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To explore whether preventive cardiovascular drugs (antihypertensive, antiplatelet, lipid lowering and hypoglycemic agents) interact together in cardiovascular prevention.We searched PubMed®, Web of science™, Embase and Cochrane library for powerful randomized placebo-controlled trials (1000 patients). We explored whether drug effect on major vascular events changed according to cross-exposure to other drug classes or to cardiovascular risk factors (hypertension or type 2 diabetes), through a meta-analysis of relative odds ratio computed by trial subgroups. A significant interaction was suggested from confidence intervals of the ratio of odds ratios, when they excluded neutral value of 1.In total, 14 trials with 178,398 patients were included. No significant interaction was observed between co-prescribed drugs or between these medications and type 2 diabetes/hypertension status.Our meta-analysis is the first one to evaluate drug-drug and drug-hypertension/type 2 diabetes status interactions in terms of cardiovascular risks: we did not observe any significant interaction. This indirectly reinforces the rationale of using several contrasted mechanisms to address cardiovascular prevention; and allows the combination effect prediction by a simple multiplication of their odds ratios. The limited availability of data reported or obtained from authors is a strong argument in favor of data sharing.

In biomedical research, population differences are of central interest. Variations in the frequency and severity of diseases and in treatment effects among human subpopulation groups are common in many medical conditions. Unfortunately, the practices in terms of subpopulation labeling do not exhibit the level of rigor one would expect in biomedical research, especially when studying multifactorial diseases such as cancer or atherosclerosis. The reporting of population differences in clinical research is characterized by large disparities in practices, and fraught with methodological issues and inconsistencies. The actual designations such as "Black" or "Asian" refer to broad and heterogeneous groups, with a great discrepancy among countries. Moreover, the use of obsolete concepts such as "Caucasian" is unfortunate and imprecise. The use of adequate labeling to reflect the scientific hypothesis needs to be promoted. Furthermore, the use of "race/ethnicity" as a unique cause of human heterogeneity may distract from investigating other factors related to a medical condition, particularly if this label is employed as a proxy for cultural habits, diet, or environmental exposure. In addition, the wide range of opinions among researchers does not facilitate the attempts made for resolving this heterogeneity in labeling. "Race," "ethnicity," "ancestry," "geographical origin," and other similar concepts are saturated with meanings. Even if the feasibility of a global consensus on labeling seems difficult, geneticists, sociologists, anthropologists, and ethicists should help develop policies and practices for the biomedical field.

Drug-related problems (DRPs) are one of the leading causes of hospital readmissions. Children with chronic diseases are more likely to experience DRPs than adults. The burden and characteristics of drug-related readmissions at and after hospital discharge in children remain unclear.We aimed to summarize the impact of DRPs at and after hospital discharge on the risk of readmissions in children with chronic diseases.We conducted a systematic review searching PubMed from inception until January 2022. Study selection criteria were studies assessing the impact of different factors at discharge and after discharge on the risk of hospital readmissions in children with chronic diseases, reporting an assessment of DRPs. DRP could be the only risk factor assessed or one among others. Included studies were assessed with the Risk of Bias in Non-Randomized Studies - of Exposure (ROBINS-E) tool. We summarized the qualitative impact of the reported DRPs on hospital readmission as conclusive (significant association) or inconclusive.Of the 4734 studies initially identified, 13 met inclusion criteria. Eleven studies were retrospective, using electronic health records. The studies assessed the impact of DRPs at or after discharge according to the type of medication (in 6 studies), number of medication (in 5 studies) and medication nonadherence (in 2 studies). From the 44 reported associations between DRPs and the risk of readmission 26 (59% [95% CI, 43%-73%]) were conclusive, of which 81% increased the risk and 19% decreased the risk, and 17 (39% [95% CI, 24%-55%]) were inconclusive.The impact of DRPs on hospital readmissions in children with chronic diseases displayed conflicting results, estimated associations having potentially a serious risk of bias. We need more evidence with a lower risk of bias.

The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results.

Ondansetron is increasingly used off label to treat nausea and vomiting during pregnancy. The main objective of this study was to evaluate the risk of major congenital malformations (MCM), cardiac defects and orofacial clefts associated with first trimester exposure to ondansetron using a meta-analytic approach. MEDLINE, ClinicalTrials.gov and Scopus were searched until November 2019. All comparative cohort and case-control studies on MCM, cardiac or orofacial defects and use of ondansetron during pregnancy were included. A team of paired reviewers independently extracted data using a proprietary collaborative WEB-based meta-analysis platform (metaPreg.org). Pooled odd ratios with corresponding 95% CIs were calculated using random effects models. From 214 records initially retrieved, 12 studies were included. Using all available information to date, first trimester exposure to ondansetron was found to be associated with an increased risk of (a) ventricular septal defects (VSD) (OR 1.11, 95% CI 1.00-1.23; p < .05; n = 6 studies; I2 = 0%) and (b) oral clefts (OR 1.22, 95% CI 1.00-1.49; p < .05; n = 4 studies; I2 = 0%). No significant association was observed for the risk of cleft palate but, when excluding the study that contributed to the study heterogeneity, we found an OR of 1.48 (95% CI 1.19-1.84; p < .01; n = 5 studies; I2 = 0%). No statistically significant association was found for MCM, overall cardiac malformations, atrial septal defects and cleft lip with or without cleft palate. Exploratory investigations of other malformations showed an increased risk of diaphragmatic hernia, hypoplastic left heart and "respiratory system anomalies."

International audience; AIMS/HYPOTHESIS: Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes. METHODS: We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i. RESULTS: A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection. CONCLUSIONS/INTERPRETATION: Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation. TRIAL REGISTRATION: OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

International audience; Le séquençage du génome est aujourd’hui accessible à la population mais il n’existe que peu de preuves de son utilité comme outil diagnostique, thérapeutique et pronostique. En France, le plan France médecine génomique 2025 a été lancé en 2015 avec pour objectif d’intégrer les analyses génomiques dans la pratique clinique pour des indications validées et de développer une filière nationale de la médecine génomique incluant des partenariats industriels. Une réflexion sur les applications scientifiques et les enjeux opérationnels et sociétaux est nécessaire afin de formuler des recommandations pour permettre de mieux associer la génomique et la médecine de demain. Dans la perspective d’une médecine factuelle personnalisée, il convient de promouvoir des études avec un niveau d’exigence méthodologique approprié et d’approfondir la définition du niveau de preuve. Les nombreux enjeux opérationnels nécessitent de mettre en place des organisations et des moyens afin de fluidifier le circuit de rendu des résultats ainsi que des adaptations réglementaires sur les statuts des professions impliquées, la gestion des données générées et le consentement des patients. En parallèle des actions de formation en génétique à destination des professionnels de santé et des actions de sensibilisation sur les tests génétiques vis-à-vis du grand public doivent être envisagées. Les enjeux éthiques doivent également être pris en compte, notamment sur la participation du patient aux décisions le concernant en fonction de ses attentes et en intégrant la notion d’incertitude dans l’information délivrée. Les effets sociologiques sur le vécu et les attentes des patients et de la population générale vis-à-vis de la médecine génomique doivent également être évalués pour améliorer l’information, la prévention et l’accompagnement des personnes. Enfin, des études médicoéconomiques doivent être conduites pour éclairer les décideurs sur le caractère coût-efficace du séquençage complet du génome pour la santé des populations.

To compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain.The MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models.Of the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low.This meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs.The protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387).

