Publications by authors named "Caroline Elie"

95 Publications

Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in megakaryocyte maturation, platelet production and functions: a study in patients with Lowe syndrome.

Br J Haematol 2021 Mar 2;192(5):909-921. Epub 2021 Feb 2.

Université de Paris, Innovations Thérapeutiques en Hémostase, Paris, INSERM U1140, France.

Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.
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http://dx.doi.org/10.1111/bjh.17346DOI Listing
March 2021

One-way self-expanding rod for early-onset scoliosis: early results of a clinical trial of 20 patients.

Eur Spine J 2021 Mar 24;30(3):749-758. Epub 2021 Jan 24.

Clinical Research Unit, Necker Hospital, Université de Paris, Assistance Publique Hôpitaux de Paris, 149, Rue de Sevres, Paris, 75015, France.

Purpose: Progressive early-onset scoliosis raises major challenges for surgeons, as growth must be preserved. With traditional growing rods, the need for repeated surgery is associated with numerous complications, high costs, and heavy psychosocial burden on the patient and family. We assessed the safety and efficacy of a new one-way self-expanding rod (OWSER).

Methods: This prospective single-centre phase 2 study included two groups of children with progressive EOS treated by the OWSER in 2016-2017: Ten received a unilateral construct to treat progressive non-neuromuscular curves and 10 others a bilateral construct for neuromuscular scoliosis. Clinical and radiological data were assessed at surgery and 3, 6, 12, 18 months later. The primary endpoint was success defined as the absence of repeated surgery at 12 months.

Results: In the non-neuromuscular group, rod expansion occurred in 5 of 10 patients [95% CI 19-81]; in the five other patients, rotational conflict inside the domino prevented rod expansion, four of them required surgery within the first 12 months. Rod expansion occurred spontaneously and during monthly traction sessions in all 10 neuromuscular patients [95% CI 69-100], without mechanical or device-related complications. Residual pelvic obliquity was improved by -3° [- 6.0 to 9.5] at 18 months. Lung function improved in the non-neuromuscular group.

Conclusion: In neuromuscular diseases, the OWSER bilateral construct seems to be safe and less aggressive. Used as unilateral construct in non-neuromuscular group, it was less effective. Accordingly, we recommend the bilateral construct for all aetiologies. That device could avoid further surgery and reduce the rate of complications after long follow-up.
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http://dx.doi.org/10.1007/s00586-021-06732-4DOI Listing
March 2021

Vitamin D and pregnancy outcomes: Overall results of the FEPED study.

J Gynecol Obstet Hum Reprod 2020 Oct 27;49(8):101883. Epub 2020 Jul 27.

Service de Gynécologie-Obstétrique, Hôpital Antoine Béclère, Assistance Publique des Hôpitaux de Paris, Université Paris Saclay, Clamart, France.

Vitamin D insufficiency is highly prevalent in children and adults including pregnant women. During pregnancy, maternal vitamin D insufficiency could increase risks of several pregnancy complications and adverse birth outcomes. The FEPED study was designed to assess the effects of maternal vitamin D status in the first trimester during pregnancy on risks of preeclampsia, gestational diabetes mellitus (GDM), preterm birth and small-for-gestational age (SGA) at birth. This observational prospective cohort included 3129 women with a singleton pregnancy between April 2012 and July 2014 in six maternity units in France and Belgium. The aim of this review is to summarize the results of the FEPED study. At the first trimester the mean 25(OH)D concentration was 21.9 ± 10.4 ng/mL and 25(OH)D concentration was <20 ng/mL in 46.5 % of patients. After matching 83 cases of preeclampsia with 319 controls, a significant decrease in the risk of preeclampsia was associated with maternal vitamin D levels ≥ 30 ng/mL in the third trimesters (OR = 0.34; 95 % CI: 0.13-0.86. P = 0.023). In the first trimester, the risk for preeclampsia was decreased in these patients, but did not achieve statistical significance (OR = 0.57 95 % CI, 0.30-1.01; p = 0.09). For the 250 cases with GDM matched with 941 controls, no linear relationship was found between GDM and 25OHD levels in the first trimester of pregnancy. Finally, 2813 pregnant women were included in analyses of risks of preterm and SGA birth. No association was found between low maternal vitamin D levels in the first trimester and the risks of preterm birth (aOR = 1.53; 95 % CI: 0.97-2.43) or SGA (aOR = 1.07; 95 % CI: 0.75-1.54). Further investigation is needed to understand the mechanisms behind the association between vitamin D and birth outcomes.
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http://dx.doi.org/10.1016/j.jogoh.2020.101883DOI Listing
October 2020

Relationship between vitamin D status in the first trimester of pregnancy and gestational diabetes mellitus - A nested case-control study.

Clin Nutr 2021 Jan 25;40(1):79-86. Epub 2020 Apr 25.

Gynécologie-Obstétrique, Hôpital Antoine-Béclère, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud, Clamart, France; Fondation PremUp, Paris, France.

Background & Aims: Gestational diabetes mellitus (GDM) is one of the most frequent medical complications during pregnancy. It has been associated with many adverse pregnancy, fetal and neonatal outcomes, as well as with an increased risk for mothers and children in the long term. There is a growing interest in vitamin D and its potential role in the development of metabolic disorders. However, the medical literature is not consensual. The aim of this study was to assess the risk of GDM according to vitamin D status during the first trimester.

