Publications by authors named "Valerie Biran"

59 Publications

Bedside functional monitoring of the dynamic brain connectivity in human neonates.

Nat Commun 2021 02 17;12(1):1080. Epub 2021 Feb 17.

Physics for Medicine Paris, Inserm U1273, CNRS UMR 8063, ESPCI Paris, PSL University, Paris, France.

Clinicians have long been interested in functional brain monitoring, as reversible functional losses often precedes observable irreversible structural insults. By characterizing neonatal functional cerebral networks, resting-state functional connectivity is envisioned to provide early markers of cognitive impairments. Here we present a pioneering bedside deep brain resting-state functional connectivity imaging at 250-μm resolution on human neonates using functional ultrasound. Signal correlations between cerebral regions unveil interhemispheric connectivity in very preterm newborns. Furthermore, fine-grain correlations between homologous pixels are consistent with white/grey matter organization. Finally, dynamic resting-state connectivity reveals a significant occurrence decrease of thalamo-cortical networks for very preterm neonates as compared to control term newborns. The same method also shows abnormal patterns in a congenital seizure disorder case compared with the control group. These results pave the way to infants' brain continuous monitoring and may enable the identification of abnormal brain development at the bedside.
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http://dx.doi.org/10.1038/s41467-021-21387-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889933PMC
February 2021

Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

J Pediatr 2020 Dec 24. Epub 2020 Dec 24.

Inserm U1141, University Paris Diderot, Sorbone Paris Cité, Paris, France; Division of Neonatology and Pediatric Intensive Care, Children's University Hospital of Geneva and University of Geneva, Geneva, Switzerland. Electronic address:

Objective: To define nomograms of serum cortisol values before 24 hours of postnatal life for extremely preterm infants and determine whether baseline cortisol values affect the benefit/risk ratio of prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia (BPD).

Study Design: We performed a predefined secondary analysis of the multicenter randomized controlled PREMILOC trial that included inborn infants delivered before 28 weeks of gestation. Nomograms of baseline serum cortisol values measured in 325 enrolled patients were determined for male and female neonates and correlated to perinatal events. BPD-free survival and severe adverse events were analyzed in placebo and hydrocortisone groups according to the cortisol z score in multivariate logistic regression models.

Results: Increased cortisol levels measured before 24 hours following birth were associated with a significantly higher chance of BPD-free survival only in placebo-treated infants (aOR [95% CI] 1.57 [1.08-2.27], P = .02) based on sex-specific nomograms for baseline cortisol levels. The cortisol z score for infants treated with prophylactic hydrocortisone predicted a risk of high-grade intraventricular hemorrhage (aOR [95% CI] 1.82 [1.06-3.15], P = .03) and spontaneous intestinal perforation (aOR [95% CI] 4.81 [1.34-17.22], P = .02).

Conclusions: We found no predictive value of baseline cortisol levels for BPD-free survival in infants born extremely preterm treated with hydrocortisone. However, high cortisol levels early after birth were associated with a greater risk of severe intraventricular hemorrhage and spontaneous intestinal perforation in infants treated with hydrocortisone and, therefore, a lower benefit/risk ratio for the treatment.

Trial Registration: EudraCT 2007-002041-20, ClinicalTrial.gov: NCT00623740.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.057DOI Listing
December 2020

Misdiagnosing Midgut Volvulus in Very Preterm Infants: What is the Impact of Delay Before Surgery?

Indian J Pediatr 2021 Jan 15;88(1):89-90. Epub 2020 Jul 15.

Department of General Pediatric Surgery, Robert-Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1007/s12098-020-03446-1DOI Listing
January 2021

Invasive Infections in <3-Month-Old Infants in France: Clinical and Laboratory Features.

Front Pediatr 2020 6;8:204. Epub 2020 May 6.

Université de Paris, IAME, INSERM, Paris, France.

