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Abstract Background Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. Methods The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. Discussion This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. Trial registration ClinicalTrials.gov NCT02384876 . Registered on March 2015.

Introduction Mental health regional differences during pregnancy through the COVID-19 pandemic is understudied. Objectives We aimed to quantify the impact of the COVID-19 pandemic on maternal mental health during pregnancy. Methods A cohort study with a web-based recruitment strategy and electronic data collection was initiated in 06/2020. Although Canadian women, >18 years were primarily targeted, pregnant women worldwide were eligible. The current analysis includes data on women enrolled 06/2020-11/2020. Self-reported data included mental health measures (Edinburgh Perinatal Depression Scale (EPDS), Generalized Anxiety Disorders (GAD-7)), stress. We compared maternal mental health stratifying on country/continents of residence, and identified determinants of mental health using multivariable regression models. Results Of 2,109 pregnant women recruited, 1,932 were from Canada, 48 the United States (US), 73 Europe, 35 Africa, and 21 Asia/Oceania. Mean depressive symptom scores were lower in Canada (EPDS 8.2, SD 5.2) compared to the US (EPDS 10.5, SD 4.8) and Europe (EPDS 10.4, SD 6.5) (p

Introduction For populations with intellectual disability and autism spectrum disorder, it is essential to complete cognitive assessment with an adaptive behavior scale. Objectives To translate VABS-II from English to French and establish norms for the French population. Methods We used the Parent/Caregiver form in order to assess psychometric characteristics of the VABS-II and to develop norms for the French population. VABS-II comprises 4 domains, 11 subdomains, and an optional maladaptive behavior index. The French translation of the VABS-II followed standard cross-cultural translation methods. The study was performed in the Rhône-Alpes-Auvergne department comprising 12 % of France inhabitants and well representing the French general population. Results From 4576 VABS-II questionnaires distributed, 1707 were returned and 1654 were analyzed. The reason for exclusion was the impossibility to score one of the subdomains. From 174 questionnaires included in the test-retest, 95 were analyzed, and 79 questionnaires were excluded because 86 under 34 days, 8 > 3 months, and one participant that changed age group between test and retest. Scores based on French norms fluctuated around values based on US norms on all subdomains. Conclusions The French Vineland questionnaire is the single test with the adequate norms to allow identifying children with adaptive behavior difficulties. It should be used as a complement of the assessment of the intellectual quotient, according to DSM V, for the diagnosis of intellectual disabilities. It must be done in reference to the developmental and cultural standards specific to the environment in which the person is evolving. Disclosure No significant relationships.

Introduction There is a lack of objective evaluation with validated tools in school children with intellectual disability (ID). Standardized and validated tools, allowing children evaluations and follow-up, exist but are poorly used. Our action-study wishes to develop evaluation practices to better adapt to the specific needs of children with ID. Objectives We evaluated the multidimensional profiles (cognitive, adaptative and behavioral) of children with ID attending regular or adapted school system. Methods School children, aged 5 to 13 years old, with mild to moderate ID were enrolled in this French cohort study. The multidimensional evaluation consisted of a school evaluation grid proposed by the French educational system, a scale of school needs (GEVA-sco), an intellectual assessment (WISC IV), a behavior adaptative scale (Vineland II) and a behavior rating scale (the French Nisonger Child Behavior Rating Form (Nisonger CBRF)). The results of this multidimensional assessment were analyzed. Results Between November 2014 and June 2016, 121 children were enrolled, 3 children were lost to follow-up. Analysis was performed on 118 children. Seventy one (60.2 %) were male. Fifty-two (44.1%) were aged 6 to 9 years. Sixty-eight (57.6%) children were in regular schools and 50 (42.4%) in adapted schools. Children in regular schools had a higher mean IQ score (57.5) than children in adapted schools (43.5). The adaptative behavior profile of children in regular school is less severe than in children in adapted schools. Conclusions Multidimensional evaluations allow optimizing and personalizing support. Evaluation of adaptative behavior is more informative than cognitive profile which does not differentiate between children skills Disclosure No significant relationships.