Methods: This study is a nested case-control study performed from a multicenter prospective observational cohort of pregnant women assessed for 25-hydroxyvitamin D levels (25OHD). Three hundred ninety-three patients were included in the initial cohort. After applying exclusion criteria, a total of 1191 pregnant women were included. Two hundred fifty women with GDM (cases) were matched to 941 women without GDM (controls) for parity, age, body mass index before pregnancy, the season of conception, and phototype. This study was funded by a grant from the "Programme Hospitalier de Recherche Publique 2010".

Results: The GDM risk was significantly greater for patients with 25OHD levels <20 ng/mL (OR = 1∙42, 95% CI 1∙06-1∙91; p = 0∙021). However, there was no significant relationship with other thresholds. The study of 25OHD levels with the more precise cutting of 5 units intervals showed a variable relationship with GDM risk, as the risk was low for very low 25OHD levels, increased for moderated levels, decreased for normal levels, and finally increased for higher levels.

Conclusion: According to our study, there seems to be no linear relationship between GDM and 25OHD levels in the first trimester of pregnancy since GDM risk does not continuously decrease as 25OHD concentrations increase. Our results most probably highlight the absence of an association between 25OHD levels and GDM risk.
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http://dx.doi.org/10.1016/j.clnu.2020.04.028DOI Listing
January 2021

Faecal calprotectin and gut microbiota do not predict enteropathy in very preterm infants.

Acta Paediatr 2021 01 1;110(1):109-116. Epub 2020 Sep 1.

Faculty of Pharmacy, INSERM, U1139, Paris, France.

Aim: Very preterm birth is associated with a high risk of enteropathies. Diagnosis is challenging, especially in mild forms, leading to unnecessary periods of cessation of enteral feeding. This study aimed at establishing a prognosis score of enteropathy combining clinical parameters and faecal calprotectin concentration.

Methods: This prospective multicentric study included preterm neonates born at a gestational age of 33 weeks or less. Stools were collected weekly until hospital discharge, and daily in case of digestive events for calprotectin measurement (ELISA and immunochromatography) and microbiota analyses (16S rRNA gene sequencing).

Results: Among the 121 neonates included, 21 experienced at least one episode of enteropathy, mainly mild forms. By ELISA testing, median faecal calprotectin was 88 (8-798) µg/g faeces. No statistically significant association was found between the outset of enteropathy and maternal and neonatal characteristics, and calprotectin levels. The agreement between ELISA and immunochromatography assay was moderate (intra-class correlation coefficient 0.58, 95%CI [0.47-0.66]). Comparison of species diversity and relative bacterial abundance profiles between infants with or without enteropathy revealed no specific alterations associated with enteropathy.

Conclusion: The study failed to propose a prognostic score of enteropathy, probably due the large inter- and intra-individual variability of faecal calprotectin in very preterm neonates.
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http://dx.doi.org/10.1111/apa.15354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818215PMC
January 2021

First Trimester Maternal Vitamin D Status and Risks of Preterm Birth and Small-For-Gestational Age.

Nutrients 2019 Dec 13;11(12). Epub 2019 Dec 13.

Department of Obstetrics and Gynaecology, Antoine Béclère Hospital, AP-HP, University Paris Saclay, F-92140 Clamart, France.

Maternal 25-hydroxyvitamin D (25-OHD) deficiency during pregnancy may increase the risk of preterm and small-for-gestational age (SGA) birth, but studies report conflicting results. We used a multicenter prospective cohort of 2813 pregnant women assessed for 25-OHD levels in the first trimester of pregnancy to investigate the association between maternal 25-OHD concentrations and risks of preterm birth (<37 weeks) and SGA (birthweight <10th percentile). Odds ratios were adjusted (aOR) for potential cofounders overall and among women with light and dark skin separately, based on the Fitzpatrick scale. 25-OHD concentrations were <20 ng/mL for 45.1% of the cohort. A total of 6.7% of women had a preterm birth. The aOR for preterm birth associated with the 1st quartile of 25-OHD concentrations compared to the 4th quartile was 1.53 (95% confidence interval (CI): 0.97-2.43). In stratified analyses, an association was observed for women with darker skin (aOR = 2.89 (95% CI: 1.02-8.18)), and no association with lighter skin. A total of 11.9% of births were SGA and there was no association overall or by skin color. Our results do not provide support for an association between maternal first trimester 25-OHD deficiency and risk of preterm or SGA birth overall; the association with preterm birth risk among women with darker skin requires further investigation.
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http://dx.doi.org/10.3390/nu11123042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950733PMC
December 2019

Insights into determinants of spleen injury in sickle cell anemia.

Blood Adv 2019 08;3(15):2328-2336

Biologie Intégrée du Globule Rouge, Unité Mixte de Recherche S1134, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Université de la Réunion, Université des Antilles, Paris France.

