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1. Correction to 'Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study)' [The Lancet Regional Health – Europe 41 (2024) 100915]

Author: Pascal Demoly, Mathieu Molimard, Jean-François Bergmann, Bertrand Delaisi, Amandine Gouverneur, Jade Vadel, Cédric Collin, Laurence Girard, Silvia Scurati, and Philippe Devillier
Subjects: Public aspects of medicine, RA1-1270
Published: 2024
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2. Transition of care from adolescence to early adulthood in severe asthmatic patients treated with omalizumab in real life

Author: Camille Taillé, Marc Humbert, Arnaud Bourdin, Céline Thonnelier, Audrey Lajoinie, Jules Chassetuillier, Mathieu Molimard, and Antoine Deschildre
Subjects: Medicine
Published: 2024
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3. Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study)Research in context

Author: Pascal Demoly, Mathieu Molimard, Jean-François Bergmann, Bertrand Delaisi, Amandine Gouverneur, Jade Vadel, Cédric Collin, Laurence Girard, Silvia Scurati, and Philippe Devillier
Subjects: Asthma, Rhinitis, Allergic, Sublingual immunotherapy, Precision medicine, Public aspects of medicine, RA1-1270
Abstract: Summary: Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60–0.63], sensitive: 0.77 [0.76–0.78], and specific: 0.67 [0.61–0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.
Published: 2024
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4. Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

Author: Hyacinthe Johnson-Ansah, Benjamin Maneglier, Françoise Huguet, Laurence Legros, Martine Escoffre-Barbe, Martine Gardembas, Pascale Cony-Makhoul, Valérie Coiteux, Laurent Sutton, Wajed Abarah, Camille Pouaty, Jean-Michel Pignon, Bachra Choufi, Sorin Visanica, Bénédicte Deau, Laure Morisset, Emilie Cayssials, Mathieu Molimard, Stéphane Bouchet, François-Xavier Mahon, Franck Nicolini, Philippe Aegerter, Jean-Michel Cayuela, Marc Delord, Heriberto Bruzzoni-Giovanelli, and Philippe Rousselot
Subjects: imatinib, therapeutic drug monitoring, chronic myelogenous leukemia, Pharmacy and materia medica, RS1-441
Abstract: The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug’s efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51–81) compared to 39% (95% CI, 24–55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.
Published: 2022
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5. Prioritising outcomes for evaluating eosinophil-guided corticosteroid therapy among patients with acute COPD exacerbations requiring hospitalisation: a Delphi consensus study

Author: Romain Kessler, Alain Didier, Mathieu Molimard, A Bourdin, Thierry Chinet, Chantal Raherison, Nicolas Roche, Carey Meredith Suehs, Maéva Zysman, Cécile Chenivesse, Pierre-Régis Burgel, F Couturaud, Gaëtan Deslee, Patrick Berger, Gilles Devouassoux, Christophe Brousse, Philippe Devillier, Pascal Chanez, Yan Martinat, and Olivier Le Rouzic
Subjects: Medicine
Abstract: Objectives Presently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes.Design A modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ≥70% of experts indicated that the outcome was essential for interpreting study results.Setting COPD exacerbation management in France.Participants 34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds.Results 105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation.Conclusions This Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients.Study registration The eo-Delphi project/protocol was registered on 23 January 2018 at https://osf.io/4ahqw/.
Published: 2020
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6. An observational cohort study of the use of five-grass-pollen extract sublingual immunotherapy during the 2015 pollen season in France

Author: Patrick Blin, Pascal Demoly, Martine Drouet, Bruno Falissard, Séverine Lignot-Maleyran, Hélène Maizi, Simon Lorrain, Régis Lassalle, Cécile Droz-Perroteau, Nicholas Moore, and Mathieu Molimard
Subjects: Allergic rhinitis, Sublingual immunotherapy, Pollen season, France, Immunologic diseases. Allergy, RC581-607
Abstract: Abstract Background Allergic rhinitis affects around one quarter of the Western European population. Prophylactic allergen immunotherapy may be useful to reduce the risk of acute symptomatic attacks (hayfever). A five-grass pollen extract sublingual immunotherapy (5GPE-SLIT) has been developed for the treatment of allergic rhinitis to grass pollen. The objective of this study was to describe real-world treatment patterns with 5GPE-SLIT in France with respect to the prescribing information. Methods This prospective cohort study was conducted by 90 community and hospital allergists. Adults and children (> 5 years old) starting a first treatment with 5GPE-SLIT prior to the 2015 pollen season were eligible. Data was collected at the inclusion visit and at the end of the pollen season. The primary outcome variable was compatibility of 5GPE-SLIT prescription with the prescribing information. This was determined with respect to four variables: (1) interval between 5GPE-SLIT initiation and onset of the pollen season ≥ 3 months, (2) age of patient ≥ 5 years, (3) intermittent symptoms or mild symptom severity (4) confirmatory diagnostic test. At study end, symptoms reported during the pollen season and any modifications to treatment or adverse events were documented. Results 280 adults and 203 children were enrolled. The prescribing information was respected for 82.5% of adults and 86.7% of children. A skin test was performed for all patients. 5GPE-SLIT was started 3–5 months before the pollen season for 85.3%. Treatment was discontinued before the start of the pollen season in 11.0% of patients overall, generally because of an adverse event (78.8% of discontinuations). The mean duration of treatment was 5.2 months in adults and 5.6 months in children. At the end of follow-up, symptoms during the pollen season were intermittent for 75.0% of adults and 85.7% of children, and severity was mild for 61.8 and 66.0% respectively. During 5GPE-SLIT, the following symptoms reported during the previous year were not reported again in > 50% of patients: nasal congestion, rhinorrhoea, repeated sneezing, conjunctivitis and nasal pruritus. Conclusions 5GPE-SLIT use was generally consistent with prescribing recommendations and was associated with an improvement of AR severity, with resolution of the principal AR symptoms in around half the patients treated. Trial registration EUPAS9358. Registered 13 May 2015. Not prospectively registered. http://www.encepp.eu/encepp/viewResource.htm?id=16229
Published: 2018
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7. Comorbidities and COPD severity in a clinic-based cohort

Author: Chantal Raherison, El-Hassane Ouaalaya, Alain Bernady, Julien Casteigt, Cecilia Nocent-Eijnani, Laurent Falque, Frédéric Le Guillou, Laurent Nguyen, Annaig Ozier, and Mathieu Molimard
Subjects: COPD, Comorbidities, Cluster analysis, Management, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality around the world. The aim of our study was to determine the association between specific comorbidities and COPD severity. Methods Pulmonologists included patients with COPD using a web-site questionnaire. Diagnosis of COPD was made using spirometry post-bronchodilator FEV1/FVC
Published: 2018
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8. The sustainable impact of an educational approach to improve the appropriateness of laboratory test orders in the ICU.

Author: Benjamin Clouzeau, Marie Caujolle, Aurelie San-Miguel, Jerome Pillot, Nathalie Gazeau, Christophe Tacaille, Vincent Dousset, Fabienne Bazin, Frederic Vargas, Gilles Hilbert, Mathieu Molimard, Didier Gruson, and Alexandre Boyer
Subjects: Medicine, Science
Abstract: IntroductionFew studies described strategies to improve the use of diagnostic tests in intensive care units (ICU). No study assessed whether their impact was sustained or not. In this study, we assessed whether a multi-faceted intervention for more appropriate use of laboratory testing can decrease the number of tests, is sustainable, is not associated with additional morbidity and represents a potential cost saving.Material and methodsAn open-label prospective cohort study in two separated units of the same medical intensive care unit (ICU) including respectively 3315 and 2392 consecutive patients. After the observation period (2010), a reduction in ICU A of unnecessary diagnostics tests as part of a program including senior supervisory of juniors' orders, encouragements for orders containment at each everyday round discussions (period 2; 2011). Period 3 (2012) consisted in the prolongation of the protocol as a routine care without supervision; Period 4 (2013) was a new period of observation without intervention. No modification was implemented in ICU B in periods 2-4.ResultsAfter the intervention, a decrease in the overall number of tests per ICU-patient-days (37.3±5.5 (baseline) to 15.2±3.2 (- 59%); pConclusionsLaboratory test containment is effective, likely safe and sustainable provided that an educational program is repeatedly promoted, that it makes sense for the whole team, that senior and junior physicians are both committed in the program, and that encouragements for laboratory orders containment at each everyday round discussions.
Published: 2019
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9. What place for intelligent automation and artificial intelligence to preserve and strengthen vigilance expertise in the face of increasing declarations?

Author: Antoine, Pariente, Joëlle, Micallef, Amir, Lahouegue, Mathieu, Molimard, Marine, Auffret, Laurent, Chouchana, Bernard, Denis, Jean Luc, Faillie, Aurelie, Grandvuillemin, Louis, Letinier, Evelyne, Pierron, Catherine, Pons, Iris, Pujade, Heather, Rubino, and Francesco, Salvo
Subjects: Pharmacology (medical)
Abstract: In 2018, the "Ateliers de Giens" (Giens Workshops) devoted a workshop to artificial intelligence (AI) and led its experts to confirm the potential contribution and theoretical benefit of AI in clinical research, pharmacovigilance, and in improving the efficiency of care. The 2022 workshop is a continuation of this reflection on AI and intelligent automation (IA) by focusing on its contribution to pharmacovigilance and the applications and tasks could be optimized to preserve and strengthen medical and pharmacological expertise in pharmacovigilance. The evolution of pharmacovigilance work is characterized by many tasks with low added value, a growing volume of pharmacovigilance reporting of suspected side effects, and a scarcity of medical staff with expertise in clinical pharmacology and pharmacovigilance and human resources to support this growing need. Together, these parameters contribute to an embolization of the pharmacovigilance system at risk of missing its primary mission: to identify and characterize a risk or even a health alert on a drug. The participants of the workshop (representatives of the Regional Pharmacovigilance Centres (CRPV), the French National Agency for Safety of Medicinal Products (ANSM), patients, the pharmaceutical industry, or start-ups working in the development of AI in the field of medicine) shared their experiences, their pilot projects and their expectations on the expected potential, theoretical or proven, AI and IA. This work has made it possible to identify the needs and challenges that AI or IA represent, in the current or future modes of organization of pharmacovigilance activities. This approach led to the development of a SWOT matrix (strengths, weaknesses, opportunities, threats), a basis for reflection to identify critical points and consider four main recommendations: (1) preserve and develop business expertise in pharmacovigilance (including research and development in methods) with the integration of new technologies; (2) improve the quality of pharmacovigilance reports; (3) adapt technical and regulatory means; (4) implement a development strategy for AI and IA tools at the service of expertise.
Published: 2023

10. Quelle place pour l’automatisation intelligente et l’intelligence artificielle pour préserver et renforcer l’expertise en vigilance devant l’augmentation des déclarations ?

Author: Antoine Pariente, Joëlle Micallef, Amir Lahouegue, Mathieu Molimard, Marine Auffret, Laurent Chouchana, Bernard Denis, Jean Luc Faillie, Aurelie Grandvuillemin, Louis Letinier, Evelyne Pierron, Catherine Pons, Iris Pujade, Heather Rubino, and Francesco Salvo
Subjects: Pharmacology (medical)
Published: 2023

11. A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

Author: Joris Guyon, Marine Novion, Virginie Fulda, Dominique Ducint, Mathieu Molimard, Lionel Couzi, Hannah Kaminski, Francesco Salvo, and Stéphane Bouchet
Subjects: Ritonavir, SARS-CoV-2, Tandem Mass Spectrometry, Structural Biology, Humans, Reproducibility of Results, Chromatography, High Pressure Liquid, Immunosuppressive Agents, Tacrolimus, Spectroscopy, Biological Monitoring, Chromatography, Liquid, COVID-19 Drug Treatment
Abstract: Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice.
Published: 2022

12. Benefit-risk balance of COVID drugs. New prospects

Author: Jean-Luc Cracowski, Vincent Richard, and Mathieu Molimard
Subjects: SARS-CoV-2, COVID-19, Humans, Pharmacology (medical), Risk Assessment
Published: 2022

13. Prevention of risks associated with inappropriate use/unnecessary consumption of medicines

Author: Jean-Luc Cracowski, Sophie Muller, Isabelle Anglade, Gilles Bonnefond, Béatrice Bouhanick, Sylvain Bouquet, Sandrine Cabut, Pascale Daynès, Bernard Denis, Dorothée Durand, Annie-Pierre Jonville-Béra, Amir Lahouegue, Magali Léo, Joëlle Micallef, Mathieu Molimard, Catherine Penfornis, and Valérie Querol-Ferrer
Subjects: Male, Drug-Related Side Effects and Adverse Reactions, COVID-19, coronavirus disease-2019, Misuse, SARS-CoV-2, COVID-19, Information, Humans, Training, Female, Pharmacology (medical), Public Health, Drug, Giens Workshops 2021/Health and economy, Marketing authorisation
Abstract: In the code of public health, misuse is defined as intentional and inappropriate use of a medicine or product, which is not in accordance with the terms of the marketing authorisation or the registration as well as with good practice recommendations. Very often this involves an individual or the interaction of several individuals including the patient, his/her carers, prescriber(s) and/or dispensers. Misuse is common; it is the source of medicinal adverse effects for which a significant part is avoidable. Medicines initially prescribed or dispensed in the context of their marketing authorization (MA) can also be the subject of primary dependency and misappropriation. Companies which develop medicines nationally make declarations to the ANSM (French National Agency for the Safety of Medicines and Health Products) and implement measures to limit non-compliant use of their products. Recently, the coronavirus disease-2019 (COVID-19) pandemic has highlighted the influence and societal impact of drug misuse. The finding of the existence of systemic misuse, the impossibility of proposing simple solutions leads us to propose two main areas for improved information and the training of users and health professionals in medicines in the context of multi-faceted interventions: prevention of misuse on the one hand and its identification and treatment on the other hand.
Published: 2022

