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To identify all available trigger tools applicable to the pediatric population in hospital settings to detect adverse drug events (ADEs) and to describe their performances by positive predictive value (PPV).PubMed® was searched until December 2021. The reference sections were also consulted for new articles. Studies were selected when they used one or more triggers to identify AEs and used data on pediatric inpatient settings. Studies mentioning triggers related to AEs that were only caused by care procedures were excluded. Only triggers related to ADEs were included. PPVs of triggers were reported. Mean PPVs were calculated for multi-study triggers. The interest of each trigger in a real-time detection system was assessed.Thirty studies were included. A total of 271 unique triggers were identified, 179 of which were related to drug-induced harms. Among them, 68 could be used for prevention of ADEs, 80 for verification and 31 for reporting. Nineteen triggers (11%) had a mean PPV between 50% and 100%, including 5 that had a 100% PPV.The performances of individual triggers need to be more adequately studied. The detection of ADEs through computerized triggers and/or real-time detection systems remains an emerging field, very much needed in children especially, due to frequent off-label use.

International audience; Evidence-based medicine is the cornerstone of shared-decision making in healthcare today. The public deserves clear, transparent and trust-worthy information on drug efficacy. Yet today, many drugs are prescribed and used without solid evidence of efficacy. Clinical trials and randomized clinical trials (RCTs) are the best method to evaluate drug efficacy and side effects. In a shared medical decision-making approach, general practitioners need drug assessment to be based on patient-important outcomes. The aim of project Rebuild the Evidence Base (REB) is to bridge the gap between the data needed in clinical practice and the data available from clinical research. The drugs will be assessed on clinical patient important outcomes and for a population. Using the Cochrane tools, we propose to analyse for each population and outcome : 1) a meta-analysis based on RCTs with a low risk of bias overall ; 2) an evaluate of results of confirmatory RCTs; 3) a statistical analysis of heterrogeneity between RCTs, and 4) an analysis of publication bias. Depending on the results of these analyses, the evidence will be categorised in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting randomized clinical trials and their meta-analysis to produce quality data for general practitioners to focus on benefit-risk assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim.

The effect of the COVID-19 pandemic on maternal mental health has been described in Canada and China but no study has compared the two countries using the same standardized and validated instruments. In this study, we aimed to evaluate and compare the impact of COVID-19 public health policies on maternal mental health between Canada and China, as we hypothesize that geographical factors and different COVID-19 policies are likely to influence maternal mental health. Pregnant persons >18 years old were recruited in Canada and China using a web-based strategy. All participants recruited between 26 June 2020 and 16 February 2021 were analyzed. Self-reported data included sociodemographic variables, COVID-19 experience and maternal mental health assessments (Edinburgh Perinatal Depression Scale (EPDS), Generalized Anxiety Disorders (GAD-7) scale, stress and satisfaction with life). Analyses were stratified by recruitment cohort, namely: Canada 1 (26 June 2020–10 October 2020), Canada 2 and China (11 October 2020–16 February 2021). Overall, 2423 participants were recruited, with 1804 participants within Canada 1, 135 within Canada 2 and 484 in China. The mean EDPS scores were 8.1 (SD, 5.1) in Canada 1, 8.1 (SD, 5.2) in Canada 2 and 7.7 (SD, 4.9) in China (p-value Canada 2/China: p = 0.005). The mean GAD-7 scores were 2.6 (SD, 2.9) in China, 4.3 (SD, 3.8) in Canada 1 (p < 0.001) and 5.8 (SD, 5.2) in Canada 2 (p < 0.001). When adjusting for stress and anxiety, being part of the Chinese cohort significantly increased the chances of having maternal depression by over threefold (adjusted OR 3.20, 95%CI 1.77–5.78). Canadian and Chinese participants reported depressive scores nearly double those of other crises and non-pandemic periods. Lockdowns and reopening periods have an important impact on levels of depression and anxiety among pregnant persons.

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.