Spleen dysfunction is central to morbidity and mortality in children with sickle cell anemia (SCA). The initiation and determinants of spleen injury, including acute splenic sequestration (ASS) have not been established. We investigated splenic function longitudinally in a cohort of 57 infants with SCA enrolled at 3 to 6 months of age and followed up to 24 months of age and explored the respective contribution of decreased red blood cell (RBC) deformability and increased RBC adhesion on splenic injury, including ASS. Spleen function was evaluated by sequential Tc heated RBC spleen scintigraphy and high-throughput quantification of RBCs with Howell-Jolly bodies (HJBs). At 6 and 18 months of age, spleen filtration function was decreased in 32% and 50% of infants, respectively, whereas the median %HJB-RBCs rose significantly (from 0.3% to 0.74%). An excellent correlation was established between %HJB-RBCs and spleen scintigraphy results. RBC adhesion to laminin and endothelial cells increased with time. Adhesion to endothelial cells negatively correlated with splenic function. Irreversibly sickled cells (ISCs), used as a surrogate marker of impaired deformability, were detected at enrollment and increased significantly at 18 months. %ISCs correlated positively with %HJB-RBCs and negatively with splenic uptake, indicating a relationship between their presence in the circulation and spleen dysfunction. In the subgroup of 8 infants who subsequently experienced ASS, %ISCs at enrollment were significantly higher compared with the asymptomatic group, suggesting a major role of impaired deformability in ASS. Higher levels of %HJB-RBCs were observed after the occurrence of ASS, demonstrating its negative impact on splenic function.
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http://dx.doi.org/10.1182/bloodadvances.2019000106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693014PMC
August 2019

Retroperitoneal Approach for Ureteropelvic Junction Obstruction: Encouraging Preliminary Results With Robot-Assisted Laparoscopic Repair.

Front Pediatr 2019 28;7:209. Epub 2019 May 28.

Service de Chirurgie Viscérale et Urologie Pédiatriques, APHP, Hôpital Necker, Paris, France.

Robot-assisted laparoscopic pyeloplasty (RALP) is gaining acceptance among pediatric urologists. Few studies have evaluated the retroperitoneal approach for RALP. We share our experience from the first 2 years of a multidisciplinary pediatric robotic program in our center. We performed a retrospective analysis of prospectively collected data of children undergoing RALP for ureteropelvic junction obstruction ( = 50). Diagnosis was confirmed by ultrasound and Tc-99m mercaptoacetyltriglycine renal scan or MRI; the same criteria were used to evaluate outcome. Surgical approach was chosen according to a specific algorithm. Transperitoneal approach ( = 13) was reserved for horseshoe kidney, ectopic kidney, and redo surgery. We analyzed the 37 cases performed by a lateral retroperitoneal approach. Dismembered pyeloplasty was done for all cases and anastomosis was performed using a running monofilament 6/0 absorbable suture. All were drained by double J stent. Patient data, operating room parameters and postoperative course were recorded. The median age was 7.9 years (5.1-13.8); the youngest was 2 years old. The median weight was 23 kg (17-41) with the smallest weighing 12.4 kg. Aberrant crossing vessels were present in 18 children. Median set-up time, from skin incision until the end of the 4-port insertion, was 33 min (29-48). Median surgeon's console time was 151 min (136-182). No conversion to an open procedure was necessary. The postoperative course was free of complications, except urinary tract infection in 6 children. All but 4 patients were discharged on day one. Median follow-up was 9 months (5-13). Redo pyeloplasty was not required. Practical training of other colleagues was possible after 10 cases performed by the same surgeon. These preliminary results suggest that retroperitoneal RALP in children is feasible, safe and effective. It is an excellent option with ideal anatomical exposure. Longer term results as well as continued practice will identify and overcome any challenges and enable surgical mastery of this procedure which is still evolving.
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http://dx.doi.org/10.3389/fped.2019.00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547808PMC
May 2019

Relationship between vitamin D status in pregnancy and the risk for preeclampsia: A nested case-control study.

Clin Nutr 2020 02 15;39(2):440-446. Epub 2019 Feb 15.

Laboratoire d'Explorations Fonctionnelles, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Background & Aims: Vitamin D is thought to be involved in the pathogenesis of preeclampsia. To evaluate the relationship between vitamin D insufficiency in the first trimester of pregnancy and preeclampsia.

Methods: Nested case-control study (FEPED study) in type 3 obstetrical units. Pregnant women from 10 to 15 WA. For each patient with preeclampsia, 4 controls were selected from the cohort and matched by parity, skin color, maternal age, season and BMI. The main outcome measure was serum 25(OH)D status in the first trimester.

Results: 83 cases of preeclampsia were matched with 319 controls. Mean 25(OH)D levels in the first trimester were 20.1 ± 9.3 ng/mL in cases and 22.3 ± 11.1 ng/mL in controls (p = 0.09). The risk for preeclampsia with 25(OH)D level ≥30 ng/mL in the first trimester was decreased, but did not achieve statistical significance (OR, 0.57; 95% CI, 0.30-1.01; p = 0.09). High 25(OH)D during the 3rd trimester was associated with a significantly decreased risk of preeclampsia (OR, 0.43; 95%CI, 0.23-0.80; p = 0.008). When women with 25(OH)D levels <30 ng/mL both in the first and 3rd trimesters ("low-low") were taken as references, OR for preeclampsia was 0.59 (95% CI, 0.31-1.14; p = 0.12) for "low-high" or "high-low" women and 0.34 (95% CI, 0.13-0.86; p = 0.02) for "high-high" women.

