Risk factors for severe bronchopulmonary dysplasia in a Chinese cohort of very preterm infants.

OBJECTIVES: To examine the risk factors for severe bronchopulmonary dysplasia (BPD) in a cohort of very preterm infants (VPIs) in China, as BPD is common among VPIs and associated with a high mortality rate. METHODS: In this multicenter retrospective study, medical records from infants with BPD born at gestation age (GA) of <32 weeks with birth weight (BW) of <1,500 grams (g) in 7 regions of China were included. The cohort was stratified into different BPD severity groups based on their fraction of inspired oxygen requirement at a modified GA of 36 weeks or post discharge. Risk factors were identified using logistic regression analysis. RESULTS: A significant inverse correlation was revealed between BPD severity and both GA and BW (p<0.001). Independent risk factors for severe BPD (sBPD) were identified as invasive mechanical ventilation (≥7d), multiple blood transfusion (≥3), nosocomial infection (NI), hemodynamically significant patent ductus arteriosus (hsPDA), delayed initiation of enteral nutrition, and longer time to achieve total caloric intake of 110 kcal/kg. Conversely, administration of antenatal steroids was associated with reduced risk of sBPD. CONCLUSION: Our study not only reaffirmed the established risk factors of low GA and BW for sBPD in VPIs, but also identified additional, potentially modifiable risk factors. Further research is warranted to explore whether intervention in these modifiable factors might reduce the risk of sBPD.Clinical Trial Reg. No.: ChiCTR1900023418.

Hyperglycemia in pregnancy did not worsen the short-term outcomes of very preterm infants: a propensity score matching study.

Background: Hyperglycemia in pregnancy (HGP) has generally been considered a risk factor associated with adverse outcomes in offspring, but its impact on the short-term outcomes of very preterm infants remains unclear. Methods: A secondary analysis was performed based on clinical data collected prospectively from 28 hospitals in seven regions of China from September 2019 to December 2020. According to maternal HGP, all infants were divided into the HGP group or the non-HGP group. A propensity score matching analysis was used to adjust for confounding factors, including gestational age, twin or multiple births, sex, antenatal steroid administration, delivery mode and hypertensive disorders of pregnancy. The main complications and the short-term growth status during hospitalization were evaluated in the HGP and non-HGP groups. Results: A total of 2,514 infants were eligible for analysis. After matching, there were 437 infants in the HGP group and 874 infants in the non-HGP group. There was no significant difference between the two groups in main complications including respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, patent ductus arteriosus, culture positive sepsis, intraventricular hemorrhage, periventricular leukomalacia, anemia, feeding intolerance, metabolic bone disease of prematurity, or parenteral nutrition-associated cholestasis. The incidences of extrauterine growth retardation and increased growth retardation for weight and head circumference in the non-HGP group were all higher than those in the HGP group after matching (P < 0.05). Conclusions: HGP did not worsen the short-term outcomes of the surviving very preterm infants, as it did not lead to a higher risk of the main neonatal complications, and the infants' growth improved during hospitalization.

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

Associations of MMP9 polymorphism with the risk of severe pneumonia in a Southern Chinese children population.

BACKGROUND: Severe pneumonia frequently causes irreversible sequelae and represents a major health burden for children under the age of 5. Matrix Metallopeptidase 9 (MMP9) is a zinc-dependent endopeptidase that is involved in various cellular processes. The correlation between MMP9 and the risk of severe childhood pneumonia remains unclear. METHODS: Here we assemble a case-control cohort to study the association of genetic variants in MMP9 gene with severe childhood pneumonia susceptibility in a Southern Chinese population (1034 cases and 8426 controls). RESULTS: Our results indicate that the allele G in rs3918262 SNP was significantly associated with an increased risk of severe pneumonia. Bioinformatic analyses by expression quantitative trait loci (eQTL), RegulomeDB and FORGEdb database analysis showed that rs3918262 SNP has potential regulatory effect on translational efficiency and protein level of MMP9 gene. Furthermore, MMP9 concentrations were significantly up-regulated in the bronchoalveolar lavages (BALs) of children with severe pneumonia. CONCLUSION: In summary, our findings suggest that MMP9 is a novel predisposing gene for childhood pneumonia.

Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.

OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories. METHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations. RESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported. SIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2. PLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.