Introduction: We aimed to measure the impact of the COVID-19 pandemic on maternal mental health, stratifying on pregnancy status, trimester of gestation, and pandemic period/wave.Methods: Pregnant persons and persons who delivered in Canada during the pandemic, >18 years, were recruited, and data were collected using a web-based strategy. The current analysis includes data on persons enrolled between 06/2020-08/2021. Maternal sociodemographic indicators, mental health measures (Edinburgh Perinatal Depression Scale (EPDS), Generalized Anxiety Disorders (GAD-7), stress) were self-reported. Maternal mental health in pregnant women (stratified by trimester, and pandemic period/wave at recruitment) was compared with mental health of women who had delivered; determinants of severe depression were identified with multivariate logistic regression models.Results: 2,574 persons were pregnant and 626 had already delivered at recruitment. Participants who had delivered had significantly higher mean depressive symptom scores compared to those pregnant at recruitment (9.1 (SD, 5.7) vs. 8.4 (SD, 5.3), p=0.009). Among those who were pregnant at recruitment, depressive symptoms were significantly higher in women recruited in their third trimester, and those recruited during the 2nd wave of the pandemic. Maternal anxiety (aOR 1.51; 95%CI 1.44-1.59) and stress (aOR 1.35; 95%CI 1.24-1.48) were the most significant predictors of severe maternal depression (EDPS˃13) in pregnancy. Conclusion: The COVID-19 pandemic had a significant impact on maternal depression during pregnancy and in the post-partum period. Given that gestational depression/anxiety/stress have been associated with preterm birth and childhood cognitive problems, it is essential to continue following women/children, and develop strategies to reduce COVID-19’s longer-term impact.

Purpose Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. Methods We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. Results Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. Conclusions and relevance Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.

Resume Objectif Analyser et decrire l’incidence des effets indesirables des agents biologiques chez des enfants atteints de maladies inflammatoires, dans une cohorte suivie en situation reelle. Methodes Cette etude observationnelle retrospective multicentrique internationale a evalue, par la methode de Kaplan–Meier, la survenue d’effets indesirables chez des enfants recevant un traitement biologique et suivis dans le reseau JIRcohorte de rhumatologie pediatrique (JIR, Juvenile Inflammatory Rheumatism). Un modele de Cox a ete elabore pour identifier des facteurs predictifs independants d’effets indesirables. Resultats Au total, 813 patients totalisant 3439 patients-annee (p-a) d’agents biologiques ont ete inclus. Le principal diagnostic etait l’arthrite juvenile idiopathique (AJI) (84 %). Au total, 222 patients (27,3 %) ont presente 419 effets indesirables, soit un taux d’incidence de 12,2 pour 100 p-a, IC 95 % [11,0 ; 13,4]. L’incidence globale des effets indesirables graves etait de 3,9 pour 100 p-a, IC 95 % [3,2 ; 4,6]. Le tocilizumab et l’infliximab ont ete associes de maniere significative a des effets indesirables et le canakinumab a des effets indesirables graves. L’analyse univariee et multivariee des effets indesirables et des effets indesirables graves a montre qu’ils etaient plus frequents chez les patients prenant des agents biologiques en association avec des immunosuppresseurs (autres que le methotrexate). Conclusion Cette etude suggere que la securite des agents biologiques est globalement acceptable chez les enfants atteints de maladies rhumatismales inflammatoires traites par des agents biologiques. Cependant, la prescription d’immunosuppresseurs associee cree un risque notable d’effets indesirables.