Conclusions: No significant association between preeclampsia and vitamin D insufficiency in the first trimester was evidenced. However, women with vitamin D sufficiency during the 3rd trimester and both in the first and 3rd trimesters had a significantly lower risk of preeclampsia.
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http://dx.doi.org/10.1016/j.clnu.2019.02.015DOI Listing
February 2020

Glibenclamide oral suspension: Suitable and effective in patients with neonatal diabetes.

Pediatr Diabetes 2019 05 21;20(3):246-254. Epub 2019 Feb 21.

Pediatric diabetes and endocrinology, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Results of genetic have led to off-label glibenclamide treatment in patients with neonatal diabetes (NDM) because of potassium channel mutations. No pediatric form of glibenclamide was available. Glibenclamide was designated an orphan drug designation for NDM and a suspension was developed. As a part of the pediatric plan investigation, we assessed its acceptability, efficiency, and safety.

Methods: In this Phase II, prospective, non-randomized, single-center study, patient received glibenclamide tablets for 1 month then the suspension for 3 months. We assessed acceptability using hedonic scales and patient questionnaires, effectiveness using glycated hemoglobin (HbA1C) assays and safety based on hypo and hyperglycemia, and other adverse events.

Results: We included 10 patients (0.1-16.2 years, 6 < 5 years) were included. Younger patients preferred the suspension and older the tablets. All parents were satisfied with the ease of suspension administration. The parents of 5 of 6 younger children preferred the suspension over the tablets and kept it. Switching from tablets to suspension did not affect the excellent metabolic control (median HbA1c change, -0.40%, [-1.3% to 0.5%] P = 0.08). Median frequencies of hypoglycemia and hyperglycemia were less than 5% of routine blood glucose assays and were similar with both dosage forms. Two patients each experienced one episode of hypoglycemia below 35 mg/dL highlighting the need for dosage titration when switching from tablets to suspension. Transient and non-severe abdominal pain or diarrhea occurred in three patients. None of the patients discontinued the treatment.

Conclusion: The glibenclamide oral suspension Amglidia, the first anti-diabetic drug specifically developed for pediatric patients, is acceptable, effective, and safe in patients with NDM (NCT02375828).

Clinical Trial Registration: Glibentek in Patients with Neonatal Diabetes Secondary to Mutations in K + -ATP Channels, clinicaltrials.gov, NCT02375828, https://clinicaltrials.gov/ct2/show/NCT02375828.
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http://dx.doi.org/10.1111/pedi.12823DOI Listing
May 2019

Comparison of the Quality of Pediatric Randomized Controlled Trials Published in Both Nursing and Medical Journals: Adherence to the CONSORT Statement.

Worldviews Evid Based Nurs 2018 Dec 15;15(6):447-454. Epub 2018 Oct 15.

Pharmacology and Drug Evaluation in Children and Pregnant Women, Paris Descartes University, Sorbonne Paris Cité, France.

Background: Nursing care should be based on scientific evidence. However, studies must be performed rigorously with accurate reporting for their findings to be applicable to practice. Since the body of scientific nursing literature is broad, the quality and validity of its findings should be regularly controlled and verified to ensure their application and their practical impact.

Purpose: To compare reporting quality of pediatric randomized controlled trial (RCT) articles in nursing and medical journals.

Methods: Randomly selected articles were reviewed and scored to assess the number of CONSORT items that were adequately reported, generating a CONSORT score. The CONSORT scores for 28 items were compared between the two journal types.

Results And Discussion: The CONSORT scores by journal type were not significantly different: (19.2 [16.2; 22] for medical journals and 19.5 [16.1; 21.5] for nursing journals, p = .77). The reporting of CONSORT items was poor for both journal types. However, there were two significant differences: item 19 (Declaration of all important harm or unintended effects, p = .0006) and item 23 (Registration number of the study, p = .0003), were reported more often in medical journals. The adherence of journals to the CONSORT statement and large sample size was associated with better quality of the reporting of studies.

Conclusions: Based on reporting quality, nursing studies have the same scientific credibility and rigor as medical studies in the pediatric field.

Linking Evidence To Action: The findings of this study could help researchers improve the reporting of their studies and highlight the importance of reporting quality for future knowledge transfer and practical use. The quality of research and its reporting is necessary to improve knowledge transfer into practice.
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http://dx.doi.org/10.1111/wvn.12329DOI Listing
December 2018

Prenatal education of overweight or obese pregnant women to prevent childhood overweight (the ETOIG study): an open-label, randomized controlled trial.

Int J Obes (Lond) 2019 02 21;43(2):362-373. Epub 2018 Sep 21.

AP-HP, CRNH-IdF, CINFO, COMUE Sorbonne-Paris-Cité, Department of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, Bondy, France.

Background: We aimed to evaluate whether pre and perinatal education of pregnant women would reduce childhood overweight.

Methods: Four French centers included women at ≤21 gestational weeks (GWs) with body mass index (BMI) >25 kg/m before pregnancy. Patients were randomized to a control group (routine care including at least one dietary visit) or an intervention group (2 individuals (26 and 30 GW) and 4 group sessions (21, 28, 35 GW, 2 months postpartum)) aimed at educating the future mother regarding infant and maternal nutrition. The primary objective was to reduce post-natal excessive weight gain in the infant from birth to 2 years (NCT00804765). This project was funded by a grant from the National Programme for Hospital Research (PHRC-2007 French Ministry of Health).