In the world, the impact of environmental conditions on the number of scorpion events was evaluated in North Africa,Middle East, and the Amazonian region but not in Europe. In mainland France, scorpion species described are Buthus occitanus (Amoreux, 1789), Belisarius xambeui (Simon, 1879) and 4 Euscorpiidae: Euscorpius concinnus (Koch, 1837), Euscorpius italicus (Herbst, 1800), Euscorpius tergestinus (Koch, 1837), and Tetratrichobothrius flavicaudis (De Geer, 1778). We aimed to describe the impact of environmental conduction on the number of scorpion events. For this, a retrospective multi-center study was conducted with data from the French poison control centers files about scorpion events between 1 January 2011 and 31 December 2020. During the study period, 975 incoming calls for scorpion events were recorded and 574 were related to scorpions native to mainland France and Corsica: B. occitanus (n = 86), Euscorpiidae species (n = 222), B. xambeui (n = 1), and undetermined species (n = 265). Cases were mostly reported along the Mediterranean coast, along rivers, and in cities with a trading port. The number of scorpion events was linked to the rivers' water level, rivers' flow, temperature, sunshine, and pluviometry (P < 0.05 for all variables). B. occitanus need warmest and driest environment than Euscorpiidae spp. A link between the severity of the envenoming and climatic condition or seasonality was not demonstrated.

Summary Objective.- To re-assess the effect of tight glycaemic control on diabetic microvascular complications. Method.- Meta-analysis and trial sequential analyses of randomised trials included in Hemmingsen et al that specifically assessed glycaemic control with a specific HbA1c level targeted in the intervention group, and compared intensive glycaemic control versus standard glycaemic control. Results.- Seven clinical trials that randomised 28 614 participants with type 2 diabetes (15 269 to intensive control and 13 345 to conventional control), including 3 sub-studies, were included. Strict control of blood glucose levels is associated with a reduction of retinopathy progression (RR = 0.77, 95% CI 0.66–0.89, I 2 = 33%), incidence or progression of macular oedema (RR = 0.66, 95% CI 0.40–0.99, I 2 = 0%), number of photocoagulations (RR = 0.84, 95% CI 0.73–0.97, I 2 = 0%), risk of microalbuminuria (RR = 0.76, 95% CI 0.64–0.9, I 2 = 76%) and risk of “macroalbuminuria or proteinuria” (RR = 0.68, 95% CI 0.55–0.85, I 2 = 36%). Conclusion.- This meta-analysis has shown that a tight control of blood glucose levels is associated with a decrease of specific microvascular complication of diabetes: photocoagulation, progression of diabetic retinopathy, incidence or progression of macular oedema, risk of microalbuminuria and risk of macroalbuminuria or proteinuria. Regarding all the other outcomes (vision loss, surgery of cataract, proliferative or non-proliferative retinopathy, death related to kidney disease, development of kidney disease, doubling of serum creatinine, neuropathy), no significant result was found.

Introduction Les inhibiteurs de checkpoint immunitaire (ICI) sont une avancee majeure en Oncologie en raison de leur efficacite et de leurs effets indesirables moindres compares aux chimiotherapies cytotoxiques. Ils sont dorenavant la pierre angulaire du traitement du melanome metastatique. Neanmoins, ils sont pas denues d’effets secondaires et sont a l’origine de nouveaux effets indesirables d’origine immunologique. Ces effets peuvent en theorie etre le temoin d’une reponse immunitaire anti-tumorale mais leur association avec le pronostic des patients reste discutee. La prise en charge de ces effets indesirables est multidisciplinaire avec l’implication des dermatologues, gastroenterologues, endocrinologues, hematologues, et internistes. L’objectif de notre travail est donc d’etudier la relation entre les parametres de survie (survie globale en contexte metastatique et survie sans recidive en contexte adjuvant) et l’apparition d’effets indesirables auto-immuns (incluant le vitiligo) chez les patients traites pour un melanome. Materiels et methodes De nombreuses bases de donnees ont ete interrogees (Web of science, Pubmed, ClinicalTrials, WHOTrials) jusqu’en aout 2020. Tous les essais cliniques de phase 3 controles, randomises concernant les ICI dans le melanome en contexte metastatique ou adjuvant ont ete inclus. L’ensemble des ICI utilises dans le melanome ont ete inclus, quelle que soit leur classe, comprenant Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab. L’extraction des donnees a ete realisee par 2 auteurs de maniere independante parmi tous les articles selectionnes. L’evaluation de la qualite des etudes a ete realisee a l’aide de l’echelle validee par la Cochrane (ROB2). Une metaregression a ete realisee pour estimer cette correlation. Resultats 18 essais cliniques de phase 3 comprenant 10 572 patients ont ete inclus, avec une mediane d’âge de 61,1 ans. Aucune correlation n’a ete mise en evidence entre la survie globale (melanome metastatique) ou la survie sans recidive (melanome en contexte adjuvant) et l’apparition d’effets indesirables auto-immuns (Beta 0,078, p = 0,311 ; et Beta 0,057 ; p 0,592 respectivement). Par ailleurs, aucune association n’a ete trouvee entre l’apparition d’un vitiligo sous ICI et les parametres de survie. Discussion Les ICI sont desormais utilises dans de nombreux cancers. Nous avons choisi de cibler le melanome etant le premier cancer ou les inhibiteurs de checkpoint ont ete utilises. L’apparition d’un vitiligo au cours du melanome metastatique est connu pour etre un bon facteur pronostique independamment de tout traitement dans les etudes de cohortes. Notre etude ne retrouve d’association significative entre l’apparition d’effets indesirables auto-immuns qu’elle que soit leur nature et les parametres de survie. Notre etude ne retrouve pas non plus d’association entre l’apparition d’un vitiligo et une meilleur survie. Neanmoins, les atteintes cutanees ne sont pas forcement decrites dans toutes les etudes ce qui limite l’interpretation de nos resultats. Ces resultats questionnent les etudes anterieures rapportant une meilleure reponse en cas d’effets indesirables d’origine immunologique. Conclusion Bien que limitee par l’heterogeneite des inhibiteurs de checkpoint immunitaire inclus dans la meta-regression, notre etude suggere l’absence d’association entre l’apparition d’un effet indesirable auto-immun et le pronostic des patients traites pour un melanome. Ces evenements doivent donc etre consideres comme une toxicite des ICI, sans benefice a long terme pour les patients.

From before the coronavirus disease 2019 (COVID-19) pandemic, the effect of dipeptidyl peptidase 4 inhibitors (DPP-4i) on respiratory infections (RI) remains unclear. The meta-analysis of Yang et al. (1) specifically assessed the risk of infection with DPP-4i. However, cardiovascular outcomes trials (CVOTs) did not appear in their meta-analysis for RI (1). In addition, the meta-analyses of CVOTs did not report assessment of RI for DPP-4i. Meta-analyses and pharmacovigilance studies showed some discrepancies (2). Recently published practical recommendations did not suggest discontinuation of DPP-4i because of the COVID-19 pandemic (3,4). The dipeptidyl peptidase 4 enzyme could be a target for treating COVID-19 (2). We aimed to provide a powerful and less biased estimate of the effect of DPP-4i on the overall risk of RI and thus verify the validity of the recent recommendations for the management of diabetes during the COVID-19 pandemic (3,4). We updated a previous systematic review and meta-analysis, focusing our primary analysis on RI in placebo-controlled CVOTs assessing a DPP-4i in patients with type 2 diabetes, using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), up to 27 January 2020. In line with the previous meta-analysis of Yang et al. (1), our primary outcome was “any respiratory infection” (defined as influenza, nasopharyngitis, sinusitis, pharyngotonsillitis, pharyngitis, bronchitis, respiratory tract infection [RTI], upper RTI, lower RTI, or pneumonia). Secondary outcomes …

