Genetic architecture in neonatal intensive care unit patients with congenital heart defects: a retrospective study from the China Neonatal Genomes Project.

BACKGROUND: Congenital heart defects (CHDs) are the most common type of birth defects. The genetic aetiology of CHD is complex and incompletely understood. The overall distribution of genetic causes in patients with CHD from neonatal intensive care units (NICUs) needs to be studied. METHODS: CHD cases were extracted from the China Neonatal Genomes Project (2016-2021). Next-generation sequencing results and medical records were retrospectively evaluated to note the frequency of genetic diagnosis and the respective patient outcomes. RESULTS: In total, 1795 patients were included. The human phenotype ontology term of atrial septal defect, patent ductus arteriosus and ventricular septal defect account for a large portion of the CHD subtype. Co-occurring extracardiac anomalies were observed in 35.1% of patients. 269 of the cases received genetic diagnoses that could explain the phenotype of CHDs, including 172 copy number variations and 97 pathogenic variants. The detection rate of trio-whole-exome sequencing was higher than clinical exome sequencing (21.8% vs 14.5%, p<0.05). Further follow-up analysis showed the genetic diagnostic rate was higher in the deceased group than in the surviving group (29.0% vs 11.9%, p<0.05). CONCLUSION: This is the largest cohort study to explore the genetic spectrum of patients with CHD in the NICU in China. Our findings may benefit future work on improving genetic screening and counselling for NICU patients with CHD.

Comparison of two novel diagnostic criteria for bronchopulmonary dysplasia in predicting adverse outcomes of preterm infants: a retrospective cohort study.

BACKGROUND: This study aimed to compare the predictive value of two diagnostic criteria for bronchopulmonary dysplasia (BPD) in preterm infants with gestational age (GA) < 32 weeks for death or severe respiratory morbidity at corrected age of 18-24 months. METHODS: In this retrospective cohort study, clinical data from July 2019 to September 2021 were classified by 2018 National Institute of Child Health and Human Development (NICHD) and 2019 Jensen definitions of BPD. Based on the follow-up results, the enrolled population was divided into adverse outcome group and normal outcome group. Logistic regression and receiver operating characteristic (ROC) curve analyses were conducted to explore the risk factors of adverse outcomes and evaluate the predictive value of both diagnostic criteria. RESULTS: Of 451 infants, 141 (31.3%) had adverse outcomes, which increased with increasing severity of BPD. Logistic regression analysis showed only BPD was an independent risk factor for adverse outcomes in preterm infants. ROC analysis revealed that both diagnostic criteria showed similar predictive values (2018 NICHD definition AUC = 0.771 vs. 2019 Jensen definition AUC = 0.770), with specificities of 93.5% and 96.8%, respectively; however, combining them separately with GA or birth weight did not improve their predictive values. CONCLUSIONS: The two novel definitions of BPD demonstrate similar predictive values in predicting death or severe respiratory morbidity at corrected age of 18-24 months, with higher specificity observed in both.

Outcome Analysis of Severe Hyperbilirubinemia in Neonates Undergoing Exchange Transfusion.

OBJECTIVE: Severe neonatal hyperbilirubinemia can cause neurological disability or mortality if not effectively managed. Exchange transfusion (ET) is an efficient treatment to prevent bilirubin neurotoxicity. The purpose of this study was to evaluate outcomes in severe neonatal hyperbilirubinemia with ET and to identify the potential risk factors for poor outcomes. METHODS: Newborns of ≥28 weeks of gestational age with severe hyperbilirubinemia who underwent ET from January 2015 to August 2019 were included. Demographic data were recorded and analyzed according to follow-up outcomes at 12 months of corrected age. Poor outcomes were defined as death due to bilirubin encephalopathy or survival with at least one of the following complications: cerebral palsy, psychomotor retardation (psychomotor developmental index < 70), mental retardation (mental developmental index < 70), or hearing impairment. RESULTS: A total of 524 infants were eligible for recruitment to the study, and 62 infants were lost to follow-up. The outcome data from 462 infants were used for grouping analysis, of which 398 cases (86.1%) had normal outcomes and 64 cases (13.9%) suffered poor outcomes. Bivariate logistic regression analysis showed that peak total serum bilirubin (TSB) (odds ratio [OR] = 1.011, 95% confidence interval [CI] = 1.008-1.015, p = 0.000) and sepsis (OR = 4.352, 95% CI = 2.013-9.409, p < 0.001) were associated with poor outcomes of hyperbilirubinemia. Receiver operator characteristic curve analysis showed that peak TSB ≥452.9 µmol/L could predict poor outcomes of severe hyperbilirubinemia. CONCLUSION: Peak TSB and sepsis were associated with poor outcomes in infants with severe hyperbilirubinemia, and peak TSB ≥452.9 µmol/L could predict poor outcomes.