Results: We included 275 women (BMI: 32.5 kg/m). The rate of post-natal excessive weight gain was similar in the intervention (n = 132) and control (n = 136) groups by intention to treat (ITT: 59.1% vs 60.3% respectively, p = 0.84) in available data (AD, n = 206) and by per-protocol analysis (PP, n = 177). Two years after delivery, normalization of maternal BMI and number of infants with BMI < 19 kg/m were not significantly different in the interventional group in ITT and in the control group. Although not significantly different in ITT, normalization of maternal BMI was more frequent in AD (n = 149: 12.9% vs 3.8%, p = 0.04) and 2-year-old infant BMIs were less likely to be >19 kg/m in the intervention group in AD (n = 204: 0% vs 6.8%, p = 0.014) and PP (n = 176: 0% vs 6.4%, p = 0.03).

Conclusions: An education and nutritional counseling program for overweight women, starting after 3 months of gestation, did not significantly change post-natal excessive weight gain of infants or prevent overweight in mothers and children 2 years after delivery.
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http://dx.doi.org/10.1038/s41366-018-0205-zDOI Listing
February 2019

Vitamin D status during pregnancy and in cord blood in a large prospective French cohort.

Clin Nutr 2019 10 31;38(5):2136-2144. Epub 2018 Aug 31.

Fondation PremUp, Paris, France; Department of Obstetrics and Gynecology, Antoine-Béclère Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud, Clamart, France.

Background & Aims: Vitamin D status during pregnancy and in newborns has never been studied in France. This study aims at determining the vitamin D status during the first and third trimesters of pregnancy (T1, T3) and in cord blood (CB) in the middle-north of France.

Methods: We conducted a prospective cohort study in five French centers (latitude 47.22 to 48.86°N). Serum 25(OH)-vitamin D (25(OH)D) concentrations were measured using a radioimmunoassay during T1, T3 and in CB. According to the French guidelines, pregnant women received cholecalciferol, 100,000 IU, in the seventh month.

Results: Between April 2012 and July 2014, 2832 women were included, of whom 2803 were analyzed (mean ± SD age: 31.5 ± 5.0 years; phototypes 5-6: 21.8%). Three and 88.6% of participants received supplementation during the month before inclusion and in the seventh month, respectively. At T1, T3, and CB, mean 25(OH)D concentrations were 21.9 ± 10.4, 31.8 ± 11.5, and 17.0 ± 7.2 ng/mL, respectively, and 25(OH)D was <20 ng/mL in 46.5%, 14.0%, and 68.5%, respectively. At T1, body mass index ≥25 kg/m, dark phototypes, sampling outside summer, and no supplementation before inclusion were independently associated with vitamin D insufficiency (25(OH)D < 20 ng/mL). Women who received cholecalciferol supplementation in month 7 had higher 25(OH)D at T3 than non-supplemented women (32.5 ± 11.4 versus 25.8 ± 11.4 ng/mL, p = <0.001) and marginally higher 25(OH)D in CB (17.2 ± 7.2 versus 15.5 ± 7.1 ng/mL, p = 0.004).

Conclusions: Despite the recommended supplementation, vitamin D insufficiency is frequent during pregnancy and in newborns in France.
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http://dx.doi.org/10.1016/j.clnu.2018.08.035DOI Listing
October 2019

Prognostic factors of disease severity in infants with sickle cell anemia: A comprehensive longitudinal cohort study.

Am J Hematol 2018 11 21;93(11):1411-1419. Epub 2018 Sep 21.

Service de Pédiatrie et Maladies Infectieuses, Hôpital Universitaire Necker-Enfants Malades, Paris, France.

In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi-center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sβ°) during the first 2 years of life (ClinicalTrials.gov: NCT01207037). Time to first occurrence of a severe clinical event-acute splenic sequestration (ASS), vaso-occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death-was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ±1 months. Median follow-up was 19.4 months. During the study period, 38.6% of infants experienced ≥1 severe event: 14% ASS, 22.8% ≥ 1 VOC (median age: 13.4 and 12.8 months, respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or ϒ-globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43), respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for subsequent severe complications, who might maximally benefit from early disease modifying treatments.
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http://dx.doi.org/10.1002/ajh.25260DOI Listing
November 2018

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial.

JAMA 2018 08;320(6):557-565

Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France.

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated.

Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.

Design, Setting, And Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.

Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.

Main Outcomes And Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.

Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).

Conclusions And Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.

Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.
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http://dx.doi.org/10.1001/jama.2018.9396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583003PMC
August 2018

Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients.

Am J Obstet Gynecol 2018 09 21;219(3):281.e1-281.e9. Epub 2018 Jul 21.

Department of Pediatric Endocrinology, Gynecology, and Diabetology, Assistance Publique - Hôpitaux de Paris, Hôpital Necker, Paris, France; Université Paris Descartes, Paris, France.

Background: Vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon's preferences rather than on quality comparative studies and validated protocols.

Objective: We sought to compare dilation and surgical management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population.

Study Design: Our multicenter study included 131 patients >18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale-Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal-Wallis, Wilcoxon, and Student exact test.

Results: Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8-34.8] and 24.7 [2.6-34.4], respectively) than the intercourse group (30.2 [7.8-34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale-Revised median scores were, respectively, 17 [0-52], 20 [0-47], and 10 [10-40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5-12]) compared to surgery group (11 cm [6-15]) and intercourse group (11 cm [6-12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas <6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation.