Introduction Early screening of children at-risk to develop Autism Spectrum Disorder (ASD) needs to be improved to propose early interventions. This detection should allow diagnosis of ASD before the age of 3. An early screening performed at the general practitioner of the family should facilitate accessibility to diagnosis and a better collaboration between professionals. Objectives Our primary objective is to estimate the positive predictive value of an early detection kit composed of 2 questionnaires (First screening: M-CHAT-R/F™ + CSBS DP™-ITC) and a confirmation of the detection with a phone call by a neuropsychologist. Patients with confirmed positive M-CHAT-R/F™ and/or CSBS DP™-ITC scores are referred to a level 2 team for pre-diagnosis and diagnosis assessment. Methods The KitCAT study is a cohort study of 1,700 children aged 16 to 24 months seen in routine care in general or pediatric practices, or in nurseries and child care centers. Results Seven hundred and five children have already been enrolled in the study. Twenty nine patients, ie 4.1%, (with a confirmed positive M-CHAT-R/F™ and/or CSBS DP™-ITC scores) were referred to a level 2 team where a pre-diagnosis assessment was conducted by using the following test: ADI-R, ADOS 2, BLR, WPPSI-IV and Vineland II. The diagnosis of ASD (using the same test than the pre-diagnosis) was confirmed for the first two patients aged of 3. Conclusions The preliminary results confirm that the use of 2 questionnaires may optimize the reliability of the screening. A thousand children are still needed for the final analysis and further results are expected. Disclosure No significant relationships.

Background and Purpose: Disabling dystonia despite optimal medical treatment is common in Wilson disease (WD). No controlled study has evaluated the effect of deep brain stimulation (DBS) on dystonia related to WD. This study was undertaken to evaluate the efficacy of DBS on dystonia related to WD., Methods: A meta-analysis of an N-of-1 prospective, randomized, double-blind, multicenter DBS study was conducted at two French WD reference centers. Main inclusion criteria were patients with WD, stabilized for at least 6 months with significant disability due to dystonia despite optimized medical treatment. The subthalamic nucleus (STN) was targeted for bradykinetic patients with tonic dystonia, and the internal globus pallidus (GPi) was chosen for patients with hyperkinetic dystonia. Each patient underwent two periods of DBS "on" and two periods of DBS "off," each lasting 4 months. The order of stimulation conditions was randomized. The primary outcome was the change in the Canadian Occupational Performance Measure Performance (COPM-P) and Satisfaction scores after each 4-month period. Secondary outcomes were changes in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores and Unified Wilson's Disease Rating Scale (UWDRS) scores., Results: Between 12 May 2016 and 7 October 2022, three patients were included. Two patients received bilateral GPi DBS, and one received bilateral STN DBS. There was no change of COPM-P (p = 0.956), BFMDRS, and UWDRS scores. No serious adverse events were reported., Conclusions: STN or GPi DBS are ineffective on dystonia related to WD., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: To describe the PHAGEinLYON Clinic programme, set up in 2022 to improve access to phage therapy in France using pharmaceutical-grade phages., Methods: All phage therapy requests received during 2022 were collected prospectively, and reviewed retrospectively to analyse the decision and the patient care pathway (NCT05883995)., Results: Of 143 requests for phage therapy, the indication was confirmed at a multidisciplinary team meeting for 57 (40%) patients. Forty-four patients were infected with bacteria that could be targeted easily by phages in France. Finally, 33 patients were treated, including 26 at the study institution, through a compassionate access programme or in a clinical trial. The main indication were complex bone and joint infections, endovascular infection and lung infection. In order to manage these patients, 172 pharmaceutical phage cocktails targeting Staphylococcus aureus and/or Pseudomonas aeruginosa were prepared: 57 for local injection and 99 for intravenous injection. During follow-up, 18 (69%) patients showed a favourable clinical evolution, and six (23%) patients required subsequent phage therapy, either with the same phage with greater exposure, or with a different phage from elsewhere., Conclusions: Implementation of the PHAGEinLYON Clinic programme in 2022 was associated with groundbreaking access to phage therapy in France., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endocrine disrupting chemicals (EDCs) may impact children's health, with medicines as a possible exposure source. Objective: to assess the potential impact of substances in paediatric medications and essential oils on children as EDC. It is a systematic review of five databases including Medline following the PECOT approach. The review focused on publications about children exposed to medication (active ingredients or excipients of interest) and having developed clinical signs of endocrine dysfunction. Out of 946 studies identified, 28 studies were included. They revealed that parabens, lavender essential oils and anti-epileptics are the most identified pharmaceutical products. The reported outcomes relate to puberty, thyroid disorders, obesity and growth. The evidence indicates potential risks, but the overall quality of available data is limited. This systematic review exposes a lack of robust evidence linking paediatric medication exposure to EDC, predominantly relying on case reports. It cautions about potential conflicts of interest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Toxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent efficacy and safety data are needed. Our objective was to determine whether a randomised clinical trial (RCT) assessing intravenous IG in TSS in children is feasible., Methods: We performed a multicentre, feasibility, double-blind RCT assessing efficacy of high-dose intravenous IG versus albumin 4% (control group) within the first 12 hours of shock onset. Included patients were aged above 1 month and below 18 years with suspected TSS and septic shock. Feasibility was assessed by measuring inclusion rate, protocol compliance and missing data regarding death and the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) Score. Other secondary clinical outcomes were evaluated during hospital stay, at 60 day and 1 year., Results: 28 patients, admitted in 6 paediatric intensive care units during 36 consecutive months and followed for 1 year, received the allocated treatment: 13 in intravenous IG group, 15 in control group. The median age was 10.6 years and the sex ratio was 1. Inclusion rate was above 50%, protocol deviations were below 30% and missing data regarding death and PELOD-2 Score below 10%. No difference concerning secondary clinical outcomes between groups was observed, and more adverse events were reported in the control group., Conclusion: It seems to be feasible to conduct an RCT assessing intravenous IG efficacy and safety in paediatric TSS but must be realised internationally, with choice of a clinically relevant endpoint and a specific design in order to be realistic., Trial Registration Number: NCT02219165., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Endocrine disruptors (ED) are ubiquitous pollutants, possibly implicated in chronic disease. Exposure of vulnerable populations; including neonates, infants and children; must therefore be limited. Informing parents is now a public health challenge. We conducted a quantitative cross-sectional study at the Lyon Mother and child Hospital. We used questionnaires to assess the beliefs and knowledge about ED of parents and pediatric healthcare professionals in the pediatric ward in Lyon, France. A total of 746 questionnaires were completed: 444 for professionals and 302 for parents. The majority of both populations had already heard of ED but only 10% of parents and 5% of professionals felt sufficiently informed. Professionals answered better than parents (73% vs. 60%). The main source of information was similar: media. Only 20% of professionals had read a scientific article about ED and 4% have followed a training. Environmental exposure and EDs is an increasing concern for parents but specific knowledge remains scare for parents and professionals. Specific training is needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Portefaix, Loppinet, Tourvieilhe, Balice, de Veron de La Combe, Kassai and Bacchetta.)