[Clinical characteristics and genetic analysis of a pedigree affected with neonatal central core disease].

OBJECTIVE: To investigate the possible causative factors of central core disease(CCD), the clinical features of a neonatal case with CCD and five patients in the pedigree line were analyzed for RYR1 gene variant. METHODS: Medical and family history inquiries and detailed clinical examinations were performed in the proband. High-throughput sequencing technology was applied to analyze the gene variant of the proband, and Sanger sequencing was applied to verify the pedigree distribution of the variant. RESULTS: The whole exon sequencing results showed that the proband has a missense variant of c. 14591A>C (p.Tyr4864Ser) in the RYR1 gene which was unreported previously; Sanger sequencing results showed that the father, grandfather, the eldest aunt and second aunt of the proband all carried the same variant. The c.14591 A>C variant of RYR1 gene was predicted to be a likely pathogenic (PM2+PM5+PP1+PP3) according to the American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION: The RYR1 gene c.14591A>C (p.Tyr4864Ser) variant may be the genetic cause of the pedigree and genetic testing helps to clarify the diagnosis. Identification of this variant has enriched the variant spectrum of the RYR1 gene.

Evaluation of the clinical effect of an artificial intelligence-assisted diagnosis and treatment system for neonatal seizures in the real world: a multicenter clinical study protocol. / æ–°ç”Ÿå„¿æƒŠåŽ¥æ™ºèƒ½è¯Šç–—ç³»ç»ŸçœŸå®žåœºæ™¯ä¸´åºŠå®žæ–½æ•ˆæžœç»¼åˆè¯„ä»·çš„å¤šä¸­å¿ƒä¸´åºŠç ”ç©¶æ–¹æ¡ˆ.

Neonatal seizures are the most common clinical manifestations of critically ill neonates and often suggest serious diseases and complicated etiologies. The precise diagnosis of this disease can optimize the use of anti-seizure medication, reduce hospital costs, and improve the long-term neurodevelopmental outcomes. Currently, a few artificial intelligence-assisted diagnosis and treatment systems have been developed for neonatal seizures, but there is still a lack of high-level evidence for the diagnosis and treatment value in the real world. Based on an artificial intelligence-assisted diagnosis and treatment systems that has been developed for neonatal seizures, this study plans to recruit 370 neonates at a high risk of seizures from 6 neonatal intensive care units (NICUs) in China, in order to evaluate the effect of the system on the diagnosis, treatment, and prognosis of neonatal seizures in neonates with different gestational ages in the NICU. In this study, a diagnostic study protocol is used to evaluate the diagnostic value of the system, and a randomized parallel-controlled trial is designed to evaluate the effect of the system on the treatment and prognosis of neonates at a high risk of seizures. This multicenter prospective study will provide high-level evidence for the clinical application of artificial intelligence-assisted diagnosis and treatment systems for neonatal seizures in the real world.

Diagnostic and clinical utility of next-generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project.