SummaryBackgroundAssociation between DPP4 inhibitors and respiratory infection remains unclear. CardioVascular Outcomes Trials (CVOTs) conducted before the COVID-19 pandemic are available. We aimed to estimate the effect of DPP4 inhibitors on the risk of respiratory infections.MethodsWe updated a previous systematic review and meta-analysis, searching for CVOTs assessing a DPP4 inhibitor in patients with type 2 diabetes mellitus. We focused on placebo-controlled CVOTs. Our primary outcome was ‘any respiratory infection’. We added a sensitivity analysis integrating non-CVOTs and active-controlled CVOTs.FindingsWe included 47 714 patients in five placebo-controlled CVOTs. Median follow-up ranged from 1·5 years to 3 years. 4 369 events of overall respiratory infection were reported (rate of 9·2%). DPP4 inhibitors were not associated with a different risk compared to placebo (RR = 0·99 [95% CI: 0·93; 1·04]). The sensitivity analysis integrating the non-CVOTs studies and the active-controlled CVOT reached 11 349 events among 82 644 participants (rate of 13·7%). DPP4 inhibitors were not associated with a different risk of overall respiratory infection (RR = 1·00 [95% CI: 0·97; 1·03]).InterpretationOur up-dated meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. We did not find any effect of the DPP4 inhibitors on the risk of respiratory infection. Our results support the recently published practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.FundingNo source of fundingPanel: Research in contextEvidence before this studyFrom before the COVID19 pandemic, respiratory infections are considered potential adverse effects of DPP4 inhibitors. Randomized trials assessing DPP4 inhibitors in patients with type 2 diabetes (T2D), their meta-analyses and pharmacovigilance studies reported conflicting results. Since the last meta-analyses assessing the risk of infections with DPP4 inhibitors, powerful cardiovascular outcomes randomized trials (CVOTs) became available. Recent practical recommendations for the management of diabetes during COVID-19 suggested that DPP4 inhibitors could be continued. We updated our previous meta-analysis of CVOTs and focused to the overall risk of respiratory infection associated with DPP4 inhibitors. We searched for published and unpublished CVOTs in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov, up to January 27, 2020, using key word as “diabetes mellitus”, “hypoglycemic agents”, “glucose control”, “randomized controlled trial”, “cardiovascular diseases”.Added value of this studyWe included CVOTs comparing a DPP4 inhibitor versus placebo, in people with T2D, and analysed the risk of respiratory infection with DPP4 inhibitors. We focused on placebo-controlled CVOTs to avoid the pitfalls of small study effect and heterogeneous comparators. We added a sensitivity analysis integrating non-CVOTs and non-placebo CVOTs to challenge our results and to increase the statistical power. Our meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. Our analyses integrated 11 349 events of any respiratory infections through 82 644 patients from randomized trials. Our results did not find any association between DPP4 inhibitors use and risk of non-COVID respiratory infections.Implications of all the available evidenceThe current COVID-19 pandemic has raised some questions about pros and cons of certain cardiovascular drugs. Our results support the recent practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.

BackgroundTo assess the efficacy and safety of topiramate in treating binge eating disorder (BED), using a systematic review and meta-analysis of the available randomized clinical trials (RCTs).MethodsThe RCTs assessing topiramate vs placebo with or without adjunctive psychotherapy in BED were reviewed using a systematic search in the PubMed, Web of Science, PsycINFO, Cochrane Database of Systematic Review, and ClinicalTrials.gov search Websites, from inception to November 2019. Main outcomes were the changes in binge frequency, quality of life, and weight, respectively. Effect estimates were pooled using random-effect models and presented as risk ratios (RRs) or mean differences (MDs) and their 95% confidence interval (95% CI). Data extraction was performed by two independent reviewers.ResultsThree studies were eligible for inclusion, involving 528 BED patients. Topiramate was found to be significantly more efficacious than placebo in reducing: (a) the number of binge episodes per week (MD = −1.31; 95% CI = −2.58 to −0.03; I2 = 94%); (b) the number of binge days per week (MD = −0.98; 95% CI = −1.80 to −0.16; I2 = 94%); and (c) weight (MD = −4.91 kg; 95% CI = −6.42 to −3.41; I2 = 10%). However, participants in the topiramate groups withdrew significantly more frequently for safety reasons, relative to placebo participants (RR = 1.90; 95% CI = 1.13-3.18, I2 = 0%).ConclusionsPreliminary findings support a possible efficacy of topiramate for the treatment of BED, even if safety concerns could limit the practical use of this treatment in BED subjects.

International audience; Aim: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS).Methods: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis.Results: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%).Conclusion: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Summary The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Summary The importance of reducing waste and increasing value when conducting research has been emphasized by a series of articles published in the Lancet in 2014. A survey indicates that, one year later, these articles have not influenced how research is conducted. In this review, we explore four stages described by Moher et al. in research production that lead to waste. We show that all four stages including, questions relevant to users, appropriate design conduct and analysis, accessible full research, unbiased and usable reports, efficient research regulation and management of biomedical research are also producing an important waste in pediatric research. We conclude that methods to improve research quality and limit waste need to be implemented in pediatric research and recognized by authorities as a priority.

Objectifs Une hausse du nombre d’appels recus au Centre Antipoison et de Toxicovigilance (CAP-TV) de Lyon pour des intoxications impliquant l’ammoniaque, utilisee par les usagers de drogue pour synthetiser de la cocaine freebase a partir de chlorhydrate de cocaine, a ete suspectee. Notre objectif etait de verifier cette hypothese et de decrire les caracteristiques des expositions accidentelles a l’ammoniaque par voies orale et buccale dans un contexte de toxicomanie. Methode Les cas d’exposition a l’ammoniaque (concentration > 10 %) par voies orale et buccale survenant entre le 01/01/2009 et le 31/12/2018 ont ete extraits de la Base Nationale des CAP-TV. Les cas d’expositions volontaires et les actes de malveillances ont ete exclus. La gravite des cas (codee selon le Poison Severity Score), la voie et la circonstance d’exposition ont ete systematiquement revues. La description portait sur les cas d’expositions dans un contexte de toxicomanie avere (d’apres le commentaire du narratif). L’augmentation du nombre de cas a ete etudiee par regression, la gravite des cas dans un contexte de toxicomanie a ete comparee a la gravite des autres cas inclus (cas controle) par un test de Cochran-Armitage. L’objectif secondaire etait de quantifier dans le groupe controle, les cas pour lesquels un contexte de toxicomanie pouvait etre suspecte par la presence d’au moins 4 criteres parmi : âge entre 21 et 39 ans, sexe masculin, deconditionnement, heure d’exposition entre 20 h et 7h59, contexte festif, exposition concomitante a des substances psychoactives, cooperation limitee. Resultats Sur 1576 cas extraits, 1238 ont ete inclus, dont 975 cas controle et 263 cas avec un contexte de toxicomanie avere. Dans un contexte de toxicomanie, il s’agissait tres majoritairement d’hommes (76 %) et d’adultes jeunes (20-49 ans) (95 %). Les deconditionnements etaient frequents (89 %), majoritairement dans des bouteilles d’eau, d’alcool ou flacon de methadone. Un usage concomitant de substances psychoactives etait mentionne dans 25 % des cas (principalement alcool, cocaine, cannabis). L’utilisation d’ammoniaque pour baser la cocaine etait explicite dans 20 % des cas. La personne exposee etait majoritairement l’utilisateur (83 %). Le nombre de cas d’intoxication par de l’ammoniaque dans un contexte de toxicomanie entre 2009 et 2018 a augmente (p Conclusion Cette etude n’a pas montre d’augmentation significative du nombre d’appels recus par les CAP-TV pour des intoxications par de l’ammoniaque chez des patients toxicomanes. Cependant, leur gravite est plus importante que lors d’expositions accidentelles sans contexte de toxicomanie. Notre etude presente cependant des limites, du fait de son caractere retrospectif et de l’absence de validation anterieure des criteres d’identification des cas de toxicomanie suspectee. Cependant, ces criteres pourraient permettre de mieux identifier les patients a risques et de les orienter vers une prise en charge addictologique (CSAPA, ELSA). Des actions de prevention sont encore necessaires pour sensibiliser les professionnels de sante et les usagers de drogue a cette problematique probablement sous-estimee.