We encountered a case of mushroom intoxication complicated by "toxic-like" myocarditis. Because of the lack of systematized knowledge on this subject, we performed a systematic review of the literature on cardiac toxicity in mushroom poisoning (MP). The aim of this study was to identify and describe the severity, the causal relationship, and the mushroom species involved in other reported cardiac events associated with MP. We included 39 studies in our review. We found 106 cases of cardiac events associated with MP, including 18 deaths. A wide variety of cardiac manifestations were reported, ranging from the simple elevation of cardiac enzymes (n = 61) to ventricular tachycardia (n = 14), acute heart failure (n = 18), and myocarditis (n = 7). Causal relationship between cardiac manifestations and mushroom poisoning was assessed for 42 patients, applying the algorithm validated by the French Toxicovigilance Coordination Committee. Twenty-three cases (54.8%) had a "possible" causal relationship, eight cases (19%) a "probable" relationship, and ten cases (23.8%) a "very probable" relationship. Several fungal genera were involved in reported cases, including Amanita but also rarer ones like Russula and Tricholoma . In conclusion, we showed that cases of cardiac toxicity following MP have been documented in the existing literature, and for some of them, we assessed a strong causal relationship.

Purpose: MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results., Patients and Methods: Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification., Results: Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15)., Conclusions: Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors., Competing Interests: Conflicts of interest and sources of funding: The authors have no conflicts of interest to declare. P.-A.B. received funding from the Hospices Civils de Lyon Foundation, Banque Populaire AURA, and the Flavien Foundation for their financial support., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials., Methods: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software., Results: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence., Discussion: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials., Trial Registration Information: ANSM Registration Number 2010-A00327-32.

