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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.)

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.

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.

Background and Objectives: Identifying 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., Design: This 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., Results: The 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., Conclusion: These 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Objective: To assess the net benefit of biological agents (BA) used in JIA., Methods: We systematically searched databases up to March 2019 for randomized controlled trials (RCT) performed in JIA disease. Separate random-effects meta-analyses were conducted for efficacy (ACR paediatric score 30%, ACRpedi30) and serious adverse events for safety. In order to standardize the baseline risk, we performed a meta-analysis of baseline risk in the control group (for both efficacy and safety meta-analysis). The net benefit was determined as the risk difference of efficacy subtracted by the risk difference of safety., Results: We included 19 trials: 11 parallel RCTs (754 patients) and 8 withdrawal RCTs (704 patients). The net benefit ranged from 2.4% (adalimumab) to 17.6% (etanercept), and from 2.4% (etanercept) to 36.7%, (abatacept) in parallel and withdrawal trials assessing non-systemic JIA, respectively. In the systemic JIA category, the net benefit ranged from 22.8% (rilonacept) to 70.3% (canakinumab), and from 32.3% (canakinumab) to 58.2% (tocilizumab) in parallel and withdrawal trials, respectively., Conclusion: The results suggest that a greater number of patients experienced therapeutic success without serious adverse events in the systemic onset JIA category compared with the BAs for non-systemic JIA categories. Baseline risk, design of trial and JIA categories impact the measure of net benefit of BAs in JIA patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Based on the 'European Child-Rare-Euro-Simulation' (CRESim) project, this article proposes a generalizable strategy utilizing datasets analysis in combination with modeling and simulation, in order to optimize the clinical drug development applied in the field of rare diseases. The global process includes: (i) the simulation of a realistic virtual population of patients (modeled from a real dataset of patients), (ii) the modeling of disease pathophysiological components and of pharmacokinetic-pharmacodynamic relations of the drug(s) of interest, (iii) the modeling of several randomized controlled clinical trials (RCTs) designs and (iv) the analysis of the results (multi-dimensional approach for RCTs durations and precision of the estimation of the treatment effect). However, whereas modeling and numerical simulation may provide supplementary tools for drug development, they cannot be considered as a substitute for RCTs performed in 'real' patients., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2020. Published by Elsevier Masson SAS.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Children with chronic kidney disease suffer from excessive cardiovascular mortality and early alterations of the cardiovascular system. Tissue doppler imaging is a validated echocardiographic tool to assess early systolic and diastolic cardiac dysfunction. We hypothesized that tissue Doppler velocities would reveal reduced cardiac function in children with chronic kidney disease compared to healthy children. A standardized echocardiographic exam was performed in 128 patients of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study aged 6-17 years with an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m 2 . Tissue Doppler measurements included early (E') and late (A') diastolic and systolic (S') velocity at the mitral and septal annulus of the left ventricle. Measured values were normalized to z-scores using published reference data. Predictors of E'/A', E/E', S' and left ventricular mass index (LVMI) were assessed by multiple linear regression analyses. Tissue Doppler E' was reduced and tissue Doppler A' increased, resulting in a reduced tissue Doppler E'/A' ratio (z-score -0.14, p < 0.0001) indicating reduced diastolic function compared to healthy children. Reduced tissue Doppler E'/A' Z-Scores were independently associated with lower eGFR (p = 0.002) and increased systolic blood pressure (p = 0.02). While E/E' Z-Scores were increased (Z-score 0.57, p < 0.0001), patients treated with pharmacological RAS blockade but not with other antihypertensive treatments had significantly lower E/E' and higher E'/A' Z-Scores. Systolic tissue Doppler velocities were significantly decreased (Z-score -0.24, p = 0.001) and inversely correlated with E/E' Z-Scores (r = -0.41, p < 0.0001). LVMI was not associated with systolic or diastolic tissue Doppler velocities. Concentric left ventricular hypertrophy showed a tendency to lower S' in multivariate analysis (p = 0.13) but no association to diastolic function. Concentric left ventricular geometry was significantly associated with lower midwall fractional shortening. In summary, systolic and diastolic function assessed by tissue Doppler is impaired. eGFR, systolic blood pressure and the type of antihypertensive medications are significant predictors of diastolic function in children with CKD. Left ventricular morphology is largely independent of tissue Doppler velocities. Tissue Doppler velocities provide sensitive information about early left ventricular dysfunction in this population.