Association between bronchopulmonary dysplasia and death or neurodevelopmental impairment at 3 years in preterm infants without severe brain injury.

Objective: We investigated the association between bronchopulmonary dysplasia (BPD) and 3 years death or neurodevelopmental impairment (NDI) in very preterm infants without severe brain injury. Method: Our prospective cohort study recruited preterm infants who were born prior to 32 weeks of gestational age and survived in the neonatal intensive care unit until 36 weeks of corrected age. Upon reaching 3 years of age, each infant was assessed for death or NDI such as cerebral palsy, cognitive deficit, hearing loss, and blindness. Correlations between BPD and death or NDI were determined using multiple logistic regression analyses adjusted for confounding factors. Result: A total of 1,417 infants without severe brain injury who survived until 36 weeks of corrected age were initially enrolled in the study. Over the study period, 201 infants were lost to follow-up and 5 infants were excluded. Our final dataset, therefore, included 1,211 infants, of which 17 died after 36 weeks of corrected age and 1,194 were followed up to 3 years of age. Among these infants, 337 (27.8%) developed BPD. Interestingly, by 3 years of age, BPD was demonstrated to be independently associated with death or NDI, with an adjusted odds ratio of 1.935 (95% confidence interval: 1.292-2.899, p = 0.001), in preterm infants without severe neonatal brain injury. Conclusion: Our findings indicate that BPD is strongly associated with death or NDI in preterm infants without severe neonatal brain injury at 3 years of age. Further research is needed to understand the mechanisms linking the development of BPD with death or NDI and whether appropriate treatment of BPD may ameliorate or prevent the development of neurological complications.

Identification and verification of ferroptosis-related genes in the pathology of epilepsy: insights from CIBERSORT algorithm analysis.

Background: Epilepsy is a neurological disorder characterized by recurrent seizures. A mechanism of cell death regulation, known as ferroptosis, which involves iron-dependent lipid peroxidation, has been implicated in various diseases, including epilepsy. Objective: This study aimed to provide a comprehensive understanding of the relationship between ferroptosis and epilepsy through bioinformatics analysis. By identifying key genes, pathways, and potential therapeutic targets, we aimed to shed light on the underlying mechanisms involved in the pathogenesis of epilepsy. Materials and methods: We conducted a comprehensive analysis by screening gene expression data from the Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs) related to ferroptosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to gain insights into the biological processes and pathways involved. Moreover, we constructed a protein-protein interaction (PPI) network to identify hub genes, which was further validated using the receiver operating characteristic (ROC) curve analysis. To explore the relationship between immune infiltration and genes, we employed the CIBERSORT algorithm. Furthermore, we visualized four distinct interaction networks-mRNA-miRNA, mRNA-transcription factor, mRNA-drug, and mRNA-compound-to investigate potential regulatory mechanisms. Results: In this study, we identified a total of 33 differentially expressed genes (FDEGs) associated with epilepsy and presented them using a Venn diagram. Enrichment analysis revealed significant enrichment in the pathways related to reactive oxygen species, secondary lysosomes, and ubiquitin protein ligase binding. Furthermore, GSVA enrichment analysis highlighted significant differences between epilepsy and control groups in terms of the generation of precursor metabolites and energy, chaperone complex, and antioxidant activity in Gene Ontology (GO) analysis. Furthermore, during the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we observed differential expression in pathways associated with amyotrophic lateral sclerosis (ALS) and acute myeloid leukemia (AML) between the two groups. To identify hub genes, we constructed a protein-protein interaction (PPI) network using 30 FDEGs and utilized algorithms. This analysis led to the identification of three hub genes, namely, HIF1A, TLR4, and CASP8. The application of the CIBERSORT algorithm allowed us to explore the immune infiltration patterns between epilepsy and control groups. We found that CD4-naïve T cells, gamma delta T cells, M1 macrophages, and neutrophils exhibited higher expression in the control group than in the epilepsy group. Conclusion: This study identified three FDEGs and analyzed the immune cells in epilepsy. These findings pave the way for future research and the development of innovative therapeutic strategies for epilepsy.

Clinical and genetic characteristics of 36 children with Joubert syndrome.

