Neurological outcome in WDR62 primary microcephaly.

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.

Are transition preparation consultations for adolescents with chronic conditions valuable? A mixed-methods study.

Our objective was to assess the value of transition preparation consultations (TPC) offered by the AD'venir unit (R. Debré hospital, Paris) as a new service of transitional care, from the perspective of adolescents with chronic conditions (CCs) and their referring healthcare providers (RHCPs). TPCs included a face-to-face interview with pediatricians trained in adolescent medicine, exploring the adolescent's past (CC history), present (daily life, Treatment Burden Questionnaire, family/peer relationships, school, hobbies, sexuality, drugs), and future (global life project, transition, Good2Go questionnaire). The mixed-methods design included the following: a qualitative analysis within a multidisciplinary group (clinicians/sociologists/psychologist/public health researchers) of audio-recordings of TPCs (n = 27/girls = 56%/median age = 17.7 years) and phone interviews with adolescents 2 years post-TPC (n = 26); and a quantitative analysis of the Treatment Burden and Good2Go questionnaires and the benefits perceived by RHCPs (questionnaire 6 months post-TPC). TPCs were a form of training for adult care, adolescents meeting a practitioner alone often for the first time. Naming their CC was difficult. All complained of limitations experienced in social life (diet, fatigue, laboratory/medical appointments), but not the treatment itself; most adolescents willingly talked about sexuality. Adolescents' feelings about transition were various, with poor representations of adult healthcare. Transfer was frequently unplanned. After TPCs, RHCPs modified their practices. Transition in the 2 years post-TPC was usually successful. Conclusion What is Known: • In adolescents with chronic conditions, it is advocated to personalize transition care according to the clinical and social context, pointed out as potentially impacting. • Little is known about the most effective ways to prepare patients according to their needs. What is New: • Based on a global approach to adolescent health, transition preparation consultations are delivered by specially trained physicians. • They are a feasible and valuable way to highlight facilitators and barriers to successful transition and initiate the adolescents' own vision of their future.

Bone Health in Pediatric Patients With Crohn Disease.

OBJECTIVE: The aim of our study was to examine longitudinal changes in bone mineral density (BMD) of children and adolescents with Crohn disease (CD), and risk factors related to low BMD. PATIENTS AND METHODS: All patients ages from 2 to 18 years with CD who underwent dual-energy X-ray absorptiometry (DXA) at diagnosis and at the end of follow-up between 1999 and 2018 were considered for inclusion in this retrospective study. Factors related to changes in BMD at diagnosis and during follow-up were investigated. RESULTS: One hundred and ninety-three patients had the two DXA required. At diagnosis, 36 patients (18.7%) had a low BMD.At the end of follow-up, 31 patients (16%). One hundred and sixty-four patients did not have the two DXA required.In included CD, BMD values were lower in the lumbar spine (LS) than in total body less head (TBLH), as well at diagnosis (P < 0.0001) or at the end of follow-up (P = 0.001).At diagnosis, only growth impairment or low BMI was associated with low BMD (P < 0.0001), only cumulative dose of corticosteroid at the end of follow-up (P = 0.01). CONCLUSION: The high prevalence of low BMD in children and adolescents with IBD highlights the importance of evaluating BMD in these patients at the time of diagnosis and throughout the course of their treatment. Special attention must be given to patients with height delay or low BMI at diagnosis. Long-term glucocorticoid therapy is the main clinical risk factor associated with low BMD at the end of follow-up.

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Validation of the "Good2Go": the first French-language transition readiness questionnaire.