Purpose: We described the medication use during pregnancy in the French population using the French Pregnancy Cohort (FPC)., Methods: The FPC was built with the sampling of all pregnant women included in the French Echantillon généraliste des bénéficiaires (EGB), which is a 1/97th representative sample of the population covered by the French health insurance. The EGB includes anonymized information on the socio-demographic and medical characteristics of beneficiaries, and the health care services they have received such as diagnoses and procedure codes as well as data on filled reimbursed medication; EGB also includes data on hospital stays in all public and private French health facilities. Each filled prescription record contains information on drug brand and generic names, date of prescription and date of dispensing, quantity dispensed, mode of administration, duration of prescription, dosage, and prescribing physician specialty. FPC includes data on all pregnancies of women in the EGB (2010-2013). Date of entry in the FPC is the first day of pregnancy regardless of pregnancy outcome (spontaneous abortions or planned abortions (with or without medical reasons), deliveries), and data on women are collected retrospectively for a period of one year before pregnancy, and prospectively during pregnancy, and up to one year after delivery. The prevalence of prescribed medications before, during and after pregnancy was compared; comparison was also done between trimesters. Pregnancy outcomes are described and include spontaneous and planned abortions, livebirths, and stillbirths., Results: FPC includes data on 36,065 pregnancies. Among them, 27,253 (75.6%) resulted in a delivery including 201 stillbirths (0.7%). The total number of spontaneous abortions was 6,718 (18.6%), and planned abortions 2,094 (5.8%). The prevalence of filled medication use was 91.1%, 89.9%, and 95.6% before, during and after pregnancy, respectively. Although there was a statistically significant decrease in the proportion of use once the pregnancy was diagnosed (first trimester exposure, 76.4% vs. exposure in the year prior to pregnancy, 91.1% (p < .01)), post-pregnancy medication use was above the pre-pregnancy level (95.6%). Maternal depression was the most prevalent comorbidity during pregnancy (20%), and post-partum depression was higher in those who delivered a stillborn infant (38.8%) as well as in those with a spontaneous (19.5%) or planned abortion (22.4%) compared to those with a liveborn (12.0%)., Conclusion: FPC is an excellent tool for the study of the risk and benefit of drug use during the perinatal period. FPC has the advantage of including a representative sample of French pregnant women, and study medications only available in France in addition to others available worldwide., Competing Interests: The authors have declared that no competing interests exist.

Background: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure., Methods: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups., Results: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008)., Conclusion: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome., Trials Registration: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

Objective: The objectives of this study are to carefully describe the context of methotrexate medication errors, to details medical consequences and management approaches, and to determine the rate of fatal outcome., Methods: Data on methotrexate medication errors were obtained from the French network of poison control and pharmacovigilance centres, which collected and documented reported drug-induced adverse effects. Cases were included if the intake was more than 2-fold the intended weekly dose or a weekly cumulative dose ≥ 30 mg and a follow-up of at least 4 days after the last dose. Data were analysed for demographics, treatment indication, prescribed dose, drug interactions, clinical complications and medical outcomes., Results: Seventy four patients were included. The causes of methotrexate errors resulted from an erroneous prescription renewal (23.3%), incomprehensiveness of the weekly schedule by patients or at-home caregivers (56.2%) and administration of a wrong dose by a health care professional (20.5%). Of the 70 patients who took methotrexate daily, the mean daily dose received over the whole duration of the error was 9.6 ± 4.1 mg (range 2.5-22.5) with a mean duration of the error of 11.7 ± 12.2 days (range 2 to 90). Thirteen (18%) patients remained asymptomatic and 61 (82%) developed complications of which 46 (62.2%) were severe. Nine (14.8%) patients died within 11 to 45 days after the first dosing error. Compared to patients with no or mild symptoms, those with severe symptoms were more likely to be older (75.6 ± 10.8 vs. 69.5 ± 12.9 years) and to be exposed to a higher cumulative dose (94.8 ± 46.2 vs. 68.0 ± 45.7 mg)., Conclusions: This study confirms that dosing errors with methotrexate can be lethal and persisted despite several warnings from drug agencies. Further measures are awaited from the European Medicine Agency., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose., Methods: 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., Results: 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., Conclusions: 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.