14. Prévention des risques liés à un usage inapproprié/consommation inutile des médicaments

Author: Jean-Luc Cracowski, Sophie Muller, Isabelle Anglade, Gilles Bonnefond, Béatrice Bouhanick, Sylvain Bouquet, Sandrine Cabut, Pascale Daynès, Bernard Denis, Dorothée Durand, Annie-Pierre Jonville-Béra, Amir Lahouegue, Magali Léo, Joëlle Micallef, Mathieu Molimard, Catherine Penfornis, and Valérie Querol-Ferrer
Subjects: Pharmacology (medical)
Published: 2022

15. Direct and rapid identification of sepsis causative micro-organisms from blood cultures using SCOUT-MRM proteomics assay

Author: Maud Gregson, Iulia Macavei, Romain Carrière, David Cox, Yves Le Blanc, Tiphaine Cecchini, Roxane Prat, Chloé Desbiolles, Delphine Arquier, Francis Deforet, Eva Peyrache, Mathieu Molimard, Olivier Dauwalder, François Vandenesch, Jérôme Lemoine, ANABIO-MS - Analyse biomoléculaire par spectrométrie de masse - Biological Analysis by Mass Spectrometry, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), SCIEX, Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL), Centre National de Reference des Staphylocoques, Université de Lyon, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-18-RHUS-0013,IDBIORIV,Concomitant Identification, AntiBIOtic ResIstance and Virulence evaluation of bacterial pathogens with targeted mass spectrometry(2018)
Subjects: proteomics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, microbial detection, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, mass spectrometry
Abstract: International audience
Published: 2022

16. Performance Characteristics of Breezhaler® and Aerolizer® in the Real-World Setting

Author: Sonja Lederhilger, Mathieu Molimard, Juergen Jauernig, Ioannis Kottakis, Ivan Nikolaev, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Budesonide, medicine.medical_specialty, Inhalation, business.industry, Inhaler, Airflow, Usability, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, 030226 pharmacology & pharmacy, Dry-powder inhaler, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pharmacology (medical), In patient, Intensive care medicine, business, medicine.drug, Asthma
Abstract: The evaluation of errors in use with different inhaler devices is challenging to quantify as there are a number of definitions of critical and non-critical errors with respect to inhaler use; in addition, performance characteristics of the device, such as airflow resistance, can also influence effective use in the real-world setting. Repeated observations and checking/correcting inhaler use are essential to optimise clinical effectiveness of inhaled therapy in patients. Breezhaler® is a single unit-dose dry powder inhaler used in chronic obstructive pulmonary disease and in asthma (budesonide) that has low airflow resistance, making it easier for patients of varying disease severities to achieve the inhalation flow rate required for lung deposition of treatment. Similar to Breezhaler®, the Aerolizer® is a single unit-dose dry powder inhaler used in asthma management with low airflow resistance. Studies have shown relatively low rates of critical errors with Breezhaler® and Aerolizer®, with similarities in the critical errors reported; these data on critical errors together with similarities in the usability of Breezhaler® and Aerolizer® further support the functional similarity between the two devices in both asthma and chronic obstructive pulmonary disease. Breezhaler® also has patient-feedback features, including use of a transparent drug capsule that can be checked after inhalation to see it is empty. The low resistance of the dose-confirming Breezhaler® results in less inspiratory effort being required by patients for its effective use, which allows the device to be used effectively across a wide age range of patients and disease severities.
Published: 2021

17. Safety profile of drugs for advanced melanoma: A report based on 2008–2018 US Food and Drug Administration Data

Author: Louis Létinier, Francesco Salvo, Anne Pham-Ledard, Emilie Casarotto, Mathieu Molimard, and Pernelle Noize
Subjects: Drug, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, media_common.quotation_subject, medicine.medical_treatment, 030226 pharmacology & pharmacy, Food and drug administration, Pharmacovigilance, 03 medical and health sciences, Adverse Event Reporting System, 0302 clinical medicine, Adverse Drug Reaction Reporting Systems, Humans, Medicine, Endocrine system, Pharmacology (medical), 030212 general & internal medicine, Intensive care medicine, Melanoma, Advanced melanoma, media_common, Pharmacology, United States Food and Drug Administration, business.industry, Immunotherapy, medicine.disease, United States, 3. Good health, Pharmaceutical Preparations, business
Abstract: We described the safety profiles of all drug classes used for the treatment of advanced melanoma from the United States Food and Drug Administration Adverse Event Reporting System over the period 2008 to 2018. Adverse reactions reported in 25,900 pharmacovigilance cases were described for chemotherapies, immunomodulators, targeted therapies, and immunotherapies. There was a sharp increase in the number of cases over time, with peaks associated with the launch of new treatments. The adverse reactions diversified over time; notably, skin (alopecias, dermatitis) and retinal disorders were frequently associated with targeted therapies and endocrine disorders (hypothalamus, thyroid and adrenal dysfunctions) with immunotherapies. Less well-known reactions were also detected, such as neuropsychiatric disorders with targeted therapies and gastrointestinal ulcers, pneumothorax, and pleural effusions with immunotherapies. The findings highlight the need for various health professionals (including medical specialists or trained nurses) to enhance management of complications.
Published: 2020

18. Urine biomonitoring of occupational exposure to methotrexate using a highly sensitive UHPLC-MS/MS method in MRM

Author: Antoine, Villa, Kevin, Tremolet, Béatrice, Martinez, Murielle, Petit, Xavier, Dascon, Jérémie, Stanek, Dominique, Ducint, Karine, Titier-Debeaupuis, Catherine, Verdun-Esquer, Mathieu, Molimard, and Mireille, Canal-Raffin
Subjects: Methotrexate, Tandem Mass Spectrometry, Occupational Exposure, Humans, Chromatography, High Pressure Liquid, Biological Monitoring
Abstract: Methotrexate (MTX) is widely used as antineoplastic drug (AD) and as an immunosuppressive. As a result, many healthcare professionals are exposed to this drug which is classified as dangerous to handle due to its reproductive toxicity in humans. Since the 1990 s, cases of internal contamination of professionals handling this molecule have been reported in the literature and even recently MTX was detected in the urine of professionals. To date, there is no toxicological reference value for occupational exposure to MTX. Given the toxicity of this molecule, the internal contamination of professionals must be reduced and kept as low as possible according to the ALARA principle (as low as reasonably achievable). The aim of this work was to develop an UHPLC-MS/MS method in MRM (Multiple Reaction Monitoring) and MRM
Published: 2022

19. Management of drug-drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: Guidelines from the French Society of Pharmacology and Therapeutics (SFPT)

Author: Florian Lemaitre, Matthieu Grégoire, Caroline Monchaud, Stéphane Bouchet, Béatrice Saint-Salvi, Elisabeth Polard, Sihem Benaboud, Laurent Chouchana, Jean-Luc Cracowski, Milou-Daniel Drici, Rodolphe Garraffo, Romain Guilhaumou, Annie-Pierre Jonville-Bera, Mathieu Molimard, Patric Muret, Gilles Peytavin, Vincent Richard, Caroline Solas, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), and Jonchère, Laurent
Subjects: Ritonavir, SARS-CoV-2, [SDV]Life Sciences [q-bio], Paxlovid, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Antiviral Agents, Drug monitoring, COVID-19 Drug Treatment, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacodynamics, Cysteine Proteases, Chymotrypsin, Humans, Drug Interactions, Pharmacology (medical), Pharmacokinetics, Antiviral
Abstract: International audience; OBJECTIVES: Nirmatrelvir in association with ritonavir (PAXLOVID™, Pfizer) is an antiviral agent targeting the 3-chymotrypsin-like cysteine protease enzyme (3C-like protease or Mpro) which is a key enzyme of the viral cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination with a well-known pharmacokinetic enhancer leads to a high risk for drug-drug interactions in a polymedicated elected population for treatment. The aim of this work was to provide recommendations on behalf of the national French society of pharmacology (French Society of Pharmacology and Therapeutics; SFPT), by suggesting optimal and pragmatic therapeutic strategies if nirmatrelvir/ritonavir is to be given together with drugs commonly used, in order to ensure secured physicians’ prescription. METHODS: Six clinical pharmacologists search the scientific literature to provide a first draft of recommendations. Thereafter, twelve other clinical pharmacologists verified the recommendations and proposed modifications. The final draft was then validated by all 18 participants. RESULTS: Five distinct recommendations were issued: i) contra-indications, ii) "PAXLOVID™ not recommended with the comedication", iii) "PAXLOVID™ possible whether the comedication is discontinued", iv) "PAXLOVID™ possible only after an expert advice" and v) "PAXLOVID™ possible without modification of the associated treatment". The final document comprises recommendations for 171 drugs/therapeutic classes aiming to secure prescription. In complex situations, clinicians are advised to contact their pharmacology department to obtain specific recommendations on the management of drug-drug interactions with nirmatrelvir/ritonavir. CONCLUSION: These recommendations intend to be a help for clinicians willing to prescribe nirmatrelvir/ritonavir and to prevent drug-drug interactions leading to adverse drug reactions or loss of efficacy. They constitute a guideline for primary care situations. Of course, some complex situations may require expert advices and here, again, clinical pharmacologists are at the forefront in providing therapeutic advice.
Published: 2022

20. Comment intéresser les médecins aux métiers du médicament et des dispositifs médicaux ?

Author: Marie Lang, Nadine Karam, Christine Trillou, Lauren Demerville, Dominique Deplanque, Nathalie Billon, Philippe Barthélémy, Mathieu Molimard, Alain Cariou, Driss Berdaï, Bénédicte Lebrun-Vignes, Ségolène de Retz, Hélène Peyro Saint Paul, Joëlle Micallef, Olivier Demarcq, and Eric Bellissant
Subjects: Pharmacology (medical)
Abstract: Resume Maintenir, voire renforcer, la medicalisation des metiers dans le champ des produits de sante au sein des structures publiques et privees est aujourd’hui un enjeu majeur. Force est de constater en France le manque de medecins a meme d’exercer dans ces domaines, les structures publiques ou privees ayant en effet d’importantes difficultes a pourvoir les postes disponibles. A la difference de ce qui existe ailleurs en Europe et en dehors des parcours complexes imposes aux hospitalo-universitaires, les cursus francais de formation ne permettent pas de former des medecins veritablement specialistes des produits de sante. Pourtant, des carrieres a la fois nombreuses et variees sont possibles. Les metiers restent, cependant, insuffisamment visibles tant des futurs medecins que du grand public. Pour repondre aux nombreux besoins des structures publiques et des entreprises privees, il est necessaire de proposer un cursus dedie plus specialise. Il convient, cependant, que ce cursus s’appuie sur une formation initiale clinique solide, socle indispensable quel que soit le metier reellement exerce dans le futur. Pour une meilleure visibilite, la creation d’une specialite en pharmacologie medicale et en therapeutique doit etre accompagnee et soutenue par les differentes instances nationales. Dans le contexte d’activites largement mondialisees, disposer en France de specialistes des produits de sante est determinant pour conserver sur le territoire national la maitrise d’activites a forts impacts economiques et de sante publique.
Published: 2020

21. How to attract doctors to careers in the fields of pharmaceutical medicine and medical devices?

Author: Mathieu Molimard, Alain Cariou, Ségolène de Retz, Philippe Barthélémy, Marie Lang, Eric Bellissant, Dominique Deplanque, Lauren Demerville, Christine Trillou, Hélène Peyro Saint Paul, Olivier Demarcq, Bénédicte Lebrun-Vignes, Nathalie Billon, Joëlle Micallef, Nadine Karam, Driss Berdaï, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Career Choice, Education, Medical, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Public health, education, Specialty, Public institution, Public relations, Private sector, Product (business), Equipment and Supplies, Physicians, Health care, Pharmaceutical medicine, medicine, Humans, Pharmacology (medical), Curriculum, France, Business, ComputingMilieux_MISCELLANEOUS, Specialization
Abstract: It has become a major challenge not only to retain but also to attract medical professionals to a career in the healthcare products field whether in the public or private sector. There is no denying that France has a shortage of doctors qualified to work in these fields and that public or private organisations alike are experiencing great difficulty in filling vacancies. Unlike elsewhere in Europe, and with the exception of complex pathways imposed on university hospital professors, French training courses do not really provide doctors with specialised training in healthcare products. Many and varied careers nevertheless do exist. However, these careers are not sufficiently visible to future doctors or to the general public. A more dedicated specialist curriculum is called for to meet the many needs of public institutions and private companies. Any such curriculum should be underpinned by solid initial clinical training as an indispensable foundation regardless of future career path. To improve visibility, specialty training in Clinical Pharmacology and Therapeutics must be set up with the support and assistance of the various national bodies. Against a backdrop of activities with a largely globalised reach, the availability in France of healthcare product specialists is key to maintaining national control of activities that exert a significant impact on the economy and on public health.
Published: 2020

22. Minors and young adult's hospitalizations after 'chimique' consumption in Mayotte Island: Which substances are involved?