The use of transition readiness questionnaires is strongly recommended in adolescents with chronic conditions. The aim of our study was to validate "Good2Go," the first French-language transition readiness questionnaire. We analyzed the data from 2 multicentric studies (Canada and France) involving adolescents with chronic conditions (type 1 diabetes, inflammatory bowel disease, cystic fibrosis, epilepsy, juvenile idiopathic arthritis). Content and construct validity were examined using factorial and Rasch analysis (structural validity), Spearman's correlation, and Mann-Whitney test (external validity). Cronbach's α and intra-class correlation coefficients explored reliability. Cognitive interviews assessed wording comprehension and item appropriateness. Good2Go was completed by 321 participants (boys = 51%; mean age = 16.4 years (standard deviation = 1.5; min = 14.0; max = 18.0); Canada = 51.1%). Factor analysis identified 3 domains: "health self-advocacy," "knowledge about chronic conditions," and "self-management skills." The 3-domain structure showed a satisfying Rasch fit, internal consistency, and test-retest reliability. Good2Go domain scores were significantly higher in participants over 17 years of age, indicating satisfactory external validity.Conclusion: Good2Go is a valid 20-item questionnaire to assess transition readiness in adolescents with chronic conditions and may be useful in routine care to propose individually tailored preparation for their transfer to adult healthcare. Further research is now needed to analyze correlation between domain scores and success of transition.What is Known:• In adolescents with chronic conditions, the use of transition readiness questionnaires is recommended to propose individually tailored preparation for their transfer to adult healthcare.• However, no French-language questionnaire has been so far validated.What is New:• Based on a complete validation methodology, this study highlights that the French-language 20-items Good2Go questionnaire has good psychometric properties.• It explores all transition key points though 3 scored domains: "health self-advocacy", "knowledge about chronic disease" and "self-management skills".

Is there an optimal strategy for real-time continuous glucose monitoring in pediatrics? A 12-month French multi-center, prospective, controlled randomized trial (Start-In!).

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, and parallel-group design was conducted. After 3 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 hemoglobin A1c (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 3 months costs the national medical insurance system €2629 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 3 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.

Practical generic guidelines for paediatric-to-adult transition for adolescents with chronic disease.

BACKGROUND: The last 20 years have seen many attempts to improve transition to adult healthcare for adolescents with chronic disease, but there is currently no established consensus on generic practices. Our goal was to identify relevant and pragmatic guidelines for transition practice for each step of this process (before, during and after transfer), applicable to a wide range of chronic illnesses and health services, via a participatory approach involving all the key stakeholders. METHODS: We conducted interviews and a literature review to elaborate a questionnaire for use in an online 2-round Delphi survey. The survey panel included 36 French health and social professionals from different care settings, and young adults and parents with an experience of healthcare transition related to all types of chronic disease. RESULTS: The survey consensus identified 19 items on feasibility and relevance criteria, which form the guidelines. It is composed of five practices to be adopted during preparation in paediatrics, seven practices in the active phase of transition and seven in adult care. Two guidelines achieved complete consensus: having a longer consultation for the first appointment with the adult doctor, and keeping the same adult doctor throughout follow-up. A further 36 items met the criterion of relevance, but were deemed unfeasible. CONCLUSIONS: Taking into account all stakeholder views and the real-world applicability of care practices enabled us to elaborate consensual guidelines whose implementation requires no additional health service resources.

Melatonin Levels in Preterm and Term Infants and Their Mothers.

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.

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.

Strategies to determine positive anti-SARS-CoV-2 memory T lymphocyte response during the evolution of an epidemic.

During SARS-CoV-2 pandemic, the assessment of immune protection of people at risk of severe infection was an important goal. The appearance of VOCs (Variant of Concern) highlighted the limits of evaluating immune protection through the humoral response. While the humoral response partly loses its neutralizing activity, the anti-SARS-CoV-2 memory T cell response strongly cross protects against VOCs becoming an indispensable tool to assess immune protection. We compared two techniques available in laboratory to evaluate anti-SARS-CoV-2 memory T cell response in a cohort of infected or vaccinated patients with different levels of risk to develop a severe disease: the ELISpot assay and the T-Cell Lymphocyte Proliferation Assay respectively exploring IFNγ production and cell proliferation. We showed that the ELISpot assay detected more anti-Spike memory T cell response than the Lymphocyte Proliferation Assay. We next observed that the use of two different suppliers as antigenic source in the ELISpot assay did not affect the detection of anti-Spike memory T cell response. Finally, we explored a new approach for defining the positivity threshold, using unsupervised mixed Gaussian modeling, challenging the traditional ROC curve used by the supplier. That will be helpful in endemic situation where it could be difficult to recruit "negative" patients.