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., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Off-label drug prescribing is a public health and economic issue. The aim of this study was to describe off-label prescription in general practice in France, in terms of frequency and nature, and to identify its main determining factors., Design: Multicentre cross-sectional study SETTING: Twenty-three training general practice offices PARTICIPANTS: All the voluntary patients coming for a medical consultation or visited at home over a cumulative period of 5 days per office between November 2015 and January 2016., Methods: Eleven interns, acting as observers, collected data. Two reviewers analysed the drugs prescribed by the trainers, in order to identify those prescribed off-label in terms of their indication or the age of the patient. We used a univariate, then a multivariate model, based on hierarchical mixed-effects logistic regression., Results: Among the 4932 drug prescriptions registered, 911 (18.5%[95% CI17.4% to 19.6%]) were off-label, of which 865 (17.6%) due to the indication of the drug and 58 (1.2%) due to the age of the patient. The prescription never mentioned the off-label use, neither was the patient informed of it, as required by the French law. With the multivariate analysis, variables contributing to off-label prescription were the number of drugs (OR=1.05 for each additional drug), the initiation of new drug therapy (OR=1.26) and the non-specific goal of the prescription (OR=1.43); the age of the patient ≤14 years (OR=1.42); the rural location of the physician's practice (OR=1.38) and the low frequency of the visits of national health insurance representatives (OR=0.93)., Conclusion: Almost one out of five drugs prescribed in French general practice was off-label. It seems necessary to better train physicians in clinical pharmacology, to provide them with more effective drug prescription software, to reinforce postmarketing surveillance and to clearly define off-label use by consensus., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The objectives of this study were to describe the characteristics and natural history of beta-lactam-induced severe neutropaenia and to evaluate the risk of recurrences after another beta-lactam readministration. Reports of pure agranulocytosis associated with a beta-lactam exposure within the 10 days preceding the neutropaenia were extracted from the French Pharmacovigilance Database over the year 2010. Cases with another evident cause or more likely attributable to another drug were excluded. Data were analyzed for demographics, clinical and biological features, prognosis factors, granulocyte colony stimulating factors administration and outcome. Sixty-two cases were included (median age: 65 years). The median duration of treatment before neutropaenia was 16 days. In 47% of cases, the diagnosis was made on a systematic blood cell count. The median neutrophil count at nadir was 0.125 × 10 9 /L, and bone marrow examination evidenced features of neutrophilic maturation arrest or aplasia in 21 patients, hyperplasia of granulopoietic cells in three and normal findings in five. Three patients developed severe sepsis. All but one recovered a normal blood cell count within 2-56 days after beta-lactam discontinuation. The last patient died from recurrent severe septic shock. No significant effect of granulocyte colony stimulating factor on the mean duration of haematological recovery was found. Among the 21 patients who later received another beta-lactam, two experienced recurrence of the neutropaenia after receiving a beta-lactam from another subfamily. Beta-lactam-induced agranulocytosis was usually observed after prolonged treatment, and severe complications are uncommon. In most patients, a subsequent treatment with another beta-lactam was well tolerated., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Objective: To evaluate research priority setting approaches in childhood chronic diseases and to describe the priorities of stakeholders including patients, caregivers/families and health professionals., Design: We 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., Results: We 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., Conclusions: Research 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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: 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., Methods: 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)., Results: 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/1.73m 2 (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., Conclusions: 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.