Author: Ruben Goncalves, Alexandre Peyré, Nadège Castaing, Thomas Beeken, Sophie Olivier, Patrice Combe, Ghada Miremont-Salamé, Karine Titier, Mathieu Molimard, and Amélie Daveluy
Subjects: Pharmacology (medical)
Abstract: Over the last 10 years, the use of an unknown drug called "chimique" has emerged, among adolescents and young adults in precarious situations in Mayotte Island. To date, the exact composition of "chimique" is still poorly documented, but seizures made on the Island at the same time indicated that it would be mainly composed of synthetic cannabinoids receptor agonists (SCRAs). The objective of this study was to identify which substances, among those consumed under the name of "chimique", leading to hospital admissions.Between 1Twelve patients were included: 11 males and 1 female. The mean age was 26 years (median age: 22). There were 2 minors. Clinical presentations varied, mainly psychiatric and neurologic disorders were observed. No death was reported. Toxicological analysis identified psychoactive substances such as THC and/or its metabolites (n=3) and MDMB-4en-PINCA (n=2). The other substances identified were mainly part of the patients' treatment.This is the first study conducted in the Indian Ocean confirming the presence of SCRAs in the "chimique". For a while, the consumption of SCRAs in France seemed to be of limited importance. However, their use has become important in the Indian Ocean since the spread of "chimique" in Mayotte. It continues to spread especially in Reunion Island since 2017 under the name of "chamane".
Published: 2022

23. Real-life omalizumab exposure and discontinuation in a large nationwide population-based study of pediatric and adult asthmatics

Author: Marc Humbert, Arnaud Bourdin, Camille Taillé, Driss Kamar, Céline Thonnelier, Audrey Lajoinie, Alexandre Rigault, Antoine Deschildre, Mathieu Molimard, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Hospitalization, Pulmonary and Respiratory Medicine, Treatment Outcome, Adrenal Cortex Hormones, [SDV]Life Sciences [q-bio], Humans, Omalizumab, Anti-Asthmatic Agents, Child, Asthma
Abstract: BackgroundThis real-life study aimed to assess omalizumab treatment patterns in adult and paediatric asthma patients, and to describe asthma control and healthcare resource use (HCRU) at omalizumab initiation and discontinuation.MethodsThe French healthcare database system (Système National des Données de Santé (SNDS)) was used to identify asthma patients aged ≥6 years who initiated omalizumab for at least 16 weeks from 2009 to 2019. We examined omalizumab treatment patterns using dispensation records.ResultsWe identified 16 750 adults and 2453 children initiating omalizumab. Median treatment persistence before discontinuation (TSTOP) was 51.2 (95% CI 49.3–53.4) months in adults and 53.7 (95% CI 50.6–56.4) months in children. At 2 years of omalizumab exposure, rate of hospitalisation for asthma decreased by 75% and use of oral corticosteroids (OCS) by 30%, in adults and children. Among adults who discontinued omalizumab while asthma was controlled, 70%, 39% and 24% remained controlled and did not resume omalizumab at 1, 2 and 3 years after discontinuation, respectively. These proportions were higher in children (76%, 44% and 33%, respectively). Over 2 years of follow-up after discontinuation, HCRU remained stable in adults and children, notably rate of hospitalisations for asthma (none before TSTOP, 1.3% and 0.6% at 2 years) and use of OCS (in adults and children, respectively: 20.0% and 20.2% before TSTOP, 33.3% and 24.6% at 2 years).ConclusionThis is the first large-scale study describing omalizumab real-life exposure patterns in adult and paediatric asthma patients in France with >10 years of follow-up. We showed the long-term maintenance of low HCRU in adults and children who discontinued omalizumab while asthma was controlled, notably for OCS use and hospitalisations for asthma.
Published: 2022

24. Involuntary MDMB-4en-PINACA intoxications following cannabis consumption: clinical and analytical findings

Author: Alexandre Peyré, Ruben Goncalves, Amélie Daveluy, Mathieu Molimard, Nadège Castaing, Magali Labadie, and Simon Chouraqui
Subjects: Cannabinoid Receptor Agonists, medicine.medical_specialty, biology, Cannabinoids, business.industry, Nausea, Public health, Amnesia, General Medicine, Toxicology, biology.organism_classification, Altered Mental Status, Hallucinogens, medicine, Vomiting, Humans, Anxiety, Cannabis, medicine.symptom, Headaches, Psychiatry, business
Abstract: Background and aims MDMB-4en-PINACA is a synthetic cannabinoid receptor agonist (SCRA) that has recently emerged. Data regarding clinical presentations in the event of intoxication is scarce. This study presents MDMB-4en-PINACA identification in cannabis consumers with clinical and analytical descriptions. Methods Between November 2020 and March 2021, all patients with unexpected or unusually severe effects and Poisoning Severity Score (PSS) greater than or equal to 2 after cannabis consumption were included. Blood and/or urine samples were collected for toxicological analysis. When available, drug material samples were also collected for analysis. Results Between November 2020 and March 2021, 13 patients were included. All cases typically presented with altered mental status (n = 13), and nearly all had returned to a normal or quasi-normal state after around 11 h of observation. Neurological symptoms included headaches (n = 3), hallucinations (3), mydriasis (3), amnesia (2) and seizures (5). Psychiatric symptoms were paranoia (6) and anxiety (2). Digestive symptoms were nausea (2) and vomiting (6). No deaths were recorded. All patients were positive for the SCRA MDMB-4en-PINACA in urine, blood and/or drug material sample. Results from toxicology testing paired with case history showed the potential for MDMB-4en-PINACA to cause or contribute to different clinical disorders. Conclusions: This study highlights the risk of intoxication by SCRAs when taking low-THC cannabis products. Forensic scientists, public health and public safety officials, law enforcement personnel and clinicians should be aware of the impact that these emergent SCRAs may have in their work, especially MDMB-4en-PINACA.
Published: 2021

25. Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE)

Author: Alexandre Duvignaud, Edouard Lhomme, Racha Onaisi, Rémi Sitta, Ambre Gelley, Julie Chastang, Lionel Piroth, Christine Binquet, Julie Dupouy, Alain Makinson, Benjamin Lefèvre, Jean-Marc Naccache, Caroline Roussillon, Roland Landman, Cédrick Wallet, Sophie Karcher, Valérie Journot, Duc Nguyen, Thierry Pistone, Stéphane Bouchet, Marie-Edith Lafon, Mathieu Molimard, Rodolphe Thiébaut, Xavier de Lamballerie, Jean-Philippe Joseph, Laura Richert, Olivier Saint-Lary, Sarah Djabarouti, Linda Wittkop, Xavier Anglaret, Denis Malvy, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Département de médecine générale, Sorbonne Université (SU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Groupe Hospitalier Paris Saint-Joseph (hpsj), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microbiologie Fondamentale et Pathogénicité (MFP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-20-COVI-0040,COVERAGE,Traitement à domicile des personnes infectées par le SRAS-CoV-2 sans signe de gravité mais à risque de complications: un essai randomisé à plusieurs bras et en plusieurs étapes (MAMS) pour évaluer l'efficacité de plusieurs antiviraux(2020), Richert, Laura, Traitement à domicile des personnes infectées par le SRAS-CoV-2 sans signe de gravité mais à risque de complications: un essai randomisé à plusieurs bras et en plusieurs étapes (MAMS) pour évaluer l'efficacité de plusieurs antiviraux - - COVERAGE2020 - ANR-20-COVI-0040 - COVID-19 - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)
Subjects: Microbiology (medical), Male, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Ciclesonide, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Pregnenediones, Outpatients, Adults, Humans, Aged, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Inhaled corticosteroids, SARS-CoV-2, COVID-19, General Medicine, Middle Aged, COVID-19 Drug Treatment, Treatment, Oxygen, Infectious Diseases, Treatment Outcome, Randomized controlled trial, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female
Abstract: International audience; Objectives: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness.Methods: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here.Results: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms.Discussion: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.
Published: 2021

26. Pharmacokinetics and therapeutic drug monitoring of anticancer protein/kinase inhibitors

Author: Stéphane Bouchet and Mathieu Molimard
Subjects: Neoplasms, Humans, Pharmacology (medical), Drug Monitoring, Protein Kinase Inhibitors
Abstract: Over the past two decades, protein/kinase inhibitors, as targeted therapies, raised in number and have become increasingly mainstream in the treatment of malignant diseases, thanks to the ease of oral administration and the minimal adverse drug reactions. These drugs have similar pharmacokinetic properties: a relatively good absorption and distribution, a strong hepatic metabolism, and a mainly biliary excretion. However, this pharmacokinetic and route of administration has the disadvantage of resulting in a large inter- and intra-individual variability. Despite this significant variability, these drugs are largely prescribed at the same initial dose for quite all patients (flat dose), even though this variability would require individualized adaptation for each patient and/or each new circumstance. Promptly after their commercialization, scientific teams have performed concentration measurements of several drugs and showed the existence of efficacy or toxicity thresholds. This has contributed to the development of therapeutic drug monitoring as one of the strategies to improve the response and reduce the adverse reactions of these drugs. There is still a need to determine precise thresholds for the remaining drugs and to evaluate the impact of TDM in therapeutic management. In order to determine the current state of the art, this article reviews indications, pharmacokinetics and TDM data for 49 marketed PKIs.
Published: 2021

27. Identification and analysis of clinical phenotypes in COPD patients: PALOMB Cohort

Author: Claire Bon, Frederic Pilard, Remi Veillon, Chantal Raherison-Semjen, Emmanuel Monge, Maeva Zysman, Laura Petrov, Elodie Blanchard, Mohammed Staali, Christophe Roy, Jean Moinard, Frédéric Le Guillou, Emilie Berteaud, Jean Michel Dupis, Mathieu Molimard, Mohammed Aliati, Yannick Daoudi, Marc Sapene, Cécilia Nocent-Ejnaini, Xavier Demant, Leo Grassion, Esther Iglesias, L. Falque, J. Casteigt, A. Bernady, El-hassane Ouaalaya, Julie Macey, Marie Line Quinquenel, Laurent Nguyen, Annaig Ozier, Marielle Sabatini, and A. Prudhomme
Subjects: COPD, medicine.medical_specialty, Copd patients, business.industry, Mortality rate, Disease cluster, medicine.disease, Phenotype, respiratory tract diseases, Chronic cough, Diabetes mellitus, Internal medicine, Cohort, medicine, medicine.symptom, business
Abstract: In recent years, several researchers have attempted to identify COPD phenotypes using different cluster analysis. This study aimed to determine the most optimal cluster analysis (supervised vs unsupervised) to robustly identify clinical phenotypes. 2,968 COPD patients have been included from January 2014 until February 2020. General information (age, BMI, smoking, comorbidities), lung function, exacerbations and symptoms were collected. After 5 years of follow-up, vital status was recorded. A hierarchical classification on the principal components (HCPC) was performed, followed by two unsupervised classification algorithms: k-means and PAM (Partition Around Medoids). Robustness was defined according to three different indices of validation (Connectivity, Dunn and silhouette). The mean age was 70 years, 63.7% of males, current smokers: 38.7%, mean FEV1: 61.3% predicted, ≥2 exacerbations: 43.6%, mMRC dyspnea grade≥2: 56.3%, chronic cough: 58%. The 5-year mortality rate was 11.3%. Based on our hypothesis, four phenotypes were described, using the PAM method. The phenotype A (24.2%) consisted of elderly patients with severe airflow limitation, low symptoms, cardiovascular comorbidities, diabetes and a higher mortality. The phenotype B (23.9%) contained more female patients, young patients with moderate airflow limitation and a high rate of current smokers. The phenotype C (25.5%) contained patients with very severe airflow limitation, more symptoms and low BMI. The Phenotype D (26.2%) was composed of patients with mild airflow limitation and low dyspnoea. These results showed the superiority of PAM classification compared with two other algorithms (k-means and HCPC) in terms of the robustness.
Published: 2021

28. Omalizumab exposure patterns in real-life: An 11-year French population-based study of 19,203 patients with severe asthma

Author: Marc Humbert, Mathieu Molimard, Alexandre Rigault, Driss Kamar, Camille Taillé, Audrey Lajoinie, Céline Thonnelier, Arnaud Bourdin, and Antoine Deschildre
Subjects: Population based study, Pediatrics, medicine.medical_specialty, business.industry, Severe asthma, In real life, Medicine, Omalizumab, business, medicine.drug
Published: 2021

29. Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients

Author: Martine Escoffre-Barbe, P. Rousselot, Pascale Cony-Makhoul, Stéphane Bouchet, Lambert Busque, Caroline Dartigeas, Franck E. Nicolini, Valérie Coiteux, Françoise Huguet, Laurence Legros, Lydia Roy, Delphine Rea, François Guilhot, Joelle Guilhot, Emilie Cayssials, Francois-Xavier Mahon, Luigina Mollica, Agnès Guerci, Martine Gardembas, Jean-Michel Cayuela, Anne Bergeron, Gabriel Etienne, Viviane Dubruille, Aude Charbonnier, Mathieu Molimard, Centre Hospitalier de Versailles André Mignot (CHV), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hôpital Maisonneuve-Rosemont, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Léon Bérard [Lyon], Institut Bergonié [Bordeaux], UNICANCER, Hôpital Paul Brousse, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Claude Huriez [Lille], CHU Lille, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche clinique appliquée à l'hématologie (URP_3518), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux Ségalen [Bordeaux 2], CHU de Bordeaux Pellegrin [Bordeaux], Bristol-Myers Squibb, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, medicine.drug_class, Pleural effusion, Dasatinib, Antineoplastic Agents, Gastroenterology, Tyrosine-kinase inhibitor, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, hemic and lymphatic diseases, Clinical endpoint, Humans, Medicine, Cumulative incidence, Prospective Studies, Adverse effect, Protein Kinase Inhibitors, Aged, 030304 developmental biology, Aged, 80 and over, Pharmacology, 0303 health sciences, Dose-Response Relationship, Drug, medicine.diagnostic_test, business.industry, Tyrosine kinases, Hematology, Middle Aged, medicine.disease, Effective dose (pharmacology), 3. Good health, Pleural Effusion, Treatment Outcome, Therapeutic drug monitoring, 030220 oncology & carcinogenesis, Chronic leukaemia, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Monitoring, business, medicine.drug
Abstract: International audience; Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
Published: 2021

30. Comment améliorer l’acceptabilité vaccinale (évaluation, pharmacovigilance, communication, santé publique, obligation vaccinale, peurs et croyances)