Resume Objectif Cette etude vise a decrire avec precision le contexte de survenue des erreurs medicamenteuses liees au methotrexate, d’en detailler les consequences cliniques et les approches therapeutiques, et de determiner le taux de mortalite lie a ces erreurs. Methodes Les donnees sur les erreurs de medicamenteuses liees au methotrexate ont ete obtenues aupres du reseau francais des centres antipoison et de pharmacovigilance qui recueillent et documentent les effets indesirables ou toxiques des medicaments leur ayant ete notifies. Ont ete inclus les cas ou la dose recue etait plus de deux fois superieure a la dose hebdomadaire prevue ou avec une dose hebdomadaire cumulee ≥ 30 mg et comportant un suivi d’au moins 4 jours apres la derniere dose administree. Les caracteristiques demographiques, l’indication therapeutique, la dose prescrite, les interactions medicamenteuses, les complications cliniques et l’evolution ont ete analysees. Resultats Soixante-quatorze patients ont ete inclus. Les causes d’erreurs etaient dues a une erreur lors du renouvellement de l’ordonnance (23,3 %) ou a la non-observance du schema d’administration hebdomadaire par les patients ou un aidant (56,2 %), ou par un professionnel de sante (20,5 %). Sur les 70 patients ayant pris du methotrexate tous les jours, la dose quotidienne moyenne recue pendant la duree de l’erreur etait de 9,6 ± 4,1 mg (extremes : 2,5 a 22,5) avec une duree moyenne de l’erreur de 11,7 ± 12,2 jours (extremes 2 a 90). Treize (18 %) patients sont restes asymptomatiques et 61 (82 %) ont presente des complications, dont 46 (62,2 %) etaient severes. Neuf patients (14,8 %) sont decedes dans les 11 a 45 jours suivant la premiere erreur de dose. Par rapport aux patients asymptomatiques ou presentant des symptomes mineurs, ceux qui presentaient des symptomes severes etaient plus âges (75,6 ± 10,8 ans vs 69,5 ± 12,9 ans) et avaient ete exposes a une dose cumulee plus elevee (94,8 ± 46,2 mg contre 68,0 ± 45,7 mg). Conclusions Cette etude confirme que les erreurs de posologie du methotrexate peuvent etre fatales et persistent malgre plusieurs mises en garde des agences nationales du medicament. De nouvelles mesures sont attendues de l’Agence europeenne des medicaments.

Background Recent studies show a rapid growth among pregnant women using high potency opioids for common pain management during their pregnancy. No study has examined the duration of treatment among strong opioid users and weak opioid users during pregnancy. We aimed to investigate the prevalence of prescribed opioid use during pregnancy, in Quebec; and to compare the duration of opioid treatment between strong opioid users and weak opioid users. Methods Using the Quebec Pregnancy Cohort (1998–2015), we included all pregnancies covered by the Quebec Public Prescription Drug Insurance Program. Opioid exposure was defined as filled at least one prescription for any opioid during pregnancy or before pregnancy but with a duration that overlapped the beginning of pregnancy. Prevalence of opioids use was calculated for all pregnancies, according to pregnancy outcome, trimester of exposure, and individual opioids. The duration of opioid use during pregnancy was analyzed according to 8 categories based on cumulative duration ( Results Of 442,079 eligible pregnancies, 20,921 (4.7%) were exposed to opioids. Among pregnancies ending with deliveries (n = 249,234), 5.4% were exposed to opioids; the prevalence increased by 40.3% from 3.9% in 1998 to 5.5% in 2015, more specifically a significant increase in the second and third trimesters of pregnancy. Weak opioid, codeine was the most commonly dispensed opioid (70% of all dispensed opioids), followed by strong opioid, hydromorphone (11%), morphine (10%), and oxycodone (5%). The prevalence of codeine use decreased by 47% from 4.3% in 2005 to 2.3% in 2015, accompanied by an increased use of strong opioid, morphine (0.029 to 1.41%), hydromorphone (0.115 to 1.08%) and oxycodone (0.022 to 0.44%), from 1998 to 2015. The average durations of opioid exposure were significantly longer among pregnancies exposed to strong opioid as compared to weak opioid regardless of the cumulative duration or duration of action (P Conclusions Given the differences in the safety profile between strong opioids and the major weak opioid codeine, the increased use of strong opioids during pregnancy with longer treatment duration raises public health concerns.

The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs.The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k).Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05).Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

To identify the 10 drugs most frequently administered to children in liquid dosage forms which are eligible for replacement with suitable authorized solid dosage forms and to assess the expected economic impact of this substitution.The health record data from 312,152 oral drug administrations were analyzed. Ten drugs were selected according to their frequency of administration in liquid dosage forms, the availability of solid form alternatives, and the suitability of these alternatives for the children receiving the corresponding liquid forms. Potential hospital cost savings of the suggested substitutions were calculated.The 10 drugs identified as most frequently administered and for which suitable solid forms were available were: paracetamol, cyamemazine, valproic acid, clonazepam, furosemide, prazepam, hydroxyzine, alfacalcidol, amitriptyline, and levetiracetam. Thirty-four point six of the administrations of these drugs in liquid dosage forms could be delivered using suitable solid dosage forms without additional cost.Opportunities exist for substituting liquid dosage forms with market-available solid dosage forms suitable in size and dosage for the pediatric population.