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., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Clinical trials and inconclusive meta-analyses have investigated the effects of omega-3 supplements in children with Attention-Deficit Hyperactivity Disorder (ADHD). We performed a randomised placebo-controlled trial to evaluate the efficacy of omega-3 fatty acids., Methods: Children aged 6-15 years with established diagnosis of ADHD were randomised 1:1 to receive either supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or a placebo for 3 months. Psychotropic or omega-3-containing treatments were not authorised during the study. The primary outcome was the change in the Attention-Deficit Hyperactivity Disorder Rating Scale version 4 (ADHD-RS-IV). Other outcomes included safety, lexical level (Alouette test), attention (Test of Attentional Performance for Children-KiTAP), anxiety (48-item Conners Parent Rating Scale-Revised-CPRS-R), and depression (Children's Depression Inventory-CDI)., Results: Between 2009 and 2011, 162 children were included in five French child psychiatry centres. The mean age was 9.90 (SD 2.62) years and 78.4% were boys. The inclusion ADHD-RS-IV at was 37.31 (SD 8.40). The total ADHD-RS-IV score reduction was greater in the placebo group than in the DHA-EPA group: -19 (-26, -12)  % and -9.7 (-16.6, -2.9) %, respectively, p = 0.039. The other components of the Conners score had a similar variation but the differences between groups were not significant. Two patients in the DHA-EPA group and none in the placebo group experienced a severe adverse event (hospitalisation for worsening ADHD symptoms)., Conclusion: This study did not show any beneficial effect of omega-3 supplement in children with mild ADHD symptoms.

Objective: Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE., Methods: GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov #NCT01992666). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE (n=10) and familial SLE (n=12) - both presumed to have a strong genetic component - and other forms of early-onset SLE (n=42)., Results: The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE (P<0.05) and a lower frequency of joint manifestations in familial SLE., Conclusions: In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability., (Copyright © 2016. Published by Elsevier SAS.)

Background: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]., Methods: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries., Results: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis., Conclusions: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.

Background: A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach., Methods: A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect., Results: For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = -1.83; P < 0.001), subjective outcomes (β = -0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect., Conclusion: The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.

Background: In congenital adrenal hyperplasia (CAH), adjusting hydrocortisone dose during childhood avoids reduced adult height. However, there are currently no CAH-specific charts to monitor growth during treatment. Our objective was to elaborate growth reference charts and bone maturation data for CAH patients., Methods: We conducted a retrospective observational cohort study, in 34 French CAH centers. Patients were 496 children born 1970-1991 with genetically proven 21-hydroxylase deficiency. Their growth and bone maturation data were collected until age 18 together with adult height, puberty onset, parental height, and treatment. The mean (SD) heights were modeled from birth to adulthood. The median±1 SD and ±2 SDs model-generated curves were compared with the French references. A linear model for bone maturation and a logistic regression model for the probability of short adult height were built., Results: Growth charts were built by sex for salt wasting (SW) and simple virilizing (SV) children treated before 1 year of age. In girls and boys, growth was close to that of the general French population up to puberty onset. There was almost no pubertal spurt and the mean adult height was shorter than that of the general population in girls (-1.2 SD, 156.7 cm) and boys (-1.0 SD, 168.8 cm). Advanced bone age at 8 years had a strong impact on the risk of short adult height (OR: 4.5 per year advance)., Conclusions: The 8-year bone age is a strong predictor of adult height. It will help monitoring the growth of CAH-affected children.