Conclusion: Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second-line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.
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http://dx.doi.org/10.1016/j.ajog.2018.07.015DOI Listing
September 2018

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis.

Ann Rheum Dis 2018 07 23;77(7):1003-1011. Epub 2017 Dec 23.

Department of Ophthalmology, University Hospital Pitie-Salpetriere, Paris, France.

Objectives: To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX).

Methods: Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab.

Results: At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment.

Conclusions: This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy.

Trial Registration Number: NCT01385826.
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http://dx.doi.org/10.1136/annrheumdis-2017-212089DOI Listing
July 2018

Performances and Limitations of Several Ultrasound-Based Elastography Techniques: A Phantom Study.

Ultrasound Med Biol 2017 10 29;43(10):2402-2415. Epub 2017 Jul 29.

Adult Radiology Department- Necker Enfants-Malades Hospital-Université, Paris Descartes, Sorbonne Paris Cite, Paris, France.

The objective of this study is to assess strain and shear wave (SW) elastography performance in terms of accuracy by performing in vitro measurements on a calibrated elastography phantom. Acquisitions were done on a phantom containing 4 inclusions (12-74 kPa) embedded in a homogeneous background material (30 kPa). We performed qualitative assessment on elastograms, semiquantitative assessment with strain or elasticity ratios between each inclusion and the background and quantitative evaluation with SW acquisitions. Ratio and elasticity estimations were compared with expected values. Biases, relative errors and 95% confidence intervals (95% CI) were calculated. All techniques adequately classified inclusions as harder or softer than the background. For stiffness ratio estimation, SW methods were more precise than strain methods and had significantly higher percentages of correctly classified measurements (p = 0.008). Quantitative stiffness measurements were reproducible despite constant biases. SW elastography methods provide more reproducible estimations of tissue stiffness ratio than strain methods, as well as reproducible quantitative tissue stiffness despite constant biases.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.06.008DOI Listing
October 2017

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders.

J Med Genet 2018 02 28;55(2):131-136. Epub 2017 Jul 28.

Universitè Paris Descartes - Sorbonne Paris Citè, Institut Imagine, INSERM UMR1163, Laboratoire des Maladies Mitochondriales, Paris, France.

Background: Mitochondrial DNA (mtDNA) disorders have a high clinical variability, mainly explained by variation of the mutant load across tissues. The high recurrence risk of these serious diseases commonly results in requests from at-risk couples for prenatal diagnosis (PND), based on determination of the mutant load on a chorionic villous sample (CVS). Such procedures are hampered by the lack of data regarding mtDNA segregation in the placenta.The objectives of this report were to determine whether mutant loads (1) are homogeneously distributed across the whole placentas, (2) correlate with those in amniocytes and cord blood cells and (3) correlate with the mtDNA copy number.

Methods: We collected 11 whole placentas carrying various mtDNA mutations (m.3243A>G, m.8344A>G, m.8993T>G, m.9185T>C and m.10197G>A) and, when possible, corresponding amniotic fluid samples (AFSs) and cord blood samples. We measured mutant loads in multiple samples from each placenta (n= 6-37), amniocytes and cord blood cells, as well as total mtDNA content in placenta samples.

Results: Load distribution was homogeneous at the sample level when average mutant load was low (<20%) or high (>80%) at the whole placenta level. By contrast, a marked heterogeneity was observed (up to 43%) in the intermediate range (20%-80%), the closer it was to 40%-50% the mutant load, the wider the distribution. Mutant loads were found to be similar in amniocytes and cord blood cells, at variance with placenta samples. mtDNA content correlated to mutant load in m.3243A>G placentas only.

Conclusion: These data indicate that (1) mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes; (2) the m.3243A>G mutation behaves differently from other mtDNA mutations with respect to the impact on mtDNA copy number, as previously shown in human preimplantation embryogenesis.
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http://dx.doi.org/10.1136/jmedgenet-2017-104615DOI Listing
February 2018

Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood.

Endocr Connect 2017 10 9;6(7):422-429. Epub 2017 Aug 9.

P Touraine, Endocrinology and reproductive medicine, Hopitaux Universitaires Pitie Salpetriere-Charles Foix, Paris, France.

Background: Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life.

Methods: Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the quality of life (WHOQoL -BREF).

Results: Seventy three patients were included in the study, among them 59/73 (81%) were transferred to adult endocrinologist by their pediatricians for transition. WHOQoL -BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global quality of life than the group without regular follow-up after transition.

Conclusion: Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and with better QoL in adults with CAH.
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http://dx.doi.org/10.1530/EC-17-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551429PMC
October 2017

Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France.

Clin Infect Dis 2017 03;64(6):767-775

Service de Maladies Infectieuses et Tropicales, Centre d''Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, France.

Background: Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points.

Method: Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry.

Results: Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood.

Conclusions: Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.
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http://dx.doi.org/10.1093/cid/ciw837DOI Listing
March 2017

Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome.

PLoS One 2017 3;12(3):e0172147. Epub 2017 Mar 3.

Hématologie clinique, Hôpital Saint Vincent de Paul, Université Catholique de Lille, Lille, France.