Multiple congenital anomalies (MCAs) at birth have emerged as an important cause of neonatal morbidity and mortality. This study aimed to investigate the genetic causes and characteristics of clinical outcomes in a large cohort of neonates with MCAs. Clinical exome sequencing/exome sequencing/genome sequencing were undertaken from December 1, 2016 to December 1, 2019 to detect single nucleotide variations (SNVs) and copy number variations (CNVs) simultaneously in individuals who met the inclusion criteria. A total of 588 neonates with MCAs were enrolled. One hundred sixty-one patients received diagnosis, with 71 CNVs and 90 SNVs detected, the overall diagnostic rate being 27.38%. Cardiovascular malformation was the most common anomaly (60%) and accounted for the top symptomatic proportion in both CNVs and SNVs. As the number of involved system increased from 2 to 3-4, and then to ≥5, the overall diagnostic rate increased gradually from 23.1% to 30.5%, and then to 52.2%, respectively. Patients who received genetic diagnoses were offered better clinical management or were referred to the specific disease clinic. In conclusion, this large cohort study demonstrates that both CNVs and SNVs contribute to the genetic causes of MCAs, and earlier genetic assertion may lead to better clinical management for patients.

Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project.

OBJECTIVES: To determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants. DESIGN: In this prospective study, samples from critically ill infants were analyzed using both proband-only clinical exome sequencing and trio-rapid genome sequencing (proband and biological parents). The study occurred between April 2019 and December 2019. SETTING: Thirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved. PARTICIPANTS: Critically ill infants (n = 202), from birth up until 13 months of life were enrolled based on eligibility criteria (e.g., CNS anomaly, complex congenital heart disease, evidence of metabolic disease, recurrent severe infection, suspected immune deficiency, and multiple malformations). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 202 participants, neuromuscular (45%), respiratory (22%), and immunologic/infectious (18%) were the most commonly observed phenotypes. The diagnostic yield of trio-rapid genome sequencing was higher than that of proband-only clinical exome sequencing (36.6% [95% CI, 30.1-43.7%] vs 20.3% [95% CI, 15.1-26.6%], respectively; p = 0.0004), and the average turnaround time for trio-rapid genome sequencing (median: 7 d) was faster than that of proband-only clinical exome sequencing (median: 20 d) (p < 2.2 × 10-16). The metagenomic analysis identified pathogenic or likely pathogenic microbes in six infants with symptoms of sepsis, and these results guided the antibiotic treatment strategy. Sixteen infants (21.6%) experienced a change in clinical management following trio-rapid genome sequencing diagnosis, and 24 infants (32.4%) were referred to a new subspecialist. CONCLUSIONS: Trio-rapid genome sequencing provided higher diagnostic yield in a shorter period of time in this cohort of critically ill infants compared with proband-only clinical exome sequencing. Precise and fast molecular diagnosis can alter medical management and positively impact patient outcomes.

[Clinical characteristics and molecular genetics of seven neonates with congenital nephrogenic diabetes insipidus].

OBJECTIVE: To explore the clinical characteristics, genetic basis and clinical treatment of seven neonates with congenital nephrogenic diabetes insipidus (NDI). METHODS: Clinical data of the patients were collected. High-throughput sequencing was carried out to detect potential variants. Sanger sequencing was used to verify the results. RESULTS: The patients were all males, with the age of onset being 10 to 21 days. All patients were admitted to the hospital for intermittent fever as the first symptom during the neonatal period. Additional symptoms had included polydipsia and polyuria. After the treatment, 5 patients had recovered, the remainders still had NDI symptoms and developmental retardation. Five children were found to harbor pathogenic variants of the AVPR2/AQP2 gene, which included one in-frame mutation of c.645_646insGCACCTACCCTGGGTATCGCC, two missense mutations of c.541C>T and c.419C>A, and two hemizygous deletions of the AVPR2/AQP2 gene. Among these, two were unreported previously. Cases 6 and 7 were a pair of twins. Both had carried homozygous missense variants of c.538G>A of the AVPR2/AQP2 gene, which was known to be pathogenic. CONCLUSION: AVPR2/AQP2 is the main pathogenic gene for congenital NDI, for which two novel pathogenic variants have been discovered in this study. Above results have provided a basis for clinical diagnosis and genetic counseling for the affected pedigrees.

Effect of early prophylactic low-dose recombinant human erythropoietin on retinopathy of prematurity in very preterm infants.

