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Interferon-αs (IFN-αs) are crucial cytokines for inducing protective antiviral responses. The baculovirus-mediated gene transduction of mammalian cells (BacMam) is an efficient delivery tool for recombinant protein expression in mammalian cells. This study focuses on the delivery of bovine IFN-α (BoIFNα) using the BacMam system. A recombinant pACEMam1-BoIFNα bacmid was constructed, and a recombinant BacMam-BoIFNα virus was obtained. After transducing HEK293T cells with this virus, BoIFNα protein was successfully secreted into the cell supernatant, displaying antiviral activities against VSV, BPIV3, BEV, and BVDV in bovine-derived cells. Additionally, the BacMam-BoIFNα virus inhibited the replication of these viruses in MDBK cells, induced the transcription of ISGs, and the expression of M × 1 in both MDBK and BT cells. These induction effects were significantly reduced following treatment with a JAK1 inhibitor, suggesting that the BacMam-BoIFNα virus exerts antiviral activity in MDBK cells through JAK-STAT signaling pathway. Furthermore, the study found that the BacMam-BoIFNα virus significantly inhibited the replication of BPIV3 in the lung and trachea of mice. Overall, this study demonstrates that the BacMam-BoIFNα virus have antivirus activities both in vitro and in vivo , signaling through JAK-STAT pathway, and provides an efficient interferon gene delivery tool for combating bovine viral infections.

Intense anthropogenic activities in a karst area will inevitably change the regional groundwater environment and affect the characteristics of the karst groundwater, such as the hydrochemistry and water quality. It is of great importance to study the evolution characteristics of the hydrochemistry and water quality of karst groundwater under intense anthropogenic activities to ensure the stability and sustainable development of karst ecosystems. In this study, a representative synclinal basin-type karst groundwater system in northern China was used as the study object, and the effects of intense anthropogenic activities on the evolution of the hydrochemistry and water quality of the karst groundwater were analyzed using a comprehensive application of a groundwater quality assessment, a multivariate statistical analysis, a hydrogeochemical analysis, and multi-factor regime monitoring of the karst groundwater quality. The results showed that during the time scale from 1991 to 2019, major ion components, such as Na + +K + , Ca 2+ +Mg 2+ , Cl - , SO 4 2- , NO 3 - , HCO 3 - , and total dissolved solids (TDS), in the karst groundwater in discharge area increased by 1.73-4.59 times. In addition, the ion component contents primarily displayed a fluctuating equilibrium state from 2019 to 2023. At the spatial scale, the primary ion components in the karst groundwater in the discharge area were considerably higher than those in the recharge and runoff areas, and they also showed a gradual increasing trend from upstream to downstream and from the surrounding to the middle. CONCLUSION: Intense anthropogenic activities changed the circulation conditions of karst groundwater and deteriorated the karst groundwater quality. The primary human activity factors that controlled the evolution of the karst groundwater during the different periods were different. The large-scale exploitation of karst groundwater and other human activities primarily affected the karst groundwater quality. The construction of the Zhuangli Reservoir had a positive impact and improved the karst groundwater quality downstream, but its long-term impact on the karst groundwater environment requires long-term monitoring and study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: When multiple tasks are learned consecutively, the old model parameters may be overwritten by the new data, resulting in the phenomenon that the new task is learned and the old task is forgotten, which leads to catastrophic forgetting. Moreover, continual learning has no mature solution for image denoising tasks., Methods: Therefore, in order to solve the problem of catastrophic forgetting caused by learning multiple denoising tasks, we propose a Triplet Neural-networks Collaboration-continuity DeNosing (TNCDN) model. Use triplet neural networks to update each other cooperatively. The knowledge from two denoising networks that maintain continual learning capability is transferred to the main-denoising network. The main-denoising network has new knowledge and can consolidate old knowledge. A co-training mechanism is designed. The main-denoising network updates the other two denoising networks with different thresholds to maintain memory reinforcement capability and knowledge extension capability., Results: The experimental results show that our method effectively alleviates catastrophic forgetting. In GS, CT and ADNI datasets, compared with ANCL, the TNCDN(PromptIR) method reduced the average degree of forgetting on the evaluation index PSNR by 2.38 (39%) and RMSE by 1.63 (55%)., Conclusion: This study aims to solve the problem of catastrophic forgetting caused by learning multiple denoising tasks. Although the experimental results are promising, extending the basic denoising model to more data sets and tasks will enhance its application. Nevertheless, this study is a starting point, which can provide reference and support for the further development of continuous learning image denoising task., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xianhua Zeng reports financial support was provided by National Natural Science Foundation of China. Xianhua Zeng reports financial support was provided by ChongqingTalent Plan Project., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recent research has underscored the significance of circular RNAs (circRNAs) in various cancers, including neuroblastoma (NB). Specifically, circ-SHPRH, a unique circRNA, has been revealed to inhibit tumor growth by sequestering miRNAs or producing the SHPRH-146aa protein. To explore circ-SHPRH's involvement in NB and its potential application in gene therapy, this study examined circ-SHPRH expression in 94 NB tissues and cell lines (SK-N-BE(2), SH-SY5Y) using real-time PCR and fluorescence in situ hybridization (FISH). Functional assays encompassing both overexpression and knockdown experiments in NB cell lines, as well as in vivo investigations, were conducted. RNA-seq analysis revealed a correlation between circ-SHPRH and the pathway of P21 (CDKN1A), a pivotal cell cycle regulator. Validation through PCR and other techniques confirmed that circ-SHPRH upregulated P21 expression. Furthermore, the regulatory role of circ-SHPRH in the P21-CDK pathway was corroborated through SHPRH-146aa expression analysis. Notably, adenovirus-mediated circ-SHPRH overexpression effectively curbed NB tumor growth in NSG mice, while combining circ-SHPRH with everolimus exhibited potential for NB treatment. This study elucidates the remarkable significance of circ-SHPRH in NB and its prospective utility in gene therapy, thereby paving the way for innovative therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To investigate the function and underlying mechanism of cysteine and glycine-rich protein 2 (CSRP2) in neuroblastoma (NB)., Methods: The correlation between the expression level of CSRP2 mRNA and the prognosis of NB children in NB clinical samples was analyzed in R2 Genomics Analysis and Visualization Platform. The small interfering RNA (siRNA) targeting CSRP2 or CSRP2 plasmid were transfected to NB cell lines SK-N-BE(2) and SH-SY5Y. Cell proliferation was observed by crystal violet staining and real-time cellular analysis. The ability of colony formation of NB cells was observed by colony-forming unit assay. Immunofluorescence assay was used to detect the expression of the proliferation marker Ki-67. Flow cytometry analysis for cell cycle proportion was used with cells stained by propidium iodide (PI). Annexin V/7AAD was used to stain cells and analyze the percentage of cell apoptosis. The ability of cell migration was determined by cell wound-healing assay. The level of protein and mRNA expression of CSRP2 in NB primary tumor and NB cell lines were detected by Western blot and quantitative real-time PCR (RT-qPCR)., Results: By analyzing the NB clinical sample databases, it was found that the expression levels of CSRP2 in high-risk NB with 3/4 stages in international neuroblastoma staging system (INSS) were significantly higher than that in low-risk NB with 1/2 INSS stages. The NB patients with high expression levels of CSRP2 were shown lower overall survival rate than those with low expression levels of CSRP2 . We detected the protein levels of CSRP2 in the NB samples by Western blot, and found that the protein level of CSRP2 in 3/4 INSS stages was significantly higher than that in 1/2 INSS stages. Knockdown of CSRP2 inhibited cell viability and proliferation of NB cells. Overexpression of CSRP2 increased the proliferation of NB cells. Flow cytometry showed that the proportion of sub-G1, G0/G1 and S phase cells and Annexin V positive cells were increased after CSRP2 deficiency. In the cell wound-healing assay, the healing rate of NB cells was significantly attenuated after knockdown of CSRP2 . Further mechanism studies showed that the proportion of the proliferation marker Ki-67 and the phosphorylation levels of extracellular signal-regulated kinases 1/2 (ERK1/2) were significantly decreased after CSRP2 knockdown., Conclusion: CSRP2 is highly expressed in high-risk NB with 3/4 INSS stages, and the expression levels of CSRP2 are negatively correlated with the overall survival of NB patients. CSRP2 significantly increased the proliferation and cell migration of NB cells and inhibited cell apoptosis via the activation of ERK1/2. All these results indicate that CSRP2 promotes the progression of NB by activating ERK1/2, and this study will provide a potential target for high-risk NB therapy.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Most of the existing object detection algorithms are trained on medical datasets and then used for prediction. When the features of an object are not obvious in an image, these models are prone to mislocalize and misclassify it. In this paper, we propose a medical Object Detection algorithm jointly driven by Knowledge and Data (ODKD). It enables medical semantic knowledge provided by specialized physicians to be effective and helpful when traditional models have difficulty in correctly detecting objects relying on features alone. Our model consists of a base object detector together with a fusion module: the base object detector is trained based on medical datasets to obtain data-driven results; then we use a graph to represent external semantic knowledge and map the data-driven results to the nodes embedding of this graph structure. In the fusion module, a graph convolution network is used to fuse the data-driven results with the external semantic knowledge to output category adjustment coefficients. Finally, the adjustment coefficients are used to adjust the data-driven results to obtain results jointly driven by knowledge and data. Experiments show that professional medical semantic knowledge can effectively correct the erroneous results of the base detector, and the effect of our model outperforms Faster Rcnn, YOLOv5, YOLOv7, etc. on three medical datasets, Camus, Synapse, and AMOS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xianhua Zeng reports financial support was provided by National Natural Science Foundation of China. Xianhua Zeng reports financial support was provided by ChongqingTalent Plan Project., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: With the development of the novel coronavirus disease 2019 (COVID-19), China implemented measures in an attempt to control the infection rate. We conducted a single-center, cross-sectional study to ascertain the impact of the COVID-19 pandemic on the equitable availability of medical resources for children diagnosed with malignant solid tumors in China., Methods: Data on the demographics, clinical characteristics, and medical expenses of 876 patients diagnosed with neuroblastoma, rhabdomyosarcoma (RMS), Wilms tumor, hepatoblastoma (HB), Ewing sarcoma (ES), and central nervous system (CNS) tumors from 2019 to 2021, during the COVID-19 pandemic, were retrospectively collected from the National Center for Children's Health. The Pearson χ 2 test and Mann-Whitney test were performed to analyze the differences among variables., Results: Except for the regional origin of children with tumors during the epidemic, no significant differences were found in the demographic or clinical characteristics of patients at initial diagnosis. The number of patients from northern China and northeastern China who attended Beijing Children's Hospital (BCH) increased after the outbreak of COVID-19 (P=0.001). There was no significant alteration observed in the frequency of hospitalizations per individual per annum (P=0.641) or the mean expense incurred per individual per hospitalization (P=0.361). In addition, the medical insurance coverage rate of real-time settlement increased year by year., Conclusions: After the COVID-19 outbreak, the origin of patients with solid tumor who visited BCH was concentrated in the northern region of China. COVID-19 had no impact on the other demographic factors, clinical characteristics, or economic burden of patients with pediatric malignant solid tumors., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-480/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Neuroblastoma (NB) is a challenging pediatric extracranial solid tumor characterized by a poor prognosis and resistance to chemotherapy. Identifying targets to enhance chemotherapy sensitivity in NB is of utmost importance. Increasing evidence implicates long noncoding RNAs (lncRNAs) play important roles in cancer, but their functional roles remain largely unexplored. Here, we analyzed our RNA sequencing data and identified the upregulated lncRNA ZNF674-AS1 in chemotherapy non-responsive NB patients. Elevated ZNF674-AS1 expression is associated with poor prognosis and high-risk NB. Importantly, targeting ZNF674-AS1 expression in NB cells suppressed tumor growth in vivo. Further functional studies have revealed that ZNF674-AS1 constrains cisplatin sensitivity by suppressing pyroptosis and promoting cell proliferation. Moreover, ZNF674-AS1 primarily relies on CA9 to fulfill its functions on cisplatin resistance. High CA9 levels were associated with high-risk NB and predicted poor patient outcomes. Mechanistically, ZNF674-AS1 directly interacted with the RNA binding protein IGF2BP3 to enhance the stability of CA9 mRNA by binding with CA9 transcript, leading to elevated CA9 expression. As a novel regulator of CA9, IGF2BP3 positively upregulated CA9 expression. Together, these results expand our understanding of the cancer-associated function of lncRNAs, highlighting the ZNF674-AS1/IGF2BP3/CA9 axis as a constituting regulatory mode in NB tumor growth and cisplatin resistance. These insights reveal the pivotal role of ZNF674-AS1 inhibition in recovering cisplatin sensitivity, thus providing potential therapeutic targets for NB treatment., (© 2024. The Author(s).)