Few data are available on invasive group A (GAS) infections (IGASIs) in infants. We described initial clinical and laboratory features and outcomes of <3-month-old infants hospitalized for an IGASI between 2007 and 2016 in France. Patients were identified from the French National Reference Centre for streptococci. IGASI was defined by the isolation of GAS from blood cultures or from other usually sterile sites. Data collection was performed by assessing the patients' hospitalization reports. Twenty-six patients (15 males; 57.7%) were included. Among 19 cases with available data, 14 (73.7%) were household contacts of a GAS infection, reaching 8/9 (88.9%) in neonates. The diagnoses were bacteremia ( = 18; 69.2%), pleural effusion or pneumonia ( = 6; 23.1%), meningitis with brain abscess ( = 1; 3.8%), and septic arthritis ( = 1; 3.8%). Fever ( = 10; 38.5%), hemodynamic disorders ( = 11; 42.3%), respiratory disorders ( = 7; 26.9%), thrombocytopenia ( = 7; 26.9%), and neutropenia ( = 5; 19.2%) were frequently observed. The main -genotype was -1 ( = 8; 30.8%). Thirteen (50.0%) infants have been admitted to the intensive care unit, and two (7.7%) died. Respiratory disorders, high C-reactive protein level, and the need for transfusion were significantly associated with severity. IGASI remains uncommon in <3-month-old children but leads to a high morbidity. Whether an antibiotic prophylaxis for contact neonates of a patient with GAS infection decreases the risk of infection remains to be determined.
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http://dx.doi.org/10.3389/fped.2020.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217982PMC
May 2020

In-line filtration in very preterm neonates: a randomized controlled trial.

Sci Rep 2020 03 19;10(1):5003. Epub 2020 Mar 19.

Assistance Publique-Hôpitaux de Paris, Neonatal intensive care unit, Robert Debré children's hospital, Paris, France.

In-line filtration is increasingly used in critically-ill infants but its benefits, by preventing micro-particle infusion in very preterm neonates, remain to be demonstrated. We conducted a randomized controlled trial among very preterm infants allocated to receive either in-line filtration of all the intra-venous lines or standard care without filters. The primary outcome was differences greater than 20% in the median changes in pro-inflammatory cytokine serum concentrations measured at day 3 and day 8 (+/-1) using a Luminex multianalytic profiling technique. Major neonatal complications were analyzed as secondary predefined outcomes. We randomized 146 infants, assigned to filter (n = 73) or control (n = 73) group. Difference over 20% in pro-inflammatory cytokine concentration between day 3 and day 8 was not found statistically different between the two groups, both in intent-to-treat (with imputation) and per protocol (without imputation) analyses. The incidences of most of neonatal complications were found to be similar. Hence, this trial did not evidence a beneficial effect of in-line filtration in very preterm infants on the inflammatory response syndrome and neonatal morbidities. These data should be interpreted according to local standards in infusion preparation and central line management.
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http://dx.doi.org/10.1038/s41598-020-61815-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081338PMC
March 2020

Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality.

Arch Dis Child Fetal Neonatal Ed 2020 Sep 24;105(5):520-525. Epub 2020 Jan 24.

Inserm U1141, University of Paris, Paris, France

Objective: To determine whether early low-dose hydrocortisone treatment in extremely preterm infants is associated with brain damage assessed by MRI at term equivalent of age (TEA).

Patients And Outcomes: This is a predefined secondary analysis of brain abnormalities, observed by MRI at TEA, of patients randomly assigned to receive either placebo or hydrocortisone in the PREMILOC trial. Outcomes were based on brain abnormalities graded according to Kidokoro scores.

Results: Among 412 survivors at TEA, 300 MRIs were performed and 295 were suitable for analysis. Kidokoro scoring was completed for 119/148 and 110/147 MRIs in the hydrocortisone and placebo groups, respectively. The distribution of the Kidokoro white matter (WM) subscore and other subscores was not significantly different between the two groups. There was, however, a significant association between a higher overall Kidokoro score and hydrocortisone treatment (5.84 (SD 3.51) for hydrocortisone and 4.98 (SD 2.52) for placebo; mean difference, 0.86; 95% CI 0.06 to 1.66; p=0.04). However, hydrocortisone was not statistically associated with moderate-to-severe brain lesions (Kidokoro overall score ≥6) in a multivariate logistic regression model accounting for potential confounding variables (adjusted OR (95% CI) 1.27 (0.75 to 2.14), p=0.38). Bronchopulmonary dysplasia at 36 weeks postmenstrual age significantly predicted both WM damage (adjusted OR (95% CI) 2.70 (1.03 to 7.14), p=0.04) and global brain damage (adjusted OR (95% CI) 2.18 (1.19 to 3.99), p=0.01).