Objectifs La chloroquine (CQ) et l’hydroxychloroquine (HCQ) ont ete proposees comme traitement de la COVID-19, avec une certaine iatrogenie. En effet, les intoxications aigues avec ces traitements sont connues pour leur gravite. Les doses toxiques de la CQ sont bien etablies, contrairement a celles de l’HCQ. Notre objectif etait de comparer la gravite des intoxications a l’HCQ par rapport a celles a la CQ. Methode Il s’agit d’une etude retrospective menee sur les cas d’intoxication aigue (prise unique) ou subaigue (plusieurs prises pendant moins de 7 jours) a la CQ et a l’HCQ, survenus entre 1999 et 2019 inclus, dans la region Auvergne-Rhone-Alpes (AuRA), present dans la base de donnees du centre antipoison de Lyon. Les criteres d’exclusion concernaient les intoxications chroniques, ou avec une dose supposee ingeree (DSI) inferieure aux posologies maximales recommandees. La gravite des cas (score PSS de 0–aucune–a 3–severe–) a ete verifiee a la lumiere du dossier clinique, par une meme personne, repondeur du centre antipoison, en ouvert du traitement. Les caracteristiques des cas inclus ont ete decrites pour chacun des deux groupes (CQ vs HCQ) : effectif, âge, sexe, circonstances de l’intoxication, DSI (en g/jour). Les scores de gravite entre les deux groupes (CQ vs HCQ) ont ete compares par regression logistique. Notre critere de jugement principal etait la gravite, ajustee sur la DSI/jr (une prise unique equivalent a 1 jour, la DSI totale sur plusieurs jours etaient divisee par le nombre de jour pour les intoxications subaigues). Les statistiques ont ete realisees avec le logiciel Stata. Une p value nominale a 5 % etait consideree significative sans correction pour test multiple. Resultats Parmi les 71 cas extraits, 50 ont ete exclus (6 intoxications chroniques, 12 aides a la prescription, 31 doses therapeutiques, 1 sans information). Vingt et un cas ont ete inclus : 15 (71 %) avec l’HCQ et 6 (29 %) avec la CQ. La proportion d’homme etait de 27 % et de 33 %, l’âge median de 40 ans (intervalles interquartiles (IQR) 25-59 ans) et de 27 ans (IQR, 21-34 ans) et la DSI mediane etait de 2,0 g/j (IQR 2,4-4,4) et de 3,6 g/j (IQR 0,8-6,0), respectivement pour HCQ et CQ. Dans les groupes HCQ et CQ, les circonstances d’intoxication etaient respectivement une conduite suicidaire (80 % vs 83 %), une erreur therapeutique (20 % vs 0 %), un mesusage (0 % vs 17 %), avec une intoxication aigue (93 % vs 83 %) ou subaigue (7 % vs 17 %) ; de gravite nulle PPS0 (27 % vs 0 %), faible PSS1 (20 % vs 0 %), moderee PSS2 (33 % vs 67 %) ou severe PSS3 (20 % vs 33 %). Les symptomes caracterisant la gravite severe des cas inclus etaient les suivant : troubles de la repolarisation, hypokaliemie, hypoglycemie, etat de choc, Glasgow score 0,05) sur la difference de gravite entre les deux molecules, ajustee sur la DSI/jour. Conclusion Notre etude pilote presentaient plusieurs limites (effectif limite, caractere retrospectif). Nos resultats etaient non concluants sur la difference de gravite entre les cas d’intoxication a l’HCQ ou a la CQ. Neanmoins, la CQ n’etait impliquee que dans des cas de gravite moderee ou severe. Atteindre un echantillon plus important de patients permettrait une plus grande puissance pour montrer une difference significative entre une gravite moderee pour l’HCQ versus severe pour la CQ. Il serait necessaire d’etendre cette etude a l’echantillon national des 8 CAP francais.

Introduction Pour limiter les effets secondaires induits par la corticotherapie tout en maintenant la remission chez les patients atteints d’arterite a cellules geantes (ACG), plusieurs medicaments immunosuppresseurs et agents biologiques ont ete evalues. Parmi eux, le tocilizumab et le methotrexate ont prouve leur efficacite et participent a l’arsenal therapeutique. L’objectif principal de la presente etude est de comparer, dans le cadre d’une meta-analyse en reseau, l’effet therapeutique des agents epargnant la corticotherapie dans l’ACG, avec une attention particuliere envers le tocilizumab et le methotrexate. Materiels et methodes Une revue systematique des bases de donnees MedLine (PubMed) et Clinical Trial a ete conduite jusqu’en janvier 2020. Les criteres d’inclusion etaient : patients presentant une ACG selon les criteres ACR nouvellement diagnostiquee ou en rechute, patients randomises entre un epargneur de corticotherapie et un placebo, presence d’au moins un des criteres de jugement parmi le nombre de rechutes, le nombre de rechutes majeures, le nombre d’effets indesirables graves et le nombre d’infections. La rechute a ete definie comme la recurrence d’un symptome ou la reapparition d’un syndrome inflammatoire biologique necessitant l’augmentation ou la reprise d’une corticotherapie, et l’amelioration par cette derniere. La duree de la corticotherapie a ete dichotomisee : courte (≤ 6 mois) ou prolongee (> 6 mois). Le risque de rechute et la tolerance ont ete estimes a l’aide d’une meta-analyse en reseau avec un modele frequentiste a effet aleatoire. Resultats Parmi les 96 etudes examinees, 8 essais randomises ont ete inclus representant 572 patients. Toutes les etudes ont compare la corticotherapie et un agent epargnant la corticotherapie : tocilizumab (k = 2), methotrexate (k = 3), infliximab (k = 1), etanercept (k = 1) et adalimumab (k = 1). La prevalence cumulee des rechutes de l’ACG etait de 52,6 % (95 % IC 38,1–66,9). Le tocilizumab reduisait de maniere significative le risque de rechute par rapport au methotrexate (RR = 0,41, 95CI 0,17–0,97), a une corticotherapie prolongee (RR = 0,41, 95CI 0,20–0,83) et a une corticotherapie courte (RR = 0,32, 95CI 0,16–0,66). Le risque de rechute n’etait pas significativement different avec le methotrexate par rapport a une corticotherapie courte (RR = 0,79, 95CI 0,48–1,31) et prolongee (RR = 0,95, 95CI 0,31–2,89). Le tocilizumab reduisait significativement les rechutes majeures comparees a la corticotherapie courte et prolongee fusionnees (RR = 0.08, 95 %CI 0,01–0,66). Il n’y avait pas de difference significative pour les rechutes majeures entre le methotrexate et la corticotherapie. L’adalimumab etait associe a des effets indesirables graves moins importants que la corticotherapie prolongee (RR = 0,31, 95CI 0,13–0,75). Toutes les autres comparaisons pour les effets indesirables graves n’etaient pas significatives. Le taux d’infection n’etait pas different selon les differents traitements. Conclusion Cette meta-analyse fournit les premieres donnees dans la hierarchie des agents epargnant la corticotherapie, et suggere que le tocilizumab pourrait etre le meilleur traitement pour prevenir la rechute dans l’ACG.

