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The improvement of delivery room care, according to the 2015 International Consensus, may affect neonatal outcome, especially in very-low-birth-weight infants. We aimed to investigate the current practice of neonatal resuscitation by year and analyze the association with neonatal outcomes. A total of 8142 very-low-birth-weight infants, registered in the Korean Neonatal Network between 2014 and 2017 were included. A significant decreasing trend of intubation (64.5% vs 55.1%, P < 0.0001) and markedly increasing trend of positive pressure ventilation (PPV) (11.5% vs 22.9%, P < 0.0001) were noted. The annual PPV rate differed significantly by gestation (P < 0.0001). The highest level of resuscitation was also shown as an independent risk factor for mortality within 7 days and for bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and periventricular leukomalacia. PPV and intubation were associated with significantly decreased risk of mortality and morbidities compared to epinephrine use. When considering association, the incidence of mortality within 7 days, IVH, PVL, and BPD or mortality showed significant differences by combination of year, gestational age, and level of resuscitation. According to updated guidelines, changes in the highest level of resuscitation significantly associated with reducing mortality and morbidities. More meticulous delivery room resuscitation focusing on extreme prematurity is needed.

Background In neonatal intensive care unit (NICU) patients with intubation status, fluoroscopic evaluation for the bowel is limited. This study was to evaluate the utility of bedside upper gastrointestinal (UGI) series with delayed radiographs (DR) for assessing duodenojejunal junction (DJJ) and small bowel passage in NICU patients with nonspecific bowel ultrasonography and contrast enema findings. Methods We reviewed clinical and imaging data for bedside UGI with DR of NICU patients from 2014 to 2019. Five abdominal radiographs were obtained at fixed time intervals of immediately after, 1 min, 5 min, 1 h, and 2 h following the administration of 5 cc/kg isotonic water-soluble contrast agent via the nasogastric tube. Results Twenty bedside UGI with DR were performed in 17 patients (weight range: 520-3620 g, age range: 0–4 months). Confidence identifying the DJJ was either good ( n  = 7) or equivocal ( n  = 8) at immediate or 1 min radiographs. The DJJ could not be evaluated in five from four delayed passage (including two meconium plug syndrome and one gastric volvulus) and one inadequate timing. There was only one case of intestinal malrotation, which was not detected on ultrasonography, but detected at the first UGI examination with good DJJ confidence. Conclusions Bedside UGI with DR can evaluate intestinal malrotation using immediate and 1 min delay and small bowel passage using 1 and 2 h delay images in NICU patients with nonspecific ultrasonographic and contrast enema findings. The majority with delayed contrast passages can have bowel pathology. Because of a small number of patients in this study, further studies with more infants are needed.

Purpose Hypothermia at admission is associated with increased mortality and morbidity in preterm infants. We performed a quality improvement (QI) effort to determine the impact of a decrease in admission hypothermia in preterm infants. Methods The study enrolled very low birth weight (VLBW) infants born at Gangnam Severance Hospital between January 2013 and December 2016. This multidisciplinary QI effort included the use of occlusive wraps, warm blankets, and caps; the delivery room temperature was maintained above 23.0˚C, and a check-list was used for feedback. Results Among 259 preterm infants, the incidence of hypothermia (defined as body temperature <36.0˚C) decreased significantly from 68% to 41%, and the mean body temperature on neonatal intensive care unit admission increased significantly from 35.5˚C to 36.0˚C. In subgroup analysis of VLBW infants, admission hypothermia and neonatal outcomes were compared between the pre-QI (n=55) and post-QI groups (n=75). Body temperature on admission increased significantly from 35.4˚C to 35.9˚C and the number of infants with hypothermia decreased significantly from 71% to 45%. There were no cases of neonatal hyperthermia. The incidence of pulmonary hemorrhage was significantly decreased (P=0.017). Interaction analysis showed that birth weight and gestational age were not correlated with hypothermia following implementation of the protocol. Conclusion Our study demonstrated a significant reduction in admission hypothermia following the introduction of a standardized protocol in our QI effort. This resulted in an effective reduction in the incidence of massive pulmonary hemorrhage.

Neonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology. Neonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells. AAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions. This study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

The establishment of versatile biomaterial interfaces that can facilitate cellular adhesion is crucial for elucidating the cellular processes that occur on biomaterial surfaces. Furthermore, biomaterial interfaces can provide physical or chemical cues that are capable of stimulating cellular behaviors by regulating intracellular signaling cascades. Herein, a method of creating a biomimetic functional biointerface was introduced to enhance human neural stem cell (hNSC) adhesion. The hNSC-compatible biointerface was prepared by the oxidative polymerization of the neurotransmitter norepinephrine, which generates a nanoscale organic thin layer, termed poly(norepinephrine) (pNE). Due to its adhesive property, pNE resulted in an adherent layer on various substrates, and pNE-coated biointerfaces provided a highly favorable microenvironment for hNSCs, with no observed cytotoxicity. Only a 2-hour incubation of hNSCs was required to firmly attach the stem cells, regardless of the type of substrate. Importantly, the adhesive properties of pNE interfaces led to micropatterns of cellular attachment, thereby demonstrating the ability of the interface to organize the stem cells. This highly facile surface-modification method using a biomimetic pNE thin layer can be applied to a number of suitable materials that were previously not compatible with hNSC technology.

Purpose The goal of nutritional support for very-low-birth-weight (VLBW) infants from birth to term is to match the in utero growth rates; however, this is rarely achieved. Methods We evaluated postdischarge growth patterns and growth failure in 81 Korean VLBW infants through a retrospective study. Weight and height were measured and calculated based on age percentile distribution every 3 months until age 24 months. Growth failure was defined as weight and height below the 10th percentile at 24 months. For the subgroup analysis, small-for-gestational age (SGA) and extremely low birth weight (ELBW) infants were evaluated. The growth patterns based on the Korean, World Health Organization (WHO), or Centers for Disease Control and Prevention (CDC) standard were serially compared over time. Results At postconception age (PCA) 40 weeks, 47 (58%) and 45 infants (55%) showed growth failure in terms of weight and height, respectively. At PCA 24 months, 20 infants (24%) showed growth failure for weight and 14 (18%) for height. Growth failure rates were higher for the SGA infants than for the appropriate-weight-for-gestational age infants at PCA 24 months (P=0.045 for weight and P=0.038 for height). Growth failure rates were higher for the ELBW infants than for the non-ELBW infants at PCA 24 months (P<0.001 for weight and P=0.003 for height). Significant differences were found among the WHO, CDC, and Korean standards (P<0.001). Conclusion Advancements in neonatal care have improved the catch-up growth of VLBW infants, but this is insufficient. Careful observation and aggressive interventions, especially in SGA and ELBW infants, are needed.

Human iPS cells made simpler Earlier this year Hans Schöler's group reported that a single transcription factor, OCT4 , was sufficient to reprogram mouse adult neural stem cells to pluripotency, making them capable of producing virtually any cell type in the right conditions. This was a striking simplification of the process — OCT4 was just one of four factors used in the early (2006/7) and classic work on producing iPS (induced pluripotent stem) cells. Now Schöler and colleagues show that OCT4 alone can also generate iPS cells from human neural stem cells. Although induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of four transcription factors, the expression of one of these four, Oct4 , is sufficient to directly reprogram adult mouse neural stem cells to iPS cells. The generation of one-factor human iPS cells from human fetal neural stem cells by ectopic expression of OCT4 alone is now reported, demonstrating that OCT4 is sufficient to reprogram human neural stem cells to pluripotency. Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of four transcription factors ( OCT4 (also called POU5F1 ), SOX2 , c-Myc and KLF4 ) 1 , 2 , 3 , 4 , 5 , 6 , 7 . We previously reported that Oct4 alone is sufficient to reprogram directly adult mouse neural stem cells to iPS cells 8 . Here we report the generation of one-factor human iPS cells from human fetal neural stem cells (one-factor (1F) human NiPS cells) by ectopic expression of OCT4 alone. One-factor human NiPS cells resemble human embryonic stem cells in global gene expression profiles, epigenetic status, as well as pluripotency in vitro and in vivo . These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human neural stem cells to pluripotency. One-factor iPS cell generation will advance the field further towards understanding reprogramming and generating patient-specific pluripotent stem cells.

