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Resume Introduction Les personnes trans sont moins bien pris en charge par la communaute medicale que la population cisgenre probablement a cause d’un manque de connaissance, d’enseignement et de confort de la part des professionnels de sante. Le but de cette etude etait d’evaluer les connaissances et le confort ressentis par les professionnels de sante dans la prise en charge des personnes trans dans un centre hospitalo-universitaire (CHU) francais. Methodes Un auto-questionnaire a ete envoye par mail a des professionnels de sante travaillant dans des services habituellement impliques dans la prise en charge de personnes transgenres dans un CHU francais « non specialise » dans la transition hormono-chirurgicale trans. Le questionnaire comprenait des questions demographiques et des echelles de Likert concernant leur connaissance et leur confort ressentis dans la prise en charge des personnes trans. Les reponses des echelles de Likert de 7 degres etaient reparties selon des groupes « faible », « moyen » et « eleve » et celles de 5 degres etaient reparties selon des groupes « en faveur », « neutre » et « en defaveur ». Resultats Cent-deux (29 %) professionnels ont repondu au questionnaire. La moitie travaillaient en chirurgie (urologie, chirurgie plastique, gynecologie), 24 % travaillaient en medecine (endocrinologie, PMA, cytogenetique) et 26 % travaillaient en psychiatrie. La majorite (60,3 %) evaluaient leur niveau de connaissance comme « faible » et 39,7 % comme « moyen ». Seize pour cent evaluaient leur niveau de confort dans la prise en charge des trans comme « faible », 72,5 % comme « moyen » et 11,5 % comme « eleve ». Une majorite (77,5 %) etaient en faveur d’une prise en charge par la securite sociale de la transition hormonale, chirurgicale ou d’un soutien psychologique, 16,4 % etaient neutres et 6 % etaient en defaveur. Les sentiments concernant la transition hormono-chirurgicale etaient tres majoritairement (96,4 %) en faveur ou neutre et 91 % souhaitaient plus de formation. Conclusion Le manque de confort des professionnels de sante d’un CHU non specialise dans la prise en charge des personnes transgenres semble etre en rapport avec un manque de connaissance et de formation et non pas avec un desaccord concernant la necessite de l’offre de soins aux personnes transgenres. Niveau de preuve 3.

A growing literature shows an improvement of chronic hepatitis C virus (HCV)-related depression after successful treatment with direct-acting antivirals. However, depression after HCV cure remains insufficiently documented in people living with HIV (PLWH) and HCV, a population with specific mental health challenges. This study aimed to (i) document the prevalence of moderate-to-severe depression (PHQ-9 score ≥10) across different age classes in HCV-cured PLWH; (ii) identify associated socio-behavioral correlates.Descriptive analyses were performed on data collected during a cross-sectional survey (February 2018 - May 2019) nested in a prospective, multicenter cohort of individuals living with HIV and HCV (ANRS CO13 HEPAVIH). Socio-behavioral correlates of moderate-to-severe depression were identified using logistic regression.Among the 398 HCV-cured individuals in the study sample (median age [IQR]: 56 [53-59] years; 73.1% men), 23.9% presented with moderate-to-severe depression (PHQ-9 score ≥10). Depressive symptom prevalence rates were as follows: anhedonia: 52.3%; feeling 'down' or feelings of hopelessness: 48.3%; sleeping problems: 65.7%; lack of energy: 70.3%; eating disorders: 51.2%; lack of self-esteem: 34.3%; difficulty concentrating: 34.9%; sluggishness (in movement and voice) or restlessness: 24.6%; suicidal ideation: 17.1%. No significant difference was detected across age classes. Female sex, unhealthy alcohol use, sedentary lifestyle, and unhealthy eating behaviors were associated with increased odds of moderate-to-severe depression.Depressive symptoms were common in this sample of HCV-cured PLWH. Unlike findings for the French general population, the prevalence of depression did not decrease with age class. Mental health remains a key issue for HIV-HCV-coinfected individuals, even after HCV cure, especially in women and in individuals with unhealthy behaviors.Despite potential improvements in mental health after successful treatment with direct-acting antivirals, many people living with HIV (PLWH) and hepatitis C virus (HCV) - even in older age classes - still face depressive symptoms after HCV cure. In this population, women and people reporting unhealthy alcohol use, sedentary lifestyle, or unhealthy eating behaviors are more prone to report depressive symptoms after HCV cure. Mental health and lifestyle-related issues should be integrated in a global care model for PLWH living with or having a history of hepatitis C.