Background: Attention-deficit hyperactivity disorder (ADHD) is a frequent comorbidity in children with epilepsy, which management mostly relies on the usual treatments of ADHD, especially methylphenidate. Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed as an alternative therapeutic approach in ADHD without epilepsy but has never been evaluated in epilepsy-associated ADHD., Methods: A multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA, in eicosapentaenoic- and docosahexaenoic-acid form, conjugated to a phospholipid vector (PS-Omega3) in children aged >6 and <16-years old, and suffering from any type of epilepsy and ADHD (inattentive or combined type) according to DSM-V. After a 4-week baseline period, patients were allocated (1:1) either to placebo group or to PS-Omega 3 group and entered a 12 week-double-blind treatment period which was followed by a 12 week-open-label treatment period. The primary outcome was the reduction of the ADHD-rating scale IV attention-deficit subscore after 12 weeks of treatment., Results: The study was stopped early because of lack of eligible participants and the expected sample size was not reached. Seventy-four patients were randomized, 44 in PS-Omega3, and 30 in the placebo group. The reduction after 12 weeks of treatment in the inattention subscore of the ADHD-IV scale was -1.57 in the PS-Omega3 group, and -2.90 in the placebo group (p = 0.33, α = 5%). Results were similar after 24 weeks of treatment and for all other ADHD-related secondary outcomes, with no difference between placebo and PS-Omega3., Conclusion: Our study remaining underpowered, no formal conclusion about the effect of Ps-Omega3 could be drawn. However, our data strongly suggested that the PS-Omega 3 formulation used in the current study did not improve ADHD symptoms in children with epilepsy., Plain Language Summary: Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed in ADHD but has never been evaluated in patients with both epilepsy and ADHD. To address this issue, we conducted a multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA in children with epilepsy and ADHD. The study was stopped early because of lack of eligible participants, hampering formal conclusion. However, the evolution of the ADHD symptoms at 12 and 24 weeks did not differ between placebo and PUFA supplementation, strongly suggesting that PUFA did not improve ADHD symptoms in children with epilepsy., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Unlicensed and off-label (UL/OL) prescriptions have been associated with an increased risk of drug-related problems. Data of their prevalence at hospital discharge remain insufficient. We aimed to describe the prevalence of UL/OL drugs in outpatient prescriptions at discharge in children., Methods: We conducted a retrospective study using the routinely collected health data of children at discharge from 2014 to 2016. The primary reference source for determining licensed labelling was the summaries of product characteristics (SPCs) in a French industry-independent formulary named Thériaque. We described the characteristics of UL/OL prescriptions at discharge and looked for predictors of UL/OL prescriptions., Results: We included 2536 prescriptions of 479 children. Licensed, OL, and UL prescriptions accounted for 58.6% (95% CI: 56.7-60.5), 39.2% (95% CI: 37.3-41.1), and 2.3% (95% CI: 1.7-2.9), respectively. A total of 323 (74%) children received at least one UL/OL drug. Among the licensed drugs, bronchodilators (8.8%) and analgesics (8.6%), and among the OL drugs, antibiotics (2.8%), were the most prescribed. The younger age of the children and higher number of drugs they received increased the probability of UL/OL prescriptions (unadjusted p -value of ≤0.05)., Conclusion: The prevalence of UL/OL prescriptions is about 40% at discharge from a pediatric university hospital in France.

Background: This study aimed to collect obstetric anesthesia practice and patient-reported outcomes as an update to the last French Obstetric Anesthesia survey from 1996., Methods: Maternity units were randomly selected across France and surveyed for 7 consecutive days from February, 2016, to January, 2017. Data was gathered prospectively by questionnaires filled out by patients and anesthesia providers., Results: There were 1885 questionnaires received from 56 units, with 379 cesarean delivery (CD) and 1506 vaginal delivery (VD) cases analyzed. The overall neuraxial labor analgesia (NLA) rate was 82.5% (95% CI [82.4-82.6]), with 70.3% (95% CI [71.4-71.6]) receiving automated administration (PCEA/PIEB). NLA was effective throughout labor in 68.2% of cases, however, severe pain was reported by 29.4% of patients. The overall rate of alternative approaches for labor analgesia was 19.5% (95%CI [19.2-19.7]). Obesity (OR 2.8; 95% CI [1.0-7.5], p < 0.04) and delivery in level I units (OR 0.6; 95% CI [0.5-0.9], p < 0.01) were associated with severe pain during VD. Satisfaction was found to be similar in patients delivering with or without NLA. The incidence of pain during CD was similar in scheduled versus non-scheduled CD. Failure of NLA during CD was associated with severe pain (OR 10.0; 95% CI [3.1-31.9], p < 0.01) and dissatisfaction (OR 26.2; 95% CI [3.0-225.1], p < 0.01)., Conclusion: Despite the high NLA rate in France, a significant proportion of women experience severe pain during labor and delivery. This study emphasizes the need for further practice guidelines in obstetric anesthesia to ensure optimal pain management and improve patients' experience during childbirth., Clinicaltrials: govNCT02853890., (Copyright © 2023. Published by Elsevier Masson SAS.)

