Use of antenatal corticosteroids among infants with gestational age at 24 to 31 weeks in 57 neonatal intensive care units of China: a cross-sectional study

Background:Antenatal corticosteroids(ACS)can significantly improve the outcomes of preterm infants.This study aimed to describe the ACS use rates among preterm infants admitted to Chinese neonatal intensive care units(NICU)and to explore perinatal factors associated with ACS use,using the largest contemporary cohort of very preterm infants in China.Methods:This cross-sectional study enrolled all infants born at 24^(+0)to 31^(+6)weeks and admitted to 57 NICUs of the Chinese Neonatal Network from January 1st,2019 to December 30th,2019.The ACS administration was defined as at least one dose of dexamethasone and betamethasone given before delivery.Multiple logistic regressions were applied to determine the association between perinatal factors and ACS usage.Results:A total of 7828 infants were enrolled,among which 6103(78.0%)infants received ACS.ACS use rates increased with increasing gestational age(GA),from 177/259(68.3%)at 24 to 25 weeks’gestation to 3120/3960(78.8%)at 30 to 31 weeks’gestation.Among infants exposed to ACS,2999 of 6103(49.1%)infants received a single complete course,and 33.4%(2039/6103)infants received a partial course.ACS use rates varied from 30.2%to 100%among different hospitals.Multivariate regression showed that increasing GA,born in hospital(inborn),increasing maternal age,maternal hypertension and premature rupture of membranes were associated with higher likelihood to receive ACS.Conclusions:The use rate of ACS remained low for infants at 24 to 31 weeks’gestation admitted to Chinese NICUs,with fewer infants receiving a complete course.The use rates varied significantly among different hospitals.Efforts are urgently needed to propose improvement measures and thus improve the usage of ACS.

Association of copy number variation in X chromosome-linked PNPLA4 with heterotaxy and congenital heart disease

Background:Heterotaxy(HTX)is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease(CHD).The aim of this study was to analyze rare copy number variations(CNVs)in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.Methods:Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients,and available samples from parents were used to confirm the inheritance pattern.Potential candidate genes in CNVs region were prioritized via the DECIPHER database,and PNPLA4 was identified as the leading candidate gene.To validate,we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model,followed by a series of transcriptomic,biochemical and cellular analyses.Results:Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients(12.5%).Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort,and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD.PNPLA4 is expressed in the lateral plate mesoderm,which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation,and in the neural crest cell lineage.Through a series of in vivo and in vitro analyses at the molecular and cellular levels,we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production.Conclusions:Our findings demonstrated a significant association between CNVs and HTX/CHD.Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.

High-risk phenotypes of genetic disease in a Neonatal Intensive Care Unit population

To the Editor: Genetic diseases contribute to 35% of deaths during the first year of life and are a significant cause of intensive care.[1] A previous study based on the China Neonatal Genomes Project investigated the genetic causes of early infant deaths and found that >25% of deceased neonates with genetic diagnoses can be cured if diagnosed in time.[2] Therefore, it is crucial to target and diagnose neonates with genetic diseases as early as possible. According to our experience, the typical phenotypes, such as special facial features or multiple congenital anomalies (MCAs), indicate a high risk of genetic disease and lead physicians to perform genetic testing in neonates as early as possible. However, in practice, infants without typical phenotypes typically undergo a long and costly diagnostic process before genetic diagnoses are confirmed. Moreover, a recent survey by the American College of Medical Genetics and Genomics (ACMG) and other national professional organizations indicated that there are insufficient numbers of qualified geneticists to fulfil genetic service needs.[3] The ACMG published the general clinical features for genetic testing indications. For example, patients with phenotypes or family history data that strongly implicate a genetic cause may undergo genetic testing.[1] However, the study indicated that many genetic conditions arise de novo or are inherited with no family history.[1] A previous study attempted to apply the non-phenotype-driven panel approach in neonates admitted to the neonate intensive care unit (NICU).[4] However, at present, the diagnostic yield is only 3.45% (1/29).[4] In addition, the economic and ethical issues associated with genomic screening remain challenging. Therefore, the available indications for genetic testing may improve the management of genetic diseases.

