Sophie Guilmin-Crépon

Background/Objectives: Congenital clubfoot is the most frequent malformation in pediatric orthopedics. In France, two treatments can be proposed: the Ponseti method and the functional method. The objective was to conduct a medico-economic and -social evaluation of those methods. Methods: Medico-economic: a cost-consequences analysis was undertaken from the societal perspective, based on the Dimeglio score at 24 months in four pediatric hospitals. Medico-social: interviews were conducted with parents (n = 16) and healthcare professionals (n = 16). Results: One hundred patients were included between January 2014 and December 2016. Whatever the treatment method, over 90% of patients presented with benign clubfoot (i.e., Dimeglio score < 5/20) at 24 months, based on multiply imputed estimates. The Functional method was associated with higher direct medical and non-medical costs (€3340–4061 vs. 889–2318; €6275–5968 vs. 576–726), and indirect costs (€15,441–4672 vs. 1416–1786), contrary to out-of-pocket expenses (€0–1 vs. €322–546). Family testimonies underscored the importance of communication from healthcare providers to reassure and guide parents. Although the choice is influenced by professionals, trust and active engagement of families are essential for adherence to treatment and its long-term success. The Ponseti method combined effectiveness with a lower perceived burden for families. Conclusions: The Ponseti method was the costliest for parents, yet more manageable. However, the most important factor is to choose a method adapted to the family in order to achieve the best degree of compliance.

Background: Reducing postoperative opioid consumption has become a significant challenge in perioperative pain management, particularly within the framework of Enhanced Recovery After Surgery protocols and the associated risk of prolonged opioid dependence. The primary objective of this study was to evaluate whether remifentanil administration guided by intraoperative nociception monitoring with the Analgesia Nociception Index (ANI) during surgery for adolescent idiopathic scoliosis reduces postoperative morphine consumption at day 1. The secondary objective was the incidence of persistent postoperative pain 6 months after surgery. Methods: The current study, a multicenter randomized controlled trial, was conducted between October 2020 and June 2023. Eligible children were randomly assigned to receive intraoperative remifentanil administration guided either by hemodynamic parameters (control group) or by the Analgesia Nociception Index (intervention group). Comparison of postoperative morphine use was adjusted to the use of nonopioid analgesics. Results: Overall, 247 patients were included, and 244 were randomized (120 in the ANI group and 123 in the control group). Postoperative morphine consumption at day 1 was similar in both groups (median [25%; 75% interquartile range], 0.4 [0.3; 0.8] vs . 0.4 [0.3; 0.5] in the ANI and control groups, respectively; median difference [95% CI] = −0.005[−0.10 to 0.09] mg · kg ⁻¹ ; P = 0.93). Intraoperative remifentanil administration decreased in the ANI group (mean difference [95% CI], 9.5 [4 to 15] μg ·kg ⁻¹ , P < 0.001). ANI-guided intraoperative remifentanil administration did not result in differences in secondary outcomes. Conclusions: The administration of remifentanil guided by intraoperative nociception monitoring during adolescent idiopathic scoliosis did not result in a reduction of postoperative opioid consumption.

Le diabète de type 1 (DT1) est à la fois l’une des maladies chroniques les plus fréquentes en pédiatrie, et l’une des plus complexes à équilibrer sur le long terme du fait de la multiplicité des composantes du traitement. La cible thérapeutique usuelle associant le niveau d’HbA1c et la fréquence des hypoglycémies présente certaines limites et pourrait être complétée par d’autres paramètres. Parmi ceux-ci, la variabilité glycémique (VG) pourrait être mieux évaluée grâce à la mise à disposition de profils de glucose par les dispositifs de mesure en continu du glucose (MCG). L’objectif principal de ce projet de recherche est de déterminer la place de la VG mesurée à partir des dispositifs de MCG dans l’arsenal thérapeutique des sujets ayant un DT1, particulièrement en pédiatrie.Notre premier travail a consisté en l’analyse d’un essai clinique randomisé. Celle-ci a d’une part conforté l’acceptation du dispositif de MCG sur le long terme en pédiatrie, et d’autre part souligné la limite à son efficacité sur le contrôle métabolique et le frein à l’appropriation de l’outil par les sujets liés probablement à la complexité des données. Notre deuxième travail, par une analyse en composante principale réalisée à partir des données de l’essai clinique, a permis de mettre en exergue les composantes du phénomène de VG et d’aider au choix d’un nombre limité de paramètres pour le mesurer. Notre troisième travail a eu pour objectif de décrire l’association entre VG et santé en population DT1, à partir d’une revue systématique de la littérature. La prise en compte des indicateurs de VG utilisés, selon la composante du phénomène qu’ils représentent, a permis de discuter les controverses soulevées par les auteurs.En précisant la définition de la VG, en distinguant ses composantes d’amplitude et de temporalité, en confortant la pertinence clinique de considérer la VG comme cible pour les sujets ayant un DT1 et en proposant des critères d’évaluation ou des outils représentant chacune de ses composantes, notre travail permet de guider vers une intégration standardisée de la VG tant pour les protocoles de recherche clinique que dans le cadre de la pratique clinique. La principale perspective désormais sera de s’assurer du caractère didactique de l’intégration de la VG comme cible thérapeutique en diabétologie pour une bonne appropriation tant par les soignants que par les patients.