International audience; Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.

BackgroundThe last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality.Methods and findingsWe conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level.ConclusionsSGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention.Trial registrationPROSPERO CRD42016043823.

Objectif Le fomepizole est l’antidote preconise des intoxications a l’ethylene glycol (EG) ou au methanol. Les doses d’entretien (hors dialyse) et la concentration d’EG pour laquelle l’arret du traitement est recommande different selon les recommandations et resumes des caracteristiques des produits (RCP) francais, europeens et americains. Nous avons effectue une revue systematique de la litterature pour evaluer le niveau de preuve des differentes recommandations. Methode La base de donnees bibliographique Pubmed avec l’utilisation du filtre « clinical trial » et les ressources documentaires du service ont ete interrogees sans limitation de temps. Nous avons inclus les etudes cliniques prospectives evaluant l’interet du fomepizole comme antidote des intoxications a l’EG ou au methanol sur des criteres cliniques. Nous avons extrait les donnees concernant les caracteristiques des etudes, leurs resultats, et le schema therapeutique utilise. Resultats Parmi les 24 etudes cliniques identifiees, 20 ont ete exclues (3 : critere de jugement non clinique, 5 : volontaires sains, 8 : retrospectives, 3 : duplicata, 1 : case report). Parmi les 4 etudes incluses, 3 utilisaient une dose de charge de 15 mg/kg suivie de doses d’entretien de 10 mg/kg toutes les 12 h puis 15 mg/kg apres 48 h, jusqu’a une concentration d’EG (ou de methanol) Discussion Le schema therapeutique « Brent » propose de majorer les doses de fomepizole en raison d’un phenomene d’auto-induction enzymatique responsable d’une augmentation de l’elimination du fomepizole apres 30–48 h de traitement. A l’inverse, la preconisation d’une diminution progressive des doses dans le RCP francais semble etre justifiee par le fait que les doses administrees permettent d’atteindre des concentrations de fomepizole tres superieures aux concentrations estimees suffisantes par des etudes de pharmacotoxicocinetique. Nous n’avons cependant pas identifie d’etude prospective validant ces modifications, qui different des recommandations nord-americaines [1] . Par ailleurs, cette meme raison amenerait a proposer un arret du fomepizole pour un seuil d’EG de 0,3 g/L [2] , [3] , seuil actuellement a 0,2 g/L pour les RCP americain et europeen et a 0,1 g/L pour le RCP francais. Conclusion Differents schemas d’administration du fomepizole co-existent, pouvant preter a confusion lors de la prise en charge d’intoxications. Il serait interessant d’avoir acces aux donnees cliniques a l’origine du RCP francais pour comparer les niveaux de preuves des differents schemas, et ainsi poursuivre la recherche d’un consensus.

Introduction The pharmacotoxicology department (PTD) of the University Hospital of Lyon is a unique organization in France, gathering three regulatory vigilances: addictovigilance (AV), pharmacovigilance (PV), and poison control (PCC) centers. Since May 2018, requests for each center are handled by one single help desk. The aim was to improve answers’ efficiency and quality through an interdisciplinary approach. Our objective was to assess the requester's satisfaction on the provided answers. Material and methods A retrospective satisfaction survey was carried out over a three-week-period on a representative part of the incoming requests (20% of PCC requests, 100% of PV and AV requests). These requests came either from patient himself, parents or relatives, or healthcare professional. The survey was proposed to the requesters by phone or email depending on how requests were received. An online questionnaire on framaform.org website was filled out using an identification number which ensures case anonymization. Results Among the 1135 received requests, 38.5% of the submitted questionnaires were completed (n = 123/319), mainly by non-healthcare professionals (76.4%). These requests mostly concerned PC (74.8%) and PV (24.4%) centers, and 63.4% of requesters contacted PTD for the first time. Contact details for the PTD were considered to be easily accessible for 87% of the requesters. The given information was assessed as very clear by 99.2% of the requesters. Moreover, 97.6% of them were fully satisfied with the provided medical and treatment advice. Regarding quality of processing and time to answer, the large majority of requesters was satisfied (99.2% and 95.1%, respectively). Discussion/Conclusion This PTD survey shows positive results with an excellent overall requesters’ satisfaction. Despite the low rate of participation, these results underline the added value of such multidisciplinary and coordinated approach, encouraging us to pursue this functioning model.

Objectif L’enseignement de la pharmacotoxicologie clinique reste un defi [1] . Les donnees de la litterature disponibles presentent des niveaux de preuves variables. La modalite de cours dite « en classe inversee » pourrait ameliorer la formation des etudiants en sante [2] . Notre hypothese etait qu’une approche « en classe inversee » serait associee a une meilleure satisfaction des etudiants, concernant leur formation a la pharmacotoxicologie clinique, par rapport au cours dit « magistral ». Methodes Nous avons realise une etude transversale retrospective. Un questionnaire a ete envoye aux etudiants accueillis entre septembre 2017 et septembre 2019 dans le service de pharmacotoxicologie des hospices civils de Lyon (qui inclut les centres antipoison, de pharmacovigilance et d’addictovigilance de Lyon). Certains etudiants avaient eu l’opportunite de realiser un cours en classe inversee (recherche documentaire, synthese et presentation orale), d’autre d’assister a une presentation orale (modalite « cours magistral »), certains les deux. Un score « d’utilite et satisfaction » de 1 (pire) a 10 (meilleur) leur permettait d’evaluer leur ressenti concernant quatre domaines : l’acquisition de connaissances en pharmacotoxicologie clinique (objectif principal), et trois objectifs secondaires : developpement de competences en pharmacotoxicologie clinique, acquisition de connaissances sur les methodes de revues systematiques, developpement de competences pour l’interpretation du niveau de preuve. Les scores « d’utilite et satisfaction » attribues pour la realisation d’un cours en « classe inversee » etaient compares aux scores attribues pour la participation a un « cours magistral ». Resultats Dix-neuf reponses sur les 56 etudiants contactes etaient exploitables (2 non exploitables, taux de reponse : 37,5 %). La plupart etaient des etudiants en medecine. Concernant le critere de jugement principal, l’approche « en classe inversee » n’etait pas associee a une augmentation du score « d’utilite et satisfaction », compare a la modalite « cours magistral » (8,1 ± 2,0 vs 7,9 ± 1,2, respectivement, p = 0,59). Aucune difference n’etait significative pour les criteres de jugements secondaires (competences en pharmacotoxicologie : 7,4 ± 2,1 vs 7,1 ± 2,5, respectivement, p = 0,93 ; methode de revue systematique : 8,2 ± 1,8 vs 7,1 ± 1,4, respectivement, p = 0,15 ; interpretation du niveau de preuve : 6,9 ± 1,9 vs 7,3 ± 1,4, respectivement, p = 0,77). Discussion Notre etude presente plusieurs limites (risque de biais de confusion, de biais de non-reponse, de biais de memorisation). L’extrapolabilite des resultats est limitee. Cependant, le niveau global de satisfaction des etudiants apparait relativement satisfaisant. Conclusion Cette premiere etude pilote n’a pas permis de montrer un avantage de la classe inversee par rapport au cours magistral dans le ressenti des etudiants pour l’apprentissage de la pharmacotoxicologie clinique. D’autres etudes sont necessaires, sur l’acquisition de connaissances et de competences des etudiants et non seulement sur leur ressenti.

