Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus.

Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

Zinc-Finger Protein ZFP488 Regulates the Timing of Oligodendrocyte Myelination and Remyelination.

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein an H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased the expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.

Dlx1/2-dependent expression of Meis2 promotes neuronal fate determination in the mammalian striatum.

The striatum is a central regulator of behavior and motor function through the actions of D1 and D2 medium-sized spiny neurons (MSNs), which arise from a common lateral ganglionic eminence (LGE) progenitor. The molecular mechanisms of cell fate specification of these two neuronal subtypes are incompletely understood. Here, we found that deletion of murine Meis2, which is highly expressed in the LGE and derivatives, led to a large reduction in striatal MSNs due to a block in their differentiation. Meis2 directly binds to the Zfp503 and Six3 promoters and is required for their expression and specification of D1 and D2 MSNs, respectively. Finally, Meis2 expression is regulated by Dlx1/2 at least partially through the enhancer hs599 in the LGE subventricular zone. Overall, our findings define a pathway in the LGE whereby Dlx1/2 drives expression of Meis2, which subsequently promotes the fate determination of striatal D1 and D2 MSNs via Zfp503 and Six3.

Multipattern graph convolutional network-based autism spectrum disorder identification.

The early diagnosis of autism spectrum disorder (ASD) has been extensively facilitated through the utilization of resting-state fMRI (rs-fMRI). With rs-fMRI, the functional brain network (FBN) has gained much attention in diagnosing ASD. As a promising strategy, graph convolutional networks (GCN) provide an attractive approach to simultaneously extract FBN features and facilitate ASD identification, thus replacing the manual feature extraction from FBN. Previous GCN studies primarily emphasized the exploration of topological simultaneously connection weights of the estimated FBNs while only focusing on the single connection pattern. However, this approach fails to exploit the potential complementary information offered by different connection patterns of FBNs, thereby inherently limiting the performance. To enhance the diagnostic performance, we propose a multipattern graph convolution network (MPGCN) that integrates multiple connection patterns to improve the accuracy of ASD diagnosis. As an initial endeavor, we endeavored to integrate information from multiple connection patterns by incorporating multiple graph convolution modules. The effectiveness of the MPGCN approach is evaluated by analyzing rs-fMRI scans from a cohort of 92 subjects sourced from the publicly accessible Autism Brain Imaging Data Exchange database. Notably, the experiment demonstrates that our model achieves an accuracy of 91.1% and an area under ROC curve score of 0.9742. The implementation codes are available at https://github.com/immutableJackz/MPGCN.

Inhibition of mitochondrial fatty acid ß-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.

Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mechanistic target of rapamycin complex 1 (mTORC1) activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (mildronate or etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through general control nondepressible 5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase general control nondepressible 5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylase histone deacetylase class II and identified histone deacetylase 7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

The role of oligodendrocyte progenitor cells in the spatiotemporal vascularization of the human and mouse neocortex.

Brain vasculature formation begins with vessel invasion from the perineural vascular plexus, which expands through vessel sprouting and growth. Recent studies have indicated the existence of oligodendrocyte-vascular crosstalk during development. However, the relationship between oligodendrocyte progenitor cells (OPCs) and the ordered spatiotemporal vascularization of the neocortex has not been elucidated. Our findings suggest that OPCs play a complex role in the vessel density of the embryonic and postnatal neocortex. Analyses of normal human and mouse embryonic cerebral cortex show that vascularization and OPC distribution are tightly controlled in a spatially and temporally restricted manner, exhibiting a positive correlation. Loss of OPCs at both embryonic and postnatal stages led to a reduction in vascular density, suggesting that OPC populations play a role in vascular density. Nonetheless, dynamic observation on cultured brain slices and staining of tissue sections indicate that OPC migration is unassociated with the proximity to blood vessels, primarily occurring along radial glial cell processes. Additionally, in vitro experiments demonstrate that OPC secretions promote vascular endothelial cell (VEC) growth. Together, these observations suggest that vessel density is influenced by OPC secretions.

mTOR pathway repressing expression of FoxO3 is a potential mechanism involved in neonatal white matter dysplasia.