BACKGROUND: Very preterm infants are at risk of developing retinopathy of prematurity (ROP). Recombinant human erythropoietin (rhEPO) is routinely used to prevent anemia in preterm infants; however, the effect of rhEPO on ROP development is still controversial. The purpose of this study was to evaluate the effect of early prophylactic low-dose rhEPO administration on ROP development in very preterm infants. METHODS: A total of 1898 preterm infants born before 32 weeks of gestation were included. Preterm infants received rhEPO (n = 950; 500 U/kg, rhEPO group) or saline (n = 948, control group) intravenously within 72 h of birth and then once every other day for 2 weeks. RESULTS: The total incidence of ROP was not significantly different between the two groups (10.2% vs. 13.2%, p = 0.055). Further analysis showed that rhEPO group had lower rates of type 2 ROP than the control group (2.2% vs. 4.1%, RR 0.98; 95% CI 0.96-1.00; p = 0.021). Subgroup analysis found that rhEPO treatment significantly decreased the incidence of type 2 ROP in infant boys (1.8% vs. 4.3%, p = 0.021) and in those with a gestational age of 28-296/7 weeks (1.1% vs. 4.9%, p = 0.002) and birth weight of 1000-1499 g (1.2% vs. 4.2%, p = 0.002). There was a small increasing tendency for the incidence of ROP in infants with a gestational age of < 28 weeks after rhEPO treatment. CONCLUSIONS: Repeated low-dose rhEPO administration has no significant influence on the development of ROP; however, it may be effective for type 2 ROP in infant boys or in infants with gestational age > 28 weeks and birth weight > 1500 g. Trial registration The data of this study were retrieved from two clinical studies registered ClinicalTrials.gov (NCT02036073) on January 14, 2014, https://clinicaltrials.gov/ct2/show/NCT02036073 ; and (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500 .

Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants. METHODS: The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age ≤ 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. RESULTS: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 ± 0.4 vs. 2.7 ± 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age < 28 weeks (p = 0.019), and the incidence of all stages NEC in preterm infants with hemoglobin < 90 g/l (p = 0.000) and 5 min Apgar score > 5 (p = 0.028). CONCLUSION: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial registration The protocol was registered retrospectively at ClinicalTrials.gov (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500.

Recombinant human erythropoietin improves neurological outcomes in very preterm infants.

OBJECTIVE: To evaluate the efficacy and safety of repeated low-dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants. METHODS: A total of 800 infants of ≤32-week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age. RESULTS: Death and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27-0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19-0.55, p < 0.001), and no excess adverse events were observed. INTERPRETATION: Repeated low-dose rhEPO treatment reduced the risk of long-term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24-34.

[Efficacy of heated humidified high-flow nasal cannula in preterm infants aged less than 32 weeks after ventilator weaning].

OBJECTIVE: To investigate the efficacy of heated humidified high-flow nasal cannula (HHHFNC) and nasal continuous positive airway pressure (nCPAP) in preterm infants aged 26-31(+6) weeks with respiratory distress syndrome after ventilator weaning. METHODS: A total of 161 preterm infants were randomly divided into two groups after ventilator weaning: HHHFNC treatment (n=79) and nCPAP treatment (n=82). The two groups were subdivided into 26-28(+6) weeks and 29-31+6 weeks groups according to the gestational age. The treatment failure rate, reintubation rate within 7 days after extubation, incidence of complications, and mortality during hospitalization were compared between the two groups. RESULTS: The treatment failure rate and reintubation rate showed no significant differences between the HHHFNC and nCPAP groups. The preterm infants aged 26-28(+6) weeks in the HHHFNC group had a significantly higher treatment failure rate than those in the nCPAP group (P<0.05), while the reintubation rate showed no significant difference. As for the preterm infants aged 29-31(+6) weeks, the treatment failure rate and reintubation rate showed no significant differences between the two groups. The incidence of complications and mortality showed no significant differences between the HHHFNC and nCPAP groups. CONCLUSIONS: In preterm infants aged 29-31(+6) weeks, HHHFNC has a similar efficacy as nCPAP after ventilator weaning, while in those aged less than 29 weeks, HHHFNC should be used with great caution if selected as the first-line noninvasive respiratory support.

Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial.