Objectif Les benefices d’un traitement par N-Acetylcysteine (NAC) lors de la prise en charge tardive des surdosages aigus ou subaigus en paracetamol sont incertains, sans consensus sur la duree et le mode d’administration de la NAC. L’objectif de ce travail est de decrire les modalites de prise en charge de ces patients et d’estimer l’incidence des reactions anaphylactoides associees a une perfusion tardive de NAC. Methode Tous les cas d’intoxication par du paracetamol survenues chez des patients de plus de 15 ans, avec un delai de prise en charge entre la premiere prise et l’hospitalisation superieur a 24 h et pour lesquels le CAP de Lyon a ete contacte entre le 01/01/2015 et le 31/12/2018 ont ete revus. Seuls les cas avec bilan hepatique a l’admission ont ete conserves en classant la severite de l’atteinte hepatique en grade 1 a 4 selon la Common Terminology Criteria for Adverse Events. Les cas ont ete separes en deux groupes : groupe 1 pour les intoxications aigues avec une prise unique ≥ 150 mg/kg ; groupe 2 pour les intoxications subaigues correspondant a des prises repetees ≥ 150 mg/kg/j sur une duree ≤ 72 h ou ≥ 100 mg/kg/j sur une duree de plus de 72 h. Resultats Cinquante-deux patients (92 % de moins de 60 ans) dont 26 du groupe 1 et 26 du groupe 2 ont ete inclus. Dans le groupe 1, la dose supposee ingeree (DSI) mediane etait de 372 mg/kg (150 a 1150 mg/kg), le grade de severite de 1 et 2 (n = 11), 3 (n = 6) et 4 (n = 9), et la paracetamolemie 2 a l’admission. Enfin, tous les patients ayant un grade 3/4 a l’admission ont recu de la NAC vs 14 des 33 patients ayant un grade 1/2. Tous les patients ont gueri. Discussion A la prise en charge, le grade de severite de l’atteinte hepatique etait plus eleve dans les intoxications aigues que dans les intoxications subaigues. Une perfusion de NAC a ete realisee presque systematiquement pour ces intoxications aigues, et ce quel que soit le stade de severite a l’admission. Pour les intoxications subaigues, et si une proportion moindre de patients a recu de la NAC, on peut souligner que 7 (64 %) de ceux-ci avaient un grade de 1 ou 2. Un taux de reaction anaphylactoide plus important que celui habituellement decrit dans la litterature a ete note, possiblement en lien avec l’absence de paracetamol circulant. Conclusion Les modalites de prises en charge retardee des intoxications au paracetamol different selon qu’il s’agit d’intoxications suicidaires ou de prises reparties sur plusieurs jours.

Introduction L’utilisation de descripteurs de population est tres repandue dans la litterature scientifique medicale. La plupart des articles traitant d’etudes cliniques, biologiques ou fondemantales classent les patients par groupes selon des criteres communement definis comme « raciaux », « ethniques » et « geographiques ». Ces descripteurs varient selon les auteurs ou les recommdantions nationales et peuvent impacter l’uniformite des resultats obtenus. L’objectif de la presente revue systematique est de decrire l’utilisation actuelle des descripteurs de population dans les essais controles randomises (ECT) publies dans cinq grandes revues medicales (JAMA, NEJM, BMJ, Lancet, Ann Intern Med). Materiels et methodes Les recherches ont ete effectuees retrospectivement a partir du 26 octobre 2019 dans la base de donnees PubMed jusqu’a obtenir environ 200 articles eligibles consecutifs. Seuls les ECTs ont ete pris en compte. Les articles etaient eligibles lorsque les auteurs mentionnaient au moins un groupe de population humaine a l’aide de descripteurs de population. Afin d’en identifier les principaux termes, les recommandations de differentes autorites de sante (FDA, UK, EMA) concernant la collecte de ces donnees dans les ECTs ont ete prealablement etudiees. Les descripteurs de population ont ensuite ete classes en deux categories : descripteurs consideres comme “raciaux” (“race”), “ethniques” (“ethnicity”) et descripteurs consideres comme “geographiques” (ex Europa, Italy). Selon un protocole predefini, deux groupes de deux auteurs ont extrait les donnees independamment. Un examinateur independant a ete sollicite afin de garantir l’exactitude et l’evaluation critique en cas de doute. Resultats Sur 350 articles analyses, 209 etaient eligibles. Dans 71,8 % des cas, les auteurs utilisaient le terme “race” et dans 67,0 % le terme “ethnicity”. Dans 31,1 % des cas, ils employaient le terme “race/ethnicity”, ne faisant pas la distinction entre les deux notions. Le nombre moyen de termes rattaches a ces denominations etait de 5,42 par article. Au total, 173 termes differents ont ete comptes. En soustrayant les termes rattaches a des pays ou sous-continents, 19 variants ont ete trouves pour la population d’origine africaine, 14 variants pour celle d’origine europeenne, ainsi que 12 variants pour celle d’origine asiatique, celle des americains dits “natifs” et celle d’origine hispanique. Le terme “mixed” a ete quant a lui decline en 11 variants. La denomination etait choisie principalement par le patient (85,8 % des cas) parmi des categories fixes definies prealablement (89,1 % des cas). L’utilisation de ces termes etait justifiee par les auteurs dans 47,5 % des cas par la presomption a priori d’une possible interaction statistique entre les criteres d’evaluation de l’etude et les differentes populations humaines. Parmi les 209 articles eligibles, 74 (35,4 %) ont utilise des descripteurs geographiques tels que “Europe”, “North America” or “Middle East”. L’utilisation de ces termes etait justifiee par les auteurs dans 75,7 % des cas par la presomption a priori d’une possible interaction entre les criteres d’evaluation de l’etude et les differentes populations humaines. Cependant, seulement 5 articles sur les 209 eligibles ont formule une hypothese precise et explicite concernant l’influence de certaines populations sur les criteres d’etude. Conclusion Dans les cinq grandes revues medicales selectionnees, la plupart des articles utilisaient des descripteurs “raciaux” au detriment des descripteurs “geographiques” et “ethniques”. L’extreme heterogeneite des descripteurs de population pointe le defaut d’un accord sur la delimitation d’une terminologie consensuelle des populations humaines. De plus, des descripteurs bases sur la couleur de la peau (“white”, “black”) ou sur des concepts depasses (“Caucasian”, “race”) posent des questions societales, en l’absence de rationnel pharmacologique, genetique ou anthropologique. Enfin, les agregats de sous-populations humaines paraissent trop gros pour permettre la detection d’une interaction basee sur des variants genetiques influant sur la pharmacocinetique des medicaments. Ce constat plaide en faveur de la mise en place d’un consensus international afin d’utiliser des criteres scientifiques plus pertinents et de delimiter des populations genetiquement plus homogenes.