Genetic primary microcephaly (PM) is a defect in early brain development leading to congenital microcephaly, mostly recessively inherited, and mild-to-moderate intellectual disability. PM has been largely elucidated, thanks to exome and genome sequencing. However, radial microbrain, the most severe form of genetic PM or micrencephaly described in the 1980s, which leads to early lethality or very severe intellectual handicap, remains without a molecular diagnosis. We sought to identify the cause of radial microbrain by analyzing the genotype of children/adults and fetuses with an extremely small brain. We searched for individuals with the smallest head circumference among patients with a confirmed diagnosis of PM included in 2 French and European observational studies coordinated at the Robert Debré Children's Hospital in Paris. Their neurodevelopment and brain imaging were analyzed, as well as next-generation sequencing for a panel of microcephaly genes or exome sequencing. Neuropathologic and immunohistologic analyses of extremely severe microcephalic fetal brains and stage-matched controls were performed. A nonparametric test and Mann-Whitney post-test were used to compare the cortical thickness between groups. We identified 5 individuals (4 female patients, 7 years 10 months–19 years) with a particularly small brain among a series of 50, all suffering from a severe neurodevelopmental disorder with no ability to communicate verbally and, in 3 of them, no ability to walk. Genetic analysis revealed in all individuals the presence of the same homozygous variant c.2953A>G (p.R985G) in the RTTN gene (ROTATIN). The same variant was found in 2 fetuses whose neuropathologic evaluation showed a major reduction in the thickness of the ventricular zone and neuronal heterotopias. The cortical plate was reduced by 70% compared with controls, irrespective of the region considered. Immunostaining with vimentin showed a 50% loss of radial glial columns, characteristic of radial microbrain. Our data show that the homozygous c.2953A>G substitution in RTTN is a recurrent variant responsible for radial microbrain, the most severe form of primary microcephaly. Our combined neurologic, imaging, and histopathologic approaches provide a better understanding of the severity of this condition and its prognosis. ClinicalTrials.gov number: NCT01565005.

Aim To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)-related primary microcephaly. Method In this observational study, we describe the developmental, neurological, cognitive, and brain imaging characteristics of 17 patients (six males, 11 females; mean age 12y 3mo standard deviation [SD] 5y 8mo, range 5y–24y 6mo) and identify 14 new variants of WDR62. We similarly analyse the phenotypes and genotypes of the 59 previously reported families. Results Brain malformations, including pachygyria, neuronal heterotopia, schizencephaly, and microlissencephaly, were present in 11 out of 15 patients. The mean full-scale IQ of the 11 assessed patients was 51.8 (standard deviation [SD] 12.6, range 40–70). Intellectual disability was severe in four patients, moderate in four, and mild in three. Scores on the Vineland Adaptive Behavior Scales obtained from 10 patients were low for communication and motor skills (mean 38.29, SD 7.74, and 37.71, SD 5.74 respectively). The socialization score was higher (mean 47.14, SD 12.39). We found a significant difference between scores for communication and daily living skills (mean 54.43, SD 11.6; p=0.001, one-way analysis of variance). One patient displayed progressive ataxia. Interpretation WDR62-related cognitive consequences may be less severe than expected because 3 out of 11 of the assessed patients had only mild intellectual disability and relatively preserved abilities of autonomy in daily life. We identified progressive ataxia in the second decade of life in one patient, which should encourage clinicians to follow up patients in the long term.