International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.

OBJECTIVE: To analyse and report the incidence of side effects of biological agents in paediatric patients with inflammatory diseases using of real-life follow-up cohort. METHODS: In this international, observational, retrospective, multicentre study of children treated by biological agents and followed in the Juvenile Inflammatory Rheumatism (JIR) cohort (JIRcohorte) network, a Kaplan-Meier method was used to estimate the occurrence of adverse events. A Cox model was constructed to identify independent predictors of adverse events. RESULTS: Overall 813 patients totalling 3439 patients-year (PY) of biological agents were included. The main diagnosis was juvenile idiopathic arthritis (84%). A total of 222 patients (27.3%) had 419 adverse events, representing an incidence rate of 12.2 per 100 PY 95% CI [11.0; 13.4]. The overall incidence rate of serious adverse events was 3.9 per 100 PY 95% CI [3.2; 4.6]. Tocilizumab and infliximab were significantly associated with adverse events and canakinumab with serious adverse events. Univariate and multivariable analysis of adverse events and serious adverse events indicated that patients under biological agents with concomitant immunosuppressive drugs (excluding methotrexate) suffered from more of these events. CONCLUSION: This study suggests an overall an acceptable safety of biologic agents in children with inflammatory rheumatic diseases treated with biological agents. However, the concomitant prescription of immunosuppressive drugs with biological agents represents a substantial risk of adverse events. ispartof: JOINT BONE SPINE vol:86 issue:3 pages:343-350 ispartof: location:France status: published

To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose.All cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact.One hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment.Risperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose ≤0.15 mg/kg.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro

ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS).MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients.ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation.ConclusionsOur findings argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 T cell expansion.Key messagesWhat is already known about this subject ?MIS-C occurs 3-5 weeks after acute SARS-CoV2 infection and overlap features of Toxic Shock syndrome and Kawasaki disease.MIS-C appears different in term of cytokine and autoantibodies generation from KD with subtle signs of T cells activationWhat does this study add?This study demonstrates that Vβ21.3+ CD4 and CD8 T cells are highly increased in about 50% of MIS-C and distinctive of the Vβ2+ expansion observed in toxic shock syndrome in This reflects a specific T cell activation and cytokine release syndrome similar to toxic shock syndromeHow mich this impact on clinical practice or future developments?Vβ21.3+ signature can be available on a short term basis by flowcytometry and represents a signature of the MIS-C.As for TSS, immunomodulating therapies may revert the superantigenic activation and resolve this life threatening pediatric condition.

Introduction Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature children with life-threatening apnoeas receive stimulants such as methylxanthines (mainly, caffeine) or doxapram (an analeptic unlicensed in children under 15). However, these products have undesirable effects (hyperarousal, irritability, sleep disorders, tachycardia) and are not always effective because apnoea does persist in some premature newborns. Previous studies have indicated that odorant stimulation, a non-invasive intervention, may stimulate the respiratory rhythm. The objective of the present protocol is to reduce the occurrence of apnoeic episodes in premature newborns by controlled odorant stimulation added to current pharmacological treatments. Methods and analysis The project is a randomised open-label Latin-square trial with independent evaluation of the main endpoint. It will include 60 preterm neonates from two university hospital neonatal intensive care units over 2 years (2021–2023). Each newborn will receive no (S0), sham (S1) or real olfactory stimulation (S2) in random order. During S2, three distinct odorants (mint, grapefruit and vanilla) will be delivered successively, in puffs, over 24 hours. Mint and grapefruit odours stimulate the main and the trigeminal olfactory pathways, whereas vanilla odour stimulates only the main olfactory pathway. A statistical analysis will compare the incidence of apnoeic episodes during S1 versus S2 using a mixed effects Poisson model. Ethics and dissemination Ethical approval was obtained from the Comité de Protection des Personnes Île-de-France XI (# 2017-AO13-50-53). The results will be disseminated through various scientific meetings, specialised peer-reviewed journals and, whenever possible, posted on appropriate public websites. Trial registration number NCT02851979; Pre-results.

Background Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source. Methods Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998–2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations. Results Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11–3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31–1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01–4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41–2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25–4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00–1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51–4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02–2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02–1.19; 747 exposed cases) exposures were associated with MCM. Conclusions Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.