Variations in length of stay among survived very preterm infants admitted to Chinese neonatal intensive care units

Background This study aimed to describe length of stay(LOS)to discharge and site variations among very preterm infants(VPIs)admitted to 57 Chinese neonatal intensive care units(NICUs)and to investigate factors associated with LOS for VPIs.Methods This retrospective multicenter cohort study enrolled all infants<32 weeks’gestation and admitted to 57 NICUs which had participated in the Chinese Neonatal Network,within 7 days after birth in 2019.Exclusion criteria included major congenital anomalies,NICU deaths,discharge against medical advice,transfer to non-participating hospitals,and missing discharge date.Two multivariable linear models were used to estimate the association of infant characteristics and LOS.Results A total of 6580 infants were included in our study.The overall median LOS was 46 days[interquartile range(IQR):35-60],and the median corrected gestational age at discharge was 36 weeks(IQR:35-38).LOS and corrected gestational age at discharge increased with decreasing gestational age.The median corrected gestational age at discharge for infants at 24 weeks,25 weeks,26 weeks,27-28 weeks,and 29-31 weeks were 41 weeks,39 weeks,38 weeks,37 weeks and 36 weeks,respectively.Significant site variation of LOS was identified with observed median LOS from 33 to 71 days in different hospitals.Conclusions The study provided concurrent estimates of LOS for VPIs which survived in Chinese NICUs that could be used as references for medical staff and parents.Large variation of LOS independent of infant characteristics existed,indicating variation of care practices requiring further investigation and quality improvement.

Characteristics of home oxygen therapy for preterm infants with bronchopulmonary dysplasia in China:results of a multicenter cohort

Background Home oxygen therapy(HOT)is indicated upon discharge in some preterm infants with severe bronchopulmonary dysplasia(BPD).There is a lack of evidence-based consensus on the indication for HOT among these infants.Because wide variation in the institutional use of HOT exists,little is known about the role of regional social-economic level in the wide variation of HOT.Methods This was a secondary analysis of Chinese Neonatal Network(CHNN)data from January 1,2019 to December 31,2019.Infants at gestational ages<32 weeks,with a birth weight<1500 g,and with moderate or severe BPD who survived to discharge from tertiary hospitals located in 25 provinces were included in this study.Infants with major congenital anomalies and those who were discharged against medical advice were excluded.Results Of 1768 preterm infants with BPD,474 infants(26.8%)were discharged to home with oxygen.The proportion of HOT use in participating member hospitals varied from 0 to 89%,with five of 52 hospitals’observing proportions of HOT use that were significantly greater than expected,with 14 hospitals with observing proportions significantly less than expected,and with 33 hospitals with appropriate proportions.We noted a negative correlation between different performance groups of HOT and median GDP per capita(P=0.04).Conclusions The use of HOT varied across China and was negatively correlated with the levels of provincial economic levels.A local HOT guideline is needed to address the wide variation in HOT use with respect to different regional economic levels in countries like China.

The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ

Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identified IL-37a as a nuclear cytokine for the first time.Compared to IL-37b,IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock.The full-length(FL)form of IL-37a and the N-terminal fragment,which is processed by elastase,could translocate into cell nuclei through a distinctive nuclear localization sequence(NLS)/importin nuclear transport pathway.These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor(PPARγ).This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.

Monkeypox and the perinatal period:what does maternal-fetal medicine need to know?

Background After the global elimination of smallpox,monkeypox has become the most threatening orthopoxvirus to human health.Very few studies have been reported on pregnant women and newborns.In the case of monkeypox infection,the virus can cause serious adverse pregnancy events in women,which can lead to fetal or neonatal death.Data sources We made a comprehensive review after an extensive literature search in the PubMed/Medline database and websites concerning smallpox and monkeypox.Results Two case reports reported a total of nine pregnant women,six of whom had fetal deaths.In the autopsy of a stillbirth,researchers found that the placenta was infected with monkeypox virus,but the mechanism of infection remains unclear.Smallpox vaccine should be administered to acutely exposed pregnant women and newborns.Several novel recombinant vac-cinia immunogloblin(rVIG)and human-specific monoclonal antibodies are being developed for the prevention and treatment of monkeypox virus infection.After the fetus was delivered,the newborn should take a bath as soon as possible to remove the amniotic fluid and dirt from the body.The appropriate isolation protocol for the newborn should be selected according to the infection status of the mother.It is not known whether monkeypox virus is present in breast milk,and pasteurized breast milk can be given to newborns when breastfeeding is considered.Conclusion This review presents an overview of monkeypox in the perinatal period and guides the future research direction.