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336214PMC
August 2017

Diabetes knowledge in adolescents with type 1 diabetes and their parents and glycemic control.

Pediatr Diabetes 2017 Nov 11;18(7):559-565. Epub 2016 Oct 11.

Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Necker-Enfants malades, Paris, France.

Objective: To evaluate diabetes knowledge and skills (DKS) in adolescents (>10 year) with type 1 diabetes (T1D) and their parents, and its effect on glycemic control.

Methods: A ready-to-use program and a standardized questionnaire comprising 50 true-false questions based on this program, were elaborated by a National Committee, to help dispensing education at diagnosis of T1D. The questionnaire was completed by 2933 T1D patients (49% girls, 51% boys; 14.1 ± 2.5 year), 2180 mothers and 798 fathers, in 115 pediatric centers. Associations between DKS score (number of correct answers), glycated hemoglobin (HbA1c) and sociofamilial characteristics were assessed.

Results: DKS score increased with age, and was higher in girls than in boys and in mothers than in fathers; it correlated strongly between adolescents and their own parents; it was higher when adolescents had previously participated in diabetes camp and when parents had higher academic levels. HbA1c decreased significantly with parents' higher DKS score and academic level, and when both parents lived together. Mean adolescent DKS score was significantly higher in patients with HbA1c below 8% or 8.5% than for patients with HbA1c above these thresholds.

Conclusion: A large survey in T1D children and adolescents and their parents showed associations between DKS and glycemic control, and the major role of sociofamilial factors.
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http://dx.doi.org/10.1111/pedi.12458DOI Listing
November 2017

Preoperative risk factors for intra-operative bleeding in pediatric liver transplantation.

Pediatr Transplant 2016 Dec 29;20(8):1065-1071. Epub 2016 Sep 29.

Pediatric surgery unit, Hôpital Necker enfants malades, Paris, France.

This study analyzes the preoperative risk factors for intra-operative bleeding in our recent series of pediatric LTs. Between November 2009 and November 2014, 84 consecutive isolated pediatric LTs were performed in 81 children. Potential preoperative predictive factors for bleeding, amount of intra-operative transfusions, postoperative course, and outcome were recorded. Cutoff point for intra-operative HBL was defined as intra-operative RBC transfusions ≥1 TBV. Twenty-six patients (31%) had intra-operative HBL. One-year patient survival after LT was 66.7% (CI 95%=[50.2-88.5]) in HBL patients and 83.8% (CI 95%=[74.6-94.1]) in the others (P=.054). Among 13 potential preoperative risk factors, three of them were identified as independent predictors of high intra-operative bleeding: abdominal surgical procedure(s) prior to LT, factor V level ≤30% before transplantation, and ex situ parenchymal transsection of the liver graft. Based on these findings, we propose a simple score to predict the individual hemorrhagic risk related to each patient and graft association. This score may help to better anticipate intra-operative bleeding and improve patient's management.
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http://dx.doi.org/10.1111/petr.12794DOI Listing
December 2016

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population.

Horm Res Paediatr 2016 28;86(5):309-318. Epub 2016 Sep 28.

Department of Pediatrics and Medical Genetics, Brabois Hospital, Vandoeuvre-lès-Nancy, France.

Background: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation.

Methods: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis.

Results: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications.

Conclusions: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.
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http://dx.doi.org/10.1159/000448282DOI Listing
April 2017

Efficacy and safety of i.v. sodium benzoate in urea cycle disorders: a multicentre retrospective study.

Orphanet J Rare Dis 2016 Sep 23;11(1):127. Epub 2016 Sep 23.

Reference Centre for Inherited Metabolic Disorders (MaMEA), Hôpital Necker-Enfants Malades, Institut Imagine, Université Paris Descartes, 149 rue de Sèvres, 75743, Paris, Cedex 15, France.

Background: The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. However, published data do not provide a clear picture of the benefits and risks of this drug. We report a retrospective multicentre study on the use of i.v. sodium benzoate in patients treated for UCD between 2000 and 2010 in the 6 French reference centres for metabolic diseases.

Results: Sixty-one patients with UCDs - 22 ornithine transcarbamylase (20 confirmed, 2 suspected), 18 arginino-succinate synthetase, 15 carbamoyl phosphate synthetase, 3 arginosuccinate lyase, 1 arginase deficiency, 1 N-acetylglutamate synthetase, 1 HHH syndrome - required i.v. sodium benzoate over the course of 95 acute episodes (NH3 > 100 μmol/L or high-risk situations, i.e., gastroenteritis, surgery). Forty out of 61 patients experienced only one episode of decompensation (neonatal coma, 68.6 %). The most frequent cause of late decompensation was infection (55.5 %). A loading dose of i.v. sodium benzoate (median 250 mg/kg over 2 h) was administered for 41/95 acute episodes. The median maintenance dose was 246.1 mg/kg/day, administered via peripheral venous infusion in all cases except one via a central line. The total median duration of i.v. sodium benzoate treatment per episode was 2 days (0-13 days). The median durations of hospitalization in intensive care and metabolic units were 4 days (0-17 days) and 10 days (0-70 days), respectively. Eight patients died during the neonatal coma (n = 6) or surgery (n = 2). The median plasma ammonium level before treatment was 245.5 μmol/L (20.0-2274.0 μmol/L); it decreased to 40.0 μmol/L in patients who were alive (13.0-181.0 μmol/L) at the end of treatment with i.v. sodium benzoate. A decrease in ammonium level to ≤ 100 μmol/L was obtained in 92.8 % of episodes (64/69 of the episodes recorded for the 53 surviving patients). Five patients required another treatment for hyperammonemia (sodium phenylacetate + sodium benzoate, haemofiltration). Eighteen side effects were reported related to the i.v. infusion (local diffusion, oedema).