Summary Introduction To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. Methods In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients’ electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. Strength and limitations of this study For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

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; INTRODUCTION: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. METHODS: Patients with confirmed NC, aged \textgreater 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. RESULTS: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m(2)/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients \textgreater 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine. CONCLUSION: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are medications that are frequently used by athletes. There may also be some abuse of these substances, although it is unclear whether NSAIDs in fact enhance performance. We performed a systematic review and meta-analysis to evaluate the effect of NSAIDs on sport performance indices. Methods We selected randomized trials from the PubMed and Cochrane Library databases investigating the effects of NSAIDs on sport performance. Volunteers could be healthy adult men and women. Any NSAID, administered by any route, taken prior to any type of exercise, and for any duration could be used. The control intervention could be a placebo, an active substance, or no intervention. We included double-blind, single-blind, and open-label studies. The primary outcome was the maximum performance in exercises as defined in each study. The secondary outcomes were the time until self-reported exhaustion and the self-reported pain. Results Among 1631 records, we retained thirteen parallel-group and ten crossover studies, totaling 366 and 148 subjects, respectively. They were disparate regarding treatments, dose and duration, and the type of exercise. There was neither significant difference in the maximum performance between NSAIDs and control groups nor in the time until exhaustion nor in self-perceived pain. Conclusions The existence of an ergogenic effect of NSAIDs on sport performance indices was unable to be concluded, since the level of evidence of the studies is low, the doses tested, and the exercises performed are very heterogeneous and far from those observed in real-life practices. More studies are required.

Summary Background Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE. Methods For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium. Findings After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10−11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution. Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity. Funding European Research Council.

International audience; Background and objectives: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed.Methods: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI‐Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S‐desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk‐to‐plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation.Results: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight‐adjusted maternal SCIT dose on average.Conclusion: The moderate between‐subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants

International audience; Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required. In this article, we provide an overview of a successful collaboration in nephropathic cystinosis (NC), focusing on what was the key of success, the interactions between academics, the pharmaceutical company and patients organizations. NC is considered as a very rare disease. In 2010, a new formulation of cysteamine, the only available treatment to improve renal outcome of the disease, was proposed by a small American company. Studies were implemented in France under the coordination of an expert of the disease and the clinical investigation center of Lyon. The collaboration resulted in a good recruitment and retention of the patients in the study and most of all in the availability of the new formulation in France. Patients could have facilitated the research by being involved in the early stages of the studies. Involving patients and public early in the process is particularly important in rare diseases as the patient is a great source of knowledge and has his own expectations. Priorities of research, design, conduct and reporting of clinical trials can be defined in collaboration with adults but also with young patients or public, the first concerned in rare diseases. This concept is still to be developed and improved especially with paediatric patients.

Background and objectivesIdentifying virilisation of the genitalia in female newborns early during the neonatal period is important to diagnose pathologies. However, there is no clear threshold for clitoromegaly or for the anogenital ratio. The objective of this study was to define reference values for the external genitalia of full-term and pre-term female neonates.DesignThis was a prospective study of all females born in the study centre between May 2014 and July 2016. Clitoral length and anogenital ratio were measured in 619 newborns with a gestational age of 24+2 to 41+3 weeks during their first 3 days of life. Associations between the values at day 3 and gestational age, birth weight and other newborn characteristics were examined by linear regression.ResultsThe mean clitoral length at day 3 of life was 3.69±1.53 mm (n=551; 95th percentile, 6.5 mm; maximum, 8 mm), and the mean anogenital ratio was 0.42±0.09 (95th percentile, 0.58). There was no significant variation with gestational age or birth weight, and no significant difference between the results at day 0 and day 3.ConclusionThese results suggest that clitoromegaly can be defined as a clitoral length >6.5 mm. Values ≥8 mm should prompt further investigations. An anogenital ratio >0.6 should be considered a sign of virilisation. Since clitoral size does not vary with gestational age or birth weight, clitoromegaly should not be attributed to prematurity.

