Pros and cons of internal limiting membrane peeling during epiretinal membrane surgery: a randomised clinical trial with microperimetry (PEELING).

BACKGROUND: After idiopathic epiretinal membrane (iERM) removal, it is unclear whether the internal limiting membrane (ILM) should be removed. The objective was to assess if active ILM peeling after iERM removal could induce microscotomas. METHODS: The PEELING study is a national randomised clinical trial. When no spontaneous ILM peeling occurred, patients were randomised either to the ILM peeling or no ILM peeling group. Groups were compared at the month 1 (M1), M6 and M12 visits in terms of microperimetry, best-corrected visual acuity (BCVA) and optical coherence tomography findings. The primary outcome was the difference in microscotoma number between baseline and M6. RESULTS: 213 patients were included, 101 experienced spontaneous ILM peeling and 100 were randomised to the ILM peeling (n=51) or no ILM peeling group (n=49). The difference in microscotoma number between both groups was significant at M1 (3.9 more microscotomas in ILM peeling group, (0.8;7.0) p=0.0155) but not at M6 (2.1 more microscotomas in ILM peeling group (-0.5;4.7) p=0.1155). Only in the no ILM peeling group, the number of microscotomas significantly decreased and the mean retinal sensitivity significantly improved. The ERM recurred in nine patients in the no ILM peeling group (19.6%) versus zero in the ILM peeling group (p=0.0008): two of them underwent revision surgery. There was no difference in mean BCVA and microperimetry between patients experiencing or not a recurrence at M12. CONCLUSION: Spontaneous ILM peeling is very common. Active ILM peeling prevents anatomical ERM recurrence but may induce retinal impairments and delay visual recovery. TRIAL REGISTRATION: NCT02146144.

Effects of the delivery of physiotherapy on the treatment course of elderly fallers presenting to the emergency department: Protocol for a randomized clinical trial.

The use of physiotherapy (PT) in the hospital emergency department (ED) has shown positive results including improvements in patient waiting time, treatment initiation, discharge type, patient outcomes, safety and acceptability of the intervention by medical staffs. These findings originate from studies that primarily focus on musculoskeletal and orthopaedic conditions. Despite a significant number of people visiting the ED, there is a shortage of literature evaluating PT in the ED for elderly populations. The objective of this study is the evaluate the effect of delivering PT in the ED (versus no delivery) in patients aged 75 and over with 'falls' complaints. The main objective is the evaluate the effect on the discharge disposition (discharge home, hospitalization). Secondarily, we will evaluate the effect delivering PT on patient-length of stay, the number of falls at 7 days after admission to the ED, changes between the initial and final medical decision regarding patient orientation, and medical staff satisfaction. This study will follow a prospective longitudinal design involving participants aged 75 years and over. We plan to recruit a total n = 336 patients admitted to the ED with a 'fall' chief complaint. After consent, participants will be randomized into either the 'PT-group' (receiving a prescription and execution of PT within the ED), or to the 'no-PT group' (no delivery of PT within the ED). The PT intervention will involve a standardized assessment of motor capacities using validated clinical examinations, and the delivery of rehabilitative exercises based on individual needs. Outcomes will be recorded from the patient's medical record, and a phone call at 7 days. A questionnaire will be sent to medical staff. The results of this study will help to determine whether PT might be beneficial for the management of this increasing proportion of individuals who come to the ED. Trial registration: (Trial registration number: ClinicalTrials.gov NCT05753319). https://classic.clinicaltrials.gov/ct2/show/NCT05753319.

Observational and prospective study: evaluation of beliefs and representations of chronic treatments of polymedicated patients hospitalised in a vascular medicine and surgery department.

OBJECTIVES: Today, the involvement of patients in their care is essential. As the population ages increases, the number of patients with chronic diseases is increasing. In the vascular medicine and surgery departments, patients are polymedicated and mostly suffer from several chronic diseases. Approximately 50% of patients with a chronic disease are not adherent. Among the factors that can influence therapeutic adherence are the beliefs and representations of patients.To evaluate the beliefs and representations of chronic treatments in patients with multiple medications and hospitalised in a vascular medicine and surgery department, and to evaluate the medication adherence, the knowledge and the importance patients attach to their treatments. DESIGN: Observational, prospective and a single-centre study. SETTING: The study was conducted in a French tertiary hospital centre of around 3000 beds in 9 institutions. PARTICIPANTS: Adult polymedicated (ie, minimum of five chronic treatments) patients hospitalised in a vascular medicine and surgery department were included after application of the exclusion criteria. METHODS: Patient interviews were carried out in the department and were based on three interviewer-administered questionnaires (a global questionnaire, the Belief Medical Questionnaire and the GIRERD questionnaire). RESULTS: Our study showed that patients perceived their treatments as beneficial rather than worrying. A correlation between medication adherence and beliefs was observed. 'Non-adherent'patients had a more negative overall view of medication than 'adherent' patients. The level of compliance and knowledge of our patients was low. Only 11% of the patients were 'good adherent', 16% of the patients could perfectly name their treatment and 36% knew all the indications. CONCLUSION: Knowledge of treatment representation and beliefs are central to understanding patient behaviour. Considering patients' representations will allow the identification of levers, and the development of actions and educational tools adapted to improve their adherence, their knowledge and therefore their drug management.

Evaluation of a scoring system for the detection of central sensitization among women with chronic pelvic pain.

BACKGROUND: Central sensitization is frequently associated with chronic pelvic pain and requires specific management. The pain is described as hypersensitivity to an innocuous stimulus that is both widespread and persistent. However, no study has evaluated if central sensitization can be measured objectively with neurophysiological tests in the pelvic and perineal area to prove this concept in women with chronic pelvic pain. OBJECTIVE: This study aimed to evaluate nociceptive thresholds (primary objective) and spatial and temporal diffusion of pain among women with chronic pelvic pain and high or low scores of central sensitization. STUDY DESIGN: This prospective, assessor-blinded, comparative study compared a cohort of women with chronic pelvic pain and a high (>5/10; n=29) vs low (<5/10; n=24) score of sensitization according to the Convergences PP criteria. Participants underwent a noninvasive bladder sensory test, a rectal barostat test, and a muscular (algometer) and a vulvar (vulvagesiometer) sensory test. Poststimulation pain (minutes), quality of life (Medical Outcomes Study 36-Item Short Form Survey), and psychological state, comprising anxiety (State-Trait Anxiety Inventory), depression (Beck Depression Inventory Short Form), and catastrophizing (Pain Catastrophizing Scale), were assessed. RESULTS: The participants mostly suffered from endometriosis (35.8%), irritable bowel syndrome (35.8%), bladder pain syndrome (32.1%), and vestibulodynia (28.3%). Baseline characteristics were similar. Women with a high sensitization score had more painful diseases diagnosed (2.7±1.3 vs 1.6±0.8; P=.002) and suffered for longer (11±8 vs 6±5 years; P=.028) than participants with a low score. The bladder maximum capacity was equivalent between participants (399±168 vs 465±164 mL; P=.18). However, the pain felt at each cystometric threshold was significantly increased in women with a high sensitization score. No difference was identified for the rectal pain pressure step (29.3±5.5 vs 30.7±6.5 mm Hg; P=.38). Rectal compliance was decreased in women with a high sensitization score with a considerable increase in pain felt. The average of pain pressure thresholds at the 5 vulvar sites tested was decreased in these participants (162.5±90.5 vs 358.7±196.5 g; P=.0003). Similar results were found for the average of the pain pressure thresholds at 6 muscles tested (1.34±0.41 vs 2.63±1.52 kg/m2; P=.0002). A longer period was needed for patients with high sensitization score to obtain a VAS <3 out of 10 after the stimulation of the bladder (4.52±5.26 vs 1.27±2.96 minutes; P=.01), the rectum (3.75±3.81 vs 1.19±1.23 minutes; P=.009), and the muscles (1.46±1.69 vs 0.64±0.40 minutes; P=.002). The psychological state was equivalent between groups. No association was found between the sensory thresholds and the psychological state results. The physical component of the quality of life score was reduced in women with high sensitization score (P=.0005), with no difference in the mental component. CONCLUSION: Using neurophysiological tests, this study showed that there are objective elements to assess for the presence of central sensitization, independently of psychological factors.

Mortality After Total Thyroidectomy for Amiodarone-Induced Thyrotoxicosis According to Left Ventricular Ejection Fraction.

OBJECTIVE: To report cardiac outcomes after total thyroidectomy for amiodarone-induced thyrotoxicosis according to the baseline left ventricular ejection fraction in a tertiary referral center. STUDY DESIGN: Retrospective, monocentric. SETTING: The tertiary health care system. METHODS: Patients who underwent total thyroidectomy for amiodarone-induced thyrotoxicosis between 2010 and 2020 with age >18 and available preoperative left ventricular ejection fraction were included in this study. Patients were dichotomized into: group 1 with left ventricular ejection fraction ≥40% (mildly reduced/normal ejection fraction), and group 2 with left ventricular ejection fraction <40% (reduced ejection fraction). RESULTS: There were 34 patients in group 1 and 17 to group 2. The latter were younger (median 58.4 [Q1-Q3 48.0-64.9] vs. 69.8 years in group 1 [59.8-78.3], p = .0035) and they presented more cardiomyopathy (58.8 vs. 26.5%, p = .030). Overall, the median time until surgery referral was 3.1 [1.9-7.1] months and 47.1% underwent surgery after restoration of euthyroidism. Surgical complications accounted for 7.8%. In group 2, the median left ventricular ejection fraction was significantly improved after surgery (22.5 [20.0-25.0] vs. 29.0% [25.3-45.5], p = .0078). Five-year cardiac mortality was significantly higher in group 2 (p < .0001): 47.0% died of cardiac causes versus 2.9% in group 1. A baseline left ventricular ejection fraction <40% and a longer time until surgery referral were significantly associated with cardiac mortality (multivariable Cox regression analysis, p = .015 and .020, respectively). CONCLUSION: These results reinforce the idea that surgery, if chosen, should be performed quickly in patients with left ventricular ejection fraction <40%.

Effect of Active Physiotherapy With Positive Airway Pressure on Pulmonary Atelectasis After Cardiac Surgery: A Randomized Controlled Study.

OBJECTIVES: The authors investigated the effect of active work with positive airway pressure (PAP) in addition to chest physiotherapy (CP) on pulmonary atelectasis (PA) in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: A randomized controlled study. SETTING: At a single-center tertiary hospital. PARTICIPANTS: Eighty adult patients undergoing cardiac surgery (coronary artery bypass grafting, valve surgery, or both), and presenting with PA after tracheal extubation on postoperative days 1 or 2, were randomized from November 2014 to September 2016. INTERVENTION: Three days of CP, twice daily, associated with active work with PAP effect (intervention group) versus CP alone (control group). Pulmonary atelectasis was assessed by using the radiologic atelectasis score (RAS) measured from daily chest x-rays. All radiographs were reviewed blindly. MEASUREMENTS AND MAIN RESULTS: Among included patients, 79 (99%) completed the trial. The primary outcome was mean RAS on day 2 after inclusion. It was significantly lower in the intervention group (mean difference and 95% CI: -1.1 [-1.6 to -0.6], p < 0.001). The secondary outcomes were the sniff nasal inspiratory pressure measured before and after CP and clinical variables. Sniff nasal inspiratory pressure was significantly higher in the intervention group on day 2 (7.7 [3.0-12.5] cmH2O, p = 0.002). The respiratory rate was lower in the intervention group (-3.2 [95% CI -4.8 to -1.6] breaths/min, p < 0.001) on day 2. No differences were found between the 2 groups for percutaneous oxygen saturation/oxygen requirement ratio, heart rate, pain, and dyspnea scores. CONCLUSIONS: Active work with the PAP effect, combined with CP, significantly decreased the RAS of patients undergoing cardiac surgery after 2 days of CP, with no differences observed in clinically relevant parameters.

PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited. Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence. METHODS: Our hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals. DISCUSSION: Due to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients' physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05025826. First published on August 27, 2021.

Effects of wearing removable dentures and aging on palatal mucosa blood flow by laser doppler.

Aim: The purpose of this work is to analyze the effects of removable dental prostheses and aging on blood microcirculation in the palatal mucosa. Settings and Design: Blood flow was measured in two groups using the Laser Doppler Flowmeter at three specific anatomical sites: Retro incisive papilla, medial raphe, and Schroeder area. Materials and Methods: Group 1 included young, healthy dentulous individuals (mean age: 23 ± 3 years), and Group 2 contained elderly edentulous individuals (mean age: 62 ± 11.69 years). For Group 1, measurements were taken in a single session; for Group 2, the measurements were taken in two sessions: The first just before the prosthetic load (E1) and again 1 week after new dentures were provider (E2). Statistical Analysis Used: Statistical analyses were performed using SAS software, Version 9.4 of the SAS System for Windows, Copyright © 2017 SAS Institute Inc. (Cary, NC, USA). A P < 0.05 was classified as statistically significant. Results: Measurements of blood flow of the palatal mucosa showed that the healthy young dentulous participants had significantly lower perfusion unit values than the elderly edentulous participants at all three anatomical sites (P < 0.05). For Group 2, the comparisons between the measurements taken before (E1) and after (E2) new dentures were provided showed no significant differences. Conclusion: Our results indicate that the process of aging significantly modifies the blood flow of the palatal mucosa while wearing removable dental prostheses does not modify the blood flow of the palatal mucosa in a 1week period. These results are not influenced by systemic pathology (e.g., diabetes, cardiovascular diseases) or smoking.

Mapping of colorectal carcinoma diseases with activation of Wnt/beta-catenin signalling pathway using hierarchical clustering approach.

AIMS: To map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles. METHODS: Mapping 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. RESULTS: Nuclei 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. CONCLUSIONS: MSS 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.

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic).

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 < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4). 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.

Botulinum toxin infiltrations versus local anaesthetic infiltrations in pelvic floor myofascial pain: Multicentre, randomized, double-blind study.

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.

Muscle biopsy in anti-neutrophil cytoplasmic antibody-associated vasculitis: diagnostic yield depends on anti-neutrophil cytoplasmic antibody type, sex and neutrophil count.

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.

The effectiveness of the BuzzyⓇ device to reduce or prevent pain in children undergoing needle-related procedures: The results from a prospective, open-label, randomised, non-inferiority study.

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.

Does internal limiting membrane peeling during epiretinal membrane surgery induce microscotomas on microperimetry? Study protocol for PEELING, a randomized controlled clinical trial.

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.

Potential Role of the Micro-Immunotherapy Medicine 2LALERG in the Treatment of Pollen-Induced Allergic Inflammation.

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.

Cost-utility analysis of curative and maintenance repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant unipolar depression: a randomized controlled trial protocol.

BACKGROUND: Depression is a debilitating and costly disease for our society, especially in the case of treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy in treatment-resistant unipolar and non-psychotic depression. It can be applied according to two therapeutic strategies after an initial rTMS cure: a further rTMS cure can be performed at the first sign of relapse or recurrence, or systematic maintenance rTMS (M-rTMS) can be proposed. TMS adjuvant to treatment as usual (TAU) could improve long-term prognosis. However, no controlled study has yet compared the cost-effectiveness of these two additional rTMS therapeutic strategies versus TAU alone. METHODS/DESIGN: This paper focuses on the design of a health-economic, prospective, randomized, double-blind, multicenter study with three parallel arms carried out in France. This study assesses the cost-effectiveness of the adjunctive and maintenance low frequency rTMS on the right dorsolateral prefrontal cortex versus TAU alone. A total of 318 patients suffering from a current TRD will be enrolled. The primary endpoint is to investigate the incremental cost-effectiveness ratio (ICER) (ratio costs / quality-adjusted life-years [QALY] measured by the Euroqol Five Dimension Questionnaire) over 12 months in a population of patients assigned to one of three arms: systematic M-rTMS for responders (arm A); additional new rTMS cure in case of mood deterioration among responders (arm B); and a placebo arm (arm C) in which responders are allocated in two subgroups: sham systematic M-rTMS and supplementary rTMS course in case of mood deterioration. ICER and QALYs will be compared between arm A or B versus arm C. The secondary endpoints in each three arms will be: ICER at 24 months; the cost-utility ratio analysis at 12 and 24 months; 5-year budget impact analysis; and prognosis factors of rTMS. The following criteria will be compared between arm A or B and arm C: rates of responders; remission and disease-free survival; clinical evolution; tolerance; observance; treatment modifications; hospitalization; suicide attempts; work stoppage; marital / professional statues; and quality of life at 12 and 24 months. DISCUSSION: The purpose of our study is to check the cost-effectiveness of rTMS and we will discuss its economic impact over time. In the case of significant decrease in the depression costs and expenditures associated with a good long-term prognosis (sustained response and remission) and tolerance, rTMS could be considered as an efficient treatment within the armamentarium for resistant unipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03701724. Registered on 10 October 2018. Protocol Amendment Version 2.0 accepted on 29 June 2019.

Comparison of two techniques used in routine care for the treatment of inflammatory macular oedema, subconjunctival triamcinolone injection and intravitreal dexamethasone implant: medical and economic importance of this randomized controlled trial.

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.

Tacrolimus- versus sirolimus-based immunosuppression after simultaneous pancreas and kidney transplantation: 5-year results of a randomized trial.

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).

Cost-utility analysis of transcranial direct current stimulation (tDCS) in non-treatment-resistant depression: the DISCO randomised controlled study protocol.

INTRODUCTION: Depression 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 ANALYSIS: This 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 DISSEMINATION: This 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 NUMBER: RCB 2018-A00474-51; NCT03758105.