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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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamin D deficiency is frequent in pediatric nephrology. The 2017 European guidelines recommend keeping 25OH vitamin D (25-D) levels within the 75-120 nmol/L range, ideally with daily supplementation. Intermittent supplementation with D3 has also been proposed. We aimed to assess the influence of our local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months. VITATOL is a prospective single-center study performed in our tertiary unit in children and teenagers followed for chronic kidney disease (CKD), kidney transplantation, or stable chronic nephrotic syndrome with 25-D levels below 75 nmol/L. Intermittent oral cholecalciferol (100,000 IU) was administered depending on baseline vitamin D levels and body weight. The primary outcome was the change in 25-D levels between baseline and 2 months. Secondary outcomes were the evolution of the main mineral biomarkers. Thirty-seven patients were included. Two months after beginning supplementation, corresponding to a median(min-max) of 46 (14-79) days after the last dose of vitamin D, 25-D levels increased from 50 to 76 nmol/L (p 0.001), 18 patients having 25-D levels within the target range and 2 above. All patients displayed 25-D levels above 50 nmol/L. There were no significant changes in phosphate, PTH, alkaline phosphatase, and FGF23 levels before and after supplementation. Calcium levels increased from 2.39 to 2.44 mmol/L (p = 0.017), but no differences in calciuria and urinary calcium/creatinine ratio were observed.Conclusion: This vitamin D supplementation protocol using intermittent moderate doses of cholecalciferol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria. What is Known: • Vitamin D deficiency is frequent in pediatric nephrology. • The 2017 European guidelines recommend keeping 25OH vitamin D levels within the 75-120 nmol/L range ideally with daily supplementation, but intermittent supplementation with D3 has also been proposed. What is New: • We assessed the influence of a local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months in children and teenagers followed in pediatric nephrology. • The intermittent cholecalciferol supplementation protocol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria.

Objective To describe pain assessment, the pattern of analgesic and sedative drug use, and adverse drug reactions in a neonatal intensive care unit (NICU) during the postsurgery phase. Method Demographic characteristics, pain scores, and drug use were extracted and analyzed from electronic patient medical files for infants after surgery, admitted consecutively between January 2012 and June 2013. Result One hundred and sixty-eight infants were included. Acute (DAN score) and prolonged (EDIN score) pain assessment scores were used in 79% and 64% of infants, respectively, on the 1st day. This percentage decreased over the 7 days following surgery. The weekly average scores postsurgery were 2/15 (±2.2) for the EDIN score and 1.6/10 (±2.0) for the DAN score. The rates of pain control were 88% for the EDIN and 72% for the DAN. The most prescribed opiate drug was fentanyl (98 patients; 58%) with an average dose of 1.8 (±0.6) μg/kg/h. Midazolam was used in 95 patients (56%), with an average dose of 35 (±14) μg/kg/h. A bolus was administered in 7% (±7.4) of the total dose for fentanyl and 8% (±9.3) for midazolam. Similar doses were used in term and preterm neonates. Of 118 patients receiving fentanyl and/or midazolam, 40% presented urinary retention, 28% a weaning syndrome. Paracetamol (155 patients; 92%) and nalbuphine (55 patients; 33%) were the other medications most often prescribed. Conclusion The off-label use of fentanyl and midazolam was necessary to treat pain after surgery. Pain assessment should be conducted for all neonates in order to optimize their treatment. Research on analgesic and sedative medicine in vulnerable neonates seems necessary to standardize practices and reduce adverse drug reactions.

ObjectivesOff-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.DesignMulticentre cross-sectional studySettingTwenty-three training general practice officesParticipantsAll 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.MethodsEleven 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.ResultsAmong 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).ConclusionAlmost 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.