Recently, telomerase reverse transcriptase (TERT) gene rearrangements have been identified in neuroblastoma (NB), the typical pathological type of neuroblastic tumours (NTs); however, the prevalence of TERT rearrangements in other types of NT remains unknown. This study aimed to develop a practical method for detecting TERT defects and to evaluate the clinical relevance of TERT rearrangements as a biomarker for NT prognosis. A TERT break-apart probe for fluorescence in situ hybridisation (FISH) was designed, optimised, and applied to assess the genomic status of TERT in Chinese children with NTs at the Beijing Children's Hospital from 2016 to 2019. Clinical, histological, and genetic characteristics of TERT-rearranged NTs were further addressed. Genomic TERT rearrangements could be effectively detected by FISH and were mutually exclusive with MYCN amplification. TERT rearrangements were identified in 6.0% (38/633) of NTs overall, but 12.4% (31/250) in high-risk patients. TERT rearrangements identified a subtype of aggressive NTs with the characteristics of Stage 3/4, high-risk category, over 18 months old, and presenting all histological subtypes of NB and ganglioneuroblastoma nodular. Moreover, TERT rearrangements were significantly associated with elevated TERT expression levels and decreased survival chances. Multivariable analysis confirmed that it was an independent prognostic marker for NTs. FISH is an easily applicable method for evaluating TERT defects, which define a subgroup of NTs with unfavourable prognosis. TERT rearrangements would contribute to characterising NT molecular signatures in clinical practice., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on the surface of Streptococcus dysgalactiae , coded with gapC, is a glycolytic enzyme that was reported to be a moonlighting protein and virulence factor., Objective: This study assessed GAPDH as a potential immunization candidate protein to prevent streptococcus infections., Methods: Mice were vaccinated subcutaneously with recombinant GAPDH and challenged with S. dysgalactiae in vivo . They were then evaluated using histological methods. rGAPDH of mouse bone marrow-derived dendritic cells (BMDCs) was evaluated using immunoblotting, reverse transcription quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay methods., Results: Vaccination with rGAPDH improved the survival rates and decreased the bacterial burdens in the mammary glands compared to the control group. The mechanism by which rGAPDH vaccination protects against S. dysgalactiae was investigated. In vitro experiments showed that rGAPDH boosted the generation of interleukin-10 and tumor necrosis factor-α. Treatment of BMDCs with TAK-242, a toll-like receptor 4 inhibitor, or C29, a toll-like receptor 2 inhibitor, reduced cytokines substantially, suggesting that rGAPDH may be a potential ligand for both TLR2 and TLR4. Subsequent investigations showed that rGAPDH may activate the phosphorylation of MAPKs and nuclear factor-κB., Conclusions: GAPDH is a promising immunization candidate protein for targeting virulence and enhancing immune-mediated protection. Further investigations are warranted to understand the mechanisms underlying the activation of BMDCs by rGAPDH in a TLR2- and TLR4-dependent manner and the regulation of inflammatory cytokines contributing to mastitis pathogenesis., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Korean Society of Veterinary Science.)