Neonatal white matter dysplasia (NWMD) is characterized by developmental abnormity of CNS white matter, including abnormal myelination. Besides environmental factors such as suffocation at birth, genetic factors are also main causes. Signaling pathway is an important part of gene function and several signaling pathways play important roles in myelination. Here, we performed genetic analysis on a cohort of 138 patients with NWMD and found that 20% (5/25) cause genes which referred to 28.57% (8/28) patients enriched in mammalian target of rapamycin (mTOR) signaling pathway. Depletion of mTOR reduced genesis and proliferation of oligodendrocyte progenitor cells (OPC) during embryonic stage and reduced myelination in corpus callosum besides cerebellum and spinal cord during early postnatal stages which is related to not only differentiation but also proliferation of oligodendrocyte (OL). Transcriptomic analyses indicated that depletion of mTOR in OLs upregulated expression of forkhead box O3 (FoxO3), which is a repressor of expression of myelin basic protein, and downregulating expression of FoxO3 by short interfering RNA promoted OPCs develop into MBP+ OLs. Thus, our findings suggested that mTOR signaling pathway is NWMD-related pathway and mTOR is important for myelination of the entire CNS during early developmental stages through regulating expression of FoxO3 at least partially.

Development and validation of machine-learning models of diet management for hyperphenylalaninemia: a multicenter retrospective study.

BACKGROUND: Assessing dietary phenylalanine (Phe) tolerance is crucial for managing hyperphenylalaninemia (HPA) in children. However, traditionally, adjusting the diet requires significant time from clinicians and parents. This study aims to investigate the development of a machine-learning model that predicts a range of dietary Phe intake tolerance for children with HPA over 10 years following diagnosis. METHODS: In this multicenter retrospective observational study, we collected the genotypes of phenylalanine hydroxylase (PAH), metabolic profiles at screening and diagnosis, and blood Phe concentrations corresponding to dietary Phe intake from over 10 years of follow-up data for 204 children with HPA. To incorporate genetic information, allelic phenotype value (APV) was input for 2965 missense variants in the PAH gene using a predicted APV (pAPV) model. This model was trained on known pheno-genotype relationships from the BioPKU database, utilizing 31 features. Subsequently, a multiclass classification model was constructed and trained on a dataset featuring metabolic data, genetic data, and follow-up data from 3177 events. The final model was fine-tuned using tenfold validation and validated against three independent datasets. RESULTS: The pAPV model achieved a good predictive performance with root mean squared error (RMSE) of 1.53 and 2.38 on the training and test datasets, respectively. The variants that cause amino acid changes in the region of 200-300 of PAH tend to exhibit lower pAPV. The final model achieved a sensitivity range of 0.77 to 0.91 and a specificity range of 0.8 to 1 across all validation datasets. Additional assessment metrics including positive predictive value (0.68-1), negative predictive values (0.8-0.98), F1 score (0.71-0.92), and balanced accuracy (0.8-0.92) demonstrated the robust performance of our model. CONCLUSIONS: Our model integrates metabolic and genetic information to accurately predict age-specific Phe tolerance, aiding in the precision management of patients with HPA. This study provides a potential framework that could be applied to other inborn errors of metabolism.

Tumor neoantigens derived from RNA editing events show significant clinical relevance in melanoma patients treated with immunotherapy.

This study aimed to investigate the clinical significance of RNA editing (RE) and RNA editing derived (RED-) neoantigens in melanoma patients treated with immunotherapy. Vardict and VEP were used to identify the somatic mutations. RE events were identified by Reditools2 and filtered by the custom pipeline. miRTar2GO was implemented to predict the RE whether located in miRNA targets within the 3' UTR region. NetMHCpan and NetCTLpan were used to identify and characterize RED-neoantigens. In total, 7116 RE events were identified, most of which were A-to-I events. Using our custom pipeline, 631 RED-neoantigens were identified that show a significantly greater peptide-MHC affinity, and facilitate epitope processing and presentation than wild-type peptides. The OS of the patients with high RED-neoantigens burden was significantly longer ( P  = 0.035), and a significantly higher RED-neoantigens burden was observed in responders ( P  = 0.048). The area under the curve of the RED-neoantigen was 0.831 of OS. Then, we validated the reliability of RED-neoantigens in predicting the prognosis in an independent cohort and found that patients with high RED-neoantigens exhibited a longer OS ( P  = 0.008). To our knowledge, this is the first study to systematically assess the clinical relevance of RED-neoantigens in melanoma patients treated with immunotherapy.

Characteristics of red blood cell transfusion among very preterm infants in China.