International audience; Introduction: Prevalence of postpartum depression (PPD) ranges from 10 to 15 % of parturients. The impact of the PPD is major on the maternal bond and the health of both mother and child. Its physiopathological mechanisms appear to differ from other types of depression. Today, pharmacotherapy is based on nonspecific treatment, and recent therapeutic advances in this field require a comprehensive approach of the implication of the GABAergic system in the development of PPD. Neurosteroid levels during pregnancy and after parturition and the GABA-A-r modulation are thought to be involved in PPD.Objective: To evaluate if the GABAergic approach is relevant in postpartum depression management.Methods: We conducted a systematic review of literature based on the MEDLINE database with the following Medical Subject Headings (MeSH): "postpartum depression", "GABA", "ganaxolone", "brexanolone", "allopregnanolone", prior to September 2019. We selected articles in English: preclinical and clinical studies, literature review, observational and therapeutic studies.Results: Preclinical models (mouse and rat) show changes in GABAergic inhibition in the peripartum period and correlation between allopregnanolone and GABA-A-r plasticity. This plasticity in the peripartum period maintains levels of inhibition adapted despite increased neurosteroid levels. KO models for the GABA-A-r δ subunit develop depression and anxiety symptoms in the postpartum period, and a change in the expression of the gene coding for the GABA-R alpha-4 subunit was found. Artificial inhibition of progesterone metabolism during post-partum increased depression symptoms. GABAergic fluctuation seems to be interrelated with other systems such as those of oxytocins. A synthetic neurosteroid (SGE-516) was tested on mouse models of PPD, KO for δ-GABA-A-r or KCC2, and showed decreased depressive symptoms and better mothering. Clinical studies confirm neurosteroid fluctuation and changes in the GABAergic system during the peripartum period. Allopregnanolone is the neurosteroid the most studied in PPD, and it is elevated in the brain during the pregnancy. Studies disagree on the presence of significant differences in allopregnanolone plasma levels during pregnancy or postpartum between women with PPD or not. Women with a history of PPD have greater susceptibility to neurosteroid withdrawal. Imagery and genetical data also show a link between allopregnanolone and PPD. The GABA-A-r may not recover in time following a reduced number during pregnancy, and this mismatch between neurosteroid levels and their receptor may trigger PPD. Several randomized controlled trials investigated brexanolone administrated IV, a synthetic formulation of allopregnanolone, and demonstrated a rapid and well tolerated reduction in depressive symptoms. In March 2019 brexanolone obtained FDA approval in PPD indication under the name Zulresso. However, there are differences in the time of beginning of PPD, which could constitute different subgroups of this disease, and which physiopathology could respond to different mechanisms. Prenatal depression does not respond to a GABAergic approach, but women without any risk factor or previous mood disorder developing PPD in the weeks following childbirth could be particularly responsive to this kind of treatment.Conclusion: Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease.

Birds, like most animals, are expected to adjust their foraging activity in response to biotic and abiotic variations to optimize energy intake and reduce costs associated with finding and ingesting food. This may lead to temporal variation in the exploitation of food resources, which has been investigated for birds of different feeding guilds but remains poorly understood for frugivorous species. Here, we tested whether the frugivory activity of birds on Schinus terebinthifolia trees varies throughout the day during the austral autumn and winter and whether variation is related to weather conditions. For two consecutive years, we quantified frugivory events for 304 h in 19 individuals of S. terebinthifolia observed across four time periods throughout the day. We found that the number of frugivory events was similar irrespective of the time period, both for the entire assemblage (all species pooled together) and for the most common species analyzed individually. We additionally found that frugivory activity was slightly influenced by temperature and wind. The lack of any effect of daytime period on fruit consumption may relate to the high and prolonged levels of fruit availability in S. terebinthifolia and the short photoperiod of the autumn–winter, which favors frequent feeding throughout the day. Such constant removal of fruits by a diverse assemblage of generalist fruit consumers probably enhances seed dispersal and may have important implications for the population dynamics of this abundant plant. Our results also demonstrate that data on avian frugivory in temperate, open-vegetation environments can be quantified throughout the entire daytime during the cold season without temporal bias, which has important methodological implications for studies on bird–plant interactions.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

Objective Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. Design Follow-up of a cohort of consecutive patients treated by surgery. Methods Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan–Meier representation. A cox regression model was used to predict remission. Results Median follow-up was 18.2 months (range: 2.8–155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33–41.8) after surgery. From Kaplan–Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6–96.4%) and 81% (95% CI: 71.2–92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. Conclusions In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