Background Patients' and families' expectation that a cure for cystic fibrosis (CF) will be found is high. In other debilitating conditions, high expectation has been shown to drive a strong placebo response (PR). Therefore, our goal was to evaluate PR on objective continuous outcomes (FEV1, BMI) and the CF Questionnaire Revised-Respiratory Domain (CFQR-RD) monitored during randomised clinical trials (RCTs) for CF. Methods We conducted a meta-analysis after a systematic review of the literature carried out to identify RCTs with FEV1, CFQR-RD and BMI as outcome measures. The standardised mean difference (SMD) was calculated to estimate the PR. A meta-regression analysis was conducted to assess other contributing factors on PR such as study design, trial duration, patient age and disease severity. Results Out of 289 RCTs found in the search, we identified 61 articles (published from 1987 to 2017) with respectively 59, 17 and 9 reporting FEV1, CFQR-RD and BMI at the start and at the end of the RCTs. No significant PR was found on FEV1 or CFQR-RD. However, a small but significant PR was found on BMI SMD, 0.09 (95% CI (0.01; 0.17); p = 0.03). Conclusion The PR seems higher when measuring BMI. However, it is not clear whether this improvement can be explained by a PR alone.

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

International audience; AIM: Recent US recommendations indicate a target blood pressure (BP) of 130/80mmHg for patients with type 2 diabetes (T2D). Our aim was to characterize the association between risk of cardiovascular events and differences in BP decreases in randomized trials of a T2D population. METHODS: A systematic search was made for randomized clinical trials assessing the effects of antihypertensive treatments in T2D patients on mortality, and fatal and non-fatal cardiovascular events, using a meta-regression technique to explore the influence of BP decreases on treatment effects. RESULTS: A total of 88,503 patients from 44 randomized trials were included. There was no significant association between BP decreases and risk of all-cause or cardiovascular mortality, cardiovascular events or myocardial infarction. However, stroke risk was influenced by BP decreases: compared with no reduction, a 10-mmHg reduction in systolic BP was associated with a relative odds ratio (OR) decrease of 33% (OR: 0.67, 95% CI: 0.54-0.82), and a 5-mmHg diastolic BP reduction was associated with a relative OR decrease of 38% (OR: 0.62, 95% CI: 0.50-0.76). Restricting the analysis to double-blind studies did not change the results for diastolic BP. CONCLUSION: A reduction in BP lowers the risk of stroke, but does not appear to affect the risk of other cardiovascular events in a T2D population.

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. 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. 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. 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.

Summary 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.

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 6–15 years 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.

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

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 × 109 /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.

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.

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. 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). 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). This study did not show any beneficial effect of omega-3 supplement in children with mild ADHD symptoms.

International audience; Pediatric R-Tx patients are at high risk of developing EBV primary infection. Although high DNA replication is a risk factor for PTLD, some patients develop PTLD with low viral load. In this retrospective single-center study including all pediatric patients having received R-Tx (2003-2012 period), we aimed to identify risk factors for uncontrolled reactions to EBV (defined as the presence of a viral load \textgreater10~000~copies/mL or PTLD). A Cox proportional hazard model was performed. A total of 117 patients underwent R-Tx at a mean age of 9.7~\textpm~5.3~years, 46 of them being seronegative for EBV at the time of R-Tx. During follow-up, 54 patients displayed positive EBV viral load, 22 of whom presenting with primary infection. An uncontrolled reaction to EBV was observed in 24 patients, whilst 4 patients developed PTLD. Univariate and multivariate analyses suggested the following risk factors for an uncontrolled reaction: age below 5~years, graft from a deceased donor, >=5 HLA mismatches, EBV-seronegative status at the time of R-Tx, and a secondary post-Tx loss of anti-EBNA. Monitoring anti-EBNA after R-Tx may contribute to the early identification of patients at risk for uncontrolled reaction.

Rationale, aims and objectives Malnutrition screening is essential to detect and to treat patients with stunting or wasting. The aim was to evaluate the subjective perception of frequency and assessment of malnutrition by health care professionals. Research methods and procedures In a paediatric university hospital, a cross-sectional survey was conducted with a Likert scale approach to health care professionals and compared with objective measurements on a given day of frequency of malnutrition and of its screening. Results 279 health care professionals participated. The malnutrition rate, estimated versus measured, was 16.8% and 34.8%, respectively. Conversely, the estimated frequency of malnutrition screening versus measured frequency was 80.6% versus 43.1%, respectively. Furthermore, the perception of health care professionals did not differ depending on their professional category or speciality. Conclusions In conclusion, health care staff underestimates the prevalence of malnutrition in children by half and overestimates the frequency of appropriate screening practices for detection of malnutrition. This flawed/unreliable perception may disrupt both screening and the management of malnourished children. There is an urgent need to find out the reasons behind these errors caused by subjective perception in order to develop appropriate educational training to remedy the situation.