BACKGROUND AND OBJECTIVES: National-level data on the incidence of red blood cell (RBC) transfusions and outcomes among very preterm infants (VPIs) are lacking in China. This study aims to describe the use and variation of RBC transfusion among VPIs in China. MATERIALS AND METHODS: This cohort study was conducted among 70 tertiary hospitals participating in the Chinese Neonatal Network (CHNN) from 2019 to 2020 across China. All VPIs admitted to the CHNN neonatal intensive care units (NICUs) were included. RESULTS: A total of 13,447 VPIs were enrolled, of whom 7026 (52.2%) received ≥1 RBC transfusions. The mean number of transfusions per infant was 2 (interquartile range [IQR] 1-4 times) and the median age at first transfusion was 15 days (IQR 3-27 days). The transfusion rate was higher in critically ill infants compared with non-critically ill infants (70.5% vs. 39.3%). The transfusion rate varied widely (13.5%-95.0%) between different NICUs. The prevalence of death, severe intra-ventricular haemorrhage, necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP), sepsis, bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP) and cystic periventricular leukomalacia (cPVL) was significantly higher in the transfused group. Among non-critically ill infants, RBC transfusion was independently associated with BPD, severe ROP and cPVL. CONCLUSION: Our study, providing the first baseline data on RBC transfusions among VPIs in China, shows an alarmingly high RBC transfusion rate with significant site variations. There is an urgent need for national guidelines on RBC transfusions for VPIs in China.

Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.

Perinatal hypoxic-ischaemic encephalopathy is the leading cause of neonatal death and permanent neurological deficits, while the basal ganglia is one of the major nuclei that is selectively and greatly affected in the brains of hypoxic-ischaemic encephalopathy patients, especially in severe cases. Human embryonic stem cell-derived neurons have shown great potential in different types of brain disorders in adults. However, it remains unknown whether and how grafted human embryonic stem cell-derived neurons can repair immature brains with hypoxic-ischaemic encephalopathy. Here, by administrating genetically labelled human embryonic stem cell-derived striatal neural progenitors into the ipsilateral striatum of hypoxic-ischaemic encephalopathy-injured mice, we found that the grafted cells gradually matured into GABA spiny projection neurons morphologically and electrophysiologically, and significantly rescued the area loss of hypoxic-ischaemic encephalopathy-injured brains. Intriguingly, using immunohistochemical staining combined with enhanced ascorbate peroxidase-based immunoelectron microscopy and rabies virus-mediated trans-synaptic tracing, we show that the grafts start to extend axonal projections to the endogenous target areas (globus pallidus externa, globus pallidus internus, substantia nigra), form synapses with host striatal, globus pallidus and nigra neurons, and receive extensive and stable synaptic inputs as early as 2 months post-transplantation. Importantly, we further demonstrated functional neural circuits re-established between the grafted neurons and host cortical, striatal and substantial nigra neurons at 3-6 months post-transplantation in the hypoxic-ischaemic encephalopathy-injured brain by optogenetics combined with electrophysiological recording. Finally, the transplanted striatal spiny projection neurons but not spinal GABA neurons restored the motor defects of hypoxic-ischaemic encephalopathy, which were reversed by clozapine-N-oxide-based inhibition of graft function. These findings demonstrate anatomical and functional reconstruction of the basal ganglia neural circuit including multiple loops by striatal spiny projection neurons in hypoxic-ischaemic encephalopathy-injured immature brains, which raises the possibility of such a cell replacement therapeutic strategy for hypoxic-ischaemic encephalopathy in neonates.

Genetic background of neonatal hypokalemia.