International audience; The aim of this review was to update the recommendations for optimal pain management after open and laparoscopic or robotic prostatectomy. Optimal pain management is known to influence postoperative recovery, but patients undergoing open radical prostatectomy typically experience moderate dynamic pain in the immediate postoperative day. Robot-assisted and laparoscopic surgery may be associated with decreased pain levels as opposed to open surgery. We performed a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) with PROcedure SPECific Postoperative Pain ManagemenT (PROSPECT) methodology. Randomised controlled trials (RCTs) published in the English language, from January 2015 until March 2020, assessing postoperative pain, using analgesic, anaesthetic and surgical interventions, were identified from MEDLINE, EMBASE and Cochrane Databases. Of the 1797 studies identified, 35 RCTs and 3 meta-analyses met our inclusion criteria. NSAIDs and COX-2 selective inhibitors proved to lower postoperative pain scores. Continuous intravenous lidocaine reduced postoperative pain scores during open surgery. Local wound infiltration showed positive results in open surgery. Bilateral transversus abdominis plane (TAP) block was performed at the end of surgery and lowered pain scores in robot-assisted procedures, but results were conflicting for open procedures. Basic analgesia for prostatic surgery should include paracetamol and NSAIDs or COX-2 selective inhibitors. TAP block should be recommended as the first-choice regional analgesic technique for laparoscopic/robotic radical prostatectomy. Intravenous lidocaine should be considered for open surgeries.

Background Mycoplasma genitalium (MG) is an emerging pathogen among men who have sex with men (MSM) with raising rates of antibiotic resistance. This study assessed the prevalence and incidence of MG infection in MSM enrolled in the open-label phase of the ANRS IPERGAY trial with on-demand tenofovir disoproxil fumarate/emtricitabine for human immunodeficiency virus prevention and the impact of doxycycline post-exposure prophylaxis (PEP). Methods 210 subjects were tested at baseline and at 6 months by real-time PCR assays for MG detection in urine samples and oropharyngeal and anal swabs. Resistance to azithromycin (AZM), to fluoroquinolones (FQs), and to doxycycline was investigated in the French National Reference Center of Bacterial Sexually Transmitted Infections (STIs). Results The all-site prevalence of MG at baseline was 10.5% (6.3% in urine samples, 4.3% in anal swabs, 0.5% in throat swabs) and remained unchanged at 6 months whether or not PEP was used: 9.9% overall, 10.2% with PEP, 9.6% without. The overall rate of MG resistance (prevalent and incident cases) to AZM and FQs was 67.6% and 9.1%, respectively, with no difference between arms. An in vivo mutation of the MG 16S rRNA, which could be associated with tetracycline resistance, was observed in 12.5% of specimens tested. Conclusions The prevalence of MG infection among MSM on pre-exposure prophylaxis was high and its incidence was not decreased by doxycycline prophylaxis with a similar high rate of AZM and FQ resistance, raising challenging issues for the treatment of this STI and supporting current recommendations to avoid testing or treatment of asymptomatic MG infection.

The affiliation details for Geltrude Mingrone are corrected below.

Objective The ENVOL study was designed to assess the psychosocial impact of disease and therapy in a French cohort of cryopyrin-associated periodic syndromes (CAPS) patients (and caregivers) treated with canakinumab. Methods The ENVOL study was a multicenter, observational study of CAPS patients given ≥1 canakinumab dose. Data were collected before treatment, at 6 and 12 months afterward, and at the last visit. Patients and caregivers completed questionnaires assessing changes from the 12 months of pretreatment to 12 months prior to interview. Data were analyzed retrospectively. Results The study included 10 physicians and 68 patients (53 adults, 15 children). Sixty-five patients (95.6%) were still receiving canakinumab at the last visit (median 5 years after starting therapy). The mean ± SD score for patient-reported general health increased from 7 ± 2.9 before canakinumab to 2.7 ± 2.7 after treatment (P 40% of respondents. Caregivers spent a median of 3 versus 0.5 hours/week on care in the 12 months of pretreatment versus 12 months prior to interview (P