Background:Follow-up cohorts (observational studies) were initiated consecutively or simultaneously to the development of randomised controlled trials (RCTs) in JIA patients(1,2). They help to identify many complications observed only in clinical practice related to off label use, coadministration of treatments, drug misuse, and occurrence of rare or unexpected event. In addition, observational studies include a higher number of patients with a longer duration of follow-up compared to randomised trials. Hence, they have a higher power to capture the occurrence of serious adverse events (SAE) in daily clinical practice3.Objectives:To estimate the incidence of serious adverse events (SAEs) including serious infections, malignancies, and death in patients with juvenile idiopathic arthritis (JIA) treated with biological agents (BAs) in daily clinical practice, using meta-analysis techniques.Methods:We systematically searched, up to May 2019, Medline and Embase databases for observational studies performed in JIA disease under BAs treatment. Outcomes were SAEs, serious infections, malignancies and all-cause mortality. Complementary, the incidence of SAEs in randomised controlled trials (RCTs) with withdrawal and parallel designs was performed by meta-analysis.Results:A total of 31 observational studies were included (6811 patients totalizing 17530 patients-years [PY] of follow-up). The incidence rate of SAEs was similar in observational cohorts and withdrawal RCTs (4.46 events per 100 PY, 95% CI 2.85- 6.38, I2= 95%) and 3.71 events per 100 PY (95%CI 0.0-13.34), I2= 56%, respectively). The incidence of SAE was lower in parallel RCT. The incidence rate of serious infections, malignancies and death in observational cohorts was estimated at 0.74 events per 100 PY (95%CI 0.32-1.30, I2=83%), 0.10 events per 100 PY (95% CI 0.06-0.16, I2=0%) and 0.09 events per 100 PY (95% CI 0.05-0.14, I2=0%), respectively. Infections were the known cause of death in 8 of the 14 deaths. In meta-regression and subgroup analysis, variation of serious infections rates were partially explained by follow-up time (R2= 30.3%, p= 0.0008), JIA categories (all JIA versus polyarticular versus systemic JIA categories, p= 0.001) and cohort quality (Newcastle-Ottawa score ≥ to 6 versus ≤ to 5 stars, p= 0.0025).Conclusion:Our results suggest that the incidence rate of SAEs related to BAs in JIA disease is similar to those observed in randomised withdrawal trials. The overall incidence remained low. However, unsatisfactory description of SAEs prevents analysis of hospitalisation causes. Infection and, to a lesser extent, cancer and death, explain only part of burden of BAs.References:[1]Berard RA, Laxer RM. Learning the hard way: clinical trials in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(1):1–2.[2]Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva Е, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018 27;20(1):285.[3]Monti S, Grosso V, Todoerti M, Caporali R. Randomized controlled trials and real-world data: differences and similarities to untangle literature data. Rheumatol Oxf Engl. 2018 01;57(57 Suppl 7):vii54–Disclosure of Interests:None declared

Objectif Le CAPTV de Lyon et les quatre CRPV de la region AURA sont directement impliques dans le recueil et la gestion d’erreurs medicamenteuses (EM). Afin de mieux caracteriser ces EM et de pouvoir proposer a terme des pistes pour les corriger et les prevenir, nous avons mene une etude prospective collaborative en lien avec l’OMEDIT (Observatoire des medicaments, des dispositifs medicaux et des innovations therapeutiques) Rhone-Alpes en janvier et fevrier 2017. Methode Les informations concernant les cas d’EM recus au CAPTV ou par les CRPV ont ete colligees sur un questionnaire standardise puis informatisees a l’aide du logiciel Clinsight. Resultats Cinq cent quatre-vingt-un appels/signalements (537 au CAPTV, 44 aux CRPV) ont concerne 584 patients (662 EM) dont 35,8 % d’enfants d’âge inferieur ou egal a 6 ans et 19,2 % de patients d’âge superieur ou egal a 65 ans. Les EM survenaient pour 71,6 % au domicile, 14 % dans le secteur medico-social (76,8 % dans des foyers specialises et 18,3 % dans des EHPAD), 6,8 % dans des etablissements de sante, tres peu dans les collectivites ou le secteur liberal. La personne a l’origine de l’EM est majoritairement le patient ou son entourage (75,2 %), un infirmier (9,1 %), un educateur (4,3 %) ou un medecin (4,1 %). Les educateurs sont a l’origine de 29,3 % des EM survenues en secteur medico-social. Sur les 662 EM enregistrees, la nature de l’EM est une erreur de dose (36,3 %), une erreur de medicament (35,6 %), une erreur de modalites d’administration (9,1 %) ou de patients (7,9 %), ces dernieres etant survenues pour 73,1 % des cas en secteur medico-social. La cause principale retenue est une erreur d’administration (64,6 %) qui survient au domicile dans 71,3 % des cas et en lien avec des erreurs de comportement/inattention (35,7 %) et/ou de similitude entre medicaments (22,8 %). Les medicaments les plus concernes sont ceux du systeme nerveux central (34,2 %), en particulier les analgesiques (paracetamol dans 74 % des cas), les antiepileptiques et les neuroleptiques, ceux du systeme cardio-vasculaire (8,5 %), les medicaments du systeme respiratoire (8,5 %) et les anti-infectieux a usage systemique (7,4 %). La tres grande majorite des EM est restee sans consequence (64,2 %) ou sans gravite (23,8 %). Vingt-six cas graves (4,5 %) ont ete enregistres avec 2 deces dans un contexte d’administration d’insuline et de morphine. Conclusion Cette etude realisee a l’aide d’un questionnaire tres detaille a permis de recueillir un nombre consequent d’EM d’origine variee et de les caracteriser dans leur globalite. Elle permet d’envisager de nombreuses pistes d’action/prevention notamment dans le secteur medico-social (personnel non medical) ou en ville (similitude entre medicaments). Elle confirme aussi la gravite potentielle de certaines erreurs.

Objective Diphoterine® (Prevor Company, France) is an amphoteric hypertonic solution proposed for decontamination in case of cutaneous or ocular corrosive injury. Our Poison Information Center of Lyon (PIC Lyon) is regularly questioned by occupational health professionals about the benefit of diphoterine®. As new studies became available since the last review of Brent [1] , our aim was to assess systematically the available evidence on diphoterine®. Methods Non clinical studies and randomized or non-randomized trials in humans assessing the benefit of diphoterine® after cutaneous or ocular chemical burns were eligible. We searched Medline, Google and the Prevor website. After screening title and abstracts, relevant articles were selected, and the following data were extracted: study characteristics including quality assessment, type of controls and clinical outcomes (such as healing delay, burn severity), presence of potential conflict of interest. Results We identified 37 articles or abstracts of whom 12 original studies (6 sponsored by Prevor company) were included. Five controlled studies were conducted in animals (ocular exposures in three and skin in two). Sample size ranged from 16 to 30 animals. Two studies (one randomized) suggested an effect of diphoterine® use on ocular pH but not on clinical outcomes; one randomized study suggested a decrease of corneal injury; one randomized study observed a complete or almost complete healing of the burn injury in the five rats treated with diphoterine® compared to a detersion of eschar or a wound re-epithelization in the five rats treated with normal saline solution. However, these last studies reported multiple outcomes, without defining a principal, and did not correct for multiple testing. The last study, assessing the safety of diphoterine®, did not detect hypersensitivity reactions after skin exposure. Seven studies were conducted in humans with both eye and skin exposures. Sample size ranged from 5 to 180. Of the 3 retrospectives cases series, one uncontrolled study (24 subjects) did not detect adverse effects attributable to diphoterine® decontamination; one uncontrolled study (34 subjects) suggested a decrease in pain; the controlled study (131 subjects) did not show a decrease in the time to healing as compared to water (9.0 days in the diphoterine® group versus 7.0 in the non-diphoterine® group, P = 0.258). Of the 4 prospective studies, one was uncontrolled (5 subjects) and 3 compared diphoterine® to water and/or saline solution (from 65 to 180 subjects). Regarding the three controlled prospective trials, none of them were randomized; none of them controlled the alpha risk when reporting multiple outcomes; they suggested clinical benefits with less serious burns, decrease in pain or shorter time for recovery. Discussion We did not find acceptable level of evidence suggesting a clinical benefit of diphoterine®. Observations reported in the prospective clinical trials were at high risk of bias and at high risk of false positive results. Our results are consistent with previous systematic review [1] , [2] , [3] . We did not assess the financial cost of diphoterine®. Conclusion Compared to water or saline solution, the benefit of decontamination with diphoterine® is questionable. We believe that the decontamination should be performed as early as possible with the most easily accessible solution, and water should be the first option.