Mineral and bone disorders associated to chronic kidney disease (CKD-MBD) are a daily challenge for pediatric nephrologists, with a significant risk of long-term bone and vascular comorbidities. This single-center study is a prospective transversal evaluation of pediatric CKD patients of our center, part of the European 4C study. In addition to clinical and biochemical data, vascular and bone evaluation was performed: 24-h blood pressure assessment, carotid intima-media thickness (cIMT), pulse wave velocity (PWV), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the ultra-distal tibia. Results are presented as median (range). At a median age of 12.9 years (10.2–17.9), SDS height of − 1.0 (− 3.3–1.2) and estimated glomerular filtration rate (eGFR) of 33 mL/min/1.73m2 (11–72), 32 patients (8 girls) were evaluated. Median calcium, phosphate, parathyroid hormone (PTH), and 25 OHD3 levels were 2.44 mmol/L (2.24–2.78), 1.43 mmol/L (1.0–2.7), 80 pg/mL (9–359), and 70 nmol/L (32–116), respectively. Bivariate Spearman and backward multivariable analyses showed that calcium and bone trabecular thickness (Tb.Th), were positively associated with diastolic and mean arterial blood pressure (both for the 24 h, day and night assessment), whereas PTH and vitamin D did not predict blood pressure. We show that the greater the serum levels of calcium, the greater the (diastolic and mean) blood pressure; moreover, the greater the Tb. Th, the greater the (diastolic and mean) blood pressure. The role of calcium supplements to explain such findings in early pediatric CKD can be discussed.

Children and young people are seen as fundamental to the design and delivery of clinical research as active and reflective participants. In Europe, involvement of children and young people in clinical research is promoted extensively in order to engage young people in research as partners and to give them a voice to raise their own issues or opinions and for their involvement in planning and decision making in addition to learning research skills. Children and young people can be trained in clinical research through participation in young person advisory groups (YPAGs). Members of YPAGs assist other children and young people to learn about clinical research and share their experience and point of view with researchers, thereby possibly influencing all phases of research including the development and prioritization of research questions, design and methods, recruitment plans, and strategies for results dissemination. In the long term, the expansion of YPAGs in Europe will serve as a driving force for refining pediatric clinical research. It will help in a better definition of research projects according to the patients' needs. Furthermore, direct engagement of children and young people in research will be favorable to both researchers and young people.

ObjectiveTo evaluate research priority setting approaches in childhood chronic diseases and to describe the priorities of stakeholders including patients, caregivers/families and health professionals.DesignWe conducted a systematic review of MEDLINE, Embase, PsycINFO and CINAHL from inception to 16 October 2016. Studies that elicited stakeholder priorities for paediatric chronic disease research were eligible for inclusion. Data on the prioritisation process were extracted using an appraisal checklist. Generated priorities were collated into common topic areas.ResultsWe identified 83 studies (n=15 722). Twenty (24%) studies involved parents/caregivers and four (5%) children. The top three health areas were cancer (11%), neurology (8%) and endocrine/metabolism (8%). Priority topic areas were treatment (78%), disease trajectory (48%), quality of life/psychosocial impact (48%), disease onset/prevention (43%), knowledge/self-management (33%), prevalence (30%), diagnostic methods (28%), access to healthcare (25%) and transition to adulthood (12%). The methods included workshops, Delphi techniques, surveys and focus groups/interviews. Specific methods for collecting and prioritising research topics were described in only 60% of studies. Most reviewed studies were conducted in high-income nations.ConclusionsResearch priority setting activities in paediatric chronic disease cover many discipline areas and have elicited a broad range of topics. However, child/caregiver involvement is uncommon, and the methods often lack clarity. A systematic and explicit process that involves patients and families in partnership may help to inform a more patient and family-relevant research agenda in paediatric chronic disease.

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.

Resume Les prescriptions hors- ou sans autorisation de mise sur le marche (AMM) sont communes en services de pediatrie, particulierement pour les antibiotiques. Il n’a pas ete evalue si ces strategies de prescriptions hors ou sans AMM etaient justifiees par des essais randomises comparatifs de bonne qualite. Objectif Le but de cette etude etait de comparer le niveau de preuve d’efficacite des prescriptions d’antibiotiques hors/sans AMM avec celles qui respectaient l’AMM dans un hopital pediatrique. Notre hypothese etait que les prescriptions d’antibiotiques hors/sans AMM avaient un moins bon niveau de preuve d’efficacite que celles avec AMM. Methode Cette etude observationnelle evaluait les prescriptions d’antibiotiques a l’hopital femme-mere-enfant des hospices civils de Lyon. Chaque prescription a ete classee selon le type d’autorisation de mise sur le marche (avec, hors ou sans AMM) et selon son niveau de preuve disponible dans la litterature (preuves d’efficacite, preuves insuffisantes ou absence de preuve). Elles ont egalement ete classees selon qu’il existait ou non des essais randomises comparatifs, quelle que soit la qualite des essais. Les donnees ont ete collectees a partir des dossiers medicaux informatises des patients. Resultats Cent huit prescriptions ont ete identifiees, correspondant a 72 mono, bi ou triantibiotherapies, administrees a 62 patients. Aucune prescription n’etait sans AMM, 34 % (n = 37) etaient horsAMM et 66 % (n = 71) respectaient l’AMM. Trente-deux prescriptions atypiques n’ont pas ete analysees. Sur les 76 prescriptions, faisant l’objet d’une revue de la litterature, 36 etaient justifiees par des essais randomises : les prescriptions avec AMM (32/51) etaient significativement plus souvent justifiees par des essais randomises que les prescriptions horsAMM (4/25). Cependant, aucune prescription, avec ou horsAMM, ne remplissait les criteres de « preuve d’efficacite » avec deux essais randomises concluant de bonne qualite. Discussion Sur la base de cet echantillon de petite taille, nous avons montre qu’il n’existait pas d’essais randomises de bonne qualite justifiant les prescriptions d’antibiotiques dans les services de pediatrie, quel que soit leur statut vis-a-vis de l’AMM. Les prescriptions avec AMM sont mieux justifiees par des essais randomises que celles hors/sans AMM. Les prescriptions etaient en accord avec les recommandations actuelles si des recommandations existaient. Il manque des essais randomises en infectiologie pediatrique pour etablir des recommandations basees sur des preuves de bonne qualite.

To construct a sudden death risk score specifically for hypertension (HYSUD) patients with or without cardiovascular history.Data were collected from six randomized controlled trials of antihypertensive treatments with 8044 women and 17 604 men differing in age ranges and blood pressure eligibility criteria. In total, 345 sudden deaths (1.35%) occurred during a mean follow-up of 5.16 years. Risk factors of sudden death were examined using a multivariable Cox proportional hazards model adjusted on trials. The model was transformed to an integer system, with points added for each factor according to its association with sudden death risk.Antihypertensive treatment was not associated with a reduction of the sudden death risk and had no interaction with other factors, allowing model development on both treatment and placebo groups. A risk score of sudden death in 5 years was built with seven significant risk factors: age, sex, SBP, serum total cholesterol, cigarette smoking, diabetes, and history of myocardial infarction. In terms of discrimination performance, HYSUD model was adequate with areas under the receiver operating characteristic curve of 77.74% (confidence interval 95%, 74.13-81.35) for the derivation set, of 77.46% (74.09-80.83) for the validation set, and of 79.17% (75.94-82.40) for the whole population.Our work provides a simple risk-scoring system for sudden death prediction in hypertension, using individual data from six randomized controlled trials of antihypertensive treatments. HYSUD score could help assessing a hypertensive individual's risk of sudden death and optimizing preventive therapeutic strategies for these patients.

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.

International audience; Objective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.

Respiratory syncytial virus (RSV) infections may worsen cystic fibrosis (CF) lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. We aimed to determine the effectiveness of PVZ on microbiological outcomes in young children with CF. We conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140). One case was matched with at least three same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8-32.6] months) and PVZ+ (10.4 [1.2-33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0-59.0] months; PVZ-: 3.8 [0.1-74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40% vs. PVZ- 41.4%), but this proportion was higher for Sa in the PVZ+ group (97%) than in the PVZ- group (85%; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups.Systematic PVZ use did not delay key pathogen acquisition in young children with CF. What is known: • Palivizumab is the only available monoclonal antibody against respiratory syncytial virus infection. • Whether or not it is useful in infants with cystic fibrosis remains controversial. What is new: • Palivizumab does not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with cystic fibrosis. • Palivizumab does not reduce healthcare consumption or improve growth during the first 3 years of life of young children with cystic fibrosis.