Background and aims: Joubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes. However, long-term follow-up data are scarce, and further research is needed to determine the abundant phenotypes and genetics of this disorder. The study aimed to summarize clinical manifestations, particular appearance on cranial imaging, genetic data, and prognostic features of patients with JBTS. Methods: A retrospective case review of 36 cases of JBTS from May 1986 to December 2021 was performed. Clinical data of JBTS patients with development retardation and molar tooth sign on cranial imaging as the main features were analyzed. Genetic testing was performed according to consent obtained from patients and their families. The Gesell Developmental Scale was used to evaluate the intelligence level before and after treatment. The children were divided into a purely neurological JBTS (pure JBTS) group and JBTS with multi-organ system involvement group and then followed up every 3-6 months. Results: We enrolled 18 males and 18 females. Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. There was one case co-morbid with Lesch-Nyhan syndrome. Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment. JBTS could also involve the skin. Thirty-one cases (86.11%) showed a typical molar tooth sign, and five cases showed a bat wing sign on cranial imaging. Abnormal video electroencephalogram (VEEG) result was obtained in 7.69% of cases. We found six JBTS-related novel gene loci variants: CPLANE1: c.4189 + 1G > A, c.3101T > C(p.Ile1034Thr), c.3733T > C (p.Cys1245Arg), c.4080G > A(p.Lys1360=); RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys). The CHD7 gene may be potentially related to the occurrence of JBTS. Analysis showed that the prognosis of pure JBTS was better than that of JBTS with neurological and non-neurological involvement after the formal rehabilitation treatment (P < 0.05). Of the three children with seizures, two cases had epilepsy with a poor prognosis, and another case had breath-holding spells. Conclusion: Our findings indicate that early cranial imaging is helpful for the etiological diagnosis of children with unexplained developmental delay and multiple malformations. Patients with JBTS may have coexisting skin abnormalities. The novel gene loci of CPLANE1, RPGRIP1l, and CEP120 were associated with JBTS in our study and provided significant information to enrich the related genetic data. Future works investigating several aspects of the association between CHD7 gene and JBTS merit further investigation. The prognosis of children with pure JBTS is better than that of children with JBTS with non-neurological involvement.

Clinical characteristics and long-term neurodevelopmental outcomes of leukomalacia in preterm infants and term infants: a cohort study.

BACKGROUND: Leukomalacia is a serious form of neonatal brain injury that often leads to neurodevelopmental impairment, and studies on neonatal leukomalacia and its long-term outcomes are lacking. The aim of this study was to analyze the clinical manifestations, imaging features, and long-term neurodevelopmental outcomes in preterm infants and term infants with leukomalacia. METHODS: Newborns diagnosed with leukomalacia by head magnetic resonance imaging (MRI) and who were admitted to intensive care units from January 2015 to June 2020 were enrolled. All infants were followed up to June 2022 (2-7 years old), and their neurodevelopmental outcomes were evaluated. The clinical data and long- term outcomes of preterm infants and term infants was analyzed by Chi-square tests. RESULTS: A total of 218 surviving infants with leukomalacia including 114 preterm infants and 104 term infants completed the follow-up. The major typesof leukomalacia on MRI were periventricular leukomalacia in the preterm group and subcortical cystic leukomalacia in the term group, respectively (χ2 = 55.166; p < 0.001). When followed up to 2-7 years old, the incidence of neurodevelopmental impairment in the preterm group and term group was not significantly different (χ2 = 0.917; p = 0.338). However, the incidence of cerebral palsy (CP) in the preterm group was significantly higher (χ2 = 4.896; p = 0.027), while the incidence of intellectual disability (ID) (χ2 = 9.445; p = 0.002), epilepsy (EP) (χ2 = 23.049; p < 0.001), and CP combined with ID andEP (χ2 = 4.122; p = 0.042) was significantly lower than that in the term group. CONCLUSIONS: Periventricular leukomalacia mainly occurred in preterm infants while subcortical cystic leukomalacia was commonly seen in term infants. Although the long-term neurodevelopmental outcomes of leukomalacia were both poor, preterm infants were more prone to CP, while term infants were more prone to ID, EP, and the combination of CP with ID and EP.

[Analysis of ARX gene variant in a child with X-linked lissencephaly with abnormal genitalia].

OBJECTIVE: To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG). METHODS: A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software. RESULTS: The child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously. CONCLUSION: The hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.

Real-world evidence regarding the growth of very premature infants with small for gestational age after birth: a multicenter survey in China.