Author: Odile Gelpi, Laurent Simon, Stéphane Schück, Jehan-Michel Behier, Alain Dutilleul, Franck Rouby, Annick Opinel, Benoît Soubeyrand, Farid Kheloufi, Geneviève Chêne, Brigitte Autran, Soizic Courcier, Franck Gérald, Véronique Dufour, Jacques Morel, Mathieu Molimard, Géraldine Ménin, Xavier Bresse, Jean-Louis Koeck, Thomas Borel, François Faurisson, Marie-Christine Truchet, Véronique Lamarque-Garnier, Clémentine Schilte, Arnaud Gagneur, Telma Lery, Odile Launay, and Claire Roger
Subjects: 03 medical and health sciences, 0302 clinical medicine, Pharmacology (medical), 030226 pharmacology & pharmacy
Abstract: Resume Recommandation phare du Comite d’orientation de la conference citoyenne sur la vaccination, l’obligation vaccinale etendue a 11 vaccins pour les nourrissons nes depuis le 1er janvier 2018, s’inscrit dans un ensemble de recommandations devant etre considere comme un tout dont chaque composante apparait indispensable a la realisation des objectifs vises : retablir la confiance dans la vaccination et augmenter la couverture vaccinale. Les participants a la table ronde n° 6 ont identifie une dizaine d’initiatives concretes pouvant repondre, au moins pour partie, aux recommandations du Comite, parmi lesquelles : developper des systemes d’information et la generation de donnees ; simplifier le parcours vaccinal et multiplier les opportunites de vaccination ; developper la formation des professionnels de sante ; apprendre les vaccins a l’ecole ; utiliser l’entretien motivationnel en intervention educative ; entreprendre des initiatives locales ; ameliorer l’approvisionnement et communiquer sur la valeur des vaccins. Pour mener a bien ces actions, il a ete propose que soit cree, au niveau national, un Comite interministeriel regroupant les differentes parties prenantes afin d’impulser leur mise en œuvre et assurer leur suivi et au niveau regional, la mise en place d’un plan de sensibilisation des Agences regionales de sante faisant de la prevention vaccinale un axe prioritaire.
Published: 2019

31. Nurses' internal contamination by antineoplastic drugs in hospital centers: a cross-sectional descriptive study

Author: Isabelle Baldi, Dunia Sakr, Béatrice Martinez, Mireille Canal-Raffin, E. Bignon, Magali Rouyer, Antoine Villa, Catherine Verdun-Esquer, Régis Lassalle, Simone Mathoulin-Pélissier, Mathieu Molimard, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, Nursing staff, Urinary system, Nurses, Antineoplastic Agents, Urine, Urine analysis, Nursing Staff, Hospital, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Internal medicine, Humans, Medicine, Ifosfamide, 030212 general & internal medicine, Cyclophosphamide, business.industry, Public Health, Environmental and Occupational Health, Internal contamination, Middle Aged, Contamination, Occupational exposure, 030210 environmental & occupational health, Hospitals, 3. Good health, Cross-Sectional Studies, Methotrexate, Doxorubicin, Reference values, Biomonitoring, Antineoplastic Drugs, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Fluorouracil, business, Antineoplastic drugs, Exposure data, Biological Monitoring, medicine.drug
Abstract: Objective The aim of this study was to assess internal antineoplastic drugs (ADs) contamination in the nursing staff in French hospital centers, using highly sensitive analytical methods. Methods This cross-sectional study included nurses practicing in care departments where at least one of the five ADs studied was handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The nurses study participation lasted 24 h including collection of three urine samples and one self-questionnaire. All urine samples were assayed by ultra-high-performance liquid chromatography-tandem mass spectrometry methods with very low value of the lower limit of quantification (LLOQ). Results 74 nurses were included, 222 urine samples and 74 self-questionnaires were collected; 1092 urine assays were performed. The percentage of nurses with internal AD contamination was 60.8% and low levels of urinary concentrations were measured. Regarding nurses with internal contamination (n = 45), 42.2% presented internal contamination by methotrexate, 37.8% by cyclophosphamide, 33.3% by ifosfamide, 17.8% by 5-fluorouracil metabolite and 6.7% by doxorubicine. Among the positive assays, 17.9% (n = 26/145) were not explained by exposure data from the self-questionnaire but this could be due to the skin contact of nurses with contaminated work surfaces. Conclusions This study reported high percentage of nurses with internal ADs contamination. The low LLOQ values of the used analytical methods, allowed the detection of ADs that would not have been detected with the current published methods: the percentage of contamination would have been 17.6% instead of the 60.8% reported here. Pending toxicological reference values, urine ADs concentrations should be reduced as low as reasonably achievable (ALARA principle).
Published: 2021

32. COVID-19: Pharmacology has kept the science ship running during the storm

Author: Jean-Luc Cracowski, Mathieu Molimard, Vincent Richard, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 2019-20 coronavirus outbreak, History, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Storm, 030226 pharmacology & pharmacy, Virology, Running, 03 medical and health sciences, 0302 clinical medicine, Editorial, Humans, Pharmacology (medical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Ships
Abstract: Therapies - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le jeudi 10 juin 2021
Published: 2021

33. Performance Characteristics of Breezhaler

Author: Mathieu, Molimard, Ioannis, Kottakis, Juergen, Jauernig, Sonja, Lederhilger, and Ivan, Nikolaev
Subjects: Pulmonary Disease, Chronic Obstructive, Nebulizers and Vaporizers, Administration, Inhalation, Humans, Dry Powder Inhalers, Equipment Design, Review Article, Lung, Severity of Illness Index, Asthma
Abstract: The evaluation of errors in use with different inhaler devices is challenging to quantify as there are a number of definitions of critical and non-critical errors with respect to inhaler use; in addition, performance characteristics of the device, such as airflow resistance, can also influence effective use in the real-world setting. Repeated observations and checking/correcting inhaler use are essential to optimise clinical effectiveness of inhaled therapy in patients. Breezhaler® is a single unit-dose dry powder inhaler used in chronic obstructive pulmonary disease and in asthma (budesonide) that has low airflow resistance, making it easier for patients of varying disease severities to achieve the inhalation flow rate required for lung deposition of treatment. Similar to Breezhaler®, the Aerolizer® is a single unit-dose dry powder inhaler used in asthma management with low airflow resistance. Studies have shown relatively low rates of critical errors with Breezhaler® and Aerolizer®, with similarities in the critical errors reported; these data on critical errors together with similarities in the usability of Breezhaler® and Aerolizer® further support the functional similarity between the two devices in both asthma and chronic obstructive pulmonary disease. Breezhaler® also has patient-feedback features, including use of a transparent drug capsule that can be checked after inhalation to see it is empty. The low resistance of the dose-confirming Breezhaler® results in less inspiratory effort being required by patients for its effective use, which allows the device to be used effectively across a wide age range of patients and disease severities.
Published: 2021

34. Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies

Author: Bousquet, Jean, Cristol, Jean-Paul, Czarlewski, Wienczyslawa, Anto, Josep M, Martineau, Adrian, Haahtela, Tari, Fonseca, Susana C, Iaccarino, Guido, Blain, Hubert, Fiocchi, Alessandro, Canonica, G Walter, Fonseca, Joao A, Vidal, Alain, Choi, Hak-Jong, Kim, Hyun Ju, Le Moing, Vincent, Reynes, Jacques, Sheikh, Aziz, Akdis, Cezmi A, Zuberbier, Torsten, Amir Hamzah Abdul Latiff, Baharudin, Abdullah, Werner, Aberer, Nancy, Abusada, Ian, Adcock, Alejandro, Afani, Ioana, Agache, Xenofon, Aggelidis, Jenifer, Agustin, Cezmi, A Akdis, Mübeccel, Akdis, Mona, Al-Ahmad, Abou Al-Zahab Bassam, Hussam, Alburdan, Oscar, Aldrey-Palacios, Emilio Alvarez Cuesta, Hiba Alwan Salman, Ashraf, Alzaabi, Salma, Amade, Gene, Ambrocio, Rosana, Angles, Isabella, Annesi-Maesano, Ignacio, J Ansotegui, Josep, M Anto, Paula Ara Bardajo, Stefania, Arasi, Margarete, Arrais, Hasan, Arshad, Maria-Cristina, Artesani, Estrella, Asayag, Francesca, Avolio, Khuzama, Azhari, Claus, Bachert, Diego, Bagnasco, Ilaria, Baiardini, Nissera, Bajrović, Petros, Bakakos, Sergio Bakeyala Mongono, Christine, Balotro-Torres, Sergio, Barba, Cristina, Barbara, Elsa, Barbosa, Bruno, Barreto, Joan, Bartra, Xavier, Basagana, Eric, D Bateman, Lkhagvaa, Battur, Anna, Bedbrook, Martín Bedolla Barajas, Bianca, Beghé, Antra, Bekere, Elizabeth, Bel, Ali Ben Kheder, Mikael, Benson, Elena-Camelia, Berghea, Karl-Christian, Bergmann, Roberto, Bernardini, David, Bernstein, Mike, Bewick, Slawomir, Bialek, Artur, Białoszewski, Thomas, Bieber, Nils, E Billo, Maria-Beatrice, Bilo, Carsten, Bindslev-Jensen, Leif, Bjermer, Hubert, Blain, Irina, Bobolea, Malgorzata Bochenska Marciniak, Christine, Bond, Attilio, Boner, Matteo, Bonini, Sergio, Bonini, Sinthia, Bosnic-Anticevich, Isabelle, Bosse, Sofia, Botskariova, Jacques, Bouchard, Louis-Philippe, Boulet, Rodolphe, Bourret, Philippe, Bousquet, Fulvio, Braido, Andrew, Briggs, Christopher, E Brightling, Jan, Brozek, Luisa, Brussino, Roland, Buhl, Roxana, Bumbacea, Rosalva, Buquicchio, María-Teresa Burguete Cabañas, Andrew, Bush, William, W Busse, Jeroen, Buters, Fernan, Caballero-Fonseca, Moïses, A Calderon, Mario, Calvo, Paulo, Camargos, Thierry, Camuzat, R Canevari, F, Antonio, Cano, G Walter Canonica, Arnaldo, Capriles-Hulett, Luis, Caraballo, Vicky, Cardona, Kai-Hakon, Carlsen, Jonas Carmona Pirez, Jorge, Caro, Warner, Carr, Pedro, Carreiro-Martins, Fredelita, Carreon-Asuncion, Ana-Maria, Carriazo, Carme Carrion, Y Ribas, Thomas, Casale, Mary-Ann, Castor, Elizabeth, Castro, G Caviglia, A, Lorenzo, Cecchi, Alfonso Cepeda Sarabia, Maciej, Chalubinski, Ramanathan, Chandrasekharan, Yoon-Seok, Chang, Victoria, Chato-Andeza, Lida, Chatzi, Christina, Chatzidaki, Niels, H Chavannes, Claudia Chaves Loureiro, Aurora-Alejandra Chavez Garcia, Marta, Chelninska, Yuzhi, Chen, Lei, Cheng, Sharon, Chinthrajah, Tomas, Chivato, Ekaterine, Chkhartishvili, George, Christoff, Henry, Chrystyn, Derek, K Chu, Antonio, Chua, Alexander, Chuchalin, Kian Fan Chung, Alberto, Cicerán, Cemal, Cingi, Giorgio, Ciprandi, Ieva, Cirule, Ana-Carla, Coelho, Enrico, Compalati, Jannis, Constantinidis, Jaime Correia de Sousa, Elisio Manuel Costa, David, Costa, María Del Carmen Costa Domínguez, André, Coste, Cottini, M, Linda, Cox, Carlos, Crisci, Maria Angiola Crivellaro, Alvaro, A Cruz, John, Cullen, Adnan, Custovic, Biljana, Cvetkovski, Wienczyslawa, Czarlewski, Gennaro, D'Amato, Jane da Silva, Ronald, Dahl, Sven-Erik, Dahlen, Vasilis, Daniilidis, Louei Darjazini Nahhas, Ulf, Darsow, Janet, Davies, Frédéric de Blay, Giulia De Feo, Eloisa De Guia, José-Ricardo De la Torre Navarrete, Chato De Los Santos, Esteban De Manuel Keenoy, Govert De Vries, Diana, Deleanu, Pascal, Demoly, Judah, Denburg, Philippe, Devillier, Alain, Didier, Sanja Dimic Janjic, Maria, Dimou, Anh Tuan Dinh-Xuan, Ratko, Djukanovic, Maria Do Ceu Texeira, Dejan, Dokic, Margarita Gabriela Domínguez Silva, Habib, Douagui, Nikolaos, Douladiris, Maria, Doulaptsi, Gérard, Dray, Ruta, Dubakiene, Eve, Dupas, Stephen, Durham, Marzia, Duse, Mark, Dykewicz, Didier, Ebo, Natalija, Edelbaher, Thomas, Eiwegger, Patrik, Eklund, Yehia, El-Gamal, Zeinab, A El-Sayed, Shereen, S El-Sayed, Magda, El-Seify, Regina, Emuzyte, Lourdes, Enecilla, Marina, Erhola, Heidilita, Espinoza, Jesús Guillermo Espinoza Contreras, John, Farrell, Lenora, Fernandez, Paola Fimbres Jimenez, Antje Fink Wagner, Alessandro, Fiocchi, Wytske, J Fokkens, Lenia, Folletti, Joao, A Fonseca, Jean-François, Fontaine, Francesco, Forastiere, Jose Miguel Fuentes Pèrez, Emily, Gaerlan-Resureccion, Mina, Gaga, José Luis Gálvez Romero, Amiran, Gamkrelidze, Alexis, Garcia, Cecilia Yvonne García Cobas, María de la Luz Hortensia García Cruz, Valeria Garcia Ortiz, Jacques, Gayraud, Matteo, Gelardi, Bilun, Gemicioglu, Dimitra, Gennimata, Sonya, Genova, José, Gereda, Roy Gerth van Wijk, Antonio, Giuliano, René-Maximiliano, Gomez, Miguel-Ange Gonzalez Ballester, Sandra González Diaz, Maia, Gotua, Christos, Grigoreas, Ineta, Grisle, Marta, Guidacci, Nick, Guldemond, Zdenek, Gutter, Antonieta, Guzmán, Tari, Haahtela, Ramsa, Halloum, David, Halpin, Eckard, Hamelmann, Suleiman, Hammadi, Richard, Harvey, Enrico, Heffler, Joachim, Heinrich, Adnan, Hejjaoui, Birthe, Hellquist-Dahl, Luiana Hernández Velázquez, Mark, Hew, Elham, Hossny, Peter, Howarth, Martin, Hrubiško, Yunuen Rocío Huerta Villalobos, Marc, Humbert, Salina, Husain, Michael, Hyland, Guido, Iaccarino, Moustafa, Ibrahim, Nataliya, Ilina, Maddalena, Illario, Cristoforo, Incorvaia, Antonio, Infantino, Carla, Irani, Zhanat, Ispayeva, Juan Carlos Ivancevich, Edgardo Ej Jares, Deborah, Jarvis, Ewa, Jassem, Klemen, Jenko, Rubén Darío Jiméneracruz Uscanga, Sebastian, L Johnston, Guy, Joos, Maja, Jošt, Kaja, Julge, Ki-Suck, Jung, Jocelyne, Just, Marek, Jutel, Igor, Kaidashev, Omer, Kalayci, Fuat, Kalyoncu, Jeni, Kapsali, Przemyslaw, Kardas, Jussi, Karjalainen, Carmela, A Kasala, Michael, Katotomichelakis, Loreta, Kavaliukaite, Kazi, S Bennoor, Thomas, Keil, Paul, Keith, Musa, Khaitov, Nikolai, Khaltaev, You-Young, Kim, Bruce, Kirenga, Jorg, Kleine-Tebbe, Ludger, Klimek, Fanny, W Ko, Bernard Koffi N'Goran, Evangelia, Kompoti, Peter, Kopač, Gerard, Koppelman, Anja Koren Jeverica, Seppo, Koskinen, Mitja, Košnik, Tomasz, Kostka, Kosta, V Kostov, Marek, L Kowalski, Tanya, Kralimarkova, Karmen Kramer Vrščaj, Helga, Kraxner, Samo, Kreft, Vicky, Kritikos, Dmitry, Kudlay, Mikael, Kuitunen, Inger, Kull, Piotr, Kuna, Maciej, Kupczyk, Violeta, Kvedariene, Marialena, Kyriakakou, Nika, Lalek, Massimo, Landi, Stephen, Lane, Désiree, E Larenas-Linnemann, Susanne, Lau, Daniel, Laune, Jorge, Lavrut, Lan, Le, Martina, Lenzenhuber, Gualtiero, Leo, Marcus, Lessa, Michael, Levin, Jing, Li, Philip, Lieberman, Giuseppe, Liotta, Brian, Lipworth, Xuandao, Liu, Rommel, Lobo, Karin, C Lodrup Carlsen, Carlo, Lombardi, Renaud, Louis, Stelios, Loukidis, Olga, Lourenço, Jorge, A Luna Pech, Bojan, Madjar, Enrico, Maggi, Antoine, Magnan, Bassam, Mahboub, Alpana, Mair, Anke-Hilse Maitland van der Zee, Mika, Makela, Michael, Makris, Hans-Jorgen, Malling, Mariana, Mandajieva, Patrick, Manning, Manolis, Manousakis, Pavlos, Maragoudakis, Gianluigi, Marseglia, Gailen, Marshall, Mohammad Reza Masjedi, Jorge, F Máspero, Juan José Matta Campos, Marcus, Maurer, Sandra, Mavale-Manuel, Cem, Meço, Erik, Melén, Giovanni, Melioli, Elisabete, Melo-Gomes, Eli, O Meltzer, Enrica, Menditto, Andrew, Menzies-Gow, Hans, Merk, Jean-Pierre, Michel, Yann, Micheli, Neven, Miculinic, Luís, Midão, Florin, Mihaltan, Nikolaos, Mikos, Manlio, Milanese, Branislava, Milenkovic, Dimitrios, Mitsias, Bassem, Moalla, Giuliana, Moda, María Dolores Mogica Martínez, Yousser, Mohammad, Frances-Montserrat, Moharra, Mostafa, Moin, Mathieu, Molimard, Isabelle, Momas, Monique, Mommers, Alessandro, Monaco, Stephen, Montefort, Lucia-Elvira, Montenegro, Riccardo, Monti, Dory, Mora, Mario, Morais-Almeida, Ralph, Mösges, Badr Eldin Mostafa, Joaquim, Mullol, Lars, Münter, Antonella, Muraro, Ruth, Murray, Antonio, Musarra, Tihomir, Mustakov, Robert, Naclerio, Kari, C Nadeau, Rachel, Nadif, Alla, Nakonechna, Leyla, Namazova-Baranova, Gretchen, Navarro-Locsin, Hugo, Neffen, Kristof, Nekam, Angelos, Neou, Eustachio, Nettis, Daniel, Neuberger, Laurent, Nicod, Stefania, Nicola, Verena, Niederberger-Leppin, Marek, Niedoszytko, Antonio, Nieto, Ettore, Novellino, Elizabete, Nunes, Dieudonné, Nyembue, Robyn, E O'Hehir, Cvetanka, Odjakova, Ken, Ohta, Yoshitaka, Okamoto, Kimi, Okubo, Brian, Oliver, Gabrielle, L Onorato, Maria Pia Orru, Solange, Ouédraogo, Kampadilemba, Ouoba, Francisco-Javier, Padilla, Pier Luigi Paggiaro, Aris, Pagkalos, Pajno, Giovanni Battista, Gianni, Pala, P Palaniappan, S, Isabella, Pali-Schöll, Susanna, Palkonen, Stephen, Palmer, Carmen Panaitescu Bunu, Petr, Panzner, Nikos, G Papadopoulos, Vasilis, Papanikolaou, Alberto, Papi, Bojidar, Paralchev, Giannis, Paraskevopoulos, Hae-Sim, Park, Giovanni, Passalacqua, Vincenzo, Patella, Ian, Pavord, Ruby, Pawankar, Soren, Pedersen, Susete, Peleve, Simona, Pellegino, Ana, Pereira, Mariana, Pereira, Tamara, Pérez, Andrea, Perna, Diego, Peroni, Oliver, Pfaar, Nhân, Pham-Thi, Bernard, Pigearias, Isabelle, Pin, Konstantina, Piskou, Constantinos, Pitsios, Davor, Plavec, Dagmar, Poethig, Wolfgang, Pohl, Antonija Poplas Susic, Todor, A Popov, Fabienne, Portejoie, Paul, Potter, Lars, Poulsen, Alexandra, Prados-Torres, Fotis, Prarros, David, Price, Emmanuel, Prokopakis, Francesca, Puggioni, Elisa, Puig-Domenech, Robert, Puy, Klaus, Rabe, Silvia, Rabotti, Filip, Raciborski, Josephine, Ramos, Cristina, Recalcati, Marysia, T Recto, Shereen, M Reda, Frederico, S Regateiro, Norbert, Reider, Sietze, Reitsma, Susana, Repka-Ramirez, Erminia, Ridolo, Janet, Rimmer, Daniela Rivero Yeverino, José Angelo Rizzo, Carlos, Robalo-Cordeiro, Graham, Roberts, Karen, Robles, Nicolas, Roche, Mónica Rodríguez González, Eréndira Rodríguez Zagal, Giovanni, Rolla, Christine, Rolland, Regina, Roller-Wirnsberger, Miguel Roman Rodriguez, Antonino, Romano, Jan, Romantowski, Philippe, Rombaux, Joel, Romualdez, Jose, Rosado-Pinto, Nelson, Rosario, Lanny, Rosenwasser, Oliviero, Rossi, Menachem, Rottem, Philip, W Rouadi, Nikoleta, Rovina, Irma Rozman Sinur, Mauricio, Ruiz, Lucy Tania Ruiz Segura, Dermot, Ryan, Hironori, Sagara, Daiki, Sakai, Daiju, Sakurai, Wafaa, Saleh, Johanna, Salimaki, Konstantinos, Samitas, Boleslaw, Samolinski, María Guadalupe Sánchez Coronel, Mario, Sanchez-Borges, Jaime, Sanchez-Lopez, Melissa, Sansonna, Codrut, Sarafoleanu, Faradiba Sarquis Serpa, Joaquin, Sastre, Eleonora, Savi, Agne, Savonyte, Bisher, Sawaf, Glenis, K Scadding, Sophie, Scheire, Peter, Schmid-Grendelmeier, Juan Francisco Schuhl, Holger, Schunemann, Maria, Schvalbová, Jorgen, Schwarze, Nicola, Scichilone, Gianenrico, Senna, Cecilia, Sepúlveda, Elie, Serrano, Sara, Shamai, Aziz, Sheikh, Mike, Shields, Vasil, Shishkov, Nikos, Siafakas, Alexander, Simeonov, Estelle Fer Simons, Juan Carlos Sisul, Brigita, Sitkauskiene, Ingelbjorg, Skrindo, Tanja Soklič Košak, Dirceu, Solé, Martin, Sondermann, Talant, Sooronbaev, Manuel, Soto-Martinez, Manuel, Soto-Quiros, Barnaro Sousa Pinto, Milan, Sova, Michael, Soyka, Krzysztof, Specjalski, Annette, Sperl, Otto, Spranger, Sofia, Stamataki, Lina, Stefanaki, Cristiana, Stellato, Rafael, Stelmach, Timo, Strandberg, Petra, Stute, Abirami, Subramaniam, Charlotte Suppli Ulrik, Michael, Sutherland, Silvia, Sylvestre, Aikaterini, Syrigou, Luis Taborda Barata, Nadejda, Takovska, Rachel, Tan, Frances, Tan, Vincent, Tan, Ing Ping Tang, Masami, Taniguchi, Line, Tannert, Pongsakorn, Tantilipikorn, Jessica, Tattersall, Filippo, Tesi, Uta, Thieme, Carel, Thijs, Mike, Thomas, Teresa, To, Ana Maria Todo-Bom, Alkis, Togias, Peter-Valentin, Tomazic, Vesna, Tomic-Spiric, Sanna, Toppila-Salmi, Maria-José Torres Jaen, Elina, Toskala, Massimo, Triggiani, Nadja, Triller, Katja, Triller, Ioanna, Tsiligianni, Uberti, M, Ruxandra, Ulmeanu, Jure, Urbancic, Marilyn Urrutia Pereira, Martina, Vachova, Felipe, Valdés, Rudolf, Valenta, Marylin Valentin Rostan, Antonio, Valero, Arunas, Valiulis, Mina, Vallianatou, Erkka, Valovirta, Michiel Van Eerd, Eric Van Ganse, Marianne van Hage, Olivier, Vandenplas, Tuula, Vasankari, Dafina, Vassileva, Cesar Velasco Munoz, Maria Teresa Ventura, Cécilia, Vera-Munoz, Frédéric, Viart, Dilyana, Vicheva, Pakit, Vichyanond, Petra, Vidgren, Giovanni, Viegi, Claus, Vogelmeier, Leena Von