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.

International audience; BACKGROUND:There is a great need for high quality clinical research for children. The European Pediatric Regulation aimed to improve the quality of clinical trials in order to increase the availability of treatments for children. The main purpose of this study was to assess the evolution of both the number and the quality of pediatric trial protocols that were submitted to a French Institutional Review Board (IRB00009118) before and after the initiation of the EU Pediatric Regulation.METHODS:All protocols submitted to the IRB00009118 between 2003 and 2014 and conducting research on subjects under eighteen years of age were eligible. The quality of randomized clinical trials was assessed according to the guidelines developed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and ranked using the Jadad score.RESULTS:Out of 622 protocols submitted to the Institutional Review Board (IRB), 21% (133/622) included children. Among these 133 pediatric protocols, the number of submitted pediatric protocols doubled between the two studied periods. From 2003 to 2008, 47 protocols including 21 institutionally sponsored were submitted to the IRB and from 2009 until 2014, 86 protocols including 48 institutionally sponsored were submitted. No significant trend was observed on the quality of RCTs. The overall median score of RCTs on the Jadad scale was high (3.5), 70.0% of protocols had a Jadad score ≥ 3, and 30.0% had a score < 3.CONCLUSION:Following the EU Pediatric Regulation, the number of pediatric protocols submitted to the IRB00009118 tends to increase, but no change was noticed regarding their quality.

Background The biological agents (BAs) have revolutionized the care and have improved the prognosis of juvenile idiopathic arthritis (JIA). Effectiveness and short-term tolerance was well established in randomized clinical trials (RCTs), initially in JIA. However, there is an insufficient evidence for the long-term tolerance 1 . The serious adverse events (SAEs) include infections, malignancies and drug induced auto-immune diseases (e.g. uveitis). Objectives To assess the benefit/risk balance of BAs assessed by RCTs vs placebo or vs standard treatment in JIA, using meta-analysis (MA) technique. Methods All RCTs in JIA comparing BAs to placebo or standard treatment (e.g. methotrexate) published between 1950 and February 2016 were eligible. Data source: Cochrane, Medline, ClinicalTrial.gov register. The ILAR classification for JIA 2 was used and the clinical efficacy of treatment was measured by the ACR pediatric score 3 . Efficacy was analyzed considering the design of study. Effectiveness (ACRpedi30) was estimated as the measure of the benefit of the BAs and SAEs as a measure of risk by random effect models. The benefit/risk balance was analyzed using the net efficacy adjusted for risk (NEAR) 4 . An OR >1 indicates that the treatment has a beneficial effect and OR Results We included 20 RCTs conducted in JIA encompassing 1533 children. The disease duration, at the inclusion of RCTs, varies between 2 and 6 years for most studies. The maintenance of the therapeutic effect was estimated in the studies using withdrawal design in 6 studies. The maintenance of clinical response showed a large heterogeneity. Sub-groups analyses showed that the heterogeneity is marked in the systemic JIA 5 . The global NEAR OR was in favor of BAs in parallel (OR 3.83, CI 1.49–9.82) and withdrawal (OR 2.75, CI 1.51–5.01) trials. The efficacy of BAs in JIA was superior to the placebo in parallel (OR 5.46, CI 2.26–13.21) and withdrawal (OR 3.52, CI 2.15–5.77) trials. In RCTs (parallel and withdrawal design), SAEs did not differ between BAs and control (OR 1.18, CI 0.73–1.9). No death occurred at follow-up. Conclusions This is the first MA assessing all BAs used in all JIA categories combined. This MA in patients with JIA shows that the benefit/risk ratio of BAs in JIA is favorable. References Klotsche, J. et al. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). Ann. Rheum. Dis. 75, 855–861 (2016). Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31, 390–392 (2004). Consolaro, A. et al. Optimisation of disease assessments in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 32, S-126–130 (2014). Boada, J. N. et al. Net efficacy adjusted for risk (NEAR): a simple procedure for measuring risk:benefit balance. PloS One 3, e3580 (2008). Tarp, S. et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. Rheumatol. Oxf. Engl. 55, 669–679 (2016). Disclosure of Interest None declared