BACKGROUND: To analyze the real-world growth pattern of very premature infants (VPI) with small for gestational age (SGA) after birth by using the ΔZ value of weight at discharge. METHODS: The clinical data were collected from 28 hospitals in China from September 2019 to December 2020. They were divided into the EUGR(Extrauterine Growth Restriction) and the non-EUGR group according to the criterion of ΔZ value of weight at discharge < -1.28. RESULTS: This study included 133 eligible VPI with SGA. Following the criterion of ΔZ value, the incidence of EUGR was 36.84% (49/133). The birth weight, the 5-min Apgar score, and the proportion of male infants in the EUGR group were lower (P < 0.05). The average invasive ventilation time, cumulative duration of the administration of antibiotics, blood transfusion time, blood transfusion ratio, and total days of hospitalization were significantly higher in the EUGR group (P < 0.05). In the EUGR group, several factors exhibited higher values (P < 0.05), including the initiation of enteral feeding, the volume of milk supplemented with human milk fortifier (HMF), the duration to achieve complete fortification, the cumulative duration of fasting, the duration to achieve full enteral feeding, the length of parenteral nutrition (PN), the number of days required to attain the desired total calorie intake and oral calorie intake, as well as the age at which birth weight was regained. The average weight growth velocity (GV) was significantly lower in the EUGR group (P < 0.001). The incidences of patent ductus arteriosus with hemodynamic changes (hsPDA), neonatal necrotizing enterocolitis (NEC) stage≥ 2, late-onset sepsis (LOS), and feeding intolerance (FI) in the EUGR group were higher (P < 0.05). Multivariate logistic regression analysis showed that birth weight, male, and GV were the protective factors, while a long time to achieve full-dose fortification, slow recovery of birth weight, and NEC stage ≥2 were the independent risk factors. CONCLUSION: SGA in VPI can reflect the occurrence of EUGR more accurately by using the ΔZ value of weight at discharge. Enhancing enteral nutrition support, achieving prompt and complete fortification of breast milk, promoting greater GV, reducing the duration of birth weight recovery, and minimizing the risk of NEC can contribute to a decreased occurrence of EUGR. TRIAL REGISTRATION: CHICTR, ChiCTR1900023418. Registered 26/05/2019, http://www.chictr.org.cn .

Nomogram for predicting fulminant necrotizing enterocolitis.

BACKGROUND: Fulminant necrotizing enterocolitis (FNEC) is the most serious subtype of NEC and has a high mortality rate and a high incidence of sequelae. Onset prediction can help in the establishment of a customized treatment strategy. This study aimed to develop and evaluate a predictive nomogram for FNEC. METHODS: We conducted a retrospective observation to study the clinical data of neonates diagnosed with NEC (Bell stage ≥ IIB). Neonates were divided into the FNEC and NEC groups. A multivariate logistic regression model was used to construct the nomogram model. The performance of the nomogram was assessed using area under the curve, calibration analysis, and decision curve analysis. RESULTS: A total of 206 neonate cases were included, among which 40 (19.4%) fulfilled the definition of FNEC. The identified predictors were assisted ventilation after NEC onset; shock at NEC onset; feeding volumes before NEC onset; neutrophil counts on the day of NEC onset; and neutrophil, lymphocyte, and monocyte counts on day 1 after NEC onset. The nomogram exhibited good discrimination, with an area under the receiver operating characteristic curve of 0.884 (95% CI 0.825-0.943). The predictive model was well calibrated. Decision curve analysis confirmed the clinical usefulness of this nomogram. CONCLUSION: A nomogram with a potentially effective application was developed to facilitate the individualized prediction of FNEC, with the hope of providing further direction for the early diagnosis of FNEC and timing of intervention.