Background Alzheimer’s disease (AD) is an inexorable neurodegenerative disease that commonly occurs in the elderly. The cognitive impairment caused by AD is associated with abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, which are accompanied by inflammation. Neural stem cells (NSCs) are self-renewing, multipotential cells that differentiate into distinct neural cells. When transplanted into a diseased brain, NSCs repair and replace injured tissues after migration toward and engraftment within lesions. We investigated the therapeutic effects in an AD mouse model of human NSCs (hNSCs) that derived from an aborted human fetal telencephalon at 13 weeks of gestation. Cells were transplanted into the cerebral lateral ventricles of neuron-specific enolase promoter-controlled APPsw-expressing (NSE/APPsw) transgenic mice at 13 months of age. Results Implanted cells extensively migrated and engrafted, and some differentiated into neuronal and glial cells, although most hNSCs remained immature. The hNSC transplantation improved spatial memory in these mice, which also showed decreased tau phosphorylation and Aβ42 levels and attenuated microgliosis and astrogliosis. The hNSC transplantation reduced tau phosphorylation via Trk-dependent Akt/GSK3β signaling, down-regulated Aβ production through an Akt/GSK3β signaling-mediated decrease in BACE1, and decreased expression of inflammatory mediators through deactivation of microglia that was mediated by cell-to-cell contact, secretion of anti-inflammatory factors generated from hNSCs, or both. The hNSC transplantation also facilitated synaptic plasticity and anti-apoptotic function via trophic supplies. Furthermore, the safety and feasibility of hNSC transplantation are supported. Conclusions These findings demonstrate the hNSC transplantation modulates diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model. Thus, our data provide tangible preclinical evidence that human NSC transplantation could be a safe and versatile approach for treating AD patients.

Growth in preterm infants has long-term implications for neurodevelopmental outcomes. We aimed to estimate the nationwide growth outcomes from birth to 5 years in infants born under 1500 g and to analyze the effects of major morbidities in preterm infants on growth. In total, 2961 children born in 2013 with a birth weight under 1500 g who underwent an infant health checkup between 2013 and 2018 according to the National Health Insurance Service database were included. Checkups were conducted at 4–6, 9–12, 18–24, 30–36, 42–48, and 54–60 months of age. Information was obtained from the International Classification of Diseases-10 codes or a questionnaire administered during the check-up. At 60 months of age, the mean percentiles of weight, height, and head circumference fell within only the 30–40th percentile of normal growth values. About 30% of infants had growth parameters below the 10th percentile and showed worse neurodevelopmental outcomes. Using multiple logistic regression, infants with bronchopulmonary dysplasia showed a significantly higher incidence of growth restriction in all three categories of weight (odds ratio [OR] 1.50), height (OR 1.33), and head circumference (OR 1.36) at 60 months. Sepsis was associated with growth restriction in weight (OR 1.43) and head circumference (OR 1.33). Periventricular leukomalacia infants had relatively small head circumferences (OR 1.91) and poor developmental screening results (OR 2.89).Conclusion: Catch-up growth remains a major issue in infants born under 1500 g, especially those with some morbidities from preterm birth. Regular checkups to monitor and early intervention to achieve normal growth are essential. What is Known:• Growth in preterm infants has long-term implications for neurodevelopmental and cardiometabolic outcomes.• Data are lacking on the time-serial effects of many preterm morbidities simultaneously on long-term growth outcomes.What is New:• All growth parameters of VLBW infants, including weight, height, and head circumference, fell within the 30–40th percentile of normal growth for infants at 60 months of age, indicating that catch-up growth for VLBW infants remains an issue.• VLBW infants with major preterm morbidities, including BPD, PVL, and sepsis, showed difficulties in achieving normal catch-up growth and neurodevelopment at 60 months of age.

We aimed to evaluate risk factors for growth failure in very low birth weight (VLBW) infants at 18–24 months of corrected age (follow-up1, FU1) and at 36 months of age (follow-up2, FU2). In this prospective cohort study, a total of 2,943 VLBW infants from the Korean Neonatal Network between 2013 and 2015 finished follow-up at FU1. Growth failure was defined as a z-score below -1.28. Multiple logistic regression was used to analyze risk factors for growth failure after dividing the infants into small for gestational age (SGA) and appropriate for gestational age (AGA) groups. Overall, 18.7% of infants were SGA at birth. Growth failure was present in 60.0% at discharge, 20.3% at FU1, and 35.2% at FU2. Among AGA infants, male sex, growth failure at discharge, periventricular leukomalacia, treatment of retinopathy of prematurity, ventriculoperitoneal shunt status and treatment of rehabilitation after discharge were independent risk factors for growth failure at FU1. Among SGA infants, lower birth weight, pregnancy-induced hypertension, and treatment of rehabilitation after discharge were independent risk factors for growth failure at FU1. Mean weight z-score graphs from birth to 36 month of age revealed significant differences between SGA and non-SGA and between VLBW infants and extremely low birth weight infants. Growth failure remains an issue, and VLBW infants with risk factors should be closely checked for growth and nutrition.