Favorable parental perception of behaviour at two years' corrected age in very preterm-born children

Problems in behavioural and emotional outcome are amongst the long-term sequelae of preterm birth. The exact prevalence and associations with perinatal risk factors are unknown. Minimal research has been performed in pre-school aged children, compared to school age. The primary aim of this study was to determine the prevalence of parent-reported behavioural and emotional problems at the age of two in children born at less than 30 weeks' gestational age and/or birth weight less than 1000 g. The secondary aim was to determine whether perinatal factors were associated with the behavioural and emotional outcome. Perinatal characteristics of 144 preterm-born children from the NeoLiFeS cohort were collected retrospectively. Of these children, 101 parents filled out a Childs Behaviour Checklist (CBCL) at the corrected age of two. The results of the CBCL tests were presented as Z-scores, a Z-score of 0 indicating the mean of behavioural scores in the norm population. A Z-score higher than zero indicates less behavioural problems than average, a negative Z-score indicates more problems. Associations between perinatal risk factors and CBCL-scores were analysed using linear regression analyses. Prevalences of clinically relevant CBCL scores were low, 4%, 2% and 5% for total score, internalizing score or externalizing score, respectively. Being part of a twin was associated with higher internalizing Z-scores, indicating less problems in emotional behaviour. Bronchopulmonary dysplasia was associated with lower Z-scores in total and externalizing behaviour. In conclusion, in our cohort generally very few problems in behavioural and emotional outcome were reported at the age of two

The Predictive Value of Amplitude-Integrated Electroencephalography in Preterm Infants for IQ and Other Neuropsychological Outcomes at Early School Age

Background: Amplitude-integrated electroencephalography (aEEG) is used increasingly in neonatal intensive care and seems helpful in predicting outcomes at the age of 2 years, Objectives:To determine whether early aEEG patterns in preternn infants are equally useful in predicting outcomes at early school age. Methods: We recorded aEEG in 41 pre-terms (gestational age 26.0-32.9 weeks) at a median postnatal age of 9.7 h (IQR 7.0-25.3) and in 43 preternns on median day 8 (IQR 7-9). We assessed aEEG by pattern recognition and calculated the means of the aEEG amplitude centiles. At a median of 739 years, i.e., early school age, we assessed their motor, cognitive, and behavioral outcomes. Results: Depressed aEEG patterns were not associated with poorer outcomes. Cyclicity directly after birth was associated with a higher total IQ (mean 104 vs. 97, p = 0.05) and higher scores on visual perception (mean percentile 57.1 vs. 40.1, p 0,049) and visual memory (mean percentile 34.5 vs. 19.1, p = 0090). We found some associations between the aEEG amplitude centiles and cognitive outcomes, but none for motor or behavioral outcomes. There was an increased risk of abnormal scores on long-term verbal memory in cases of the lower 5th and 50th aEEG amplitude centiles directly after birth. The odds ratios were 0.65 (95% CI 0,42-0.99, p = 0.040) and 0.71 (95% CI 0.52-0.96, p = 0.025), respectively. Conclusions: In relatively healthy preternn infants the value of aEEG in predicting neuropsychological outcomes at early school age is limited. The presence of cyclicity directly after birth tends to be associated with better cognition. (C) 2018 The Author(s) Published by S. Karger AG, Base

The neurological phenotype of developmental motor patterns during early childhood