Infant colic, excessive crying of unknown cause, is a major burden to families and effects about 10-30 % of infants. Despite decades of research, the exact cause and treatment of infant colic has remained elusive. The use of Lactobacillus reuteri (DSM 17938) in infant colic is somewhat controversial and hence, we designed this study to evaluate its efficacy in infantile colic. We recruited predominantly or exclusively breastfed infants, aged less than 4 months in a placebo controlled observational randomized study. Participants' were assigned to receive L. reuteri at a dose 10(8) colony forming units (n = 21) and placebo (n = 21). Placebo was an identical formulation without live micro-organisms. Treatment was given to subjects for 21 days and they were followed for 4 weeks. Treatment success (primary outcome), daily reduction in crying time, parent satisfaction and reduction in maternal depression (secondary outcomes) were assessed at the end of study period. Treatment success was observed in all infants (100 %) of the probiotic group while it was seen in 15.7 % of the placebo group. Mean daily crying time was more significantly reduced to 32.1 ± 8.3 min/day (P < 0.01) from 200.9 ± 6.3 min/day in the probiotic group as compared to the placebo group (120.6 ± 20.0 min/day). Moreover, throughout the study period, parent's satisfaction and improvement in maternal depression (Edinburgh postnatal depression scale) was also significantly higher in the probiotic group. In our study population, reduction in crying time was significant (P < 0.01) even during first week of initiation of therapy. We conclude that L. reuteri (DSM 17938) reduces daily crying time and maternal depression during infantile colic. We suggest L. reuteri may be a safe and efficacious option for reducing infant colic.

The overexpression of epithelial cell adhesion molecule (EpCAM) in glioma.

Epithelial cell adhesion molecule (EpCAM) is overexpressed in various neoplasms as a tumor-associated antigen and absent in natural brain. However, little is known about EpCAM's expression in gliomas. To investigate the expression of EpCAM in gliomas and understand the correlation of EpCAM expression with malignancy, proliferation, angiogenesis, and prognosis, we studied the expression of EpCAM in 98 glioma samples by immunohistochemistry and by western blotting (N = 12). Correlative analysis of EpCAM overexpression with microvessel density (MVD), Ki-67 expression, age, and gender were made. Survival data was analyzed with Kaplan-Meier method and Cox Proportional Hazard Model. Immunohistochemistry results showed EpCAM was widely expressed in glioma (90.8 %). The overexpression rate of WHO grade IV gliomas was significantly higher EpCAM overexpression correlated significantly with Ki-67 expression and MVD. Western blot analysis also revealed a stepwise increase in EpCAM expression from WHO II to IV glioma. The overall survival of WHO III and IV glioma patients with EpCAM overexpression was obviously lower than that without EpCAM overexpression. EpCAM overexpression was an independent prognostic factor for overall survival in glioma patients. This study firstly shows that EpCAM overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki67), angiogenesis (MVD), and prognosis in gliomas. EpCAM may participate in tumorgenesis of gliomas.

Characteristics of respiratory distress syndrome in infants of different gestational ages.

BACKGROUND: The purpose of this study was to compare the risk factors, clinical characteristics, and complications of respiratory distress syndrome (RDS) in infants delivered very preterm, late preterm, and term in order to help optimize the management of RDS in neonates. METHODS: A retrospective study was conducted on neonates admitted to the NICU between January 2006 and December 2010. The enrolled infants with RDS were categorized as very preterm (<32(0/7) weeks gestation), moderately preterm (32(0/7)-33(6/7) weeks), late preterm (34(0/7)-36(6/7) weeks), and term (37(0/7)-42(0/7) weeks). The rates, potential risk factors, clinical characteristics, and complications of RDS of these four groups were comparatively analyzed. RESULTS: There was an increasing trend in incidence of RDS among the NICU admissions annually. Caesarean section without labor was significantly associated with RDS in term and late preterm infants (P < 0.001). Rates of requirements for ventilator and pulmonary surfactant were similar in very preterm and term infants but significantly lower in late preterm infants (P < 0.001). The oxygenation index value was not substantially lower in late preterm and term infants compared to very preterm infants, and the arterial oxygenation efficiency was improved slowly (P < 0.001). Incidence of pneumonia and occurrence of pneumothorax were significantly higher in term infants (P < 0.001). CONCLUSIONS: Term infants with RDS showed an association of RDS with caesarean section without labor and lung infection. These infants also showed slower improvement of oxygenation after surfactant administration and mechanical ventilation, and they experienced a high rate of pneumothorax complication, which was also noticed in late preterm neonates.