Background Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined. Methods In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being. Results In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = − 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS. Conclusions This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care. Graphic abstract

Background: Non-medical data, such as the amount of time that patients and caregivers spend managing their condition, may be relevant when assessing therapeutic strategies. For chronic pediatric conditions, the time that patients and caregivers spend in seeking and providing care (which are the indirect costs in an economic evaluation) can be significantly different depending on the treatment arm. To explore methods for collecting information on the care burden for caregivers and patients, we investigated whether a patient diary provided additional information compared to retrospective investigator-led interviews and whether a diary that was completed intermittently produced more or less information than a diary completed continually. The main objective of this study was to identify which type of data collection was most effective for measuring the time spent by caregivers and for estimating indirect treatment costs over 9 months. Methods: Start-In! is a randomized controlled trial comparing the efficacy of three strategies of real-time continuous glucose monitoring for 12 months in children and adolescents with type 1 diabetes. We designed an ancillary study to assess methods of collecting information on the time spent by patients and caregivers in managing their condition (indirect costs). Data were entered retrospectively in case report forms (CRFs) by investigators during quarterly follow-up visits, which were supplemented with diaries completed prospectively by children or caregivers either continuously or intermittently. Data about absences from school and work as well as the time that caregivers spent on diabetes care were collected and the three collection methods were compared. Results: At the end of the 9-month study, 42% of the study participants failed to return their diary. For the diaries that were received, less than 10% of expected data were collected versus 82% during investigators'interviews. Based on all the information collected, we calculated that over 9 months, caregivers lost on average 3.9 days of working time (€786) and 4 days of personal time, i.e. the equivalent of €526, and spent around 15 min of time on care per day, i.e. the equivalent of €1700. Conclusions: The CRFs completed by investigators during quarterly visits cannot be replaced by a diary. Completing the diaries appeared to represent an important additional burden to children and their caregivers, and the diaries provided little additional information compared to investigators’ entries in the CRF. Trial registration: ClinicalTrials.gov, NCT00949221. Registered on 30 July 2009. Registry name: Study of Insulin Therapy Augmented by Real Time Sensor in Type 1 Children and Adolescents (START-IN!).

The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin circulating levels would be lower in preterm compared to term infants. We conducted a prospective, longitudinal, multicenter study to assess melatonin, and 6-sulfatoxy-melatonin (aMT6s) concentrations, measured by radioimmunoassay. Among 209 neonates recruited, 110 were born before 34 gestational weeks (GW) and 99 born after 34 GW. Plasma melatonin concentrations, measured at birth and on Day 3 were below detectable levels (≤7 pg/mL) in 78% and 81%, respectively, of infants born before 34 GW compared to 57% and 34%, respectively, of infants born after 34 GW. The distribution of plasma melatonin concentrations was found to be correlated with gestational age at both time-points (p < 0.001). Median urine aMT6s concentrations were significantly lower in infants born before 34 GW, both on Day 1 (230 ng/L vs. 533 ng/L, p < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, p < 0.0001). In conclusion, melatonin secretion appears very low in preterm infants, providing the rationale for testing supplemental melatonin as a neuroprotectant in clinical trials.

Aim To compare the efficacy of three strategies for real‐time continuous glucose monitoring (RT‐CGM) over 12 months in children and adolescents with type 1 diabetes. Methods A French multicenter trial (NCT00949221) with a randomized, controlled, prospective, open, parallel‐group design was conducted. After three months of RT‐CGM, patients were allocated to one of three groups: return to self‐monitoring of blood glucose, continuous CGM (80% of the time), or discontinuous CGM (40% of the time). The primary outcome was HbA1c levels from 3 to 12 months. The secondary outcomes were acute metabolic events, hypoglycemia, satisfaction with CGM and cost. Results We included 151 subjects, aged 2 to 17 years, with a mean HbA1c level of 8.5% (SD0.7; 69 mmol/mol). The longitudinal change in HbA1c levels was similar in all three groups, at 3, 6, 9 and 12 months. The medical secondary endpoints did not differ between groups. The rate of severe hypoglycemia was significantly lower than that for the pretreatment year for the entire study population. Subjects reported consistent use and good tolerance of the device, regardless of age or insulin treatment. The use of full‐time RT‐CGM for three months costs the national medical insurance system €2,629 per patient. Conclusion None of the three long‐term RT‐CGM strategies evaluated in pediatric type 1 diabetes was superior to the others in terms of HbA1c levels. CGM‐use for three months decreased rates of severe hypoglycemia. Our results confirm the feasibility of long‐term RT‐CGM‐use and the need to improve educational support for patients and caregivers.