0.86% at month 6 (p = 0.2340).Total thyroidectomy in patients ≥70 years is feasible and safe. Age does not increase the morbidity. The study is registered with ClinicalTrials.gov number NCT01551914.

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

Objectives To assess the prevalence of bronchiectasis in a Western cohort with ANCA-positive granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and its correlations with disease presentation and outcome. Methods Retrospective study of ANCA-associated vasculitis (AAV) patients followed at Nantes University Hospital (2005–2015). Clinical, biological, and follow-up data were collected through chart review. Two experienced radiologists blinded to the clinical data interpreted chest high-resolution CTs according to the Feischner Society criteria. Results Fifty-eight patients were included: 30 had MPA (51.7%) and 28 had GPA (48.3%). The median age at AAV diagnosis was 65.5 years. Anti-MPO-ANCA and anti-PR3-ANCA were present in 39 (67.2%) and 19 (32.8%) patients, respectively. Overall, bronchiectasis was found in 22 patients (37.9%), all of whom had anti-MPO ANCA. In multivariate analysis, bronchiectasis was independently associated with anti-MPO-ANCA, female gender and age at AAV diagnosis. Furthermore, anti-MPO ANCA patients with bronchiectasis had more frequent peripheral nerve involvement (54.5 vs. 17.6%, p = 0.019) and less frequent renal involvement than those without bronchiectasis (40.9% vs. 82.3%, p = 0.009). Disease course, survival and risk of severe pulmonary infection were similar in patients with and without bronchiectasis on chest CT. Conclusions This study shows that bronchiectasis is a highly prevalent pre-existing respiratory condition in Caucasian patients with anti-MPO AAV. This subset of patients exhibits a distinct presentation. Further studies are needed to confirm these findings and clarify the clinical implications of this association. Whether the respiratory tract could be the site of initiation of anti-MPO auto-immunity remains to be investigated.