Association between Portal Vein Thrombosis after Umbilical Vein Catheterization and Neonatal Asphyxia.

INTRODUCTION: Neonatal portal vein thrombosis (PVT) is frequently related to umbilical venous catheterization (UVC), but risk factors remain unclear. This study aims to analyze the variables associated to PVT in near- to full-term newborns with UVC, with a focus on newborns exposed to controlled therapeutic hypothermia (CTH) for hypoxic ischemic encephalopathy (HIE). METHODS: This is retrospective cohort study of infants delivered at or after 36 weeks and with a birthweight over 1,500 g. All infants were assessed for UVC location and PVT using ultrasonography performed between day 5 and day 10 after catheterization. RESULTS: Among 213 eligible patients, PVT was diagnosed in 57 (27%); among them, 54 (95%) were localized in the left portal vein branch. With all significant factors in univariate analysis considered, higher gestational age at birth (adjusted OR 1.35; 95% CI: 1.12-1.64, p = 0.002) and duration of UVC placement (adjusted OR 1.36; 95% CI: 1.11-1.67, p = 0.004) were the main risk factors of PVT. Among 87 infants who were cooled for HIE, 31 (36%) had PVT compared to 26 (21%) in infants without CTH. Using a multivariate model including variables linked to treatment procedures only, an increased PVT incidence was statistically associated with UVC duration (adjusted OR 1.33; 95% CI: 1.08; 1.63, p = 0.01) and CTH (adjusted OR 1.94; 95% CI: 1.04-3.65, p = 0.04). CONCLUSION: Left PVT was frequently observed in near- to full-term neonates with UVC. Among factors linked to treatment procedures, both duration of UVC and CTH exposure for HIE were found to be independent risk factors of PVT.

Transfontanellar shear wave elastography of the neonatal brain for quantitative evaluation of white matter damage.

Cerebral white matter damage (WMD) is the most frequent brain lesion observed in infants surviving premature birth. Qualitative B-mode cranial ultrasound (cUS) is widely used to assess brain integrity at bedside. Its limitations include lower discriminatory power to predict long-term outcomes compared to magnetic resonance imaging (MRI). Shear wave elastography (SWE), a promising ultrasound imaging modality, might improve this limitation by detecting quantitative differences in tissue stiffness. The study enrolled 90 neonates (52% female, mean gestational age = 30.1 ± 4.5 weeks), including 78 preterm and 12 term controls. Preterm neonates underwent B-mode and SWE assessments in frontal white matter (WM), parietal WM, and thalami on day of life (DOL) 3, DOL8, DOL21, 40 weeks, and MRI at term equivalent age (TEA). Term infants were assessed on DOL3 only. Our data revealed that brain stiffness increased with gestational age in preterm infants but remained lower at TEA compared to the control group. In the frontal WM, elasticity values were lower in preterm infants with WMD detected on B-mode or MRI at TEA and show a good predictive value at DOL3. Thus, brain stiffness measurement using SWE could be a useful screening method for early identification of preterm infants at high WMD risk.Registration numbers: EudraCT number ID-RCB: 2012-A01530-43, ClinicalTrial.gov number NCT02042716.

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial.

BACKGROUND: Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients. AIMS: We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients. METHODS: We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day. RESULTS: Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006). CONCLUSIONS: Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia. TRIAL REGISTRATION: Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov .

Glucocorticoid induced adrenal insufficiency in children: Morning cortisol values to avoid LDSST.

Objectives: Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency. Study Design: We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST. Results: Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency. Conclusions: Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children.

Long-term health-related quality of life outcomes of adults with pediatric onset of frequently relapsing or steroid-dependent nephrotic syndrome.

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.

One Year of GH Treatment for Growth Failure in Children With Anorexia Nervosa: A Randomized Placebo-Controlled Trial.