Conclusions: Early hydrocortisone exposure in extremely preterm infants is not statistically associated with either WM brain damage or overall moderate-to-severe brain lesions when adjusted for other neonatal variables.

Trial Registration Number: EudraCT number 2007-002041-20, NCT00623740.
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http://dx.doi.org/10.1136/archdischild-2019-317720DOI Listing
September 2020

Cord blood procalcitonin level and early-onset sepsis in extremely preterm infants.

Eur J Clin Microbiol Infect Dis 2019 Sep 1;38(9):1651-1657. Epub 2019 Jun 1.

Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children's Hospital, University Paris Diderot, Sorbonne Paris-Cité, 75019, Paris, France.

Early-onset neonatal sepsis (EOS) is observed in 1.7% of extremely preterm infants, with high morbidity and mortality rate. Cord blood procalcitonin (PCT) is a sensitive marker of EOS in full-term newborns, but it has been rarely studied in premature infants. The diagnostic value of cord blood PCT by immunofluorescence has been assessed as an early marker of EOS in a prospective cohort of extremely preterm infants, with a threshold at 0.5 μg/L. EOS was defined by a positive bacterial culture or by the association of postnatal biological/clinical signs of EOS and antibiotic treatment for more than 72 h. Correlation between PCT serum concentrations and postnatal morbidities was also analyzed. Among a total of 186 infants, 45 (24%) were classified as EOS. Blood PCT concentration was ≤ 0.5 μg/L in 114 infants, including 11 EOS (9.6%) and PCT was > 0.5 μg/L in 72 babies including 34 EOS (47.2%). PCT concentration > 0.5 μg/L was associated with higher risk of EOS (OR 2.18; CI95% 1.58-3.02; p < 0.0001). The receiver operating characteristic curve determined a cutoff of 0.7 μg/L as the best compromise, with an area under the curve of 0.75 (sensitivity 69%, specificity 70%). In multivariate analysis, clinical chorioamnionitis was associated with PCT concentration > 0.5 μg/L (OR 2.58; CI95% 1.35-4.94; p = 0.004). Cord blood PCT is a marker significantly associated with EOS in extremely preterm infants, but its sensitivity remains low. Its added value in combination with other early marker of EOS needs to be further investigated in this high-risk population.
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http://dx.doi.org/10.1007/s10096-019-03593-0DOI Listing
September 2019

Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants.

J Antimicrob Chemother 2019 08;74(8):2128-2138

Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.

Objectives: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.

Methods: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.

Results: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.

Conclusions: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
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http://dx.doi.org/10.1093/jac/dkz158DOI Listing
August 2019

Melatonin Levels in Preterm and Term Infants and Their Mothers.

Int J Mol Sci 2019 Apr 27;20(9). Epub 2019 Apr 27.

Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children's Hospital, University Paris Diderot, Sorbonne Paris-Cité, 75019 Paris, France.

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 ( < 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, < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, < 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.
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http://dx.doi.org/10.3390/ijms20092077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540351PMC
April 2019

Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug.

Br J Clin Pharmacol 2018 05 9;84(5):997-1005. Epub 2018 Mar 9.

Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.

Aims: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug.

Methods: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM.

Results: Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CL ) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model-predicted CL are 12.5% (5-95% percentile: 3-14.9%) and 44.9% (5-95% percentile: 29.9-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant of omeprazole is 6.93 (5-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients.

Conclusions: Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation.
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http://dx.doi.org/10.1111/bcp.13526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903239PMC
May 2018

Ontogeny of human mucosal-associated invariant T cells and related T cell subsets.

J Exp Med 2018 02 16;215(2):459-479. Epub 2018 Jan 16.

Institut national de recherche médicale (INSERM) UMR1149, Center for Research on Inflammation, Paris Diderot University, Paris, France

Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2 CD161CD4 T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2 CD161 T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2 and Vα7.2 CD161 T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2 CD161 T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2 CD161 T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2 CD161 and Vα7.2 CD161 populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαβ chains recognizing MR1-restricted microbial antigens.
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http://dx.doi.org/10.1084/jem.20171739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789419PMC
February 2018

Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth.

Arch Dis Child Fetal Neonatal Ed 2019 Jan 10;104(1):F30-F35. Epub 2018 Jan 10.

Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children's Hospital, Inserm U1123 and CIC-EC 1426, University Paris Diderot, Sorbonne Paris-Cité, Paris, France.

Objective: To determine whether early hydrocortisone treatment in extremely preterm infants affects neurodevelopmental outcomes at 2 years of age according to gestational age at birth.

Patients And Methods: This is an exploratory analysis of neurodevelopmental outcomes by gestational age strata from the PREMILOC trial, in which patients were randomly assigned to receive either placebo or low-dose hydrocortisone and randomisation was stratified by gestational age groups (24-25 and 26-27 weeks of gestation). Neurodevelopmental impairment (NDI) was assessed using a standardised neurological examination and the revised Brunet-Lézine scale at 22 months of corrected age.

Results: A total of 379 of 406 survivors were evaluated, 96/98 in the gestational age group of 24-25 weeks and 283/308 in the gestational age group of 26-27 weeks. Among surviving infants born at 24-25 weeks, significant improvement in global neurological assessment was observed in the hydrocortisone group compared with the placebo group (P=0.02) with a risk of moderate-to-severe NDI of 2% and 18%, respectively (risk difference 16 (95% CI -28% to -5%)). In contrast, no statistically significant difference between treatment groups was observed in infants born at 26-27 weeks (P=0.95) with a similar risk of moderate-to-severe NDI of 9% in both groups. The incidence of cerebral palsy or other major neurological impairments were found similar between treatment groups in each gestational group.

Conclusions: In an exploratory analysis of neurodevelopmental outcomes from the PREMILOC trial, early low-dose hydrocortisone was associated with a statistically significant improvement in neurodevelopmental outcomes in infants born at 24 and 25 weeks of gestation.
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http://dx.doi.org/10.1136/archdischild-2017-313756DOI Listing
January 2019

Study of the Factors Leading to Fetal and Neonatal Dysthyroidism in Children of Patients With Graves Disease.

J Endocr Soc 2017 Jun 25;1(6):751-761. Epub 2017 Apr 25.

Department of Neonatology, Obstetrics and Gynecology, University Hospitals Paris Nord Val de Seine, Assistance Publique Hôpitaux de Paris, Beaujon Hospital, Clichy 92118, France.

Context: Neonatal hyperthyroidism was first described in 1912 and in 1964 was shown to be linked to transplacental passage of maternal antibodies. Few multicenter studies have described the perinatal factors leading to fetal and neonatal dysthyroidism.

Objective: To show how fetal dysthyroidism (FD) and neonatal dysthyroidism (ND) can be predicted from perinatal variables, in particular, the levels of anti-thyrotropin receptor antibodies (TRAbs) circulating in the mother and child.

Design And Patients: This was a retrospective multicenter study of data from the medical records of all patients monitored for pregnancy from 2007 to 2014.

Setting: Among 280,000 births, the medical records of 2288 women with thyroid dysfunction were selected and screened, and 417 women with Graves disease and positive for TRAbs during pregnancy were included.

Results: Using the maternal TRAb levels, the cutoff value of 2.5 IU/L best predicted for FD, with a sensitivity of 100% and specificity of 64%. Using the newborn TRAb levels, the cutoff value of 6.8 IU/L best predicted for ND, with a sensitivity of 100% and a specificity of 94%. In our study, 65% of women with a history of Graves disease did not receive antithyroid drugs during pregnancy but still had infants at risk of ND.

Conclusions: In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction and treated, if necessary.
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http://dx.doi.org/10.1210/js.2017-00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677510PMC
June 2017

Functional ultrasound imaging of brain activity in human newborns.

Sci Transl Med 2017 Oct;9(411)

Assistance Publique-Hôpitaux de Paris, Neonatal Intensive Care Unit, Robert Debré University Hospital, 75019 Paris, France.

Functional neuroimaging modalities are crucial for understanding brain function, but their clinical use is challenging. Recently, the use of ultrasonic plane waves transmitted at ultrafast frame rates was shown to allow for the spatiotemporal identification of brain activation through neurovascular coupling in rodents. Using a customized flexible and noninvasive headmount, we demonstrate in human neonates that real-time functional ultrasound imaging (fUSI) is feasible by combining simultaneous continuous video-electroencephalography (EEG) recording and ultrafast Doppler (UfD) imaging of the brain microvasculature. fUSI detected very small cerebral blood volume variations in the brains of neonates that closely correlated with two different sleep states defined by EEG recordings. fUSI was also used to assess brain activity in two neonates with congenital abnormal cortical development enabling elucidation of the dynamics of neonatal seizures with high spatiotemporal resolution (200 μm for UfD and 1 ms for EEG). fUSI was then applied to track how waves of vascular changes were propagated during interictal periods and to determine the ictal foci of the seizures. Imaging the human brain with fUSI enables high-resolution identification of brain activation through neurovascular coupling and may provide new insights into seizure analysis and the monitoring of brain function.
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http://dx.doi.org/10.1126/scitranslmed.aah6756DOI Listing
October 2017

Spatial and temporal postural analysis in children born prematurely.

Gait Posture 2017 09 24;57:230-235. Epub 2017 Jun 24.

UMR 1141 INSERM-Université Paris 7, Robert-Debré Paediatric Hospital, 48 Boulevard Sérurier, 75019 Paris, France; Neonatal Intensive Care Unit, Robert-Debré Paediatric Hospital, Assistance Publique Hôpitaux de Paris, 48 Boulevard Sérurier, 75019 Paris, France.

The aim of this study was to compare postural stability in a group of preterm-born children aged 4-6 years old and in a group of age-matched full-term control children by exploring both spatial and temporal analysis of the Center of Pressure (CoP). Twenty-nine children born prematurely (mean age: 5.38±0.17) and twenty-nine age-matched full-term control children participated in this study. Postural control was tested on both a stable and an unstable platform (from Framiral) in three different visual conditions: eyes open fixating a target, eyes closed, and with vision perturbed by optokinetic stimulation. We observed a significant increase of both surface area and mean velocity of the CoP in pre-term children compared to full-term control children, particularly in an unstable postural condition. The spectral power indices increased significantly in pre-term children with respect to full-term control children, while the cancelling time was not different between the two groups of children tested. We suggested that poor postural stability observed in preterm children could be due to immaturity of the cortical processes (the occipital parietal prefrontal cortex) involved in motor control. Preterm children could have an inappropriate compensation of sensory inputs when they are tested in difficult postural and/or visual conditions.
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http://dx.doi.org/10.1016/j.gaitpost.2017.06.023DOI Listing
September 2017

Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age.

JAMA 2017 04;317(13):1329-1337

Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children's Hospital, University Paris Diderot, Sorbonne Paris-Cité, Inserm U1123 and CIC-EC 1426, Paris, France.

Importance: Dexamethasone to prevent bronchopulmonary dysplasia in very preterm neonates was associated with adverse neurodevelopmental events. Early low-dose hydrocortisone treatment has been reported to improve survival without bronchopulmonary dysplasia but its safety with regard to neurodevelopment remains to be assessed.

Objective: To assess whether early hydrocortisone therapy in extremely preterm infants is associated with neurodevelopmental impairment at 2 years of age.

Design, Setting, And Participants: An exploratory secondary analysis of the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial conducted between 2008 and 2014 in 21 French neonatal intensive care units. Randomization was stratified by gestational age groups. Neurodevelopmental assessments were completed from 2010 to 2016.

Interventions: After birth, patients were randomly assigned to receive placebo or hydrocortisone (0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days).

Main Outcomes And Measures: The prespecified exploratory secondary outcome of neurodevelopmental impairment was based on a standardized neurological examination and the revised Brunet-Lézine scale (global developmental quotient score and subscores; mean norm, 100 [SD, 15]). The minimal clinically important difference on the global developmental quotient was 5 points.

Results: Of 1072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21-23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, -2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups.

Conclusions And Relevance: In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants.

Trial Registration: clinicaltrials.gov Identifier: NCT00623740.
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http://dx.doi.org/10.1001/jama.2017.2692DOI Listing
April 2017

Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach.

PLoS One 2016 21;11(12):e0166207. Epub 2016 Dec 21.

Assistance Publique - Hôpitaux de Paris, Department of Pediatric Pharmacology and Pharmacogenetics and INSERM CIC1426, Hôpital Robert Debré, Paris, France.

Objective: Proton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker.

Design: Double blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%).

Setting: Neonatal Intensive Care unit of the Robert Debré University Hospital in Paris, France.

Patients: Neonates with a postmenstrual age ≥ 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index ≥ 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth.

Intervention: Five preselected doses of oral omeprazole from 1 to 3 mg/kg/day.

Main Outcome Measures: Primary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index <5% during the 24-h pH monitoring registered 72±24 hours after omeprazole initiation.

Results: Fifty-four neonates with a reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3-99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24).

Conclusions: Omeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole doses remains to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166207PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5176365PMC
July 2017

Melatonin and the newborn brain.

Early Hum Dev 2016 11 9;102:1-3. Epub 2016 Sep 9.

Neonatal intensive care unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children's hospital, University Paris-Diderot, Sorbone Paris Cité, Inserm U1141, Paris, France. Electronic address:

Brain injury related to preterm birth and neonatal asphyxia is a leading cause of childhood neuromotor and cognitive disabilities. Unfortunately, the strategies to prevent perinatal brain damages remain limited. Among the candidate molecules, melatonin appears to be one of the most promising agents for its antioxidant and neuromodulatory action. Robust preclinical evidences and few clinical studies have suggested a neuroprotective benefit conferred by neonatal exposure to melatonin. This review recapitulates current basic research, safety and pharmacokinetic data and ongoing clinical trials on the use of melatonin as a neuroprotective agent in the newborn.
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http://dx.doi.org/10.1016/j.earlhumdev.2016.09.001DOI Listing
November 2016

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants.

Antimicrob Agents Chemother 2016 11 21;60(11):6626-6634. Epub 2016 Oct 21.

Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France

Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.
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http://dx.doi.org/10.1128/AAC.01045-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075068PMC
November 2016

Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study.

Int J Nurs Stud 2016 Jul 30;59:79-88. Epub 2016 Mar 30.

Emergency Department, Hôpital Armand-Trousseau, Paris, France; Inserm UMR 1153 Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in Pregnancy, Paris Descartes University, France; UPMC, Paris, France.

Background: Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs.

Objectives: To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure.

Design: EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study.

Setting: All 16 NICUs in the Paris region in France.

Participants: All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns.

Methods: Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first.

Results: The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia.

Conclusions: Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number.
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http://dx.doi.org/10.1016/j.ijnurstu.2016.03.014DOI Listing
July 2016

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates.

Antimicrob Agents Chemother 2016 Apr 25;60(4):2039-42. Epub 2016 Mar 25.

Department of Pharmacy, Qian-Fo-Shan Hospital, Shandong University, Jian, China Sino-French Pediatric Research Center, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China

Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.
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http://dx.doi.org/10.1128/AAC.02214-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808207PMC
April 2016

Quantitative Shear-Wave Elastography of the Liver in Preterm Neonates with Intra-Uterine Growth Restriction.

PLoS One 2015 18;10(11):e0143220. Epub 2015 Nov 18.

PremUP foundation, 75014 Paris, France.

The feasibility and reproducibility of liver stiffness measurements using Supersonic Shear-wave Imaging (SSI) in preterm neonate have not been reported. Our aim was to determine if liver stiffness differs between intra-uterine growth restriction (IUGR) and appropriate for gestational age (AGA) preterm infants with/without cholestasis. We measured liver stiffness (in kPa) in 45 AGA and 18 IUGR preterm infants, and assessed reproducibility in 26 preterms using Intraclass Correlation Coefficients (ICC) and Bland-Altman tests. Liver stiffness values were compared between AGA and IUGR with and without cholestasis and correlated with birth weight. Measurements showed high reproducibility (ICC = 0.94-0.98 for intra-operator, 0.86 for inter-operator) with good agreement (95% limits: -1.24 to 1.24 kPa). During the first postnatal week, liver stiffness was higher in IUGR (7.50 ±1.53 kPa) than in AGA infants (5.11 ±0.80 kPa, p<0.001). After day 8, liver stiffness remained unchanged in AGA but increased progressively in IUGR infants (15.57 ±6.49 kPa after day 21). Liver stiffness was higher in IUGR neonates with cholestasis (19.35 ± 9.80 kPa) than without cholestasis (7.72 ± 1.27 kPa, p<0.001). In conclusion, quantitative liver SSI in preterms is feasible and reproducible. IUGR preterms who will develop cholestasis present high liver stiffness even at birth, before biological cholestasis occurs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651533PMC
June 2016

Insulin treatment of maternal diabetes mellitus and respiratory outcome in late-preterm and term singletons.

BMJ Open 2015 Jun 2;5(6):e008192. Epub 2015 Jun 2.

Neonatal Intensive Care Unit, Université Paris Diderot, Sorbonne Paris Cité, Paris, France Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France PremUP Foundation, Paris, France.

Objectives: While the incidence of diabetes mellitus (DM) during pregnancy has been steadily increasing in recent years, the link between gestational DM and respiratory outcome in neonates has not been definitely established. We asked the question whether DM status and its treatment during pregnancy could influence the risk of neonatal respiratory distress.

Design: We studied in a large retrospective cohort the relationship between maternal DM status (non-DM, insulin-treated DM (IT-DM) and non-insulin-treated DM (NIT-DM)), and respiratory distress in term and near-term inborn singletons.

Results: Among 18,095 singletons delivered at 34 weeks of gestation or later, 412 (2.3%) were admitted to the neonatal intensive care unit (NICU) for respiratory distress within the first hours of life. The incidence of NICU admission due to respiratory distress groups was 2.2%, 5.7% and 2.1% in the non-DM, IT-DM and NIT-DM groups, respectively. Insulin treatment of DM, together with several other perinatal factors, was associated with a significant increased risk for respiratory distress. Several markers of the severity of respiratory illness, including durations of mechanical ventilation and supplemental oxygen, and hypertrophic cardiomyopathy were also found increased following IT-DM as compared with NIT-DM. In a multivariate model, we found that IT-DM, but not NIT-DM, was significantly associated with respiratory distress independent of gestational age and caesarean section, with an incidence rate ratio of 1.44 (1.00-2.08).

Conclusions: This study shows that the treatment of maternal DM with insulin during pregnancy is an independent risk factor for respiratory distress in term and near-term newborns.
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http://dx.doi.org/10.1136/bmjopen-2015-008192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458616PMC
June 2015

Paediatric use of melatonin (Author reply to D. J. Kennaway).

Eur J Paediatr Neurol 2015 Jul 5;19(4):491-3. Epub 2015 May 5.

Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejpn.2015.04.007DOI Listing
July 2015

Spatiotemporal Clutter Filtering of Ultrafast Ultrasound Data Highly Increases Doppler and fUltrasound Sensitivity.

IEEE Trans Med Imaging 2015 Nov 30;34(11):2271-85. Epub 2015 Apr 30.

Ultrafast ultrasonic imaging is a rapidly developing field based on the unfocused transmission of plane or diverging ultrasound waves. This recent approach to ultrasound imaging leads to a large increase in raw ultrasound data available per acquisition. Bigger synchronous ultrasound imaging datasets can be exploited in order to strongly improve the discrimination between tissue and blood motion in the field of Doppler imaging. Here we propose a spatiotemporal singular value decomposition clutter rejection of ultrasonic data acquired at ultrafast frame rate. The singular value decomposition (SVD) takes benefits of the different features of tissue and blood motion in terms of spatiotemporal coherence and strongly outperforms conventional clutter rejection filters based on high pass temporal filtering. Whereas classical clutter filters operate on the temporal dimension only, SVD clutter filtering provides up to a four-dimensional approach (3D in space and 1D in time). We demonstrate the performance of SVD clutter filtering with a flow phantom study that showed an increased performance compared to other classical filters (better contrast to noise ratio with tissue motion between 1 and 10mm/s and axial blood flow as low as 2.6 mm/s). SVD clutter filtering revealed previously undetected blood flows such as microvascular networks or blood flows corrupted by significant tissue or probe motion artifacts. We report in vivo applications including small animal fUltrasound brain imaging (blood flow detection limit of 0.5 mm/s) and several clinical imaging cases, such as neonate brain imaging, liver or kidney Doppler imaging.
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http://dx.doi.org/10.1109/TMI.2015.2428634DOI Listing
November 2015

Escherichia Coli Meningitis Features in 325 Children From 2001 to 2013 in France.

Clin Infect Dis 2015 Sep 5;61(5):779-86. Epub 2015 May 5.

Association Clinique Thérapeutique Infantile du Val de Marne, Saint Maur des Fossés Groupe de Pathologie Infectieuse Pédiatrique, Paris Centre de Recherche Clinique, Centre Hospitalier Intercommunal de Créteil, France.