The purpose of this study was to interview paediatric nurses on administration issues using extemporaneous capsules and marketed capsules and tablets in children younger than 6 years old, based on most frequently administered drugs in six participating wards. The 59 responding nurses estimated respectively at 7.7±1.7 and 7.3±1.8years the age from which children would properly swallow extemporaneous capsules and marketed solids, with 33% and 37% of nurses considering that children under 6 would not get their prescribed treatment using these dosage forms. Refusal of the child to take the solid was the first reason to explain administration failure (85% of nurses for extemporaneous capsules, 89% for marketed solids). Although type of formulation and requirement of chewing were factors influencing the age at which children would take solid from nurses' experience, size of conventional tablets was not among these factors. All respondents use to crush tablets in children unable to swallow whole solids; 37% of nurses systematically split the tablets to ease the swallowing in children able to swallow. Only 11 nurses had an information tool at their disposal to guide manipulation of solids, with 7 of them using it in their daily practice. Providing specific-ward questionnaires, this study gives factual information on administration practices, perceptions and issues faced by paediatric nurses., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate., Methods: We conducted a multicenter prospective observational study that included children, aged 6-16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12-16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV., Results: One hundred sixty-seven patients were included, of which 91 were seizure-free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale-IV total score was 30.4 ± (standard deviation) 9.2, the inattentive subscore was 17.3 ± 4.4, and the hyperactive subscore was 13.2 ± 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated ≥25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables., Significance: We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objective: Attention deficit hyperactivity disorder (ADHD) is a well-known comorbidity in children with epilepsy. In English-speaking countries, the scores of the original ADHD-rating scale IV are currently used as main outcomes in various clinical trials in children with epilepsy. In French-speaking countries, several French versions are in use though none has been fully validated yet. We sought here for a partial validation of a French version of the ADHD-RS IV regarding construct validity, internal consistency (i.e., scale reliability), item reliability, and responsiveness in a group of French children with ADHD and epilepsy., Method: The study involved 167 children aged 6-15years in 10 French neuropediatric units. The factorial structure and item reliability were assessed with a confirmatory factorial analysis for ordered categorical variables. The dimensions' internal consistency was assessed with Guttman's lambda 6 coefficient. The responsiveness was assessed by the change in score under methylphenidate and in comparison with a control group., Results: The results confirmed the original two-dimensional factorial structure (inattention, hyperactivity/impulsivity) and showed a satisfactory reliability of most items, a good dimension internal consistency, and a good responsiveness of the total score and the two subscores., Conclusion: The studied French version of the ADHD-RS IV is thus validated regarding construct validity, reliability, and responsiveness. It can now be used in French-speaking countries in clinical trials of treatments involving children with ADHD and epilepsy. The full validation requires further investigations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Selecting the most appropriate dosage form, that ensures safe administration and adherence of medications, is a major issue for children. Marketed drugs, however, have rarely been tested for their use in children. There is a need for more data on drug formulations administered to children to identify unmet needs, and drive future paediatric research. We observed, over a 12-month follow-up, 117,665 oral drug administrations to 1998 hospitalized children. Nine-tenths belonged to five Anatomical Therapeutic Chemical classes: Alimentary tract & metabolism, Nervous system, Cardiovascular system, Anti-infectives for systemic use and Blood & blood forming organs, one third of drug doses administered to school-age children and adolescents were liquids, and extemporaneous capsules were commonly used in younger children. Our study shows that despite the advantages of solid dosage forms and recent evidence from randomized controlled trials showing their acceptability in infants, they are seldom used in paediatric practice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials., Objective: We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients., Methods: We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2)., Results: Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups., Conclusion: We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.

Objectives: The main objective of our work was to compare different randomized clinical trial (RCT) experimental designs in terms of power, accuracy of the estimation of treatment effect, and number of patients receiving active treatment using in silico simulations., Study Design and Setting: A virtual population of patients was simulated and randomized in potential clinical trials. Treatment effect was modeled using a dose-effect relation for quantitative or qualitative outcomes. Different experimental designs were considered, and performances between designs were compared. One thousand clinical trials were simulated for each design based on an example of modeled disease., Results: According to simulation results, the number of patients needed to reach 80% power was 50 for crossover, 60 for parallel or randomized withdrawal, 65 for drop the loser (DL), and 70 for early escape or play the winner (PW). For a given sample size, each design had its own advantage: low duration (parallel, early escape), high statistical power and precision (crossover), and higher number of patients receiving the active treatment (PW and DL)., Conclusion: Our approach can help to identify the best experimental design, population, and outcome for future RCTs. This may be particularly useful for drug development in rare diseases, theragnostic approaches, or personalized medicine., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Our main objective was to see whether the therapeutic benefit observed in placebo controlled randomized controlled trials (RCTs) is different between adults and children., Study Design and Setting: We searched three electronic databases for meta-analyses that included double-blind, placebo-controlled RCTs with separate results for adults and children. The selected reviews were classified according to disease and drug used. The heterogeneity of treatment response between adults and children was measured using ratio of odds ratios (RORs)., Results: We selected 89 meta-analyses and calculated RORs for 124 drugs. Heterogeneity in the direction of the treatment effect was observed in one drug and heterogeneity in the quantity of the treatment effect for 13 drugs, indicating significantly different treatment effect in adults when compared with children. RORs were not significantly different from 1 for 110 drugs. For 36 of these drugs, the treatment effect was confirmed in both populations., Conclusion: We found different treatment benefits estimated by clinical trials performed in adults compared with those performed in children for 14 of 124 drugs. Data on dose adjustment and child age groups from RCTs were not adequately reported to investigate their influence on the treatment benefit dissimilarities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Backgrounds: Fluctuation in glycemia due to hormonal changes, growth periods, physical activity, and emotions make diabetes management difficult during adolescence. Our objective was to show that a close control of patients' self-management of diabetes by nurse-counseling could probably improve metabolic control in adolescents with type 1 diabetes., Methods: We designed a multicenter, randomized controlled, parallel group, clinical trial. Seventy seven adolescents aged 12-17 years with A1C >8% were assigned to either an intervention group (pediatrician visit every 3 months + nurse visit and phone calls) or to the control group (pediatrician visit every 3 months). The primary outcome was the evolution of the rate of A1C during the 12 months of follow-up. Secondary outcomes include patient's acceptance of the disease (evaluated by visual analog scale), the number of hypoglycemic or ketoacidosis episodes requiring hospitalization, and evaluation of A1C rate over time in each group., Results: Seventy-seven patients were enrolled by 10 clinical centers. Seventy (89.6%) completed the study, the evolution of A1C and participants satisfaction over the follow-up period was not significantly influenced by the nurse intervention., Conclusion: Nurse-led intervention to improve A1C did not show a significant benefit in adolescents with type 1 diabetes because of lack of power. Only psychological management and continuous glucose monitoring have shown, so far, a slight but significant benefit on A1C. We did not show improvements in A1C control in teenagers by nurse-led intervention., Trial Registration: Clinical Trials.gov registration number: NCT00308256, 28 March 2006.