Identification and validation of cardiac nonconserved human-specific enhancers

Congenital heart disease(CHD)is one of the most common causes of neonatal mortality.The worldwide morbidity of CHD is 9.410%o,while the proportion of CHD patients who are reported to carry mutations in coding regions is<50%.Enhancers play an important role in the spatio-temporal expression of target genes,and a lot of related variations are associated with CHD.There are conserved and nonconserved enhancers.

Current Mycoplasma pneumoniae epidemic among children in Shanghai:unusual pneumonia caused by usual pathogen

Mycoplasma pneumoniae(M.pneumoniae),primarily transmitted through respiratory droplets when infected individuals cough or sneeze,is a common cause of communityacquired pneumonia,especially among school-age children and adolescents.The infection occurs endemically with an epidemic peak every few years.The worldwide incidence confirmed by direct test methods was reported to be 8.61%between 2017 and 2020 across all age groups[1].

Progress in Biomarkers Related to Biliary Atresia

Biliary atresia(BA)is a congenital cholestatic disease that can seriously damage children’s liver function.It is one of the main reasons for liver transplantation in children.Early diagnosis of BA is crucial to the prognosis of patients,but there is still a lack of reliable non-invasive diagnostic methods.Additionally,as some children are in urgent need of liver transplantation,evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward,efficient,and less traumatic method is a major focus of doctors.In recent years,an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice:diagnosis,evaluation of the stage of liver fibrosis,and prediction of native liver survival.This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers,namely MMP-7,FGF-19,and M2BPGi.Furthermore,progress in well-known biomarkers of BA such as gamma-glutamyltransferase,circulating cytokines,and other potential biomarkers is discussed,aiming to provide a reference for clinical practice.

The signal pathways and treatment of cytokine storm in COVID-19

The Coronavirus Disease 2019(COVID-19)pandemic has become a global crisis and is more devastating than any other previous infectious disease.It has affected a significant proportion of the global population both physically and mentally,and destroyed businesses and societies.Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis,including lymphopenia,neutrophilia,dysregulation of monocytes and macrophages,reduced or delayed type I interferon(IFN-I)response,antibody-dependent enhancement,and especially,cytokine storm(CS).The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis.These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells,resulting in complicated medical symptoms including fever,capillary leak syndrome,disseminated intravascular coagulation,acute respiratory distress syndrome,and multiorgan failure,ultimately leading to death in the most severe cases.Therefore,it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19.Herein,we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved.We also discuss the induction,function,downstream signaling,and existing and potential interventions for targeting these cytokines or related signal pathways.We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

Background Maple syrup urine disease(MSUD)is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction.This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals.Methods During 2011–2018,11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry,with confirmation via gene sequencing.Novel mutations affecting protein function were predicted with Mutation-Taster,PolyPhen-2,CADD and SIFT software.3D models of the mutated proteins were generated by using the SWISS-MODEL online server,and the models were visualized in PyMOL.The characteristics and gene mutations in patients with MSUD were analyzed retrospectively.Results Seventeen mutations in the BCKDHA,BCKDHB and DBT genes were found,8 of which are novel:c.55C>/T,c.349C>T,c.565C>T,c.808G>A,c.859C>G,and c.1270dupC in BCKDHA;c.275-2A>G in BCKDHB;and c.1291C>T in DBT.Eight patients died.Two patients had severe mental retardation and were physically handicapped.One patient with the intermediate type had relatively good prognosis,with mild psychomotor retardation and adiposity.Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy;two fetuses were wild type,and two were carriers of one heterozygous mutation.Conclusions Eight novel mutations were associated with MSUD in Chinese patients.Prenatal diagnosis was successfully performed by genetic analysis.Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.

Effects of Bifidobacterium supplementation on intestinal microbiota composition and the immune response in healthy infants

Background:Intestinal microbiotas are thought to be the most important source of maturational stimuli to the development of the immune system.However,few studies have focused on the development of T helper(Th)1 immune response and antibody response to vaccinations in healthy infants,especially in a large cohort.Through this randomized,double-blind control trial,we investigated the effects of Bifidobacterium longum BB536(BB536)supplementation on intestinal microbiota composition and the immune response in term infants.Methods:In total,300 healthy newborns were recruited,randomized and fed formula either supplemented with BB536 or with no supplementation.Stool samples were analyzed at months 2,4 and 11.The representative cytokine for Th1[interferon-γ(IFN-γ)]and Th2[interleukin-4(IL-4)]secretion cells were measured using enzyme-linked immunospot assay at 4 and 7 months of age.The antibody response to vaccines was measured at months 7 and 11.Results:A total of 264 infants completed the study.The amount of bifidobacteria and the bifidobacteria/Enterobacteriaceae ratio(B/E)were signifi cantly higher in the BB536 supplementation group at months 2 and 4.The number of IFN-γsecretion cells and the ratio of IFN-γ/IL-4 secretion cells were increased in the BB536 supplementation group at 7 months.Moreover,the higher value of B/E in the early stages seems to be related to the increased Th1 response.No difference was observed between groups in the antibody response after vaccination.Conclusions:BB536 has positive effects on establishing a healthy intestinal microbiota early in life,and it also plays an important role in improving the Th1 immune response.