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 randomised 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 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 evaluation 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 categorized in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting RCTs and their meta-analysis to produce quality data for general practitioners to focus on risk-benefit assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: 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., Objective: We aimed to summarize the impact of DRPs at and after hospital discharge on the risk of readmissions in children with chronic diseases., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

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.

Aims: 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)., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Aim of the Study: 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., Methods: 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., Results: 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., Conclusion: Opportunities exist for substituting liquid dosage forms with market-available solid dosage forms suitable in size and dosage for the pediatric population., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background and Purpose: 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., Experimental Approach: 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)., Key Results: 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)., Conclusion and Implications: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background and Aims: Intracranial Hypertension (ICH) is a life-threatening complication of brain injury. The invasive measurement of intracranial pressure (ICP) remains the gold standard to diagnose ICH. Measurement of Optic Nerve Sheath Diameter (ONSD) using ultrasonography is a non-invasive method for detecting ICH. However, data on paediatric brain injury are scarce. The aim of the study was to determine the performance of the initial ONSD measurement to predict ICH occurring in children with severe brain injury and to describe the ONSD values in a control group., Methods: In this cross-sectional study, ONSD was measured in children aged 2 months-17 years old with invasive ICP monitoring: before placement of ICP probe and within the 60 min after, and then daily during 3 days. ONSD was also measured in a control group., Results: Ninety-nine patients were included, of whom 97 were analysed, with a median (IQR) age of 8.7 [2.3-13.6] years. The median (IQR) PIM 2 score was 6.6 [4.4-9.7] and the median (IQR) PELOD score was 21 [12-22]. Aetiologies of brain injury were trauma ( n = 72), infection ( n = 17) and stroke ( n = 8). ICH occurred in 65 children. The median (IQR) ONSD was 5.58 mm [5.05-5.85]. ONSD performed poorly when it came to predicting ICH occurrence within the first 24 h (area under the curve, 0.58). There was no significant difference between the ONSD of children who presented with ICH within the first 24 h and the other children, with a median (IQR) of 5.6 mm [5.1-5.9] and 5.4 mm [4.9-5.8], respectively. Infants aged less than 2 years had a median (IQR) ONSD of 4.9 mm [4.5-5.2], significantly different from children aged more than 2 years, whose median ONSD was 5.6 mm [5.2-5.9]. Age, aetiology or ICP levels did not change the results. Thirty-one controls were included, with a median age of 3.7 (1.2-8.8) years. The median (IQR) of their ONSD measurement was 4.5 mm [4.1-4.8], significantly lower than the patient group., Conclusion: In a paediatric severe brain injury population, ONSD measurement could not predict the 24 h occurrence of ICH. Severity of patients, timing and conditions of measurements may possibly explain these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cour-Andlauer, Portefaix, Wroblewski, Rabilloud, Bordet, Cogniat, Didier, Pouyau, Valla, Kassai-Koupai, Siméon, Ginhoux, Courtil-Teyssedre and Javouhey.)

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 the mental health of women who had delivered; determinants of severe depression were identified with multivariate logistic regression models. Results: 2574 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). 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 has 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.

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., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: To 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)., Methods: The 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., Results: Three 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%)., Conclusions: Preliminary 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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 . 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., (Copyright © 2021, American Association for the Advancement of Science.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age., Methods: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia., Discussion: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old., Trial Registration: ClinicalTrials.gov NCT02384876 . Registered on March 2015.

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 > 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 > 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.