Hertzen, Theodoros, Vontetsianos, Dimitris, Vourdas, Vu Tran Thien Quan, Martin, Wagenmann, Samantha, Walker, Dana, Wallace, Yun De Wang, Susan, Waserman, Katrin, Wehner, Magnus, Wickman, Sian, Williams, Dennis, Williams, Nicola, Wilson, Gary, Wong, Kent, Woo, Lucyna, Wozniak, John, Wright, Piotr, Wroczynski, Paraskevi, Xepapadaki, Plamen, Yakovliev, Masao, Yamaguchi, Kwok, Yan, Yoke Yeow Yap, Mais, Yassin, Barbara, Yawn, Panayiotis, Yiallouros, Arzu, Yorgancioglu, Shigemi, Yoshihara, Ian, Young, Osman, B Yusuf, Asghar, Zaidi, Fares, Zaitoun, Petra, Zalud, Heather, Zar, T Zedda, M, Mario, E Zernotti, Luo, Zhang, Nanshan, Zhong, Mihaela, Zidarn, Torsten, Zuberbier, Celia, Zubrinich, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Berlin Institute of Health (BIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), IMIM-Hospital del Mar, Generalitat de Catalunya, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Barts & The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsinki University Central Hospital [Finland] (HUCH), Departamento de Geociencias, Ambiente e Ordenamento do Territorio (DGAOT), Universidade do Porto = University of Porto, University of Naples Federico II = Università degli studi di Napoli Federico II, Euromov (EuroMov), Université de Montpellier (UM), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Center of Research in Health Technologies and Information Systems (CINTESIS), AgroParisTech, World Institute of Kimchi [Gwangju], Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Edinburgh, Universität Zürich [Zürich] = University of Zurich (UZH), Humboldt-Universität zu Berlin, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Helsinki, Universidade do Porto, University of Naples Federico II, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), MORNET, Dominique, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - (MGD) Service de pneumologie, Bousquet J., Cristol J.-P., Czarlewski W., Anto J.M., Martineau A., Haahtela T., Fonseca S.C., Iaccarino G., Blain H., Fiocchi A., Canonica G.W., Fonseca J.A., Vidal A., Choi H.-J., Kim H.J., Le Moing V., Reynes J., Sheikh A., Akdis C.A., Zuberbier T., Abdul Latiff A.H., Abdullah B., Aberer W., Abusada N., Adcock I., Afani A., Agache I., Aggelidis X., Agustin J., Akdis M., Al-Ahmad M., Al-Zahab Bassam A., Alburdan H., Aldrey-Palacios O., Alvarez Cuesta E., Alwan Salman H., Alzaabi A., Amade S., Ambrocio G., Angles R., Annesi-Maesano I., Ansotegui I.J., Ara Bardajo P., Arasi S., Arrais M., Arshad H., Artesani M.-C., Asayag E., Avolio F., Azhari K., Bachert C., Bagnasco D., Baiardini I., Bajrovic N., Bakakos P., Bakeyala Mongono S., Balotro-Torres C., Barba S., Barbara C., Barbosa E., Barreto B., Bartra J., Basagana X., Bateman E.D., Battur L., Bedbrook A., Bedolla Barajas M., Beghe B., Bekere A., Bel E., Ben Kheder A., Benson M., Berghea E.-C., Bergmann K.-C., Bernardini R., Bernstein D., Bewick M., Bialek S., Bialoszewski A., Bieber T., Billo N.E., Bilo M.-B., Bindslev-Jensen C., Bjermer L., Bobolea I., Bochenska Marciniak M., Bond C., Boner A., Bonini M., Bonini S., Bosnic-Anticevich S., Bosse I., Botskariova S., Bouchard J., Boulet L.-P., Bourret R., Bousquet P., Braido F., Briggs A., Brightling C.E., Brozek J., Brussino L., Buhl R., Bumbacea R., Buquicchio R., Burguete Cabanas M.-T., Bush A., Busse W.W., Buters J., Caballero-Fonseca F., Calderon M.A., Calvo M., Camargos P., Camuzat T., Canevari F., Cano A., Canonican G.W., Capriles-Hulett A., Caraballo L., Cardona V., Carlsen K.-H., Carmona Pirez J., Caro J., Carr W., Carreiro-Martins P., Carreon-Asuncion F., Carriazo A.-M., CarrionyRibas C., Casale T., Castor M.-A., Castro E., Caviglia A.G., Cecchi L., Cepeda Sarabia A., Chalubinski M., Chandrasekharan R., Chang Y.-S., Chato-Andeza V., Chatzi L., Chatzidaki C., Chavannes N.H., Chaves Loureiro C., Chavez Garcia A.-A., Chelninska M., Chen Y., Cheng L., Chinthrajah S., Chivato T., Chkhartishvili E., Christoff G., Chrystyn H., Chu D.K., Chua A., Chuchalin A., Chung K.F., Ciceran A., Cingi C., Ciprandi G., Cirule I., Coelho A.-C., Compalati E., Constantinidis J., Correia de Sousa J., Costa E.M., Costa D., del Carmen Costa Dominguez M., Coste A., Cottini M., Cox L., Crisci C., Crivellaro M.A., Cruz A.A., Cullen J., Custovic A., Cvetkovski B., D'Amato G., da Silva J., Dahl R., Dahlen S.-E., Daniilidis V., Darjazini Nahhas L., Darsow U., Davies J., de Blay F., De Feo G., De Guia E., De la Torre Navarrete J.-R., De los Santos C., De Manuel Keenoy E., De Vries G., Deleanu D., Demoly P., Denburg J., Devillier P., Didier A., Dimic Janjic S., Dimou M., Dinh-Xuan A.T., Djukanovic R., Do Ceu Texeira M., Dokic D., Dominguez Silva M.G., Douagui H., Douladiris N., Doulaptsi M., Dray G., Dubakiene R., Dupas E., Durham S., Duse M., Dykewicz M., Ebo D., Edelbaher N., Eiwegger T., Eklund P., El-Gamal Y., El-Sayed Z.A., El-Sayed S.S., El-Seify M., Emuzyte R., Enecilla L., Erhola M., Espinoza H., Espinoza Contreras J.G., Farrell J., Fernandez L., Fimbres Jimenez P., Fink Wagner A., Fokkens W.J., Folletti L., Fontaine J.-F., Forastiere F., Fuentes Perez J.M., Gaerlan-Resureccion E., Gaga M., Galvez Romero J.L., Gamkrelidze A., Garcia A., Garcia Cobas C.Y., de la Luz Hortensia Garcia Cruz M., Ortiz V.G., Gayraud J., Gelardi M., Gemicioglu B., Gennimata D., Genova S., Gereda J., Gerth van Wijk R., Giuliano A., Gomez R.-M., Gonzalez Ballester M.-A., Gonzalez Diaz S., Gotua M., Grigoreas C., Grisle I., Guidacci M., Guldemond N., Gutter Z., Guzman A., Halloum R., Halpin D., Hamelmann E., Hammadi S., Harvey R., Heffler E., Heinrich J., Hejjaoui A., Hellquist-Dahl B., Hernandez Velazquez L., Hew M., Hossny E., Howarth P., Hrubisko M., Huerta Villalobos Y.R., Humbert M., Husain S., Hyland M., Ibrahim M., Ilina N., Illario M., Incorvaia C., Infantino A., Irani C., Ispayeva Z., Ivancevich J.C., Jares E.E., Jarvis D., Jassem E., Jenko K., Jimeneracruz Uscanga R.D., Johnston S.L., Joos G., Jost M., Julge K., Jung K.-S., Just J., Jutel M., Kaidashev I., Kalayci O., Kalyoncu F., Kapsali J., Kardas P., Karjalainen J., Kasala C.A., Katotomichelakis M., Kavaliukaite L., Bennoor K.S., Keil T., Keith P., Khaitov M., Khaltaev N., Kim Y.-Y., Kirenga B., Kleine-Tebbe J., Klimek L., Ko F.W., Koffi N'Goran B., Kompoti E., Kopac P., Koppelman G., Koren Jeverica A., Koskinen S., Kosnik M., Kostka T., Kostov K.V., Kowalski M.L., Kralimarkova T., Kramer Vrscaj K., Kraxner H., Kreft S., Kritikos V., Kudlay D., Kuitunen M., Kull I., Kuna P., Kupczyk M., Kvedariene V., Kyriakakou M., Lalek N., Landi M., Lane S., Larenas-Linnemann D.E., Lau S., Laune D., Lavrut J., Le L., Lenzenhuber M., Leo G., Lessa M., Levin M., Li J., Lieberman P., Liotta G., Lipworth B., Liu X., Lobo R., Lodrup Carlsen K.C., Lombardi C., Louis R., Loukidis S., Lourenco O., Luna Pech J.A., Madjar B., Maggi E., Magnan A., Mahboub B., Mair A., Maitland van der Zee A.-H., Makela M., Makris M., Malling H.-J., Mandajieva M., Manning P., Manousakis M., Maragoudakis P., Marseglia G., Marshall G., Masjedi M.R., Maspero J.F., Matta Campos J.J., Maurer M., Mavale-Manuel S., Meco C., Melen E., Melioli G., Melo-Gomes E., Meltzer E.O., Menditto E., Menzies-Gow A., Merk H., Michel J.-P., Micheli Y., Miculinic N., Midao L., Mihaltan F., Mikos N., Milanese M., Milenkovic B., Mitsias D., Moalla B., Moda G., Mogica Martinez M.D., Mohammad Y., Moharra F.-M., Moin M., Molimard M., Momas I., Mommers M., Monaco A., Montefort S., Montenegro L.-E., Monti R., Mora D., Morais-Almeida M., Mosges R., Mostafa B.E., Mullol J., Munter L., Muraro A., Murray R., Musarra A., Mustakov T., Naclerio R., Nadeau K.C., Nadif R., Nakonechna A., Namazova-Baranova L., Navarro-Locsin G., Neffen H., Nekam K., Neou A., Nettis E., Neuberger D., Nicod L., Nicola S., Niederberger-Leppin V., Niedoszytko M., Nieto A., Novellino E., Nunes E., Nyembue D., O'Hehir R.E., Odjakova C., Ohta K., Okamoto Y., Okubo K., Oliver B., Onorato G.L., Orru M.P., Ouedraogo S., Ouoba K., Padilla F.-J., Paggiaro P.L., Pagkalos A., Pajno G., Pala G., Palaniappan S., Pali-Scholl I., Palkonen S., Palmer S., Panaitescu Bunu C., Panzner P., Papadopoulos N.G., Papanikolaou V., Papi A., Paralchev B., Paraskevopoulos G., Park H.-S., Passalacqua G., Patella V., Pavord I., Pawankar R., Pedersen S., Peleve S., Pellegino S., Pereira A., Pereira M., Perez T., Perna A., Peroni D., Pfaar O., Pham-Thi N., Pigearias B., Pin I., Piskou K., Pitsios C., Plavec D., Poethig D., Pohl W., Poplas Susic A., Popov T.A., Portejoie F., Potter P., Poulsen L., Prados-Torres A., Prarros F., Price D., Prokopakis E., Puggioni F., Puig-Domenech E., Puy R., Rabe K., Rabotti S., Raciborski F., Ramos J., Recalcati C., Recto M.T., Reda S.M., Regateiro F.S., Reider N., Reitsma S., Repka-Ramirez S., Ridolo E., Rimmer J., Rivero Yeverino D., Rizzo J.A., Robalo-Cordeiro C., Roberts G., Robles K., Roche N., Rodriguez Gonzalez M., Rodriguez Zagal E., Rolla G., Rolland C., Roller-Wirnsberger R., Roman Rodriguez M., Romano A., Romantowski J., Rombaux P., Romualdez J., Rosado-Pinto J., Rosario N., Rosenwasser L., Rossi O., Rottem M., Rouadi P.W., Rovina N., Rozman Sinur I., Ruiz M., Ruiz Segura L.T., Ryan D., Sagara H., Sakai D., Sakurai D., Saleh W., Salimaki J., Samitas K., Samolinski B., Sanchez Coronel M.G., Sanchez-Borges M., Sanchez-Lopez J., Sansonna M., Sarafoleanu C., Sarquis Serpa F., Sastre J., Savi E., Savonyte A., Sawaf B., Scadding G.K., Scheire S., Schmid-Grendelmeier P., Schuhl J.F., Schunemann H., Schvalbova M., Schwarze J., Scichilone N., Senna G., Sepulveda C., Serrano E., Shamai S., Shields M., Shishkov V., Siafakas N., Simeonov A., Simons E.F., Sisul J.C., Sitkauskiene B., Skrindo I., Soklic Kosak T., Sole D., Sondermann M., Sooronbaev T., Soto-Martinez M., Soto-Quiros M., Pinto B.S., Sova M., Soyka M., Specjalski K., Sperl A., Spranger O., Stamataki S., Stefanaki L., Stellato C., Stelmach R., Strandberg T., Stute P., Subramaniam A., Suppli Ulrik C., Sutherland M., Sylvestre S., Syrigou A., Taborda Barata L., Takovska N., Tan R., Tan F., Tan V., Tang I.P., Taniguchi M., Tannert L., Tantilipikorn P., Tattersall J., Tesi F., Thieme U., Thijs C., Thomas M., To T., Todo-Bom A.M., Togias A., Tomazic P.-V., Tomic-Spiric V., Toppila-Salmi S., Torres Jaen M.-J., Toskala E., Triggiani M., Triller N., Triller K., Tsiligianni I., Uberti M., Ulmeanu R., Urbancic J., Urrutia Pereira M., Vachova M., Valdes F., Valenta R., Valentin Rostan M., Valero A., Valiulis A., Vallianatou M., Valovirta E., Van Eerd M., Van Ganse E., van Hage M., Vandenplas O., Vasankari T., Vassileva D., Velasco Munoz C., Ventura M.T., Vera-Munoz C., Viart F., Vicheva D., Vichyanond P., Vidgren P., Viegi G., Vogelmeier C., Von Hertzen L., Vontetsianos T., Vourdas D., Tran Thien Quan V., Wagenmann M., Walker S., Wallace D., De Wang Y., Waserman S., Wehner K., Wickman M., Williams S., Williams D., Wilson N., Wong G., Woo K., Wozniak L., Wright J., Wroczynski P., Xepapadaki P., Yakovliev P., Yamaguchi M., Yan K., Yap Y.Y., Yassin M., Yawn B., Yiallouros P., Yorgancioglu A., Yoshihara S., Young I., Yusuf O.B., Zaidi A., Zaitoun F., Zalud P., Zar H., Zedda M.T., Zernotti M.E., Zhang L., Zhong N., and Zidarn M.
Subjects: MAPK/ERK pathway, ARIA group, Allergy, [SDV]Life Sciences [q-bio], NF-KAPPA-B, debelost, Review, Pharmacology, Resveratrol, PROTECTS, chemistry.chemical_compound, 0302 clinical medicine, RESPIRATORY SYNDROME CORONAVIRUS, ENDOPLASMIC-RETICULUM STRESS, Medicine and Health Sciences, Immunology and Allergy, Medicine, OXIDATIVE STRESS, COVID-19, Foods, Insulin resistance, Nrf2, Nutrients, Obesity, TRPA1, 2. Zero hunger, 0303 health sciences, RESPIRATORY, INSULIN-RESISTANCE, Muscle cell proliferation, SULFORAPHANE, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SIGNALING PATHWAY, Signal transduction, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, NRF2 ACTIVATORS, MUSCLE-CELL PROLIFERATION, Immunology, 610 Medicine & health, Lung injury, Settore MED/10 - Malattie Dell'Apparato Respiratorio, ACUTE LUNG INJURY, 03 medical and health sciences, COVID-19, Foods, Insulin resistance, Nrf2, Nutrients, Obesity, TRPA1, udc:616.9, odpornost proti inzulinu, SULFORAPHANE PROTECTS, Transcription factor, PI3K/AKT/mTOR pathway, 030304 developmental biology, Science & Technology, business.industry, SARS-CoV-2, food, medicine.disease, chemistry, hranila, SYNDROME CORONAVIRUS, business, hrana, GREEN TEA
Abstract: There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
Published: 2020