INTRODUCTION: During early childhood, typical human motor behavior reveals a gradual transition from automatic motor patterns to acquired motor skills, by the continuous interplay between nature and nurture. During the wiring and shaping of the underlying motor networks, insight into the neurological phenotype of developmental motor patterns is incomplete. In healthy, typically developing children (0-3 years of age), we therefore aimed to investigate the neurological phenotype of developmental motor patterns. METHODS: In 32 healthy, typically developing children (0-3 years), we video-recorded spontaneous motor behavior, general movements (GMs), and standardized motor tasks. We classified the motor patterns by: (a) the traditional neurodevelopmental approach, by Gestalt perception and (b) the classical neurological approach, by the clinical phenotypic determination of movement disorder features. We associated outcomes by Cramer's V. RESULTS: Developmental motor patterns revealed (a) choreatic-like features (≤3 months; associated with fidgety GMs (r = 0.732) and startles (r = 0.687)), (b) myoclonic-like features (≤3 months; associated with fidgety GMs (r = 0.878) and startles (r = 0.808)), (c) dystonic-like features (0-3 years; associated with asymmetrical tonic neck reflex (r = 0.641) and voluntary movements (r = 0.517)), and (d) ataxic-like features (>3 months; associated with voluntary movements (r = 0.928)). CONCLUSIONS: In healthy infants and toddlers (0-3 years), typical developmental motor patterns reveal choreatic-, myoclonic-, dystonic- and ataxic-like features. The transient character of these neurological phenotypes is placed in perspective of the physiological shaping of the underlying motor centers. Neurological phenotypic insight into developmental motor patterns can contribute to adequate discrimination between ontogenetic and initiating pathological movement features and to adequate interpretation of therapeutic interactions

Perinatal Anemia is Associated with Neonatal and Neurodevelopmental Outcomes in Infants with Moderate to Severe Perinatal Asphyxia

Background: Perinatal anemia may cause perinatal asphyxia. Its pathophysiology and neurodevelopmental effects are theoretically different from other causes of perinatal asphyxia. Objective: The study aimed to determine whether perinatal anemia results in different short-term and long-term outcomes than other causes of perinatal asphyxia treated with therapeutic hypothermia. Methods: We retrospectively included infants with moderate to severe hypoxic-ischemic encephalopathy, born between May 2009 and October 2015. During follow-up, we assessed cognitive and motor development at 2-3 years of age, using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). Neurodevelopmental outcome (NDO) was classified as abnormal in case of cerebral palsy with Gross Motor Function Classification System >= III and/or a BSID-III composite scor

Two-year neurodevelopmental outcome in children born extremely preterm:the EPI-DAF study

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth

The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia

Magnetic resonance spectroscopy can identify brain metabolic changes in perinatal asphyxia by providing ratios of metabolites, such as choline (Cho), creatine (Cr), N-acetyl aspartate (NAA) and lactate (Lact) [Cho/Cr, Lact/NAA, etc.]. The purpose of this study was to quantify the separate white and grey matter metabolites in a slab cranial to the ventricles and relate these to the outcome. A standard 2D-chemical shift imaging protocol was used for measuring a transverse volume of interest located cranial to the ventricles allowing for direct comparison of the metabolites in white and grey matter brain tissue in 24 term asphyxiated newborns aged 3 to 16 days. Cho, NAA and Lact showed significant differences between four subgroups of asphyxiated infants with more and less favourable outcomes. High levels of Cho and Lact in the grey matter differentiated non-survivors from survivors (P = 0.003 and P = 0.017, respectively). In perinatal asphyxia the levels of Cho, NAA and Lact in both white and grey matter brain tissue are affected. The levels of Cho and Lact measured in the grey matter are the most indicative of survival. It is therefore advised to include grey matter brain tissue in the region of interest examined by multivoxel MR spectroscopy. aEuro cent Magnetic resonance spectroscopy can identify brain metabolic changes in perinatal asphyxia. aEuro cent Choline and lactate levels in grey matter seem the best indicators of survival. aEuro cent Both grey and white matter should be examined during spectroscopy for perinatal asphyxia

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues

Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex

Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by ß-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to ß-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by ß-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.Netherlands Organization for Scientific Research (NWO). B.N. is supported by an NHMRC (Australia) CJ Martin Early Career Fellowship. N.P.R. Netherlands Heart Foundation (2012T051). N.P.R. and M.G.N. received a H2020 grant (H2020-PHC-2015-667873-2) from the European Union (grant agreement 667837). Fundação para a Ciência e Tecnologia, FCT (IF/00735/2014 to A.C., IF/00021/2014 to R.S., RECI/BBB-BQB/0230/2012 to L.G.G., and SFRH/BPD/96176/2013 to C. Cunha). The NMR spectrometers are part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). The research leading to these results received funding from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). NIH (DK43351 and DK097485) and Helmsley Trust. D.L.W. is supported, in part, by the NIH (GM53522, GM083016, GM119197, and C06RR0306551