The 2022 World Health Organization guidelines recommend use of two core anti-tuberculosis (TB) drugs, bedaquiline (BDQ) and clofazimine (CFZ), for treatment of drug-resistant (DR)-TB. However, several mutated Mycobacterium tuberculosis (MTB) genes, conferring BDQ and CFZ resistance, have been reported that predominantly arose from sporadic mutations that have not been comprehensively characterized. Herein, MTB clinical isolates collected from drug-susceptible (DS)-, multidrug-resistant (MDR)-, and extensively drug-resistant (XDR)-TB patients were cultured in vitro with BDQ or CFZ to generate progeny strains with resistance to these drugs. Progeny strains exposed to CFZ exhibited increased CFZ minimum inhibitory concentrations (MICs) that exceeded MIC increases of BDQ-exposed progeny strains. Notably, mmpR and pepQ mutations accounted for 83% and 17% of BDQ-induced spontaneous gene mutations, respectively, and 86% and 14% of CFZ-induced spontaneous gene mutations, respectively. Analyses of predicted mutation-induced changes in amino acid sequences and structures of MmpR and PepQ mutants revealed several point mutations affected sequence conversation and functionality as an underlying mechanism for observed acquired BDQ/CFZ resistance. Moreover, our results revealed differences in patterns of BDQ- and CFZ-induced acquired spontaneous mutations that may enhance our understanding of MTB BDQ/CFZ-resistance mechanisms. IMPORTANCE This study of MTB drug resistance mechanisms revealed patterns of spontaneous MTB mutations associated with acquired BDQ and CFZ resistance that arose after clinical MTB isolates were cultured in vitro with BDQ or CFZ. Results of protein sequence and structural analyses provided insights into potential mechanisms underlying associations between MTB gene mutations and DR phenotypes. Taken together, these results revealed differences in acquired BDQ and CFZ resistance mechanisms as a new perspective that may enhance our understanding of BDQ/CFZ resistance mechanisms and facilitate the development of new methods for detecting MTB drug resistance genes.

Wound healing is a common occurrence. However, delayed healing and aberrant scarring result in pathological wound healing. Accordingly, a scarless wound healing remains a significant clinical challenge. In this study, we constructed hyaluronic acid (HA)-modified and verteporfin (VP)-loaded polylactic acid (PLA) nanogels (HA/VP-PLA) to promote scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Owing to the unique structure of HA incorporating and coating in VP-loaded PLA nanoparticles, HA/VP-PLA could be topically applied on wound to achieve targeted delivery to fibroblasts. Then, HA/VP-PLA released HA and lactic acid (LA) to stimulate the proliferation and migration of fibroblasts, as well as VP to inhibit Yes-associated protein (YAP) expression and nuclear localization to suppress fibrosis. In vitro (skin fibroblasts) and in vivo (rat and rabbit models) experiments strongly suggested that HA/VP-PLA promoted scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Therefore, our work provides a feasible strategy for scarless wound healing, and the sophisticated HA/VP-PLA exhibit a great potential for clinical applications., (© 2023. The Author(s).)

High-risk neuroblastoma (HR-NB) is an aggressive childhood cancer that responds poorly to currently available therapies and is associated with only about a 50% 5-year survival rate. MYCN amplification is a critical driver of these aggressive tumors, but so far there have not been any approved treatments to effectively treat HR-NB by targeting MYCN or its downstream effectors. Thus, the identification of novel molecular targets and therapeutic strategies to treat children diagnosed with HR-NB represents an urgent unmet medical need. Here, we conducted a targeted siRNA screening and identified TATA box-binding protein-associated factor RNA polymerase I subunit D, TAF1D, as a critical regulator of the cell cycle and proliferation in HR-NB cells. Analysis of three independent primary NB cohorts determined that high TAF1D expression correlated with MYCN-amplified, high-risk disease and poor clinical outcomes. TAF1D knockdown more robustly inhibited cell proliferation in MYCN-amplified NB cells compared with MYCN-non-amplified NB cells, as well as suppressed colony formation and inhibited tumor growth in a xenograft mouse model of MYCN-amplified NB. RNA-seq analysis revealed that TAF1D knockdown downregulates the expression of genes associated with the G2/M transition, including the master cell-cycle regulator, cell-cycle-dependent kinase 1 (CDK1), resulting in cell-cycle arrest at G2/M. Our findings demonstrate that TAF1D is a key oncogenic regulator of MYCN-amplified HR-NB and suggest that therapeutic targeting of TAF1D may be a viable strategy to treat HR-NB patients by blocking cell-cycle progression and the proliferation of tumor cells., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: To identify phytochemical constituents present in the extract of flowers of Xanthoceras sorbifolia and evaluate their anti-oxidant and anti-hyperglycemic capacities., Methods: The AlCl 3 colorimetric method and Prussian Blue assay were used to determine the contents of total flavonoids and total phenolic acids in extraction layers, and the bioactive layers was screened through anti - oxidative activity in vitro . The Waters ACQUITY UPLC system and a Waters ACQUITY UPLC BEH C 18 column (2.0 mm × 150 mm, 5 μm) were used to identify the ingredients. And anti-oxidative ingredients were screened by off-line UPLC-QTOF-MS/MS-free radical scavenging. The ameliorative role of it was further evaluated in a high-fat, streptozotocin-induced type 2 diabetic rat model and the study was carried out on NADPH oxidase (PDB ID: 2CDU) by molecular docking., Results: Combined with the results of activity screening in vitro , the anti - oxidative part was identified as the ethyl acetate layer. A total of 24 chemical constituents were identified by liquid chromatography-mass spectrometry in the ethyl acetate layer and 13 main anti-oxidative active constituents were preliminarily screened out through off-line UPLC-QTOF-MS/MS-free radical scavenging. In vivo experiments showed that flowers of X. sorbifolia could significantly reduce the blood glucose level of diabetic mice and alleviate liver cell damage. Based on the results of docking analysis related to the identified phytocompounds and oxidase which involved in type 2 diabetes, quercetin 3- O -rutinoside, kaempferol-3- O -rhamnoside, isorhamnetin-3- O -glucoside, and isoquercitrin showed a better inhibitory profile., Conclusion: The ethyl acetate layer was rich in flavonoids and phenolic acids and had significant anti-oxidant activity, which could prevent hyperglycemia. This observed activity profile suggested X. sorbifolia flowers as a promising new source of tea to develop alternative natural anti-diabetic products with a high safety margin., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

Background: Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, which is highly prone to bone marrow (BM) metastasis. BM can monitor early signs of mild disease and metastasis. Existing biomarkers are insufficient for the diagnosis and treatment of NB. Bromodomain PHD finger transcription factor (BPTF) is an important subunit of the chromatin-remodeling complex that is closely associated with tumors. Here, we evaluated whether BPTF in BM plays an important role in predicting NB progression, and explore the molecular mechanism of BPTF in NB., Methods: The clinical relevance of the BPTF was predicted in the GEO (GSE62564) and TARGET database. The biological function of BPTF in NB was investigated by constructing cell lines and employing BPTF inhibitor AU1. Western blot was used to determine the changes of BPTF, TFAP4, PI3K/AKT signaling and Epithelial-mesenchymal transition (EMT) related markers. A total of 109 children with newly diagnosed NB in Beijing Children's Hospital from January 2018 to March 2021 were included in this study. RT-PCR was used to measure the BPTF and TFAP4 expression in BM. The cut-off level was set at the median value of BPTF expression levels., Results: Databases suggested that BPTF expression was higher in NB and was significantly associated with stage and grade. Proliferation and migration of NB cells were slowed down when BPTF was silenced. Mechanistically, TFAP4 could positively regulate BPTF and promotes EMT process through activating the PI3K/AKT signaling pathway. Moreover, detection of the newly diagnosed BM specimens showed that BPTF expression was significantly higher in high-risk group, stage IV group and BM metastasis group. Children with high BPTF at initial diagnosis were considered to have high risk for disease progression and recurrence. BPTF is an independent risk factor for predicting NB progression., Conclusions: A novel and convenient BPTF-targeted humoral detection that can prompt minimal residual and predict NB progression in the early stages of the disease were identified. BPTF inhibitor AU1 is expected to become a new targeted drug for NB therapy. It's also reveal previously unknown mechanisms of BPTF in NB cell proliferation and metastasis through TFAP4 and PI3K/AKT pathways., (© 2023. The Author(s).)

Background: Epidemiological characteristics of paediatric burn can help to protect children from burn injuries. Most of the previous studies have been conducted on small scale and single centre in China. This study analysed the epidemiological characteristics of paediatric burn using a large-scale and multicentre database from 23 children's hospitals in China to increase child protection against burn injuries, improve the quality of care and reduce hospitalisation costs., Methods: Excerpted information from medical records of 6741 paediatric burn cases was extracted from the Futang Research Center of Pediatric Development database from 2016 to 2019. The epidemiological characteristics of patients, including gender, age, cause of burn injuries, complication, the timing of hospitalisation (season and month) and hospitalisation length and cost, were collected., Results: Male gender (63.23%), aged 1-2 years (69.95%), and hydrothermal scald (80.57%) were significantly dominant among cases. Furthermore, complications were significantly different among groups with different age of patients. Pneumonia was the most common complication (21%). Meanwhile, most paediatric burn occurred in spring (26.73%), and hospitalisation length and cost significantly depended on the cause of the burn injuries and surgical intervention., Conclusions: This large-scale epidemiological study of paediatric burn in China revealed that boys aged 1-2 years with higher activity and lack of self-awareness are more likely to suffer from burn injuries by hydrothermal scald. In addition, complications, especially pneumonia, need attention and early prevention in paediatric burn., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Type III interferons (IFN-λs) exhibit potent antiviral activity and immunomodulatory effects in specific cells. Nucleotide fragments of the bovine ifn-λ ( boifn-λ ) gene were synthetized after codon optimization. The boifn-λ gene was then amplified by splicing using overlap extension PCR (SOE PCR), resulting in the serendipitous acquisition of the mutated boIFN-λ3 V18M . The recombinant plasmid pPICZαA-boIFN-λ3/λ3 V18M was constructed, and the corresponding proteins were expressed in Pichia pastoris with a high-level extracellular soluble form. Dominant expression strains of boIFN-λ3/λ3 V18M were selected by Western blot and ELISA and cultured on a large scale, and the recombinant proteins purified by ammonium sulfate precipitation and ion exchange chromatography yielded 1.5g/L and 0.3 g/L, with 85% and 92% purity, respectively. The antiviral activity of boIFN-λ3/λ3 V18M exceeded 10 6 U/mg, and they were neutralized with IFN-λ3 polyclonal antibodies, were susceptible to trypsin, and retained stability within defined pH and temperature ranges. Furthermore, boIFN-λ3/λ3 V18M exerted antiproliferative effects on MDBK cells without cytotoxicity at 10 4 U/mL. Overall, boIFN-λ3 and boIFN-λ3 V18M did not differ substantially in biological activity, except for reduced glycosylation of the latter. The development of boIFN-λ3 and comparative evaluation with the mutant provide theoretical insights into the antiviral mechanisms of boIFN-λs and provide material for therapeutic development.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy, characterized by BCOR internal tandem duplication (ITD), YWHAE rearrangement, BCOR-CCNB3 fusion, and lack of other consistent structural alteration. We accidentally identified TP53 deletion in CCSK, which was often associated with adverse clinical outcomes. In this study, we assessed the incidence as well as the clinical relevance of these molecules in CCSK patients. BCOR ITD, YWHAE rearrangement, BCOR-CCNB3 fusion and TP53 status were examined by polymerase chain reaction, fluorescence in situ hybridization, or Sanger sequencing in a cohort of 39 patients with CCSK. Among them, 34 cases (87.18%) had BCOR ITD, 1 (2.56%) had YWHAE rearrangement, and 1 (2.56%) had BCOR-CCNB3 gene fusion. The remaining 3 (7.69%) harbored none of these aberrations. BCOR ITD, YWHAE rearrangement and BCOR-CCNB3 were mutually exclusive. Furthermore, 25.64% of the cohort acquired TP53 aberration (10/39, 3 with both copy number deletion and point mutation, 6 with deletion only, and 1 with mutation only), all of which were associated with BCOR ITD. Patients with or without BCOR ITD or TP53 aberration did not differ in demographic characteristics such as sex, onset age, or tumor stage at diagnosis. However, the overall survival rates and progression-free survival rates of BCOR ITD or TP53 deletion groups showed obvious downward trends, albeit not all reaching statistical significance. Patients with both BCOR ITD and TP53 deletion had the poorest prognosis., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Oral non-prostanoid prostacyclin receptor agonists therapies have been recommended for pulmonary arterial hypertension in many countries., Objective: We aimed to evaluate the specific impact of non-prostanoid prostacyclin receptor agonists on pulmonary hypertension and to explore the influence of study characteristics on results., Methods: PubMed, Embase, and ClinicalTrials.gov were systematically searched from inception to July 12, 2022. Randomized controlled trials comparing non-prostanoid prostacyclin receptor agonists administration with placebo for treating pulmonary hypertension were included. Two researchers independently selected eligible studies, assessed the bias risk and extracted related data. RevMan5.1 was used for performing the statistical analysis and the assessment of bias risk of the enrolled studies. PROSPERO registered number CRD42022304172., Results: Seven trials involving 1727 patients were included. Pooled analyses indicated non-prostanoid prostacyclin receptor agonists significantly reduced clinical worsening events (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.54 to 0.74), increased 6-min walk distance (mean difference [MD], 10 m; 95% CI, 3-17 m), decreased pulmonary vascular resistance (MD, -121 dyn s/cm 5 ; 95% CI, -172 to -69 dyn s/cm 5 ) and increased cardiac index (MD, 0.38 L/min/m 2 ; 95% CI, 0.26-0.50 L/min/m 2 ) compared with the control. No significant differences in all-cause mortality (RR, 0.86; 95% CI, 0.26 to 2.78), NYHA/WHO functional class (RR, 1.16; 95% CI, 0.61 to 2.18), mean pulmonary artery pressure (MD, -0.88 mmHg; 95% CI, -2.20 to 0.44 mmHg), right atrial pressure (MD, 0.66 mmHg; 95% CI, -0.59 to 1.90 mmHg) and total adverse events (RR, 1.05; 95% CI, 0.99 to 1.10) were found between non-prostanoid prostacyclin receptor agonists group and control group., Conclusion: Non-prostanoid prostacyclin receptor agonists treatment exerted benefits on clinical worsening, pulmonary vascular resistance, and cardiac index in pulmonary hypertension patients, without increasing the incidence of total adverse events., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) recognizes exogenous double-stranded DNA and produces 2'3'-cyclic GMP-AMP (2'3'-cGAMP), activating the stimulator of interferon genes (STING) and innate immunity. Bovine cGAS functions remain poorly understood. Herein, the coding sequence of the bo-cGAS gene was obtained and its recognition function was investigated. Bo-cGAS consists of 1542 nucleotides and the encoding acid sequence contained high sequence homology to that of other livestock. Bo-cGAS was localized in the endoplasmic reticulum and was abundant in the lung. Bo-cGAS and bo-STING coexistence significantly activated the IFN-β promotor. Synthesized 2'3'-cGAMP activated the STING-dependent pathway. Upon bo-cGAS recognition of poly(dA:dT) and bovine herpesvirus type 1 (BHV-1), Viperin transcription displayed the opposite time-dependent trend. Significant restriction of IFN-β transcription but augmentation of myxovirus resistance protein 1 (Mx1) and Viperin occurred during BHV-1 infection. Thus, bo-cGAS recognized exogenous double-stranded DNA and triggered the STING-dependent IFN-β production pathway., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Getu Zhaori is the editor‐in‐chief of Pediatric Investigation. Lu Lu, Chunyan Liu, Shujing Han, and Yongli Guo are the editorial staff of Pediatric Investigation.

To examine the difference in the topological properties of brain functional network between the children with obstructive sleep apnea (OSA) and healthy controls, and to explore the relationships between these properties and cognitive scores of OSA children. Twenty-four OSA children (6.5 ± 2.8 years, 15 males) and 26 healthy controls (8.0 ± 2.9 years, 11 males) underwent resting-state fMRI (rs-fMRI), based on which brain functional networks were constructed. We compared the global and regional topological properties of the network between OSA children and healthy controls. Partial correlation analysis was performed between topological properties and cognitive scores across OSA children. When comparing the OSA children with the healthy controls, lower full-scale intelligent quotient (FIQ) and verbal intelligent quotient (VIQ) were observed. Additionally, nodal degree centrality decreased in the bilateral anterior cingulate and paracingulate gyrus, but increased in the right middle frontal gyrus, the left fusiform gyrus, and the left supramarginal gyrus. Nodal efficiency decreased in the right precentral gyrus, and the bilateral anterior cingulate and paracingulate gyrus, but increased in the left fusiform gyrus. Nodal betweenness centrality increased in the dorsolateral part of the right superior frontal gyrus, the left fusiform gyrus, and the left supramarginal gyrus. Further, the nodal degree centrality in the left supramarginal gyrus was positively correlated with FIQ. In contrast, none of global topological properties showed difference between those two groups. The outcomes of OSA may impaired the regional topological properties of the brain functional network of OSA children, which may be potential neural mechanism underlying the cognitive declines of these patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Delamanid (DLM) and pretomanid (PTM) are recent additions to the anti-tuberculosis (TB) drug armamentarium, and they offer more effective options for drug-resistant TB treatment. In particular, DLM is included in Group C, which is recommended for use in longer multidrug-resistant (MDR)-TB regimens. Previous studies have shown that resistance to DLM/PTM is caused by mutations in the ddn , fgd1 , fbiA , fbiB , fbiC , and fbiD genes, which are related to the F 420 -dependent bioactivation pathway. Herein, we conduct in vitro selection of DLM-resistant strains using clinical Mycobacterium tuberculosis (MTB) isolates with various drug resistance profiles. The spontaneous resistance frequency of drug-susceptible (DS) MTB (1.14 × 10 -6 to 1.04 × 10 -4 ) to DLM was similar to that of H37Rv (8.88 × 10 -6 to 9.96 × 10 -6 ) but higher than those of multidrug-resistant MTB (2.03 × 10 -7 to 3.18 × 10 -6 ) and extensively drug-resistant (XDR) MTB (4.67 × 10 -8 to 3.60 × 10 -6 ). Of the 100 independently selected DLM-resistant MTB mutants, 65% harbored mutations in genes associated with either DLM prodrug activation ( ddn , 39.73%; fgd1 , 16.44%) or the F 420 biosynthetic pathway ( fbiA , 16.44%; fbiB , 5.48%; fbiC , 21.92%). Of the 45 mutations we identified, 38 were not previously reported. A structure analysis revealed that several point mutations affected the ligand binding or structural stability of enzymes related to DLM resistance, which would block the enzyme activity required for prodrug activation. Our results elucidate the in vitro spontaneous DLM-resistance patterns of different clinical strains, which could improve the understanding of the causes of DLM resistance in clinical strains and of the effects on drug resistance of different mutations in genes that are related to the DLM activation pathway.

Background: Cervical neuroblastic tumors (NTs) are rare but less aggressive cancer with an above-average survival rate. Little has been published regarding the management and surgical outcomes of patients with cervical NTs based on pathology category. This study compared and identified the preoperative characteristics of cervical NTs in different pathology categories and evaluated the outcomes of patients undergoing surgical resection., Materials and Methods: Upon the institutional review board's approval, a retrospective chart review was performed at Beijing Children's Hospital from April 2013 to August 2020. Demographics of patients, imaging data, lab test results, operation details and outcomes were recorded and analyzed., Results: Of 32 cervical NTs, 24(80%) were classified as neuroblastoma (NB) /ganglioneuroblastoma-nodular (GNBn) and 8(20%) as ganglioneuroblastoma-intermixed (GNBi)/ ganglioneuroma (GN). Patients with GNBi/GN were older than those with NB/GNBn (44.5 months (IQR 16-81) vs 9 months (IQR 1-47); P = 0.001). GNBi/GN patients presented more frequently with stage 1 disease compared with NB/GNBn patients (100% vs. 29.2%, P = 0.001), less frequently with tumor-related symptoms (0% vs. 70.8%, P = 0.001), artery encased tumor (0% vs. 41.7%, P = 0.035), and surgical complications (25% vs. 70.8%, P = 0.038). GNBi/GN patients were also less likely to show elevated neuron specific enolase (NSE) (12.5% vs. 79.2%, P = 0.002)., Conclusions: Cervical NB/GNBn and GNBi/GN patients had distinct characteristic clinical presentations and surgical outcomes. For children with features suggestive of benign disease (older age, asymptomatic, normal serum tumor markers) and no artery image-defined risk factors (IDRFs), upfront resection can be considered., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

ABSTRACT Pediatric tuberculosis (TB) is a serious infectious disease that affects many children worldwide and is more likely to be extrapulmonary than adult TB. However, the clinical and epidemiological profile, and cost burden of pediatric extrapulmonary TB (EPTB) in China remain unknown. Here, we conducted a descriptive, multicenter study of pediatric TB patients from 22 hospitals across all six regions in China from October 2015 to December 2018. Of 4,654 patients, 54.23% (2,524) had pulmonary TB (PTB), 17.76% (827) had EPTB, and 28.00% (1,303) had concurrent extrapulmonary and pulmonary TB (combined TB). Compared with PTB, EPTB and combined TB were associated with lower hospitalization frequency (2.43 and 2.21 vs. 3.16 times), longer length of stay (10.61 and 11.27 vs. 8.56 days), and higher rate of discharge against medical advice (8.46% and 9.44% vs. 5.67%). EPTB was associated with higher mortality (0.97% vs. 0.24% and 0.31%), higher rate of low birth weight (17.69% vs. 6.79% and 6.22%), worse diagnosis at the first visit (21.16% vs. 34.67% and 44.47%), and worse hospitalization plan situation (4.35% vs. 7.81% and 7.44%), compared with PTB and combined TB. EPTB and combined TB had higher financial burdens (17.67% and 16.94% vs. 13.30%) and higher rates of catastrophic expenditure (8.22% and 9.59% vs. 5.03%), compared with PTB. Meningitis TB (34.18%) was the most frequent form of total extrapulmonary infection and had the highest cost burden and rate of catastrophic expenditure. In conclusion, improved screening approaches for pediatric EPTB are needed to reduce diagnostic challenges and financial burden.

Objective: To evaluate the effects of diabetes and hyperglycemia on in-hospital mortality in critically ill patients older than 75 years., Methods: This was a single-center retrospective cohort study of patients older than 75 years in the first intensive care unit stay. The patients were divided into the following 4 groups: time-weighted average glucose (TWAG) <140 mg/dL without diabetes (group 1), TWAG ≥140 mg/dL without diabetes (group 2), TWAG <180 mg/dL with diabetes (group 3), and TWAG ≥180 mg/dL with diabetes (group 4). Clinical and laboratory data were analyzed., Results: A total of 6760 patients over 75 years of age were included, including 2089 patients previously diagnosed with diabetes. The patients in group 2 had the highest in-hospital mortality (27.4%). In the fully adjusted regression model, the risk of in-hospital mortality increased by 76% (odds ratio = 1.76, 95% CI: 1.49-2.08) in group 2 as compared with group 1. Those from groups 3 and 4 exhibited risks equivalent to the risks of those in group 1; similar results were observed in the subgroup analysis. A J-shaped curve relationship and threshold effect were observed in patients without diabetes. For those with diabetes, a flatter curve pattern with a small slope was observed., Conclusion: Stress hyperglycemia was more detrimental to short-term prognosis than diabetes status in these patients. Looser glucose control may be suitable for patients older than 75 years with diabetes but unnecessary for those without diabetes. Patients with diabetes may be more resistant to the detrimental effects of glucose variations., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To estimate the impact of nonpharmaceutical interventions (NPIs) targeted at the COVID-19 pandemic on the admission number of respiratory diseases, including pneumonia, acute bronchitis & bronchiolitis, and acute upper respiratory infections (AURIs) for children in China., Methods: Continuous hospitalization records aged 0-18 years from January 1, 2016, to December 31, 2020, were collected from 26 tertiary children's hospitals. Interrupted time series analysis with a quasi-Poisson model was conducted with the start time of the COVID-19 pandemic as the interrupted timepoint and the weekly admission numbers of all-cause respiratory disease, pneumonia, acute bronchitis & bronchiolitis, and AURI as the outcome measures. Hospitalizations of childhood neoplasms were analyzed as the reference group., Results: The reduction in admission numbers following NPIs was -55.0% (-57.9 to -51.9%) for all-cause respiratory diseases, -62.7% (-65.7 to -59.5%) for pneumonia, -48.1% (-53.3 to -42.3%) for bronchitis & bronchiolitis, and -24.3% (-28.6 to -19.8%) for AURI. The effect estimates of NPIs on childhood neoplasms was -29.1% (-33.6 to -24.4%). Stratification analysis showed the reduction was most drastic for children at 4-6 and 7-12 years., Conclusion: The admission number for respiratory diseases among children in China decreased drastically after the implementation of NPIs. NPIs with low socio-economic burdens should be suggested even outside the COVID-19 pandemic., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

High-entropy alloys (HEAs) with high hardness are promising materials for advanced industrial manufacturing. In this study, the AlCrFeNiV HEA was designed and successfully prepared using a plasma instantaneous process. The hardness test showed that AlCrFeNiV had a high hardness of 1076 ± 15 HV, which was much higher than those reported in the literature. The microstructure of AlCrFeNiV was composed of two different types of body-centered cubic (BCC) structures, BCC1 (Al, Cr, Fe, and Ni) and BCC2 (enriched V and Cr). A mixture of different BCC systems produced solution strengthening, which was responsible for the superior hardness. Moreover, the reciprocating sliding wear behavior of HEA against Al 2 O 3 balls under dry and lubricated conditions at ambient temperature was investigated. The wear rates of AlCrFeNiV against Al 2 O 3 under dry wear and lubrication were 17.2 × 10 -5 mm 3 N -1 ·m -1 and 12.4 × 10 -5 mm 3 N -1 ·m -1 , respectively, which were of the same order of magnitude as the wear rates of BCC HEAs. Regardless of the dry wear or wear with lubrication, the wear mechanism of the HEA was abrasive and delamination wear.

Background: Despite the substantial burden caused by childhood cancer globally, childhood cancer incidence obtained in a nationwide childhood cancer registry and the accessibility of relevant health services are still unknown in China. We comprehensively assessed the most up-to-date cancer incidence in Chinese children and adolescents, nationally, regionally, and in specific population subgroups, and also examined the association between cancer incidence and socioeconomic inequality in access to health services., Methods: In this national cross-sectional study, we used data from the National Center for Pediatric Cancer Surveillance, the nationwide Hospital Quality Monitoring System, and public databases to cover 31 provinces, autonomous regions, and municipalities in mainland China. We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China through stratified proportional estimation. We classified regions by socioeconomic status using the human development index (HDI). Incidence rates of 12 main groups, 47 subgroups, and 81 subtypes of cancer were reported and compared by sex, age, and socioeconomic status, according to the third edition of the International Classification of Childhood Cancer. We also quantified the geographical and population density of paediatric oncologists, pathology workforce, diagnoses and treatment institutions of paediatric cancer, and paediatric beds. We used the Gini coefficient to assess equality in access to these four health service indicators. We also calculated the proportions of cross-regional patients among new cases in our surveillance system., Findings: We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China from Jan 1, 2018, to Dec 31, 2020. An estimated 121 145 cancer cases were diagnosed among children and adolescents in China between 2018 and 2020, with world standard age-standardised incidence rates of 122·86 (95% CI 121·70-124·02) per million for children and 137·64 (136·08-139·20) per million for adolescents. Boys had a higher incidence rate of childhood cancer (133·18 for boys vs 111·21 for girls per million) but a lower incidence of adolescent cancer (133·92 for boys vs 141·79 for girls per million) than girls. Leukaemias (42·33 per million) were the most common cancer group in children, whereas malignant epithelial tumours and melanomas (30·39 per million) surpassed leukaemias (30·08 per million) in adolescents as the cancer with the highest incidence. The overall incidence rates ranged from 101·60 (100·67-102·51) per million in very low HDI regions to 138·21 (137·14-139·29) per million in high HDI regions, indicating a significant positive association between the incidence of childhood and adolescent cancer and regional socioeconomic status (p<0·0001). The incidence in girls showed larger variation (48·45% from the lowest to the highest) than boys (36·71% from lowest to highest) in different socioeconomic regions. The population and geographical densities of most health services also showed a significant positive correlation with HDI levels. In particular, the geographical density distribution (Gini coefficients of 0·32-0·47) had higher inequalities than population density distribution (Gini coefficients of 0·05-0·19). The overall proportion of cross-regional patients of childhood and adolescent cancer was 22·16%, and the highest proportion occurred in retinoblastoma (56·54%) and in low HDI regions (35·14%)., Interpretation: Our study showed that the burden of cancer in children and adolescents in China is much higher than previously nationally reported from 2000 to 2015. The distribution of the accessibility of health services, as a social determinant of health, might have a notable role in the socioeconomic inequalities in cancer incidence among Chinese children and adolescents. With regards to achieving the Sustainable Development Goals, policy approaches should prioritise increasing the accessibility of health services for early diagnosis to improve outcomes and subsequently reduce disease burdens, as well as narrowing the socioeconomic inequalities of childhood and adolescent cancer., Funding: National Major Science and Technology Projects of China, National Natural Science Foundation of China, Chinese Academy of Engineering Consulting Research Project, Wu Jieping Medical Foundation, Beijing Municipal Administration of Hospitals Incubating Program., Competing Interests: Declaration of interests XN reports grants from the National Major Science and Technology Projects of China (2018ZX09721003) and the National Natural Science Foundation of China (81970867). JZhan, XN, and HW report a grant from the Chinese Academy of Engineering Consulting Research Project (2018-XY-41). ZL reports a grant from the Wu Jieping Medical Foundation (320·6750·2021–04–66). XL reports a grant from the Beijing Municipal Administration of Hospitals Incubating Program (PG2022024). GB reports a grant from the National Natural Science Foundation of China (82104470). All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To examine the short-term association between gaseous air pollutants (CO, NO 2 , SO 2 , and O 3 ) and all-cause respiratory disease, acute upper respiratory infections (AURIs) as well as acute lower respiratory infections (ALRIs) among children, we conducted the study from 25 major cities in China. Hospitalization records of children aged 0-18 years due to all-cause respiratory diseases (889,926), AURIs (97,858), and ALRIs (642,154) from 2016 to 2019 were extracted. Concentrations of CO, NO 2 , SO 2 , and O 3 were averaged across monitoring stations. Generalized additive models were used to estimate the associations between gaseous air pollutants and daily hospitalizations for all-cause respiratory disease, AURIs, and ALRIs. The meta-analysis was used to combine the city-specific estimates. A 10 mg/m 3 increase in CO at lag01, and a 10 μg/m 3 increase in NO 2 , SO 2 , and O 3 at lag01 were associated with 1.65% (95%CI, 0.41-2.91), 0.54% (95%CI, 0.30-0.79), 0.60% (95%CI, 0.22-0.99), and 0.23% (95%CI, 0.06-0.39) increase of hospitalizations due to all-cause respiratory disease, respectively. For the disease subtype, O 3 only had adverse effects on AURIs, CO and SO 2 mainly on ALRIs, and NO 2 on both AURIs and ALRIs. Children aged 4-6years were more vulnerable to the effects of CO and NO 2 , but those aged <1year were more susceptible to SO 2 and O 3 . Besides, the O 3 effect was stronger in the warm season than in the cold season. The study indicated that short-term exposure to CO, NO 2 , SO 2, and O 3 was associated with increased hospitalization for pediatric respiratory disease, and the association may vary by position of the respiratory tract, age, and season., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The pathologic features and potential predictive biomarkers for recurrence of antrochoanal polyps (ACPs) in children are not fully understood., Objectives: To identify the pathologic differences between recurrent and nonrecurrent group and to explore potential clinical markers which predict recurrence of ACPs in children., Material and Methods: A total of 11 recurrent and 21 nonrecurrent ACPs children were enrolled into this retrospect study. Clinical basic information was collected before the first surgery. The counts of vessels were evaluated by hematoxylin-eosin (HE) staining, and CD34 was detected by immunohistochemistry. Meanwhile, the percentage of each tissue inflammatory cells (eosinophils, neutrophils, lymphocytes, and plasma cells) was assessed by HE staining., Results: No statistical significance was observed between the 2 groups in the basic clinical features. Moreover, both the counts of blood vessels and the tissue neutrophils percentage were enhanced significantly in group with ACPs recurrence ( P < .05). According to the receiver operating characteristic curves, the area under the curve for the counts of blood vessels and tissue neutrophils percentage in the prediction of ACPs' recurrence was 0.779 ( P = .0105) and 0.989 ( P < .0001) respectively., Conclusions and Significance: It was concluded that the counts of blood vessels and the percentage of tissue neutrophils appeared to be potential excellent predictors of ACPs recurrence in children.

Bovine herpesvirus type 1 (BHV-1) is a neurotropic herpesvirus that causes infectious rhinotracheitis and vulvovaginitis in cattle. The virion host shutoff protein encoded by the BHV-1 UL41 gene is highly conserved in the Alphaherpesvirinae subfamily. This protein can degrade viral and host messenger RNA (mRNA) to interrupt host defense and facilitate the rapid proliferation of BHV-1. However, studies on the BHV-1 UL41 gene are limited, and BHV-1 defective virus construction using the CRISPR/Cas9 system is somewhat challenging. In this study, we rapidly constructed a BHV-1 UL41-deficient strain using the CRISPR/Cas9 system in BL primary bovine-derived cells. BHV-1 UL41-defective mutants were screened by Western blot analysis using specific polyclonal antibodies as the primary antibodies. During the isolation and purification of the defective strain, a mixed virus pool edited by an efficient single-guide RNA (sgRNA) showed a plaque number reduction. Viral growth property assessment showed that BHV-1 UL41 was dispensable for replication, but the UL41-defective strain exhibited early and slowed viral replication. Furthermore, the BHV-1 UL41-deficient strain exhibited enhanced sensitivity to temperature and acidic environments. The BHV-1 UL41-deficient strain regulated viral and host mRNA levels to affect viral replication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dai, Wu, Yang, Guo, Di, Gao and Wang.)