35. The determinants of dyspnoea evaluated by the mMRC scale: The French Palomb cohort

Author: Cécilia Nocent-Ejnaini, F. Le Guillou, El-hassane Ouaalaya, Annaig Ozier, Marielle Sabatini, L. Falque, A. Bernady, Chantal Raherison-Semjen, J.M. Dupis, Laurent Nguyen, and Mathieu Molimard
Subjects: Male, Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Multivariate analysis, Subgroup analysis, Overweight, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Forced Expiratory Volume, Internal medicine, medicine, Humans, 030212 general & internal medicine, Lung, Aged, COPD, Bronchiectasis, medicine.diagnostic_test, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, 3. Good health, Dyspnea, 030228 respiratory system, Cohort, Female, medicine.symptom, business
Abstract: Introduction and objective Dyspnoea is a major symptom in COPD patients, but the determinants that could be associated with a higher dyspnoea mMRC score in COPD patients remain unclear. Our research aimed to study the determinants of dyspnoea at the threshold of 1, 2, 3 and 4 mMRC. Patients and methods Diagnosis of COPD was made using spirometry with post-bronchodilator FEV 1 FVC 70 % . An online questionnaire has been employed by pulmonologists to recruit COPD patients. The following variables were collected: age, gender, BMI, FEV1, RV, IC, TLC, FRC, mMRC, frequency of exacerbations and comorbidities. The LASSO was used to select the variables associated with the mMRC dyspnoea scale in a subgroup (who had no missing IC, RV and FRC values) of 421 COPD patients defined by the previously mentioned variables. Results One thousand nine hundred and sevety-three patients (65.3% males, average age = 66 ± 10, 38% current smokers) were included. Dyspnoea was correlated with a low FEV1 and with the number of exacerbations in the past 12 months. Multivariate analysis showed that the determinants of dyspnoea(mMRC ≥ 2) are: FEV1: OR = 3.71[2.86–4.82]; anxiety: OR = 2.52[1.82–3.47]; cough: OR = 1.94[1.57–2.40]; bronchiectasis: OR = 1.84[1.03–3.29]; age: OR = 1.80[1.45–2.24]; hyperinflation (RV/TLC): OR = 1.68[1.34–2.11]; ischemic cardiopathy: OR = 1.63[1.22–2.18]; hypertension: OR = 1.52[1.21–1.91]; exacerbations (≥ 2): OR = 1.41[1.10–1.81]; women: OR = 1.39[1.10–1.74] and overweight: OR = 1.33[1.06–1.67]. The subgroup analysis showed that: FEV1: OR = 3.47[1.96–6.12]; exacerbations (≥ 2) OR = 2.31[1.33–4.17] and hyperinflation (IC/TLC) OR = 0.57[0.35–0.85] were associated with higher dyspnoea (mMRC ≥ 2). Conclusion Our results showed that dyspnoea is related to the severity of airflow limitation, gender, exacerbations, comorbidities and hyperinflation.
Published: 2020

36. J Chromatogr B Analyt Technol Biomed Life Sci

Author: Oscar Da Silva Cacao, Karine Titier-Debeaupuis, Mireille Canal-Raffin, Dominique Ducint, Béatrice Martinez, Benoît Atgé, Kevin Tremolet, Catherine Verdun-Esquer, Antoine Villa, Mathieu Molimard, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Anthracycline, Daunorubicin, Health Personnel, Clinical Biochemistry, Antineoplastic Agents, Urine, 030226 pharmacology & pharmacy, 01 natural sciences, Biochemistry, Analytical Chemistry, 03 medical and health sciences, 0302 clinical medicine, Limit of Detection, Tandem Mass Spectrometry, Occupational Exposure, polycyclic compounds, medicine, Humans, Anthracyclines, Doxorubicin, Chromatography, High Pressure Liquid, Chromatography, Chemistry, 010401 analytical chemistry, Reproducibility of Results, Hazardous drugs, Cell Biology, General Medicine, 0104 chemical sciences, 3. Good health, Linear Models, Antineoplastic Drugs, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Occupational exposure, Biological Monitoring, medicine.drug, Epirubicin
Abstract: Anthracycline antineoplastic drugs (doxorubicin, epirubicin, daunorubicin) are "hazardous drugs for handling" by healthcare professionals. To monitor their occupational exposure, a highly sensitive ESI-UHPLC-MS/MS method for the assay of anthracyclines in urine was developed. The urine extraction consisted of SPE extraction method. A good linearity (r > 0.996), precision (CV
Published: 2020

37. [Therapeutic education, compliance and self-medication]

Author: Pietro, Rosellini, Driss, Berdaï, Mathieu, Molimard, and Pierre-Olivier, Girodet
Subjects: Educational Status, Humans, Patient Compliance
Published: 2020

38. Medicine misuse: A systematic review and proposed hierarchical terminology

Author: Amélie Daveluy, Driss Berdaï, Pernelle Noize, Allison Singier, Francesco Salvo, Mickael Arnaud, Bernard Bégaud, Mathieu Molimard, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Pharmacology, Medical education, medicine.medical_specialty, Public health, MEDLINE, Behavioural sciences, Context (language use), PsycINFO, medicine.disease, 030226 pharmacology & pharmacy, 3. Good health, Terminology, Substance abuse, 03 medical and health sciences, 0302 clinical medicine, Family medicine, medicine, Humans, Medication Errors, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pharmacology (medical), 030212 general & internal medicine, Psychology, Medical literature
Abstract: Aim: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. Methods: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles, and Psychological and Behavioral Sciences Collection, using keywords related to misuse, appropriateness, and medicine between November 1st, 2008 and November 1st, 2018. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose, and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. Results: Of 2,901 identified records, 44 were included. A total of 63 definitions and 60 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to “intentional or unintentional prescribing not in line with clinical evidence”. Based on context, he could prescribe medicines not clinically justified, i.e. “overprescribing”, or prescribe indicated medicines incorrectly, i.e. “misprescribing”. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. Conclusion: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse, and errors.
Published: 2020

39. COPD phenotypes and 5-years mortality risk prediction: PALOMB Cohort

Author: Frederic Pilard, Annaig Ozier, Marielle Sabatini, Claire Bon, Mohammed Aliati, Marc Sapene, Cécilia Nocent-Ejnaini, Jean Michel Dupis, L. Falque, Mathieu Molimard, A. Prudhomme, Jean Moinard, Frédéric Le Guillou, Marie Line Quinquenel, Chantal Raherison-Semjen, Xavier Demant, Remi Veillon, Leo Grassion, Maeva Zysman, Laurent Nguyen, J. Casteigt, Mohammed Staali, A. Bernady, Esther Iglesias, Emmanuel Monge, Christophe Roy, Emilie Berteaud, Laura Petrov, Elodie Blanchard, Yannick Daoudi, El-hassane Ouaalaya, and Julie Macey
Subjects: COPD, medicine.medical_specialty, Exacerbation, business.industry, medicine.medical_treatment, medicine.disease, respiratory tract diseases, FEV1/FVC ratio, Oxygen therapy, Internal medicine, Cohort, Medicine, Anxiety, medicine.symptom, business, Lung cancer, Depression (differential diagnoses)
Abstract: The main factors that increase the mortality risk of COPD patients are age, comorbidities and the severity of airflow obstruction. This study aimed to validate the clinically relevant COPD phenotypes found by Burgel P-R et al [1] and analyzed their impact on 5-year mortality in the PALOMB cohort. COPD patients (post-BD FEV1/FVC 2,653 patients (66 years old, 64.27% males) were included. Application of the CART-based algorithm to Palomb cohort confirmed that it identified 5 COPD phenotypes with different clinical characteristics. In addition: The high proportion of FEV1 decline (≥100 ml/yr) belongs to phenotype 1 and 4; the majority of patients in these phenotypes were under oxygen therapy and they were associated with higher rates of exacerbation, lung cancer, anxiety and depression. These results confirmed the identification of five clinically relevant COPD phenotypes. A novel finding of this study is that FEV1 decline, frequency of exacerbations and other comorbidities were associated with the more severe phenotypes. Fundings: Bordeaux Univ Foundation, Novartis, Isis Medical, GSK, BI, Chiesi.
Published: 2020

40. Nicotine-replacement therapy, as a surrogate of smoking, and the risk of hospitalization with Covid-19 and all-cause mortality: a nationwide, observational cohort study in France

Author: Philippe Herlemont, Mahmoud Zureik, Emilie Sbidian, Jérôme Drouin, Clémentine Vabre, Jérémie Botton, Laetitia Penso, Rosermary Dray-Spira, Bérangère Baricault, Mathieu Molimard, Laura Semenzato, François Cuenot, and Alain Weill
Subjects: medicine.medical_specialty, education.field_of_study, Proportional hazards model, business.industry, Hazard ratio, Population, Lower risk, Nicotine replacement therapy, Internal medicine, Propensity score matching, medicine, Observational study, business, education, Cohort study
Abstract: IntroductionSeveral studies have reported an unexpectedly low prevalence of current smoking among hospitalized patients with Covid-19. However, these studies mostly compared observed to expected rates of smoking without direct comparison with individual controls.ObjectiveTo examine the association of nicotine-replacement therapy, as a surrogate of smoking, with hospitalization and all-cause mortality during the first wave of SARS-CoV-2 epidemic in France.MethodsWe conducted a nationwide matched “exposed/unexposed” cohort study using information from the French national health data system which covers the entire French population. We conducted two separate analyses, the first in individuals exposed to nicotine-replacement therapy without major smoking-related diseases (cancer, cardiovascular and/or respiratory diseases) and the second in those presenting these conditions. We included all individuals, aged between 18 and 75 years, who had been reimbursed at least one nicotine-replacement therapy between November 15, 2019, and February 15, 2020. For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). The three end points were a hospitalization with Covid-19, a death or an intubation in hospitalized patients with Covid-19, and all-cause mortality. We compared outcomes in individuals who were exposed to nicotine-replacement therapy with those in individuals who were not, using a multivariable Cox model with inverse probability weighting according to the propensity score.ResultsIn the first analysis, 297,070 individuals without major smoking-related diseases exposed to nicotine-replacement therapy were matched with 558,228 unexposed individuals without major smoking-related diseases. Individuals were aged on average 45.6 years (standard deviation: 12.7) and 48.8% were male.From February 15, 2020 to June 7, 2020, hospitalization with Covid-19 occurred in 647 patients (151 patients in the nicotine-replacement therapy group and 496 patients in the unexposed group). In the main multivariable analysis, nicotine-replacement therapy was associated with a decreased risk of hospitalization with Covid-19 compared with unexposed individuals (hazard ratio, 0.50; 95% CI, 0.41 to 0.61). Nicotine-replacement therapy exposure was also associated with a decreased risk of intubation or death in hospitalized individuals with Covid-19 (13 vs. 73 patients, hazard ratio, 0.31; 95% CI, 0.17 to 0.57) but with an increased risk of all-cause mortality (251 vs. 231 deaths, hazard ratio, 1.49; 95% CI, 1.24 to 1.80).In the second analysis, 128,768 individuals with major smoking-related diseases exposed to nicotine-replacement therapy were matched with 243,793 unexposed individuals. Individuals were aged on average 55.3 years (standard deviation: 11.4) and 53.3% were male. In the main multivariable analysis, nicotine-replacement therapy exposure was neither associated with risk of hospitalization with Covid-19 (240 patients in the nicotine-replacement therapy group and 398 patients in the unexposed group, hazard ratio, 1.13; 95% CI, 0.94 to 1.38) nor with risk of death or an intubation in hospitalized individuals with Covid-19 (48 vs. 61 patients, hazard ratio, 1.00; 95% CI, 0.65 to 1.54). All-cause mortality was higher in the nicotine-replacement therapy group (1040 vs. 366 deaths, hazard ratio, 3.83; 95% CI, 3.41 to 4.31).ConclusionsThis large-scale observational study suggests that smoking, measured by exposure to nicotine-replacement therapy, was associated with an increased risk of overall mortality during the first wave of SARS-CoV-2 epidemic in France, although it was associated with a lower risk of severe Covid-19 in individuals without major related-smoking diseases. Experimental and clinical studies are needed to disentangle the potential mechanisms of nicotine and/or smoking in Covid-19 risk. Whatever the nature of these associations, the global impact of smoking is harmful for health even over a short epidemic period.
Published: 2020

41. Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence

Author: Romain Guilhaumou, J. L. Montastruc, Mathieu Molimard, Silvy Laporte, M. Roustit, and M. D. Drici
Subjects: Drug, medicine.medical_specialty, SARS-Cov-2, media_common.quotation_subject, Pneumonia, Viral, Context (language use), 030226 pharmacology & pharmacy, Article, 03 medical and health sciences, 0302 clinical medicine, Chloroquine, medicine, COVID-19, novel coronavirus disease 2019, SARS-Cov, severe actue respiratory syndrome, Humans, Pharmacology (medical), Medical prescription, Intensive care medicine, Adverse effect, Pandemics, media_common, PharmacoEpi-Drugs, HCSP, French High Council of Public Health, MERS-Cov, Middle East Respiratory Sydrome Coronavirus, QTc, corrected QT interval, ADRs, adverse drug reactions, ACE2, angiotensin converting enzyme 2, medicine.diagnostic_test, business.industry, COVID-19, Hydroxychloroquine, 3. Good health, COVID-19 Drug Treatment, TNFα, tumor necrosis factor α, Coronavirus, Clinical trial, Treatment Outcome, Therapeutic drug monitoring, CYP, cytochrome P450, ECG, electrocardiogram, Drug Monitoring, business, Coronavirus Infections, medicine.drug
Abstract: Summary Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.
Published: 2020

42. Genesis of an emergency public drug information website by the French Society of Pharmacology and Therapeutics during the COVID-19 pandemic