Background: We aimed to describe features of Escherichia coli meningitis in a large population of children and the molecular characteristics of the involved strains to determine factors associated with severe disease or death.

Methods: Between 2001 and 2013, a prospective national survey collected data for 325 children hospitalized with E. coli meningitis. The national reference center genetically characterized 141 isolates.

Results: Among the 325 cases, 65.2% were term, 22.4% late preterm, and 12.5% very/extremely preterm infants. Escherichia coli meningitis was 7-fold more frequent in preterm than term infants. Median age at diagnosis was 14 days; 71.1% of infants were neonates, with 2 peaks of infection at age 0-3 days (mostly preterm neonates) and 11-15 days (mostly term neonates); 8.9% were >89 days old. In total, 51.1% patients were considered to have severe disease, and 9.2% died. B2.1 phylogenetic subgroup (56%) and O1 serogroup (27.7%) were the most frequently identified. On multivariate analysis, death was associated with preterm birth (odds ratio [OR], 3.3 [95% confidence interval {CI}, 1.3-8.4], P = .015 for late preterm infants; OR, 7.3 [95% CI, 2.7-20.9], P < .001 for very/extremely preterm infants) and cerebrospinal fluid (CSF) to blood glucose ratio <0.10 (OR, 15.3 [95% CI, 1.8-128.3], P = .012). Death was associated with uncommon O serogroup strains (P = .014) and severe disease with O7 serogroup (P = .034) and PapGII adhesin (OR, 2.3 [95% CI, 1.2-4.5], P = .015).

Conclusions: In this large study of 325 cases of E. coli meningitis, risk factors of severe disease or death were preterm birth, severe hypoglycorrhachia, CSF/blood glucose ratio <0.10, and molecular characteristics of strains, which should help optimize therapeutic management.
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http://dx.doi.org/10.1093/cid/civ367DOI Listing
September 2015

Subjective visual vertical and postural capability in children born prematurely.

PLoS One 2015 19;10(3):e0121616. Epub 2015 Mar 19.

UMR1141 INSERM-Université Paris 7, Robert Debré Hospital, 48 boulevard Sérurier, 75019, Paris, France; Neonatal Intensive Care Unit, Robert Debré Hospital, 48 boulevard Sérurier, 75019, Paris, France.

Purpose: We compared postural stability and subjective visual vertical performance in a group of very preterm-born children aged 3-4 years and in a group of age-matched full-term children.

Materials And Methods: A platform (from TechnoConcept) was used to measure postural control in children. Perception of subjective visual vertical was also recorded with posture while the child had to adjust the vertical in the dark or with visual perturbation. Two other conditions (control conditions) were also recorded while the child was on the platform: for a fixation of the vertical bar, and in eyes closed condition.

Results: Postural performance was poor in preterm-born children compared to that of age-matched full-term children: the surface area, the length in medio-lateral direction and the mean speed of the center of pressure (CoP) were significantly larger in the preterm-born children group (p < 0.04, p < 0.01, and p < 0.04, respectively). Dual task in both groups of children significantly affected postural control. The subjective visual vertical (SVV) values were more variable and less precise in preterm-born children.

Discussion-conclusions: We suggest that poor postural control as well as perception of verticality observed in preterm-born children could be due to immaturity of the cortical processes involved in the motor control and in the treatment of perception and orientation of verticality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121616PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366151PMC
February 2016

First case of pregnant women bacteraemia and probable early-onset neonatal infection due to Aerococcus urinae.

New Microbes New Infect 2015 Jan 18;3:1-3. Epub 2014 Nov 18.

Service de Microbiologie, AP-HP, Hôpital Robert Debré, Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1016/j.nmni.2014.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337935PMC
January 2015

Current role of melatonin in pediatric neurology: clinical recommendations.

Eur J Paediatr Neurol 2015 Mar 17;19(2):122-33. Epub 2014 Dec 17.

Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Italy. Electronic address:

Background/purpose: Melatonin, an indoleamine secreted by the pineal gland, plays a key role in regulating circadian rhythm. It has chronobiotic, antioxidant, anti-inflammatory and free radical scavenging properties.

Methods: A conference in Rome in 2014 aimed to establish consensus on the roles of melatonin in children and on treatment guidelines.

Results And Conclusion: The best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5 h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified.
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http://dx.doi.org/10.1016/j.ejpn.2014.12.007DOI Listing
March 2015