International audience; The aim of this study was to propose a ranking of the currently available antidiabetic drugs, regarding vascular clinical outcomes, in patients with type 2 diabetes, through a network meta-analysis approach. Randomized clinical trials, regardless of the blinding design, testing contemporary antidiabetic drugs, and considering clinically relevant outcomes in patients with type 2 diabetes mellitus will be included. The primary outcomes of this analysis will be overall mortality, cardiovascular mortality, and major cardiovascular events. Diabetic microangiopathy will be a secondary outcome. Adverse events, hypoglycemia, weight evolution, bariatric surgery, and discontinuation of the treatment will also be recorded. Each drug will be analyzed according to its therapeutic class: biguanide, alpha-glucosidase inhibitors, sulfonylureas, glitazones, glinides, insulin, DPP-4 inhibitors, GLP-1 analogs, and gliflozins. The treatment effect of each drug class will be compared using pairwise meta-analysis and a Bayesian random model network meta-analysis. Sensitivity analyses will be conducted according to the quality of the studies and the glycemic control. The report will follow the PRISMA checklist for network meta-analysis. Results of the search strategy and of the study selection will be presented in a PRISMA compliant flowchart. The treatment effects will be summarized with odds ratio (OR) estimates and their 95% credible intervals. A ranking of the drugs will be proposed. Our network meta-analysis should allow a clinically relevant ranking of the contemporary antidiabetic drugs.

Objectif Malgre une diminution ces dernieres annees de la frequence des intoxications par des alcools frelates en France, les specificites de leurs prises en charge en font un theme qui reste malheureusement d’actualite. Notre objectif est d’illustrer a partir d’un cas clinique les difficultes diagnostiques et l’importance de la collaboration entre les differents acteurs impliques dans la prise en charge de telles intoxications aigues. Description du cas Deux patients A et B, ethyliques chroniques, parlant difficilement le francais, ont ete hospitalises separement pour un tableau douloureux abdominal ayant fait suspecter une pancreatite aigue. Le bilan biologique a alors mis en evidence une acidose metabolique ainsi qu’une insuffisance renale aigue necessitant la mise sous hemodialyse des deux patients. Le centre antipoison de Lyon, contacte par le reanimateur pour orienter le bilan etiologique, a alors conseille un bilan toxicologique elargi, avec en particulier un dosage d’ethylene-glycol et de methanol. L’interrogatoire a permis secondairement de faire le lien entre les deux patients, qui auraient consomme un alcool de coings artisanal 24 a 48 h avant l’hospitalisation. L’evolution clinique des patients a ete marquee par une dysautonomie majeure. Le patient A a presente une tetraplegie flasque avec absence de reflexe du tronc cerebral, finalement en cours de recuperation ; sa fonction renale etait revenue a la normale. Le patient B recupere progressivement d’une neuropathie de reanimation, mais son insuffisance renale persiste et necessite toujours une hemodialyse. Resultats L’analyse des prelevements sanguins retrouve notamment la presence de methanol. L’analyse de l’alcool de coing par GC-FID a montre des concentrations relativement faibles d’ethanol, de methanol, ainsi qu’un pic majoritaire non identifie. Une analyse de criblage par GC-MS a permis de detecter la presence principalement de di-ethylene-glycol (DEG) ainsi que d’autres glycols (tri-ethylene-glycol, penta-ethylene-glycol). Un dosage cible d’ethylene-glycol par GC-MS a montre une concentration de 160 mmol/L. Malheureusement les delais de prise en charge n’ont pas permis de mettre en place un traitement antidotique. Compte-tenu de la possible exposition d’autres personnes a cet alcool artisanal, ces cas ont ete signales a la cellule de veille et gestion des alertes sanitaires de l’agence regionale de sante. Une enquete de police a alors ete menee. Les resultats sont presentes dans le Tableau 1 . Conclusion La symptomatologie des patients est compatible avec une intoxication aux glycols et methanol ; le tableau neurologique severe retarde d’un des patients semble pouvoir etre relie au DEG. Le diagnostic toxicologique repose sur des arguments cliniques et analytiques obtenus grâce a une cooperation entre les differents acteurs impliques, de la reanimation, du centre antipoison et du laboratoire de toxicologie.

Objectif Presenter un cas d’intoxication volontaire au chlorure de mercure avec analyse toxicocinetique du mercure plasmatique. Cas Une patiente de 32 ans est prise en charge par les pompiers a son domicile pour des douleurs abdominales intenses avec vomissements sanguinolents. Elle avoue avoir ingere 2 g de chlorure de mercure achete sur Internet et reconditionne dans des gelules d’antalgique videes au prealable (une 1 re tentative dans un yaourt s’etant solde par 24 h de vomissements incoercibles). Le centre antipoison contacte par le SAMU a recommande une administration precoce du B.A.L ® lors du transport heliporte. Compte tenu du delai de destockage (2 heures), le traitement chelateur n’a ete cependant administre qu’une fois arrive en reanimation, par voie intramusculaire et durant 14 jours. Le bilan digestif initial avec TDM thoraco-abdominale et fibroscopie œsogastroduodenale a mis en evidence une œsophagite de stade IIIB des 2/3 inferieurs avec une impregnation œsophagienne locale de mercure (hyperdensite spontanee). Cette atteinte digestive a evolue defavorablement, necessitant une oesogastrectomie avec jejunostomie a J23 suite a une perforation œsophagienne. Parallelement s’est developpee une atteinte colique diffuse avec d’importantes rectorragies necessitant de nombreuses transfusions, ainsi qu’un geste d’hemostase par voie endoscopique, puis une colostomie de derivation a J54 dans les suites d’une perforation rectale. Par ailleurs, la patiente a presente une insuffisance renale aigue necessitant le recours a l’epuration extrarenale de J2 a J29. Methode Des dosages plasmatiques (8 h 30, 12 h, 18 h, J2, J7, J10, J12, J20, J59), urinaires et pleuraux ont ete realises par ICP-MS. Un modele toxicocinetique a ete ajuste par regression non lineaire a partir des concentrations plasmatiques afin d’estimer la demi-vie d’elimination apparente du mercure. Les modeles mono et bi-compartimentaux ont ete testes. L’intervalle de confiance des parametres toxicocinetiques a ete evalue par bootstrap residuel. Resultats Le C max de mercure est atteint a J2 : 4940,6 μg/L. A J59, persiste une concentration de 248 μg/L. Le modele representant le mieux la cinetique du mercure plasmatique est un modele bi-compartimental avec (k a : constante d’absorption, V C et V P : volumes de distribution central et peripherique, Q et Cl : clairance inter-compartimentale et d’elimination). L’estimation des parametres toxicocinetiques est presentee dans la Figure 1 . La demi-vie d’elimination apparente a ete estimee a 22 h pendant la phase de distribution et a 23 jours pendant la phase d’elimination. Conclusion Le tableau clinique suite a cette ingestion volontaire de chlorure de mercure a associe une atteinte digestive majeure et une insuffisance renale d’installation rapide. La cinetique plasmatique du mercure chez cette patiente est de type bi-compartimental ce qui suppose un depot tissulaire important en coherence avec la litterature existante.