Author: Alex Hlavaty, Mathieu Molimard, Vincent Richard, Régis Bordet, Jean-Luc Cracowski, Charles Khouri, Marion Lepelley, Amelle Mouffak, Joëlle Micallef, Alexandre Bellier, Béatrice Bouhanick, Joachim Alexandre, Silvy Laporte, Pierrick Bedouch, Claire Le Jeunne, Matthieu Roustit, Laurent Bertoletti, Florian Naudet, Annie-Pierre Jonville-Béra, Louis Létinier, Manon Gabin, Louis Larrouquere, and Emmanuelle Poingt
Subjects: medicine.medical_specialty, Societies, Pharmaceutical, National Question, Population, Pneumonia, Viral, Pharmacology, 030226 pharmacology & pharmacy, Social Networking, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Political science, Agency (sociology), Pandemic, Pharmacovigilance, medicine, Humans, Pharmacology (medical), education, Pandemics, PharmacoEpi-Drugs, Service (business), education.field_of_study, Consumer Health Information, SARS-CoV-2, Public health, COVID-19, Original Articles, 3. Good health, Drug Information Services, Original Article, France, Public Health, Coronavirus Infections, Administration (government), 030217 neurology & neurosurgery
Abstract: On March 16, 2020, the French Society of Pharmacology and Therapeutics put online a national Question and Answer (Q&A) website, http://https%20%5Ch://sfpt-fr.org/covid19 on the proper use of drugs during the COVID‐19 pandemic. The working group “Drugs and COVID‐19” was composed of a scientific council, an editorial team and experts in the field. The first questions were posted online during the first evening of home‐confinement in France, March 17, 2020. Six weeks later, 140 Q&As have been posted. Questions on the controversial use of hydroxychloroquine and to a lesser extent concerning azithromycin have been the most consulted Q&As. Q&As has been consulted 226,014 times in 41 days. This large visibility was obtained through an early communication on Twitter, Facebook, traditional print and web media. In addition, an early communication through the French Ministry of Health and the French National Agency for Medicines and Health Products Safety ANSM had a large impact in terms of daily number of views. There is a pressing need to sustain a public drug information service combining the expertise of scholarly pharmacology societies, pharmacovigilance network, and the Ministry of Health to quickly provide understandable, clear, expert answers to the general population’s concerns regarding COVID‐19 and drug use and to counter fake news.
Published: 2020

43. Prise en charge de l’asthme léger en 2019–2020 :: que penser des nouvelles propositions thérapeutiques internationales (GINA 2019) ?

Author: Pierre-Olivier Girodet, Gilles Devouassoux, Antoine Deschildre, Alain Didier, Mathieu Molimard, Cécile Chenivesse, Chantal Raherison, Camille Taillé, Gilles Garcia, CHU Bordeaux [Bordeaux], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: PharmacoEpi-Drugs, Pulmonary and Respiratory Medicine, MESH: France / epidemiology, MESH: Mortality, business.industry, EPICENE, Epicene, MESH: Asthma / drug therapy, MESH: Drugs, Investigational / therapeutic use, MESH: Therapies, Investigational / trends, 03 medical and health sciences, MESH: International Cooperation, 0302 clinical medicine, 030228 respiratory system, MESH: Practice Guidelines as Topic, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Severity of Illness Index, Medicine, MESH: Asthma / epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, MESH: Therapies, Investigational / methods, business, Humanities, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

44. Cancer and Cardiovascular Comorbidities Are Associated with COPD Mortality: The French PALOMB Cohort

Author: Chantal Raherison-Semjen, Annaig Ozier, J.M. Dupis, Marielle Sabatini, Laurent Nguyen, Cécilia Nocent-Ejnaini, Mathieu Molimard, A. Bernady, El-hassane Ouaalaya, F. Le Guillou, and L. Falque
Subjects: medicine.medical_specialty, COPD, business.industry, Internal medicine, Cohort, Medicine, Cancer, business, medicine.disease
Published: 2020

45. Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

Author: Dominique Breilh, Laurent Petit, Matthieu Biais, Faustine Delzor, Stéphanie Roure, Cédric Carrié, Vincent Dubuisson, and Mathieu Molimard
Subjects: Male, medicine.medical_specialty, Critical Illness, Population, Urology, Cmax, Renal function, Microbial Sensitivity Tests, Loading dose, 03 medical and health sciences, 0302 clinical medicine, Intensive care, Sepsis, Medicine, Humans, Pharmacology (medical), education, Amikacin, Aged, Volume of distribution, Pharmacology, Open Abdomen Techniques, 0303 health sciences, education.field_of_study, medicine.diagnostic_test, Bacteria, 030306 microbiology, business.industry, 030208 emergency & critical care medicine, Middle Aged, Anti-Bacterial Agents, Infectious Diseases, Therapeutic drug monitoring, Pharmacodynamics, Wounds and Injuries, Female, Intra-Abdominal Hypertension, business, Monte Carlo Method, Negative-Pressure Wound Therapy
Abstract: The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.
Published: 2020

46. Overview of French databases available for studying anticancer drugs in real-life setting

Author: Mathieu Molimard, Bernard Bégaud, Emilie Casarotto, Driss Berdaï, Amandine Gouverneur, Pernelle Noize, and Laurie Levy-Bachelot
Subjects: Databases, Factual, Computer science, Population, Antineoplastic Agents, computer.software_genre, Health outcomes, 030226 pharmacology & pharmacy, Medical Records, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Product Surveillance, Postmarketing, In real life, Humans, Pharmacology (medical), Registries, education, Pharmacology, Biological data, education.field_of_study, Database, Medical record, Novelty, Data warehouse, France, computer, 030217 neurology & neurosurgery, Record linkage
Abstract: Considering their novelty and cost, post-marketing evaluation is highly relevant for new anticancer drugs. Identify and characterize available and potentially useful databases for post-marketing evaluation of these specific drugs is necessary. A review was conducted to identify available and accessible databases to study the post-marketing evaluation of drugs in real-life care setting. Databases identified have been classified into medico-administrative databases, medical record databases, and databases resulting from ad hoc collections. Taking as examples databases available in France, each type was described as well as its strengths and limits for a potential use in the oncology field. Record linkage of medico-administrative databases could cover almost the whole population and is now used to evaluate anticancer drugs (e.g., Systeme National des Donnees de Sante). Large medical record databases are still lacking, but efforts are currently made to give access to hospital data warehouses for research purposes. Finally, databases resulting from ad hoc collections are also available for some cancer localizations and allow to obtain highly valuable clinical and biological data. A range of important and valuable databases exist but, individually, none is enough to answer to all questions from health authorities, healthcare professionals, and patients. In order to obtain a complete overview on utilization, associated health outcomes and costs of these drugs, it seems necessary to better interlink available databases.
Published: 2020

47. Respir Med

Author: Laurent Nguyen, A. Bernady, Cécilia Nocent-Ejnaini, Frédéric Le Guillou, Maeva Zysman, L. Falque, El Hassane Ouaalaya, Chantal Raherison-Semjen, Annaig Ozier, Marielle Sabatini, Jean Michel Dupis, Mathieu Molimard, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Exacerbation, Comorbidity, Anxiety, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Aged, PharmacoEpi-Drugs, COPD, Receiver operating characteristic, business.industry, Vaccination, EPICENE, Middle Aged, medicine.disease, 3. Good health, Natural history, 030228 respiratory system, ROC Curve, Influenza Vaccines, Disease Progression, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Observational study, Female, medicine.symptom, Underweight, business, Follow-Up Studies
Abstract: Introduction Exacerbations are key events in the natural history of COPD, but our understanding of their longitudinal determinants remains unclear. We used data from a large observational study to test the hypothesis that vaccination status and comorbidities could be associated with the occurrence of exacerbations profile. Methods Diagnosed COPD patients have been included by their pulmonologists, with up to 3 years of follow-up. Data were analyzed using the KmL method designed to cluster longitudinal data and receiver operating characteristic curve analysis to determine the best threshold to allocate patients to identified clusters. Results 932 COPD patients were included since January 2014, 446 patients (65.68% males, 35.59% current smokers) were followed over a period of 3 years with complete data. 239(28.15%) patients reported two or more exacerbations in the year before enrolment (frequent exacerbations). Among them 142(16.68%) also had frequent exacerbations in the first year of the study, and 69(8.10%) who remained frequent exacerbators in the second year. Based on our hypothesis, we were able to determine four phenotypes: A (infrequent), B (frequent in underweight patients), C (transient), and D (frequent in obese patients). Frequent exacerbators had more airflow limitation and symptoms. Irrespective of cut-offs set to define the optimal number of clusters, a history of exacerbations OR: 3.72[2.53–5.49], presence of anxiety OR: 2.03[1.24–3.31] and absence of the annual influenza vaccination OR: 1.97[1.20–3.24] remained associated with the frequent exacerbator phenotypes. Conclusions The most important determinants of frequent exacerbations are a history of exacerbations, anxiety and unvaccinated against influenza.
Published: 2020

48. Spacers and Valved Holding Chambers—The Risk of Switching to Different Chambers

Author: Will Carroll, Joy Conway, Miguel Román-Rodríguez, Richard W. Costello, Nicola Scichilone, Richard Dekhuijzen, Mark L Levy, Birthe Hellqvist Dahl, Federico Lavorini, Mathieu Molimard, Celeste Barreto, Stephen Holmes, Job F M van Boven, Nicholas Roche, Omar S. Usmani, Jane Scullion, Lavorini, Federico, Barreto, Celeste, van Boven, Job F M, Carroll, Will, Conway, Joy, Costello, Richard W, Dahl, Birthe Hellqvist, Dekhuijzen, Richard P N, Holmes, Stephen, Levy, Mark, Molimard, Mathieu, Roche, Nichola, Román-Rodriguez, Miguel, Scichilone, Nicola, Scullion, Jane, Usmani, Omar S, Repositório da Universidade de Lisboa, Value, Affordability and Sustainability (VALUE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: corticosteroid, Spacer, inhalation spacer, Q1, lung, 03 medical and health sciences, 0302 clinical medicine, Drug Delivery Systems, dysphonia, RC705, Inhalers, Administration, Inhalation, Immunology and Allergy, Medicine, Humans, metered dose inhaler, 030212 general & internal medicine, Metered Dose Inhalers, human, Particle Size, snout, business.industry, Inhaler, adult, throat irritation, article, Valved holding chamber, risk assessment, R735, Equipment Design, Reduced dose, Valved Holding Chambers, Metered-dose inhaler, thrush, R1, 030228 respiratory system, Delivery system, business, valve, Biomedical engineering, Inhalation Spacers
Abstract: © 2020 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Spacers are pressurized metered-dose inhaler (pMDI) accessory devices developed to reduce problems of poor inhaler technique with pMDIs. Spacers that feature a 1-way inspiratory valve are termed valved holding chambers (VHCs); they act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a 2-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. Both spacers and VHCs have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce corticosteroid-related side effects such as throat irritation, dysphonia, and oral candidiasis commonly seen with the use of pMDIs alone. Spacers and VHCs are not all the same, and also are not interchangeable: the performance may vary according to their size, shape, material of manufacture and propensity to become electrostatically charged, their mode of interface with the patient, and the presence or otherwise of valves and feedback devices. Thus, pairing of a pMDI plus a spacer or a VHC should be considered as a unique delivery system. In this Rostrum we discuss the risk potential for a patient getting switched to a spacer or VHC that delivers a reduced dose medication.
Published: 2020

49. Toxicological screening reveals toxic epidermal necrolysis likely carbamazepine-induced rather than idiopathic

Author: Mathieu Molimard, Nadège Castaing, Brigitte Milpied, Karine Titier, Clementine Toussaint, Paola Sanchez-Pena, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: PharmacoEpi-Drugs, medicine.medical_specialty, business.industry, Carbamazepine, medicine.disease, Dermatology, Toxic epidermal necrolysis, 03 medical and health sciences, 0302 clinical medicine, Stevens-Johnson Syndrome, 030220 oncology & carcinogenesis, medicine, Humans, Immunology and Allergy, Anticonvulsants, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery, medicine.drug
Published: 2020

50. Prioritising outcomes for evaluating eosinophil-guided corticosteroid therapy among patients with acute COPD exacerbations requiring hospitalisation: a Delphi consensus study

Author: Pascal Chanez, Alain Didier, Patrick Berger, Christophe Brousse, Cécile Chenivesse, Maeva Zysman, Chantal Raherison, Francis Couturaud, Nicolas Roche, Pierre-Régis Burgel, Gilles Devouassoux, Carey M. Suehs, Y. Martinat, Gaëtan Deslée, Romain Kessler, Philippe Devillier, Thierry Chinet, Arnaud Bourdin, Olivier Le Rouzic, Mathieu Molimard, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, Hôpital Foch [Suresnes], Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Strasbourg, Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, MORNET, Dominique, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CRP Clinique du Parc, Castelnau-Le-Lez, Service de pneumologie et allergologie pédiatrique [CHU Toulouse], CHU Toulouse [Toulouse], CM PAROT, Lyon, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Delphi Technique, Exacerbation, medicine.medical_treatment, lcsh:Medicine, Therapeutics, Respiratory medicine (see thoracic medicine), [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Likert scale, Leukocyte Count, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, Adrenal Cortex Hormones, Surveys and Questionnaires, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, Intubation, Chronic airways disease, 030212 general & internal medicine, Intensive care medicine, Respiratory Medicine, PharmacoEpi-Drugs, Mechanical ventilation, Protocol (science), COPD, business.industry, lcsh:R, EPICENE, General Medicine, medicine.disease, 3. Good health, Eosinophils, Hospitalization, Pneumonia, Pulmonology, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, business
Abstract: ObjectivesPresently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes.DesignA modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ≥70% of experts indicated that the outcome was essential for interpreting study results.SettingCOPD exacerbation management in France.Participants34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds.Results105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation.ConclusionsThis Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients.Study registrationThe eo-Delphi project/protocol was registered on 23 January 2018 at https://osf.io/4ahqw/.
Published: 2020

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