Aryl hydrocarbon receptor signaling promotes ORMDL3- dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase

Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.

Effects of SARS-CoV-2 infection on neuroimaging and neurobehavior in neonates

Background We collected neonatal neurological,clinical,and imaging data to study the neurological manifestations and imaging characteristics of neonates with coronavirus disease 2019(COVID-19).Methods This case-control study included newborns diagnosed with COVID-19 in Wuhan,China from January 2020 to July 2020.All included newborns had complete neurological evaluations and head magnetic resonance imaging.We normalized the extracted T2-weighted imaging data to a standard neonate template space,and segmented them into gray matter,white matter,and cerebrospinal fluid.The comparison of gray matter volume was conducted between the two groups.Results A total of five neonates with COVID-19 were included in this study.The median reflex scores were 2 points lower in the infected group than in the control group(P=0.0094),and the median orientation and behavior scores were 2.5 points lower in the infected group than in the control group(P=0.0008).There were also significant differences between the two groups in the total scale score(P=0.0426).The caudate nucleus,parahippocampal gyrus,and thalamus had the strongest correlations with the Hammersmith neonatal neurologic examination(HNNE)score,and the absolute correlation coefficients between the gray matter volumes and each part of the HNNE score were all almost greater than 0.5.Conclusions We first compared the neurological performance of neonates with and without COVID-19 by quantitative neuroimaging and neurological examination methods.Considering the limited numbers of patients,more studies focusing on the structural or functional aspects of the virus in the central nervous system in different age groups will be carried out in the future.

Biliatresone:progress in biliary atresia study

Background Biliary atresia(BA)is one of the main causes of neonatal end-stage liver disease.Without timely diagnosis and treatment,most children with BA will develop irreversible liver fibrosis within the first two months.While current theorized causes of BA include viral infection,immune disorders,and genetic defects,the comprehensive etiology is still largely unknown.Recently,biliatresone attracted much interest for its ability to induce BA in both zebrafish and mice,so we summarized the latest progress of biliatresone research in BA and tried to answer the question of whether it could provide further clues to the etiology of human BA.Data sources We conducted a PubMed search for any published articles related to the topic using search terms including“biliary atresia”,“biliatresone”,“GSH”,and“HSP90”.Relevant data were extracted from the original text or supplementary materials of the corresponding articles.Results Biliatresone had shown its unique toxicity in multiple species such as zebrafish and mice,and pathogenic factors involved included glutathione(GSH),heat shock protein 90(HSP90)and the related pathways.In combination with epidemiological evidence and recent studies on the intestinal flora in biliary atresia,a new pathogenic hypothesis that the occurrence of biliary atresia is partly due to biliatresone or its structure-like compounds depositing in human body via vegetables or/and the altered intestinal flora structure can be tentatively established.Conclusions Based on the existing evidence,we emphasized that GSH and HSP90 are involved in the development of BA,and the maternal diet,especially higher vegetable intake of Asian women of childbearing age,accompanied by the altered intestinal flora structure,may contribute to the occurrence of biliary atresia and the higher incidence in the Asia group.However,the evidence from large sample epidemiological research is necessary.

Neuropilin-1^(high) monocytes protect against neonatal inflammation

Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis(NEC)due to their immature immune system.The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates,yet the underlying mechanisms of which remain poorly understood.In this study,we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1(Nrp1),termed Nrp1^(high) monocytes.Compared with their Nrp1low counterparts,Nrp1^(high) monocytes displayed potent immunosuppressive activity.Nrp1 deficiency in myeloid cells aggravated the severity of NEC,whereas adoptive transfer of Nrp1^(high) monocytes led to remission of NEC.Mechanistic studies showed that Nrp1,by binding to its ligand Sema4a,induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4.KLF4 transactivated Nos2 and enhanced the production of nitric oxide(NO),a key mediator of immunosuppression in monocytes.These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates.