Corrigendum: Protocol for a prospective multicenter longitudinal randomized controlled trial (CALIN) of sensory-tonic stimulation to foster parent child interactions and social cognition in very premature infants.

[This corrects the article DOI: 10.3389/fped.2022.913396.].

Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?

BACKGROUND: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions. METHODS: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress. FINDINGS: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation. INTERPRETATION: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.

Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients.

Mutations in the LPIN1 gene constitute a major cause of severe rhabdomyolysis (RM). The TLR9 activation prompted us to treat patients with corticosteroids in acute conditions. In patients with LPIN1 mutations, RM and at-risk situations that can trigger RM have been treated in a uniform manner. Since 2015, these patients have also received intravenous corticosteroids. We retrospectively compared data on hospital stays by corticosteroid-treated patients vs. patients not treated with corticosteroids. Nineteen patients were hospitalized. The median number of admissions per patient was 21 overall and did not differ when comparing the 10 corticosteroid-treated patients with the 9 patients not treated with corticosteroids. Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group. The two groups did not differ significantly in the number of RM episodes. However, for the six patients who had RM and occasionally been treated with corticosteroids, the median number of RM episodes was significantly lower when intravenous steroids had been administered. The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015. The median length of stay (10 days overall) was significantly longer for corticosteroid-treated patients but was similar after the exclusion of deceased patients. The absence of deaths and the higher severity of RM observed among corticosteroid-treated patients could suggest that corticotherapy is associated with greater survival.

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients.

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Risk factors for unfavorable outcome at discharge of newborns with hypoxic-ischemic encephalopathy in the era of hypothermia.

OBJECTIVE: To re-visit short-term outcomes and associated risk factors of newborns with hypoxic-ischemic encephalopathy (HIE) in an era where hypothermia treatment (HT) is widespread. METHODS: This is a prospective population-based cohort in French neonatal intensive care units (NICU). Neonates born at or after 34 weeks of gestational age with HIE were included; main outcomes were in-hospital death and discharge with abnormal or normal MRI. Associations of early perinatal risk factors, present at birth or at admission to NICU, with these outcomes were studied. RESULTS: A total of 794 newborns were included and HT was administered to 670 (84.4%); 18.3% died and 28.5% and 53.2% survived with abnormal and normal MRI, respectively. Severe neurological status, Apgar score at 5 mn ≤5, lactate at birth ≥11 mMoles/l, and glycemia ≥100 mg/dL at admission were associated with an increased risk of death (relative risk ratios (aRRR) (95% CI) 19.93 (10.00-39.70), 2.89 (1.22-1.62), 3.06 (1.60-5.83), and 2.55 (1.38-4.71), respectively). Neurological status only was associated with survival with abnormal MRI (aRRR (95% CI) 1.76 (1.15-2.68)). CONCLUSION: Despite high use of HT in this cohort, 46.8% died or presented brain lesions. Early neurological and biological examinations were associated with unfavorable outcomes and these criteria could be used to target children who warrant further neuroprotective treatment. TRIAL REGISTRATION: Clinical trial registry, NCT02676063, ClinicalTrials.gov. IMPACT: In this population-based cohort of newborns with HIE where 84% received hypothermia, 46.8% still had an unfavorable evolution (death or survival with abnormal MRI). Risk factors for death were high lactate, low Apgar score, severe early neurological examination, and high glycaemia. While studies have established risk factors for HIE, few have focused on early perinatal factors associated with short-term prognosis. This French population-based cohort updates knowledge about early risk factors for adverse outcomes in the era of widespread cooling. In the future, criteria associated with an unfavorable evolution could be used to target children who would benefit from another neuroprotective strategy with hypothermia.

Healthcare organizational factors associated with delayed therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: the LyTONEPAL cohort.

Initiation of therapeutic hypothermia (TH) within 6 h of life is a major concern for treating neonatal hypoxic ischemic encephalopathy (HIE). We aimed to determine clinical and healthcare organizational factors associated with delayed TH in a French population-based cohort of neonates with moderate/severe HIE. Time to reach a rectal temperature of 34 °C defines optimal and delayed (within and over 6 h, respectively) TH. Clinical and healthcare organizational factors associated with delayed TH were analysed among neonates born in cooling centres (CCs) and non-cooling centres (non-CCs). Among 629 neonates eligible for TH, 574 received treatment (91.3%). TH was delayed in 29.8% neonates and in 20.3% and 36.2% of those born in CCs and non-CCs, respectively. Neonates with moderate HIE were more exposed to delayed TH in both CCs and non-CCs. After adjustment for HIE severity, maternal and neonatal characteristics and circumstances of birth were not associated with increased risk of delayed TH. However, this risk was 2 to 5 times higher in maternities with < 1999 annual births, when the delay between birth and call for transfer (adjusted odds ratio [aOR] 2.47, 95% confidence interval [CI] [1.03 to 5.96]) or between call for transfer and admission (aOR 6.06, 95%CI [2.60 to 14.12]) was > 3 h and when an undesirable event occurred during transfer (aOR 2.66, 95%CI [1.11 to 6.37].  Conclusion: Increasing early identification of neonates who could benefit from TH and access to TH in non-CCs before transfer are modifiable factors that could improve care of neonates with HIE.  Trial registration: The trial was registered at ClinicalTrials.gov (NCT02676063). What is Known: • International recommendations are to initiate therapeutic hypothermia before 6 h of life in neonates with moderate or severe hypoxic ischemic encephalopathy. What is New: •In this French population-based cohort of infants with hypoxic ischemic encephalopathy, nearly one-third of neonates eligible for treatment did not have access to hypothermia in the therapeutic window of 6 h of life. . • Among infants born in non-cooling centres, healthcare organizational factors involved in delayed care were the small size of maternities (1999 annual births), a time interval of more than 3 h between birth and call for transfer and between call for transfer and admission in neonatology, and the occurrence of an undesirable event during transfer.

Assessment of brain two-dimensional metrics in infants born preterm at term equivalent age: Correlation of ultrasound scans with magnetic resonance imaging.

Context: Developing brain imaging is a critical subject for infants born preterm. Impaired brain growth is correlated with poor neurological outcomes, regardless of overt brain lesions, such as hemorrhage or leukomalacia. As magnetic resonance imaging (MRI) remains a research tool for assessing regional brain volumes, two-dimensional metrics (2D metrics) provide a reliable estimation of brain structures. In neonatal intensive care, cerebral ultrasound (cUS) is routinely performed to assess brain integrity. This prospective work has compared US and MRI accuracy for the measurement of 2D brain metrics and identification of overt injuries. Methods: MRI and cUS were performed at term equivalent age (TEA) in infants born before 32 weeks of gestation (GW). Demographical data and results of serial cUS (Neonatal Intensive Care Unit [NICU]-US) performed during hospitalization were gathered from medical charts. Blinded, experienced senior doctors reviewed the scans for both standard analysis and standardized, 2D measurements. The correlation of 2D metrics and inter-/intraobserver agreements were evaluated using Pearson's coefficient, Bland-Altman plots, and intraclass coefficient (ICC), respectively. Results: In total, 102 infants born preterm were included. The performance of "TEA-cUS and NICU-cUS" when compared to "TEA-MRI and NICU-cUS" was identical for the detection of high-grade hemorrhages and close for low-grade ones. However, TEA-MRI only detected nodular lesions of the white matter (WM). No infant presented a cerebellar infarct on imaging. Intra- and inter-observer agreements were excellent for all 2D metrics except for the corpus callosum width (CCW) and anteroposterior vermis diameter. MRI and cUS showed good to excellent correlation for brain and bones biparietal diameters, corpus callosum length (CCL), transcerebellar diameters (TCDs), and lateral ventricle diameters. Measures of CCW and vermis dimensions were poorly correlated. Conclusion and perspective: The cUS is a reliable tool to assess selected 2D measurements in the developing brain. Repetition of these metrics by serial cUS during NICU stay would allow the completion of growth charts for several brain structures. Further studies will assess whether these charts are relevant markers of neurological outcome.

Case reports of large and symptomatic abdominal tumors in newborns: Pitfalls, difficulties in management, and surgical decision making.

BACKGROUND: Large and rapidly growing abdominal tumors may result in fatal outcomes in newborns. In some cases, a rapidly worsening clinical condition requires surgical decision-making despite the absence of a precise histological diagnosis. In these situations, there is neither a guide nor consensus. CASE: We highlight our experience with five patients with large abdominal tumors and assess the available literature for the best possible management of a rare condition. CONCLUSION: In these cases, laparostomy should be considered as a life-saving procedure. If the liver is involved and coagulopathy is present, prognosis is often compromised.

Amplitude-Integrated EEG Monitoring in Pediatric Intensive Care: Prognostic Value in Meningitis before One Year of Age.

Pediatric morbidity from meningitis remains considerable. Preventing complications is a major challenge to improve neurological outcome. Seizures may reveal the meningitis itself or some complications of this disease. Amplitude-integrated electroencephalography (aEEG) is gaining interest for the management of patients with acute neurological distress, beyond the neonatal age. This study aimed at evaluating the predictive value of aEEG monitoring during the acute phase in meningitis among a population of infants hospitalized in the pediatric intensive care unit (PICU), and at assessing the practicability of the technique. AEEG records of 25 infants younger than one year of age hospitalized for meningitis were retrospectively analyzed and correlated to clinical data and outcome. Recording was initiated, on average, within the first six hours for n = 18 (72%) patients, and overall quality was considered as good. Occurrence of seizure, of status epilepticus, and the background pattern were significantly associated with unfavorable neurological outcomes. AEEG may help in the management and prognostic assessment of pediatric meningitis. It is an easily achievable, reliable technique, and allows detection of subclinical seizures with minimal training. However, it is important to consider the limitations of aEEG, and combinate it with conventional EEG for the best accuracy.

An Updated Overview of MRI Injuries in Neonatal Encephalopathy: LyTONEPAL Cohort.

BACKGROUND: Brain magnetic resonance imaging (MRI) is a key tool for the prognostication of encephalic newborns in the context of hypoxic-ischemic events. The purpose of this study was to finely characterize brain injuries in this context. METHODS: We provided a complete, descriptive analysis of the brain MRIs of infants included in the French national, multicentric cohort LyTONEPAL. RESULTS: Among 794 eligible infants, 520 (65.5%) with MRI before 12 days of life, grade II or III encephalopathy and gestational age ≥36 weeks were included. Half of the population had a brain injury (52.4%); MRIs were acquired before 6 days of life among 247 (47.5%) newborns. The basal ganglia (BGT), white matter (WM) and cortex were the three predominant sites of injuries, affecting 33.8% (n = 171), 33.5% (n = 166) and 25.6% (n = 128) of participants, respectively. The thalamus and the periventricular WM were the predominant sublocations. The BGT, posterior limb internal capsule, brainstem and cortical injuries appeared more frequently in the early MRI group than in the late MRI group. CONCLUSION: This study described an overview of brain injuries in hypoxic-ischemic neonatal encephalopathy. The basal ganglia with the thalamus and the WM with periventricular sublocation injuries were predominant. Comprehensive identification of brain injuries in the context of HIE may provide insight into the mechanism and time of occurrence.

Advanced Brain Imaging in Preterm Infants: A Narrative Review of Microstructural and Connectomic Disruption.

Preterm birth disrupts the in utero environment, preventing the brain from fully developing, thereby causing later cognitive and behavioral disorders. Such cerebral alteration occurs beneath an anatomical scale, and is therefore undetectable by conventional imagery. Prematurity impairs the microstructure and thus the histological process responsible for the maturation, including the myelination. Cerebral MRI diffusion tensor imaging sequences, based on water's motion into the brain, allows a representation of this maturation process. Similarly, the brain's connections become disorganized. The connectome gathers structural and anatomical white matter fibers, as well as functional networks referring to remote brain regions connected one over another. Structural and functional connectivity is illustrated by tractography and functional MRI, respectively. Their organizations consist of core nodes connected by edges. This basic distribution is already established in the fetal brain. It evolves greatly over time but is compromised by prematurity. Finally, cerebral plasticity is nurtured by a lifetime experience at microstructural and macrostructural scales. A preterm birth causes a negative and early disruption, though it can be partly mitigated by positive stimuli based on developmental neonatal care.

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature.

PURPOSE: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation. METHODS: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine-based classifier distinguishing CDK13-RD and non-CDK13-RD samples. RESULTS: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance. CONCLUSION: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.

Cerebral injuries in neonatal encephalopathy treated with hypothermia: French LyTONEPAL cohort.

BACKGROUND: Hypothermia is widely used for infants with hypoxic-ischemic neonatal encephalopathy but its impact remains poorly described at a population level. We aimed to describe brain imaging in infants born at ≥36 weeks' gestation, with moderate/severe encephalopathy treated with hypothermia. METHODS: Descriptive analysis of brain MRI and discharge neurological examination for infants included in the French national multicentric prospective observational cohort LyTONEPAL. RESULTS: Among 575 eligible infants, 479 (83.3%) with MRI before 12 days of life were included. MRI was normal for 48.2% (95% CI 43.7-52.8). Among infants with brain injuries, 62.5% (95% CI 56.2-68.5) had damage to more than one structure, 19.8% (95% CI 15.0-25.3) showed a pattern-associating injuries of basal ganglia/thalami (BGT), white matter (WM) and cortex. Overall, 68.4% (95% CI 62.0-74.3) of infants with normal MRI survived with a normal neurological examination. The rate of death was 15.4% (95% CI 12.3-19.0), predominantly for infants with the combined BGT, cortex, and/or WM injuries. CONCLUSIONS: Among infants with neonatal encephalopathy treated with hypothermia, two-thirds of those with normal MRI survived with a normal neurological examination at discharge. When present, brain injuries often involved more than one structure. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT02676063). IMPACT: In this multicentric cohort of infants with neonatal encephalopathy (LYTONEPAL) two-thirds survived with normal MRI and neurological examination at discharge. In total, 10% of newborns showed a pattern associating injuries of the basal ganglia-thalami, white matter, and cortex, which was correlated with a high risk of death at discharge. The evolution of MRI techniques and sequences in the era of hypothermia calls for a revisiting of imaging protocol in neonatal encephalopathy, especially for the timing. The neurological examination did not give evidence of brain injuries, thus questioning the reproducibility of the clinical exam or the neonatal brain functionality.

Protocol for a prospective multicenter longitudinal randomized controlled trial (CALIN) of sensory-tonic stimulation to foster parent child interactions and social cognition in very premature infants.

Introduction: Premature birth is associated with long-term somatic and neurological disorders, including cognitive, social and behavioral impairments. Moreover, the mothers of infants born preterm exhibit a higher prevalence of anxiety and depressive symptoms after birth. Early rehabilitation, developmental care, and parenting support have already been shown to have a positive impact on neurological outcome. However, no randomized controlled study has so far assessed the effects on parenting and long-term neurological outcomes of proprioceptive stimulation to trigger positive brain plasticity in very preterm babies. The CALIN project will therefore investigate the impact of sensory-tonic stimulation (STS) of extremely preterm infants by their parents on child parent interactions, infants' morphological and functional brain development and subsequent cognition (including social cognition), and parents' anxiety and depressive symptoms in the postpartum period. Methods and analysis: Infants born between 25 and 32 weeks of gestation will be randomly assigned to the "STS + Kangaroo care" or "Kangaroo care" group. The primary endpoint, child and parent interactions, will be rated at 12 months corrected age using the Coding Interactive Behavior system. Secondary endpoints include: 1/functional and anatomical brain maturation sequentially assessed during neonatal hospitalization using electroencephalogram (EEG), amplitude-integrated EEG (aEEG), cranial ultrasound and MRI performed at term-corrected age, 2/social and cognitive outcomes assessed at 15 months, 2, 4 and 6 years, and 3/parents' anxiety and depressive symptoms assessed at 7 ± 1 weeks after birth, using dedicated questionnaires. Ethics and dissemination: This study was approved by the French Ethics Committee for the Protection of Persons on 18 October 2021. It is registered with the French National Agency for the Safety of Medicines and Health Products (ANSM; no. 2020-A00382-37). The registry number on ClinicalTrials.gov is NCT04380051.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation.

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown. Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years. Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021. Exposures: Amino acid intake at 7 days after birth. Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study. Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; ß = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; ß = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; ß = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; ß = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; ß = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort. Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

OBJECTIVE: To explore the phenotypic spectrum of RHOBTB2-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals. METHODS: Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review. RESULTS: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients. CONCLUSION: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.

Automated brain MRI metrics in the EPIRMEX cohort of preterm newborns: Correlation with the neurodevelopmental outcome at 2 years.