Neonatal hypokalemia (defined as a serum potassium level <3.5 mEq/L) is the most common electrolyte disorder encountered in clinical practice. In addition to common secondary causes, primary genetic etiologies are also closely associated with hypokalemia. Currently, a systematic characterization of these genetic disorders is lacking, making early recognition challenging and clinical management uncertain. This review will aid clinicians by summarizing the genetic background of neonatal hypokalemia from two aspects: (1) increased excretion of K+, whereby genetic factors primarily lead to increased renal Na+ influx, decreased H+ efflux, or reduced Cl- influx, ultimately resulting in increased K+ efflux; and (2) decreased extracellular distribution of K+, whereby genetic factors result in abnormalities in transmembrane ion channels, reducing outward potassium currents or generating inward cation leak currents. We describe over ten genetic diseases associated with neonatal hypokalemia, which involve pathogenic variants in dozens of genes and affect multiple target organs, including the kidneys, intestines, and skeletal muscle. For example, in the renal tubules, pathogenic variants in the SLC12A1 gene encoding the Na+-K+-2Cl- cotransporter lead to renal K+ loss, causing Bartter syndrome type I; in intestinal epithelial cells, pathogenic variants in the SLC26A3 gene result in a defective Cl⁻-HCO3⁻ exchanger, causing congenital chloride diarrhea; and in skeletal muscle, pathogenic variants in the CACNA1S gene impact membrane calcium ion channels resulting in hypokalemic periodic paralysis. Given the wide variety of organs and genetic alterations that can contribute to neonatal hypokalemia, we believe this review will provide valuable insights for clinical diagnosis and treatment.

Antimicrobial resistance prediction by clinical metagenomics in pediatric severe pneumonia patients.

BACKGROUND: Antimicrobial resistance (AMR) is a major threat to children's health, particularly in respiratory infections. Accurate identification of pathogens and AMR is crucial for targeted antibiotic treatment. Metagenomic next-generation sequencing (mNGS) shows promise in directly detecting microorganisms and resistance genes in clinical samples. However, the accuracy of AMR prediction through mNGS testing needs further investigation for practical clinical decision-making. METHODS: We aimed to evaluate the performance of mNGS in predicting AMR for severe pneumonia in pediatric patients. We conducted a retrospective analysis at a tertiary hospital from May 2022 to May 2023. Simultaneous mNGS and culture were performed on bronchoalveolar lavage fluid samples obtained from pediatric patients with severe pneumonia. By comparing the results of mNGS detection of microorganisms and antibiotic resistance genes with those of culture, sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: mNGS detected bacterial in 71.7% cases (86/120), significantly higher than culture (58/120, 48.3%). Compared to culture, mNGS demonstrated a sensitivity of 96.6% and a specificity of 51.6% in detecting pathogenic microorganisms. Phenotypic susceptibility testing (PST) of 19 antibiotics revealed significant variations in antibiotics resistance rates among different bacteria. Sensitivity prediction of mNGS for carbapenem resistance was higher than penicillins and cephalosporin (67.74% vs. 28.57%, 46.15%), while specificity showed no significant difference (85.71%, 75.00%, 75.00%). mNGS also showed a high sensitivity of 94.74% in predicting carbapenem resistance in Acinetobacter baumannii. CONCLUSIONS: mNGS exhibits variable predictive performance among different pathogens and antibiotics, indicating its potential as a supplementary tool to conventional PST. However, mNGS currently cannot replace conventional PST.

Synergistic effects of achieving perinatal interventions on bronchopulmonary dysplasia in preterm infants.

To investigate the effect of perinatal interventions on the risk of severe BPD (sBPD) and death in extremely preterm infants (EPIs) and their synergistic effects. This was a secondary analysis of the prospective cohort Chinese Neonatal Network (CHNN). Infants with a birth weight of 500 to 1250 g or 24-28 weeks completed gestational age were recruited. The impacts and the synergistic effects of six evidence-based perinatal interventions on the primary outcomes of sBPD and death were assessed by univariate and multivariable logistic regression modeling. Totally, 6568 EPIs were finally enrolled. Antenatal corticosteroid (adjusted OR, aOR, 0.74; 95%CI, 0.65-083), birth in centers with tertiary NICU (aOR, 0.64; 95%CI, 0.57-0.72), preventing intubation in the delivery room (aOR, 0.65; 95%CI, 0.58-0.73), early caffeine therapy (aOR, 0.59; 95%CI, 0.52-0.66), and early extubating (aOR, 0.42; 95%CI 0.37-0.47), were strongly associated with a lower risk of sBPD and death while early surfactant administration was associated with a lower risk of death (aOR, 0.84; 95%CI, 0.72, 0.98). Compared with achieving 0/1 perinatal interventions, achieving more than one intervention was associated with decreased rates (46.6% in 0/1 groups while 38.5%, 29.6%, 22.2%, 16.2%, and 11.7% in 2/3/4/5/6-intervention groups respectively) and reduced risks of sBPD/death with aORs of 0.76(0.60, 0.96), 0.55(0.43, 0.69), 0.38(0.30, 0.48), 0.28(0.22, 0.36), and 0.20(0.15, 0.27) in 2, 3, 4, 5, and 6 intervention groups respectively. Subgroup analyses showed consistent results. CONCLUSION: Six perinatal interventions can effectively reduce the risk of sBPD and death in a synergistic form. WHAT IS KNOWN: • Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease associated with prematurity. The effective management of BPD requires a comprehensive set of interventions. However, the extent to which these interventions can mitigate the risk of severe outcomes, such as severe BPD or mortality, or if they possess synergistic effects remains unknown. WHAT IS NEW: • The implementation of various perinatal interventions, such as prenatal steroids, birth in centers with tertiary NICU, early non-Invasive respiratory support, surfactant administration within 2 hours after birth, early caffeine initiation within 3 days, and early extubation within 7 days after birth has shown promising results in the prevention of severe bronchopulmonary dysplasia (BPD) or mortality in extremely preterm infants. Moreover, these interventions have demonstrated synergistic effects when implemented in combination.