Selecting the most appropriate oral formulation is very challenging when developing medicines for children and in routine practice. Research in pediatric pharmacology has focused on oral drug formulation, determining whether the active pharmaceutical ingredient can be successfully delivered to children. Pediatric expert committees (EMA, EuFPI) recommend that children's medicines be safe, well tolerated, easy to use (palatable and requiring minimal handling), transportable, easily produced, cost effective, commercially viable, with a minimal impact on children's life-style. Oral liquid drug formulations (OLFs: solutions, syrups, suspensions) are historically considered as the most appropriate oral formulation for children, since they are easy to swallow for younger infants and palatable for children. However, OLFs present numerous disadvantages, such as low stability, potentially toxic excipients for children, and low transportability. In the long-term, dose volume and frequency of administration might lead to non-compliance. Multiple preparation steps and volume calculations are also among risk factors for medicine errors in children. An alternative to OLFs is the conventional solid oral dosage form (OSF), such as tablets and capsules. These offer the advantages of greater stability, easy dose selection, improved transportability, and ease of storage. They also allow the modification of drug pharmacokinetic parameters, minimizing administration frequency. Finally, OSFs are less costly than OLFs, since they are easier to develop, manufacture, transport, store, and deliver. Controlled study results suggest that the use of OSFs in children would be associated with greater acceptability by children, greater preference on the part of caregivers, and higher drug compliance than OLFs. Recent controlled studies, confirming that OSFs with an acceptable size for children (mini-tablets), should shift the current paradigm of OLFs as the reference for children's oral medicine. We lack evidence on OSF acceptability in children and its influence on drug compliance, particularly with appropriate-size OSFs for children. Further investigation on oral formulation should investigate the utilisation of OSFs in young children. Few OSFs are licensed for children under 6 years of age., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background/objective: To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose., Subjects/methods: A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h., Results: Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25  g groups compared with placebo, but not in the 5 and 15  g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 -h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol., Conclusions: Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis.

Introduction: Developing orphan drugs is challenging because of their severity and the requisite for effective drugs. The small number of patients does not allow conducting adequately powered randomized controlled trials (RCTs). There is a need to develop high quality, ethically investigated, and appropriately authorized medicines, without subjecting patients to unnecessary trials., Aims and Objectives: The main aim is to develop generalizable framework for choosing the best-performing drug/endpoint/design combinations in orphan drug development using an in silico modeling and trial simulation approach. The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs., Methodological Approach: In silico phase III RCT simulation will be used to find the optimal trial design and was carried out in two steps: (i) statistical analysis of available clinical databases and (ii) integrative modeling that combines mathematical models for diseases with pharmacokinetic-pharmacodynamics models for the selected drug candidates., Conclusion: There is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines. The approach presented here offers many perspectives in clinical trial conception.

Aim: To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years., Method: Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the child's age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments., Results: Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of £5K and £8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of £238K and £410K (single institution)., Conclusion: Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules., (© 2014 The British Pharmacological Society.)