PURPOSE: The purpose of this study was to identify in the EPIRMEX cohort the correlations between MRI brain metrics, including diffuse excessive high signal intensities (DEHSI) obtained with an automated quantitative method and neurodevelopmental outcomes at 2 years. MATERIALS AND METHODS: A total of 390 very preterm infants (gestational age at birth≤32 weeks) who underwent brain MRI at term equivalent age at 1.5T (n=338) or 3T (n=52) were prospectively included. Using a validated algorithm, automated metrics of the main brain surfaces (cortical and deep gray matter, white matter, cerebrospinal fluid) and DEHSI with three thresholds were obtained. Linear adjust regressions were performed to assess the correlation between brain metrics with the ages and stages questionnaire (ASQ) score at 2 years. RESULTS: Basal ganglia and thalami, cortex and white matter surfaces positively and significantly correlated with the global ASQ score. For all ASQ sub-domains, basal ganglia and thalami surfaces significantly correlated with the scores. DEHSI was present in 289 premature newborns (74%) without any correlation with the ASQ score. Metrics of DEHSI were greater at 3T than at 1.5T. CONCLUSION: Brain MRI metrics obtained in our multicentric cohort correlate with the neurodevelopmental outcome at 2 years of age. The quantitative detection of DEHSI is not predictive of adverse outcomes. Our automated algorithm might easily provide useful predictive information in daily practice.

COVID-19 Associated With Life-Threatening Apnea in an Infant Born Preterm: A Case Report.

A pandemic linked to the new coronavirus strain (SARS-CoV-2) has been raging for several months. Pediatric populations are less impacted than adults, and critical respiratory diseases seem rare (1, 2). We report the case of an infant, who presented with life-threatening apneas at home requiring basic life support. SARS-CoV-2 was subsequently identified in the patient's nasopharyngeal aspirate. He did not present with bronchiolitis or hypoxic failure as described in severe forms of COVID-19. The outcome was favorable in a few hours. The occurrence of apneas is not uncommon during viral respiratory infections in early infancy; however, there are very few descriptions related to a documented SARS-CoV-2 respiratory tract infection. In light of this clinical case, it seems necessary to quickly bring up a potential COVID-19 contamination in infants admitted for life-threatening apnea, in order to properly report and isolate these patients to avoid further nosocomial dissemination of SARS-CoV-2.

SegSRGAN: Super-resolution and segmentation using generative adversarial networks - Application to neonatal brain MRI.

BACKGROUND AND OBJECTIVE: One of the main issues in the analysis of clinical neonatal brain MRI is the low anisotropic resolution of the data. In most MRI analysis pipelines, data are first re-sampled using interpolation or single image super-resolution techniques and then segmented using (semi-)automated approaches. In other words, image reconstruction and segmentation are then performed separately. In this article, we propose a methodology and a software solution for carrying out simultaneously high-resolution reconstruction and segmentation of brain MRI data. METHODS: Our strategy mainly relies on generative adversarial networks. The network architecture is described in detail. We provide information about its implementation, focusing on the most crucial technical points (whereas complementary details are given in a dedicated GitHub repository). We illustrate the behavior of the proposed method for cortex analysis from neonatal MR images. RESULTS: The results of the method, evaluated quantitatively (Dice, peak signal-to-noise ratio, structural similarity, number of connected components) and qualitatively on a research dataset (dHCP) and a clinical one (Epirmex), emphasize the relevance of the approach, and its ability to take advantage of data-augmentation strategies. CONCLUSIONS: Results emphasize the potential of our proposed method/software with respect to practical medical applications. The method is provided as a freely available software tool, which allows one to carry out his/her own experiments, and involve the method for the super-resolution reconstruction and segmentation of arbitrary cerebral structures from any MR image dataset.

Multiscale brain MRI super-resolution using deep 3D convolutional networks.

The purpose of super-resolution approaches is to overcome the hardware limitations and the clinical requirements of imaging procedures by reconstructing high-resolution images from low-resolution acquisitions using post-processing methods. Super-resolution techniques could have strong impacts on structural magnetic resonance imaging when focusing on cortical surface or fine-scale structure analysis for instance. In this paper, we study deep three-dimensional convolutional neural networks for the super-resolution of brain magnetic resonance imaging data. First, our work delves into the relevance of several factors in the performance of the purely convolutional neural network-based techniques for the monomodal super-resolution: optimization methods, weight initialization, network depth, residual learning, filter size in convolution layers, number of the filters, training patch size and number of training subjects. Second, our study also highlights that one single network can efficiently handle multiple arbitrary scaling factors based on a multiscale training approach. Third, we further extend our super-resolution networks to the multimodal super-resolution using intermodality priors. Fourth, we investigate the impact of transfer learning skills onto super-resolution performance in terms of generalization among different datasets. Lastly, the learnt models are used to enhance real clinical low-resolution images. Results tend to demonstrate the potential of deep neural networks with respect to practical medical image applications.