Antibiotic susceptibility of Escherichia coli isolated from neonates admitted to neonatal intensive care units across China from 2015 to 2020.

Background: Escherichia coli is one of the most common pathogens causing neonatal infections. Recently, the incidence and drug resistance of E. coli have increased, posing a major threat to neonatal health. The aim of this study was to describe and analyze the antibiotic resistance and multilocus sequence typing (MLST) characteristics of E. coli derived from infants admitted to neonatal intensive care units (NICUs) across China. Methods: In this study, 370 strains of E. coli from neonates were collected. E. coli isolated from these specimens were subjected to antimicrobial susceptibility testing (by broth microdilution method) and MLST. Results: The overall resistance rate was 82.68%, with the highest rate of methicillin/sulfamethoxazole (55.68%) followed by cefotaxime (46.22%). Multiple resistance rate was 36.74%, 132 strains (35.68%) had extended-spectrum ß-lactamase (ESBL) phenotype and 5 strains (1.35%) had insensitivity to the tested carbapenem antibiotics. The resistance of E. coli isolated from different pathogenicity and different sites of infections varied, strains derived from sputum were significantly more resistant to ß-lactams and tetracyclines. Currently, the prevalence spectrum in NICUs was dominated by ST1193, ST95, ST73, ST69 and ST131 across China. And the multidrug resistance of ST410 was the most severe. ST410 had the highest resistance rate to cefotaxime (86.67%), and its most common multidrug resistance pattern was ß-lactams + aminoglycosides + quinolones + tetracyclines + sulfonamides. Conclusions: Substantial proportions of neonatal E. coli isolates were severely resistant to commonly administered antibiotics. MLST results can suggest the prevalent characteristics of antibiotic resistance in E. coli with different ST types.

Early onset critically ill infants with Schaaf-Yang syndrome: a retrospective study from the China neonatal genomes project and literature review.

Background: Schaaf-Yang syndrome (SYS) is a recently identified rare neurodevelopmental disorder characterized by neonatal hypotonia, feeding difficulty, joint contractures, autism spectrum disorder and development delay/intellectual disability. It is mainly caused by truncating variants in maternally imprinted gene MAGEL2 within the Prader-Willi syndrome critical region 15q11-q13. Clinical diagnosis of SYS is difficult for clinicians due to its rarity and highly variable phenotypes, while unique inheritance patterns also complicate genetic diagnosis. To date, no published papers have analyzed the clinical consequences and molecular changes in Chinese patients. Methods: In this study, we retrospectively investigated the mutation spectrums and phenotypic features of 12 SYS infants. The data were from a cohort of critically ill infants from the China neonatal genomes project (CNGP), sponsored by Children's Hospital of Fudan University. We also reviewed relevant literature. Results: Six previously reported mutations and six novel pathogenic variations of MAGEL2 were identified in 12 unrelated infants. Neonatal respiratory problems were the major complaint for hospitalization, which occurred in 91.7% (11/12) cases. All babies displayed feeding difficulties and a poor suck postnatally, and neonatal dystonia was present in 11 of the cases; joint contractures and multiple congenital defects were also observed. Interestingly, we found that 42.5% (57/134) of the reported SYS patients, including ours carried variants in the c.1996 site, particularly the c.1996dupC variant. The mortality rate was 17.2% (23/134), with the median age of death between 24 gestational weeks in fetuses and 1-month-old in infants. Respiratory failure was the leading cause of death in live-born patients (58.8%, 10/17), especially during the neonatal period. Conclusions: Our findings expanded the genotype and phenotype spectrum of neonatal SYS patients. The results demonstrated that respiratory dysfunction was a typical characteristic among Chinese SYS neonates that should attract physicians' attention. The early identification of such disorders allows early intervention and can further provide genetic counseling as well as reproductive options for the affected families.

Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening.

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype-phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.

Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project.

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) corresponds to a spectrum of defects. Several large-cohort studies have used high-throughput sequencing to investigate the genetic risk of CAKUT during antenatal, childhood, and adulthood period. However, our knowledge of newborns with CAKUT is limited. Methods: This multicenter retrospective cohort study explored the genetic spectrum of CAKUT in a Chinese neonatal cohort. Clinical data and whole exome sequencing (WES) data of 330 newborns clinically diagnosed with CAKUT were collected. WES data were analyzed for putative deleterious single nucleotide variants (SNVs) and potential disease-associated copy number variants (CNVs). Results: In this study, pathogenic variants were identified in 61 newborns (18.5%, 61/330), including 35 patients (57.4%) with SNVs, 25 patients (41%) with CNVs, and 1 patient with both an SNV and a CNV. Genetic diagnosis rates were significantly higher in patients with extrarenal manifestations (P＜0.001), especially in those with cardiovascular malformations (P＜0.05). SNVs in genes related to syndromic disorders (CAKUT with extrarenal manifestations) were common, affecting 20 patients (57.1%, 20/35). KMT2D was the most common gene (5 patients) and 17q12 deletion was the most common CNV (4 patients). Patient 110 was detected with both a CNV (17q12 deletion) and an SNV (a homozygous variant of SLC25A13). Among the newborns with positive genetic results, 22 (36.1%, 22/61) patients may benefit from a molecular diagnosis and change in clinical management (including early multidisciplinary treatment, disease-specific follow-up, and familial genetic counseling). Conclusion: This study shows the heterogeneous genetic etiologies in a Chinese CAKUT neonatal cohort by using WES. Patients with CAKUT who have extrarenal manifestations are more likely to harbor genetic diagnoses. Kabuki syndrome and 17q12 deletion syndrome were the most common genetic findings. Approximately 36.1% of the patients may benefit from molecular diagnoses and a change in clinical management.

The Impact of Different Degrees of Intraventricular Hemorrhage on Mortality and Neurological Outcomes in Very Preterm Infants: A Prospective Cohort Study.

Objective: Intraventricular hemorrhage (IVH) is a common complication in preterm infants and is related to neurodevelopmental outcomes. Infants with severe IVH are at higher risk of adverse neurological outcomes and death, but the effect of low-grade IVH remains controversial. The purpose of this study was to evaluate the impact of different degrees of IVH on mortality and neurodevelopmental outcomes in very preterm infants. Methods: Preterm infants with a gestational age of <30 weeks admitted to neonatal intensive care units were included. Cerebral ultrasound was examined repeatedly until discharge or death. All infants were followed up to 18-24 months of corrected age. The impact of different grades of IVH on death and neurodevelopmental disability was assessed by multiple logistic regression. Results: A total of 1,079 preterm infants were included, and 380 (35.2%) infants had grade I-II IVH, 74 (6.9%) infants had grade III-IV IVH, and 625 (57.9%) infants did not have IVH. The mortality in the non-IVH, I-II IVH, and III-IV IVH groups was 20.1, 19.7, and 55.2%, respectively (p < 0.05), and the incidence of neurodevelopmental disabilities was 13.9, 16.1, and 43.3%, respectively (p < 0.05), at 18-24 months of corrected age. After adjusting for confounding factors, preterm infants with III-IV IVH had higher rates of cerebral palsy [26.7 vs. 2.4%, OR = 6.10, 95% CI (1.840-20.231), p = 0.003], disability [43.3 vs. 13.9%, OR = 2.49, 95% CI (1.059-5.873), p = 0.037], death [55.2 vs. 20.1%, OR = 3.84, 95% CI (2.090-7.067), p < 0.001], and disability + death [73.7 vs. 28.7%, OR = 4.77, 95% CI (2.518-9.021), p < 0.001] compared to those without IVH. However, the mortality and the incidence of neurodevelopmental disability in infants with I-II IVH were similar to those without IVH (p > 0.05). Conclusions: Severe IVH but not mild IVH increased the risk of mortality and neurodevelopmental disability in very preterm infants.