[Influence of bronchopulmonary dysplasia on cerebral blood flow in preterm infants: a prospective study based on arterial spin labeling]. / åŸºäºŽåŠ¨è„‰è‡ªæ—‹æ ‡è®°æˆåƒæŠ€æœ¯æŽ¢è®¨æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯å¯¹æ—©äº§å„¿è„‘è¡€æµé‡å½±å“çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To investigate local cerebral blood perfusion in preterm infants with bronchopulmonary dysplasia (BPD) based on cerebral blood flow (CBF) values of arterial spin labeling (ASL). METHODS: A prospective study was conducted on 90 preterm infants with a gestational age of <32 weeks and a birth weight of <1 500 g who were born in the Department of Obstetrics and admitted to the Department of Neonatology in the Third Affiliated Hospital of Zhengzhou University from August 2021 to June 2022. All of the infants underwent cranial MRI and ASL at the corrected gestational age of 35-40 weeks. According to the presence or absence of BPD, they were divided into a BPD group with 45 infants and a non-BPD group with 45 infants. The two groups were compared in terms of the CBF values of the same regions of interest (frontal lobe, temporal lobe, parietal lobe, occipital lobe, thalamus, and basal ganglia) on ASL image. RESULTS: Compared with the non-BPD group, the BPD group had a significantly lower 1-minute Apgar score, a significantly longer duration of assisted ventilation, and a significantly higher incidence rate of fetal distress (P<0.05). After control for the confounding factors such as corrected age and age at the time of cranial MRI by multiple linear regression analysis, compared with the non-BPD group, the BPD group still had higher CBF values of the frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, and thalamus at both sides (P<0.05). CONCLUSIONS: BPD can increase cerebral blood perfusion in preterm infants, which might be associated with hypoxia and a long duration of assisted ventilation in the early stage.

Circ_0007706 downregulation ameliorates neonatal hypoxic ischemic encephalopathy via regulating the miR-579-3p/TRAF6 axis.

BACKGROUND: Neonatal hypoxic ischemic encephalopathy (HIE) is a main factor of neonatal death and permanent neurologic deficit. This study sought to investigate the functional role of hsa_circ_0007706 (circ_0007706) in modulating neonatal HIE. METHODS: In vitro HIE cell model was established in hBMVECs under the condition of oxygen­glucose deprivation/reperfusion (OGD/R) treatment. qRT-PCR analysis was utilized for detecting the level of circ_0007706, microRNA-579-3p (miR-579-3p) and TNF receptor-associated factor 6 (TRAF6). RNase R treatment and Oligo (dT) 18 primers were employed to verify the features of circ_0007706, and nucleocytoplasmic separation was conducted for determining the location of circ_0007706. CCK-8 assay, EdU assay, and flow cytometry were carried out to measure cell proliferation and apoptosis, respectively. The protein expression of Bax, Bcl-2 and TRAF6 was detected using western blot. Meanwhile, the levels of the pro-inflammatory factors were determined via ELISA. SOD activity and MDA level were assessed via the respective kits. Besides, dual-luciferase reporter assay and RNA pull-down were used to identify the association between miR-579-3p and circ_0007706 or TRAF6. RESULTS: Circ_0007706 was elevated in HIE newborns and OGD/R cell model. Knockdown of circ_0007706 greatly alleviated OGD/R-induced injury, inflammatory response and oxidative stress. We found that miR-579-3p was a direct target of circ_0007706, and miR-579-3p inhibitor could reverse the impact of circ_0007706 knockdown on OGD/R-caused cell damage in hBMVECs. In addition, miR-579-3p directly interacted with TRAF6, and the protective effects of miR-579-3p on OGD/R-induced injury in hBMVECs were harbored by TRAF6 overexpression. Our data indicated that circ_0007706 knockdown could downregulate the expression of TRAF6 by sponging miR-579-3p in OGD/R-treated hBMVECs. CONCLUSION: This study demonstrated that circ_0007706 knockdown assuaged HIE-induced injury by decreasing TRAF6 expression via targeting miR-579-3p.

Effect of early initiation of enteral nutrition on short-term clinical outcomes of very premature infants: A national multicenter cohort study in China.