Evolution and advances in endovascular mechanical thrombectomy of cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is a rare type of stroke and standard treatment involves anticoagulation. However, for some special CVST patients who are ineligible for anticoagulation or refractory to conservative treatment, endovascular treatment (EVT) may be an effective option. Mechanical thrombectomy (MT) is a commonly used treatment. Compared with anticoagulation treatment alone, MT may result in additional procedure-related complications, however, many studies have shown that it has a high rate of vessel recanalization and lower incidence of related complications in arterial large vessel occlusion stroke. In addition, the applicability of MT in children, patients with deep cerebral thrombosis, and patients with bleeding before treatment has been reported. MT combined with intravascular thrombolysis (IVT) and other multimodal therapeutic strategies, also has a good curative effect, and further research is needed to compare and optimize different treatment strategies. Owing to the low incidence of CVST, randomized controlled clinical trials with a large sample size to explore the safety and effectiveness of MT are scarce. In addition, devices specifically designed for cerebral venous sinus and effective endovascular therapies are currently not well-established. This article summarizes different endovascular instruments and multimodal therapies for cerebral venous thrombosis. We also discuss the limitations, prospects, prognostic factors, and applications in special cases of interventional thrombectomy.

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.

The performance of the practices associated with the occurrence of severe intraventricular hemorrhage in the very premature infants: data analysis from the Chinese neonatal network.

BACKGROUND: The occurrence of severe intraventricular hemorrhage (sIVH) was high in the very preterm infants (VPIs) in China. The management strategies significantly contributed to the occurrence of sIVH in VPIs. However, the status of the perinatal strategies associated with sIVH for VPIs was rarely described across the multiple neonatal intensive care units (NICUs) in China. We aim to investigate the characteristics of the perinatal strategies associated with sIVH for VPIs across the multiple NICUs in China. METHODS: This was a retrospective analysis of data from a prospective cohort of Chinese Neonatal Network (CHNN) dataset, enrolling infants born at 24+0-31+6 from 2019 to 2021. Eleven perinatal practices performed within the first 3 days of life were investigated including antenatal corticosteroids use, antenatal magnesium sulphate therapy, intubation at birth, placental transfusion, need for advanced resuscitation, initial inhaled gas of 100% FiO2 in delivery room, initial invasive respiratory support, surfactant and caffeine administration, early enteral feeding, and inotropes use. The performances of these practices across the multiple NICUs were investigated using the standard deviations of differences between expected probabilities and observations. The occurrence of sIVH were compared among the NICUs. RESULTS: A total of 24,226 infants from 55 NICUs with a mean (SD) gestational age of 29.5 (1.76) and mean (SD) birthweight of 1.31(0.32) were included. sIVH was detected in 5.1% of VPIs. The rate of the antenatal corticosteroids, MgSO4 therapy, and caffeine was 80.0%, 56.4%, and 31.5%, respectively. We observed significant relationships between sIVH and intubation at birth (AOR 1.52, 95% CI 1.13 to 1.75) and initial invasive respiratory support (AOR 2.47, 95% CI 2.15 to 2.83). The lower occurrence of sIVH (4.8%) was observed corresponding with the highest utility of standard antenatal care, the lowest utility of invasive practices, and early enteral feeding administration. CONCLUSIONS: The current evidence-based practices were not performed in each VPI as expected among the studied Chinese NICUs. The higher utility of the invasive practices could be related to the occurrence of sIVH.