With approximately 67 million individuals affected worldwide, autism spectrum disorder (ASD) is the fastest growing neurodevelopmental disorder (United Nations, 2011), with a prevalence estimated to be 1/100. In France ASD affects approximately 600,000 individuals (from childhood to adulthood, half of whom are also mentally retarded), who thus have a major handicap in communication and in adapting to daily life, which leads autism to be recognized as a national public health priority. ASD is a neurodevelopmental disorder that affects several domains (i.e., socio-emotional, language, sensori-motor, executive functioning). These disorders are expressed early in life with an age of onset around 18 months. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. The clinical picture is characterized by impairments in social interaction and communication and the presence of restrictive and repetitive behaviors (DSM-5, ICD-10). However, in addition to these two main dimensions there is significant comorbidity between ASD and other neurodevelopmental disorders such as attention deficit hyperactivity disorder or with genetic and medical conditions. One of the diagnostic features of ASD is its early emergence: symptoms must begin in early childhood for a diagnosis to be given. Due to brain plasticity, early interventions are essential to facilitate clinical improvement. Therefore, general practitioners and pediatricians are on the front line to detect early signs of ASD and to guide both medical explorations and early rehabilitation.

Resume Introduction Une atteinte interstitielle pulmonaire, une eruption cutanee et une elevation de l’enzyme de conversion peuvent suggerer d’autres diagnostics qu’une sarcoidose. Observation Un homme de 58 ans presentait depuis 2 ans une dyspnee avec une elevation du taux de l’enzyme de conversion et un syndrome interstitiel pulmonaire avec micronodules. Une sarcoidose etait evoquee. Une corticotherapie generale permettait l’amelioration de la dyspnee mais elle recidivait des l’arret. On notait des macules erythemateuses eczematiformes de la racine des membres, d’evolution fluctuante, avec histologiquement une folliculite aspecifique. L’identification d’une mycobacterie du complexe Mycobacterium avium (MAC) dans le lavage broncho-alveolaire faisait instaurer une antibiotherapie antimycobacterienne sans efficacite. La relecture de la tomodensitometrie pulmonaire et l’interrogatoire (utilisation quotidienne d’un jacuzzi depuis 7 ans) amenaient au diagnostic de pneumopathie d’hypersensibilite a MAC. Les lesions cutanees etaient, malgre leur aspect clinique eczematiforme, considerees comme des folliculites liees au jacuzzi (« hot tub folliculitis »). L’arret des bains bouillonnants et une breve corticotherapie generale permettaient la disparition des signes cliniques et une normalisation radiologique a 4 mois, sans recidive a 2 ans. Discussion Le « hot tub lung » est une pneumopathie d’hypersensibilite liee a la presence de MAC dans l’eau des jacuzzis. Elle regresse a l’arret de leur utilisation, sans autre traitement necessaire. La « hot tub folliculitis » liee a Pseudomonas aeruginosa se presente comme une eruption maculopapuleuse des zones couvertes (maillot) qui survient dans les 48 heures suivant une baignade et regresse en moins de deux semaines. Conclusion Notre cas est original par les atteintes pulmonaire et cutanee concomitantes liees a l’utilisation d’un jacuzzi, avec un mecanisme immuno-allergique pour la MAC et probablement infectieux pour les lesions cutanees.

Il blocco del plesso cervicale ha come indicazione principale l’anestesia per la chirurgia carotidea. Consente, inoltre, la chirurgia minore del collo. La conoscenza dell’anatomia e essenziale. Gli spazi di diffusione delimitano tre tipi di blocco del plesso cervicale (BPC): superficiale, intermedio e profondo. Quest’ultimo puo essere ottenuto mediante una o piu iniezioni, con o senza neurostimolatore. Piu moderna, la guida ecografica rende il BPC intermedio una tecnica sicura e facile da eseguire. L’apprendimento della tecnica anestetica e necessario per ridurre il rischio di sviluppare complicanze. Le complicanze sono principalmente correlate alla puntura vascolare, a un’iniezione peri- o intradurale e alla tossicita degli anestetici locali il cui assorbimento plasmatico e intenso in questa zona.

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

International audience; Les tumeurs de l’orbite représentent une pathologie relativement fréquente et posent des problèmes de diagnostic et de prise en charge. Elles peuvent être bénignes ou malignes. Tous les tissus contenus dans l’orbite peuvent être le siège d’un développement tumoral et de ce fait, elles sont très nombreuses. Parmi les tumeurs bénignes, on retiendra chez l’adulte les méningiomes et les hémangiomes caverneux et pour les tumeurs malignes, les lymphomes, les métastases, les tumeurs d’origine ORL, les tumeurs de la glande lacrymale. Elles se manifestent en général par une symptomatologie peu spécifique, le syndrome orbitaire, associant exophtalmie, troubles oculomoteurs, signes inflammatoires, douleurs et parfois masse palpable. L’imagerie (scanner RX, imagerie par résonance magnétique ou échographie Doppler couleur) confirme l’existence d’une tumeur, précise son siège, son extension, l’existence d’éventuelles métastases. La biopsie et l’examen anatomique et cytopathologique confirment le type bénin ou malin de la tumeur. À partir de ces trois éléments : clinique, imagerie et anatomie pathologique, la prise en charge est décidée, le plus souvent chirurgicale, selon l’avis d’une réunion de concertation pluridisciplinaire en cas de tumeur maligne. La radiothérapie et la chimiothérapie peuvent compléter le traitement.

Objectif Le debriefing est un element fondamental de l’apprentissage par simulation pleine echelle en sciences de la sante, mais reste un processus complexe et difficile a apprehender. L’objectif de cet article est de definir le debriefing postsimulation, d’en preciser les objectifs et de degager les grands principes du debriefing au regard des donnees de la litterature.

Introduction Le complexe de Carney (CNC) est un syndrome regroupant des neoplasies endocriniennes et non endocriniennes. Cette etude decrivant les caracteristiques des lesions mammaires des patientes avec CNC, les autres manifestations du CNC et le genotype PRKAR1A, s’est particulierement interessee aux carcinomes mammaires, cancer le plus frequent chez la femme et principale cause de deces par cancer dans le monde. Methodes Cette cohorte de 70 patients avec CNC provient d’un suivi prospectif multicentrique francais de 3 ans (Espiard et al. JCEM 2020). L’analyse des 50 femmes incluses a porte sur les manifestations de CNC (lesions mammaires particulierement), le genotype et les caracteristiques hormonales. Resultats Parmi les 38 femmes avec imagerie mammaire, dix presentaient des lesions benignes et six des carcinomes : un carcinome in-situ a 54 ans et cinq cancers invasif avant 50 ans et une recurrence controlaterale. La survenue du cancer mammaire chez les patientes avec CNC etait plus frequente et l’âge moyen 17 ans plus precoce (44,7 ans) que la population generale. Tous les cancers mammaires sont survenus chez des patientes mutees PRKAR1A, avec de bons facteurs pronostic : recepteurs hormonaux positifs, HER2 negatif, un seul cancer metastatique. Il n’y avait pas d’association entre les carcinomes mammaires et les manifestations du CNC ou facteurs de risque conventionnels. Discussion Les lesions mammaires sont frequentes chez les femmes atteintes de CNC. Le carcinome mammaire pourrait etre une « nouvelle » manifestation de cette maladie, une strategie de depistage et un suivi adequat pourraient etre proposes.

Introduction An extrafine pMDI formulation of the long-acting beta agonist formoterol fumarate (FF) was developed, and its efficacy and safety evaluated in a controlled clinical setting. Methods A double-blind, double-dummy, single dose, randomised, 4-way crossover, placebo controlled study was conducted to evaluate efficacy and safety of FF (6 µg) one puff or two puffs versus Foradil Aerolizer (FOR) 12 µg or placebo in moderate to severe asthmatic patients. Primary endpoint was 12 hour average FEV1. Secondary efficacy endpoints were onset and duration of action. Safety endpoints were vital signs, QTc, serum potassium and glucose. Results 53 asthmatic patients (mean age 34.4 years, 32 male and 21 female) were randomized and 52 were evaluable. Average FEV1 and peak FEV1 increased significantly after FF 6 and 12 µg, with a trend toward greater efficacy with the higher FF dose. Equivalence between FF 12 µg and FOR 12 µg was demonstrated. Median time to 15% onset was 10, 15 and 10 min for FF 12 µg, FF 6 µg and FOR, respectively confirming the rapid onset of action. Median time to 15% offset was 718, 480, 719 and 240 min for FF 12 µg, FF 6 µg, FOR and Placebo respectively suggesting that FF 12 µg provides an improved coverage of the 12 hour administration interval and demonstrating a marked dose-response. No clinically significant changes were observed for blood pressure and heart rate. Serum potassium and glucose remained within normal limits for the majority of subjects. QTcB was similar for all treatments and no values exceeded 470 m/sec. There were no serious adverse events. Frequency of treatment emergent adverse events was similar in the four treatments, with tremor the most common, as expected. Conclusions This study demonstrates that extrafine FF has similar efficacy and safety as compared to FOR. FF 12 µg shows a greater and more prolonged bronchodilation compared to FF 6 µg, and confirms a marked dose–response relation for FF. This has to be considered when assessing the most appropriate therapeutic dose of FF in asthmatics.