OBJECTIVES: The management of enteral nutrition in very preterm infants (VPIs) is still controversial, and there is no consensus on the optimal time point after birth at which enteral nutrition can be started. The aim of this study was to investigate the effect of early initiation of enteral nutrition on the short-term clinical outcomes of VPIs. METHODS: Data of infants (n = 2514) born before 32 wk of gestation were collected from 28 hospitals located in seven different regions of China. Based on whether enteral feeding was initiated within or after 24 h since birth, the infants were divided into an early initiation of enteral feeding (EIEF) group and a delayed initiation of enteral feeding (DIEF) group. RESULTS: Compared with the DIEF group, the EIEF group was more likely to tolerate enteral nutrition and had less need for parenteral nutrition (all P < 0.05). The EIEF group was associated with lower incidence rates of feeding intolerance, extrauterine growth restriction (EUGR), and late-onset sepsis (LOS) (all P < 0.05). There was no significant difference in the incidence of necrotizing enterocolitis (NEC) (Bell stage ≥2) between the two groups (P = 0.118). The multivariate logistic regression analysis revealed that EIEF was a protective factor against EUGR (odds ratio [OR], 0.621; 95% confidence interval [CI], 0.544-0.735; P < 0.001), feeding intolerance (OR, 0.658; 95% CI, 0.554-0.782; P < 0.001), and LOS (OR, 0.706; 95% CI, 0.550-0.906; P = 0.006). CONCLUSIONS: Early initiation of enteral feeding was associated with less frequency of feeding intolerance, EUGR, and LOS, and it may shorten the time to reach total enteral feeding without increasing the risk of NEC.

The association of γδT lymphocytes with cystic leukomalacia in premature infants.

Background: Periventricular leukomalacia (PVL) is an essential cause of cerebral palsy in preterm infants, and cystic PVL (cPVL) is the most severe form of the disease. The pathogenesis of cPVL is complex, and immune imbalances and inflammatory responses may play an essential role in it. Objective: This study aimed to investigate the correlation between peripheral blood lymphocyte subsets, especially γδT cells with the pathogenesis of cPVL in preterm infants. Methods: Peripheral blood from preterm infants with GA < 32 weeks and BW < 1,500 g was used in this study and was collected at 34 weeks corrected gestational age and within 24 h after the diagnosis with cranial MRI or cranial ultrasound. The infants were divided into cPVL groups and control groups. Flow cytometry was used to detect peripheral blood γδT, CD3+, CD4+, CD8+, and the proportion of total lymphocytes. Multiplex cell assays were used to detect the concentration of extracellular serum cytokines IL-6, IL-2, IL-8, IL-17A, IL-10, IL-1RA, eotaxin (CCL11), MCP-1 (CCL2), CXCL1, G-CSF, and IFNγ. A follow-up visit was carried out when the patient was 3 years old. Results: After correcting for confounding factors, the proportion of peripheral blood γδT in the cPVL group was significantly lower than that in the control group (ß: 0.216; 95% CI: 0.058-0.800, P < 0.022). Peripheral blood γδT (AUC: 0.722, P=0.006) and multivariate binary regression model (AUC: 0.865, P < 0.000) have good diagnostic values for cPVL. Peripheral blood γδT has some predictive power for neurodevelopmental outcomes in preterm infants (AUC: 0.743, P = 0.002). Conclusion: It seems that peripheral blood γδT cells are inversely correlated with cPVL, which is not only a risk factor for cPVL disease but also neurodevelopmental outcomes in preterm infants. However, the causality of cPVL and various lymphocytes is unclear and needs further study.

Analysis of "true extrauterine growth retardation" and related factors in very preterm infants-A multicenter prospective study in China.

Objective: To investigate the incidence and related factors of extrauterine growth retardation (EUGR) and "true EUGR" in very preterm infants (VPI) from different regions of China. Materials and methods: Clinical data of VPI were prospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. The infants were divided into a small for gestational age (SGA) group or non-SGA group at birth, with non-SGA infants at 36 weeks of gestation or at discharge being further divided into a EUGR group or a non-EUGR group. Infants in the EUGR and non-SGA group were defined as "true EUGR." The general information of VPI, such as maternal complications during pregnancy, use of enteral nutrition and parenteral nutrition, and complications during hospitalization were compared between the groups. Results: Among the 2,514 VPI included in this study, 47.3, 41.5, and 33.3% of VPI were below the 10th percentile, and 22.6, 22.4, and 16.0% of VPI were below the 3rd percentile for weight, height, and head circumference at 36 weeks of gestation or at discharge, respectively, by the percentile on the 2013 Fenton curve. The incidences of EUGR and "true EUGR" evaluated by weight were 47.3 and 44.5%, respectively. Univariate analysis showed that there were statistically significant differences in the aspects of perinatal and nutritional characteristics, treatment, and complications between the groups. Multivariate analysis showed that in non-SGA infants, the cumulative caloric intake during the first week was a protective factor for "true EUGR," while days to reach total enteral nutrition, late initiation of human milk fortifier, and moderate to severe bronchopulmonary dysplasia were independent risk factors for "true EUGR." Conclusion: More attention should be paid to the nutritional management of VPI to prevent "true EUGR." Cumulative caloric intake should be ensured and increased during the first week, total enteral nutrition should be achieved as early as possible, human milk fortifier should be added early, and moderate to severe bronchopulmonary dysplasia should be prevented. These strategies are very important for reducing the incidence of "true EUGR" in VPI.