Conclusion: This 10-year retrospective study shows that i.v. sodium benzoate associated with an emergency regimen is an effective and safe treatment for acute episodes of UCD.
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http://dx.doi.org/10.1186/s13023-016-0513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034629PMC
September 2016

Longitudinal MRI and Ferritin Monitoring of Iron Overload in Chronically Transfused and Chelated Children With Sickle Cell Anemia and Thalassemia Major.

J Pediatr Hematol Oncol 2016 10;38(7):497-502

*Department of Pediatrics ∥Clinical Research Unit †Department of Radiology, Hôpital Universitaire Necker Enfants Malades, APHP ‡Paris Descartes University §UMR 8145, MAP5, Paris, France ¶Division of Pediatric Cardiology, University of Nebraska Medical Center and Children's Hospital and Medical Center, Omaha, NE.

Iron overload is an ineluctable complication in chronically transfused children warranting accurate assessment to avoid related morbidity. We investigated longitudinally the relationships between ferritin levels and hepatic and cardiac T2* magnetic resonance imaging (MRI) in a cohort of chronically transfused children receiving chelation therapy. Thirty children with sickle cell anemia (SCA) and 7 with thalassemia major (TM) chelated similarly by deferasirox were analyzed. Sex ratio, age, median duration of transfusion programs (5 y; range, 2 to 14 y), median transfusion iron intake 0.54 mg/kg/d (range, 0.27 to 0.74 mg/kg/d), and median ferritin level (1550 mg/L; range, 184 to 6204 mg/L) were comparable in TM and SCA. A significant relation was found between ferritin level and transfusion iron intake (P<0.001) despite chelation therapy. Analysis of 73 hepatic T2* MRI performed yearly demonstrated severe hepatic iron overload (≥14 mg/g) in 38.3% cases and a strong relationship between serum ferritin level and liver iron content both in SCA and TM (P<0.001). Analysis of 55 cardiac T2* MRI measurements found no cardiac overload in patients with SCA. Cardiac iron overload was moderate in 4 cases and severe in 1 case of TM. In almost half the cases, ferritin trend correctly predicted hepatic iron trend, both in patients with SCA and TM but failed to predict cardiac iron trend, notably in TM patients. Despite chelation therapy, iron burden in chronically transfused patients remains a threat. Ferritin levels are associated with liver iron overload in chelated children with SCA and TM, but iron burden should be best monitored with MRI whenever the setting allows it.
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http://dx.doi.org/10.1097/MPH.0000000000000595DOI Listing
October 2016

Specific T cells for the treatment of cytomegalovirus and/or adenovirus in the context of hematopoietic stem cell transplantation.

J Allergy Clin Immunol 2016 09 30;138(3):920-924.e3. Epub 2016 Apr 30.

Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Lymphohematopoiesis-INSERM UMR1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.03.032DOI Listing
September 2016

Recurrence of Solid Pseudopapillary Neoplasms of the Pancreas: Results of a Nationwide Study of Risk Factors and Treatment Modalities.

Pediatr Blood Cancer 2016 09 17;63(9):1515-21. Epub 2016 May 17.

Department of Pediatric Surgery, Necker Enfants-Malades Hospital-Université Paris Descartes, Sorbonne Paris Cite, Paris, France.

Background: Solid pseudopapillary neoplasms of the pancreas (SPPN) can relapse very late, but little is known about risk factors for recurrence and optimal treatment. We aimed to identify risk factors for recurrence and to analyze treatment modalities in all French pediatric cases of SPPN over the past 20 years.

Material And Methods: Data were collected from pediatric oncologists and surgeons, and also from adult pancreatic surgeons in order to identify late recurrences.

Results: Fifty-one patients (41 girls) were identified. Median age at diagnosis was 13.1 years [8.7-17.9]. Abdominal pain was the commonest presenting symptom (32/49, 65%). The tumor was located in the pancreatic head in 24 patients (47%). Preoperative biopsy or cytology was performed in 14 cases (28%). All patients were operated with a median of 23 days [0-163] after diagnosis. The rate of postoperative morbidity was 29%. With a median follow-up of 65 months [0.3-221], the overall and event-free survival was 100% and 71%, respectively. Seven patients (13.7%) relapsed with a median of 43 months [33-94] after initial surgery. Six were treated surgically, either alone (n = 3) or with perioperative chemotherapy (n = 2) or hyperthermic intraperitoneal chemotherapy (n = 1). One patient in whom further treatment was not feasible was still alive at last news. Risk factors for recurrence were positive surgical margins (P = 0.03) and age less than 13.5 years at diagnosis (P = 0.03).

Conclusions: SPPN recurrence in this pediatric series was a rare and late event that did not undermine overall survival. Complete surgical removal of recurrent tumors appears to be the best option.
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http://dx.doi.org/10.1002/pbc.25986DOI Listing
September 2016