CONTEXT: Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV). OBJECTIVE: To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment. DESIGN AND PARTICIPANTS: In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/year) for at least 18 months, and a bone age ≤12 years for girls and ≤14 years for boys, were randomized to receive daily subcutaneous injections of human GH (0.050 mg/kg/day) or placebo for 12 months. MAIN OUTCOME MEASURES: Change in HV after 12 months. RESULTS: In total, 8 patients were assigned to the GH group and 6 to the placebo group. Patients had a median (25th-75th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after 6 months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs 3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5th-97.5th percentile) difference between the groups of 5.8 (-1.85;9.68) cm after bootstrapping. The percentage of patients with a HV > 5 cm/year during the study period was higher in the GH group than in the placebo group (100% vs 50%, P = 0.05). Adverse events occurred in similar numbers in the 2 groups, were mild or nonfatal, and did not lead to treatment being stopped. CONCLUSION: GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure.

How to collect non-medical data in a pediatric trial: diaries or interviews.

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!).

Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial.

INTRODUCTION: Guidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg's immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects. METHODS AND ANALYSIS: We conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g). ETHICS AND DISSEMINATION: The study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03560011.

Trends in childhood type 1 diabetes incidence in France, 2010-2015.

AIMS: To estimate type 1 diabetes incidence in children in France and its evolution between 2010 and 2015, based on comprehensive medico-administrative databases. METHODS: The algorithm built to identify new cases of type 1 diabetes selected children aged between 6 months and 14 years who had at least one hospital stay for diabetes, followed by their first insulin treatment, excluding children suffering from another form of diabetes. Age and sex specific annual incidence rates were estimated and time trend was analyzed using Poisson regression. RESULTS: A total of 12 067 children were identified as newly diagnosed with type 1 diabetes and the annual incidence rates increased between 2010 and 2015 (from 15.4 [95% Confidence Interval: 14.7; 16.1] to 19.1 [18.3; 19.9] per 100 000 person-years), among boys and girls, and in each age group (4 and under, 5-9, 10-14 year olds). The annual rate of increase was 4.0% [3.4; 4.6]. This trend was not significantly different between each gender, and each age group. CONCLUSIONS: Valid database information on disease incidence is essential for healthcare planning and provides a valuable resource for health research. An increase of the incidence rate of type 1 diabetes in children was highlighted in both sexes and in all age groups.

Factors Affecting Loss to Follow-Up in Children and Adolescents with Chronic Endocrine Conditions.

OBJECTIVE: Most children with endocrine diseases require long-term continuity of care. We investigated the prevalence of loss to follow-up (LTFU) in pediatric patients with chronic endocrine diseases and the risk factors associated with LTFU. METHODS: This observational cohort study included all children with chronic endocrine diseases included in the database of a single academic pediatric care center over a period of 8 years. LTFU was defined as a lack of attendance at clinical visits for over 2 years, for unknown reasons. RESULTS: LTFU was recorded for 154 of the 1,067 patients included (14%). Median age at diagnosis was 5.8 (0.3-11.8) vs. 1.2 (0.0-6.9) years, and age at last visit was 14.1 (9.7-16.1) vs. 11.7 (6.1-15.8) years, for the LTFU and no-LTFU groups, respectively. In multivariate analysis, the risk of LTFU increased with age at diagnosis (OR 1.18; 95% CI 1.12-1.24) and was higher for patients diagnosed before 2006 (vs. after 2006; OR 4.80; 95% CI 3.00-7.66), with fewer visits in the last 3 years (OR 0.72; 95% CI 0.65-0.80; p < 0.0001) and a lower health insurance classification (OR 1.79; 95% CI 1.10-2.89; p = 0.02). The risk of LTFU was higher for patients with isolated growth hormone deficiency than for those with other endocrine conditions, such as multiple pituitary deficiencies, hypogonadotropic hypogonadism, Turner syndrome, or thyroid, adrenal, or gonadal disorders (OR 5.24; 95% CI 1.13-24.37; p = 0.03). CONCLUSION: This study provides the first epidemiological data for LTFU in children and adolescents with chronic endocrine diseases. It should facilitate the targeting of interventions to improve adherence to medical care and healthcare organization during the pediatric period.