Association of neutropenia at disease onset with severe surgical necrotizing enterocolitis and higher mortality: A retrospective study.

Background: Neutrophils are among the earliest immune cells recruited to the site of an intestinal injury, but their predictive role in the progression of necrotizing enterocolitis (NEC) has not been fully elucidated. This study aimed to evaluate if a reduction in neutrophils at the onset of NEC is associated with severe surgical NEC and/or NEC-associated deaths. Methods: This is a retrospective cohort study in which neonates underwent surgery due to NEC during 2015-2020. The data on absolute neutrophil count (ANC), before and at the onset of NEC, were collected from the complete blood count results. The primary exposure was the difference in absolute neutrophil count (ΔANC) at NEC onset. The primary outcome was severe surgical NEC, defined as the residual small bowel length after intestinal resection of <30 cm. Results: A total of 157 neonates were included in this study, of which 53 were diagnosed with severe surgical NEC. A decrease in ANC at the onset of NEC was associated with an increased probability of severe surgical NEC (crude odds ratio [OR] 1.248, 95% CI 1.107-1.407; P = 0.000). ΔANC (area under the curve [AUC] 0.729, 95% CI 0.653-0.797; P < 0.001] was a good predictor for severe surgical NEC. The addition of platelets to ΔANC at NEC onset (AUC 0.738, 95% CI 0.662-0.808; P < 0.001) resulted in a higher AUC and specificity for severe surgical NEC prediction than ΔANC alone. A reduction in the neutrophil count at NEC onset (ΔANC > 0) was associated with adverse outcomes (hazard ratio [HR] 3.48, 95% CI 1.64-7.36) and a lower survival probability (χ2 10.63; P < 0.001). Conclusion: A reduction in the ANC at the onset of NEC was associated with severe surgical NEC and higher mortality. The addition of platelets to ΔANC at NEC onset resulted in a higher predictive value of severe surgical NEC. This study may provide a new insight into the bedside evaluation of NEC by analyzing data from the day of NEC onset.

[Establishment of a predictive nomogram model for predicting the death of very preterm infants during hospitalization]. / 极早产儿住院期间死亡的列线图预测模型的建立.

OBJECTIVES: To establish a nomogram model for predicting the risk of death of very preterm infants during hospitalization. METHODS: A retrospective analysis was performed on the medical data of 1 714 very preterm infants who were admitted to the Department of Neonatology, the Third Affiliated Hospital of Zhengzhou University, from January 2015 to December 2019. These infants were randomly divided into a training cohort (1 179 infants) and a validation cohort (535 infants) at a ratio of 7∶3. The logistic regression analysis was used to screen out independent predictive factors and establish a nomogram model, and the feasibility of the nomogram model was assessed by the validation set. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to assess the discriminatory ability, accuracy, and clinical applicability of the model. RESULTS: Among the 1 714 very preterm infants, 260 died and 1 454 survived during hospitalization. By the multivariate logistic regression analysis of the training set, 8 variables including gestational age <28 weeks, birth weight <1 000 g, severe asphyxia, severe intraventricular hemorrhage (IVH), grade III-IV respiratory distress syndrome (RDS), and sepsis, cesarean section, and use of prenatal glucocorticoids were selected and a nomogram model for predicting the risk of death during hospitalization was established. In the training cohort, the nomogram model had an AUC of 0.790 (95%CI: 0.751-0.828) in predicting the death of very preterm infants during hospitalization, while in the validation cohort, it had an AUC of 0.808 (95%CI: 0.754-0.861). The Hosmer-Lemeshow goodness-of-fit test showed a good fit (P>0.05). DCA results showed a high net benefit of clinical intervention in very preterm infants when the threshold probability was 10%-60% for the training cohort and 10%-70% for the validation cohort. CONCLUSIONS: A nomogram model for predicting the risk of death during hospitalization has been established and validated in very preterm infants, which can help clinicians predict the probability of death during hospitalization in these infants.