Nitrate (NO 3 - ) pollution is a common phenomenon in karst underground rivers, which are important water sources in karst landscapes. For drinking water safety and environmental protection, it is crucial to accurately identify NO 3 - sources and their migration and transformation processes in the Lihu Underground River. In this study, water samples of the Lihu Underground River in Guangxi were collected in May 2014, October 2014, January 2015, and July 2015, and water chemical and dual isotopic (δ 15 N-NO 3 - and δ 18 O-NO 3 - ) approaches were used to evaluate the NO 3 - characteristics and sources in the Lihu Underground River. The concentration of NO 3 - in the Lihu Underground River ranged from 1.16 to 19.78 mg·L -1 , with an average of 9.30 mg·L -1 , which is more than 37% of the WHO standard (10 mg·L -1 ). The concentrations of NO 3 - in the wet season (May 2014 and July 2015) were slightly lower than those in the dry season (from October 2014 to January 2015) at most sampling sites due to dilution effects. The migration and transformation processes of NO 3 - were analyzed by comparing the measured and calculated concentrations of NO 3 - in the Lihu Underground River. In the dry season (from October 2014 to January 2015), the variation in NO 3 - concentration upstream and midstream of the Lihu Underground River was affected by exogenous input and nitrification. From midstream to the outlet of Xiaolongdong, it is affected by self-purification factors, including physical processes, chemical processes, and biological processes. In the wet season (May 2014 and July 2015), the dilution and mixing effects were the main factors controlling the variation in NO 3 - concentration in the Lihu Underground River. The contribution rates of potential NO 3 - sources (incl. atmospheric precipitation (AP), NO 3 - fertilizer (NF), NH 4 + in fertilizer and rainfall (NFA), soil organic nitrogen (SON), and manure and sewage (M&S)) were quantitatively evaluated by using the IsoSource model. The results showed that in May 2014, the main sources of NO 3 - were M&S and NF, with contribution rates of 46% and 41%, respectively. In October 2014, NO 3 - sources were M&S with a contribution rate of 47%, followed by NFA with a contribution rate of 31%. In January 2015, NO 3 - sources in groundwater were M&S, with a contribution rate of 53%, followed by NFA (34%). In July 2015, the main NO 3 - sources were M&S and NF, whose contribution rates were 54% and 39%, respectively., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sclerosing epithelioid fibrosarcoma (SEF), typically arising in middle-aged and older adults, is a rare malignant fibroblastic neoplasm characterized by epithelioid fibroblasts embedded in sclerotic hyalinized stroma. This tumor frequently harbors translocation between EWSR1 and CREB3 subfamily members. Here, we describe four cases of SEF with unique genetic characteristics in children. All tumors were located in the deep soft tissue of the trunk and celom. Histopathologically, the tumors were featured by prominent hyalinized sclerotic collagenous stroma within which relatively bland and monomorphic epithelioid cells were arranged in cords, nests, or sheets. Low-grade fibromyxoid sarcoma-like zones varied among cases. MUC4 was strong and diffuse. CD99 was positive. Transmission electron microscopy demonstrated spindle or polyhedral neoplastic cells with a collagen fiber-rich stroma. Interphase fluorescence in situ hybridization (FISH) revealed local amplification of the EWSR1 locus. Whole-genome sequencing indicated translocation between EWSR1 and CREB3L1 together with low-level amplification of the fusion parts. RT-PCR and Sanger sequencing confirmed the fusion transcript. Single nucleotide polymorphism and FISH analyses demonstrated co-deletion of 11p and 22q. The consistent genetic features indicated the presence of a unique molecular variant of SEF. DATA AVAILABILITY STATEMENT: The data used to support the findings of this study are available from the corresponding author upon request., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

A fractured karst aquifer polluted by petroleum hydrocarbons (PH) for several decades was selected to study the influences of PH on the hydrochemical environment. The research was implemented using the hydrochemical indicators (Ca 2+ , Mg 2+ , Na + +K + , HCO 3 - , NO 3 - , Cl - , F - , and SO 4 2- ) and PH with the help of GIS and origin platforms, statistical analyses, and graphical methods. Results showed that PH had significant influences on the hydrochemical environment over the last several decades. The main principle elements influencing the evolution processes of hydrochemical environment were carbonates dissolution, leaking wastewater, and biodegradation processes from 1977 to 2019, and hydrochemistry types changed from HCO 3 -Ca-Mg and HCO 3 -Ca to HCO 3 -Cl-Ca-Mg and HCO 3 -Cl-Ca. The contribution rate of PH biodegradation to the representative ion increased at first, then decreased over time, which has a close relationship with the variation characteristics of PH. The dynamic evolution processes of hydrochemical environment have significances for indentifying the influencing mechanisms of hydrogeochemical reactions, which could provide valuable scientific suggestions for the local administrators to take effective efforts to optimize and protect the karst groundwater environment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the impacts of obstructive sleep apnea (OSA) on white matter (WM) integrity and cognitive functions of pediatric patients with different levels of OSA severity., Methods: Fifty-eight children with OSA and thirty-four healthy controls (HC) were recruited. All participants underwent diffusion tensor imaging (DTI) examination, polysomnography (PSG), and neurocognitive assessments. Patients were divided into mild OSA (MG) and moderate-severe OSA (SG) groups. WM integrity, PSG data, and neurocognitive assessment scores were compared among those groups., Results: For apnea hypopnea index (AHI), obstructive apnea hypopnea index (OAHI), arousal index, SpO 2 nadir, and attention, SG was worse than both MG and HC with MG worse than HC. For baseline SpO 2 and intelligence, SG was worse than both MG and HC with no significant difference between MG and HC. Impaired WM integrity was observed in bilateral anterior thalamic radiation, bilateral inferior fronto-occipital fasciculus, bilateral inferior longitudinal fasciculus, right superior longitudinal fasciculus, right hippocampus, left cingulate gyrus, right uncinate fasciculus, callosum forceps major, and callosum forceps minor only for SG than for HC. WM integrity was significantly correlated with OSA severity and neurocognitive assessment scores only for SG, but not for MG., Conclusion: Decreased baseline SpO 2 , WM impairment, and intelligence decline were all observed only for SG, but not for MG, implying an associated relationship among decreased SpO 2 , WM impairment and WM impairment. Thus, for SG, additional assessments of brain damage and cognitive function decline are needed for prognostic evaluation of OSA., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Mei et al.)

In this study, we investigated a fractured karst aquifer polluted by chlorinated hydrocarbons to determine the contamination characteristics of the main hydrocarbon components. The natural attenuation processes of representative components were simulated and forecasted using TMVOC and hydro-chemical components (NO 3 - , SO 4 2- , HCO 3 - Cl - and δ 13 C DIC ). The impact of hydrocarbon compounds on the hydro-chemical ions were estimated, and their historical contamination characteristics were also reconstructed. Results showed that the dynamic characteristics of Trichloromethane and 1,1,2-Trichlorethane can indicate those of chlorinated hydrocarbons, where the rate of natural attenuation was observed to decrease with decreasing concentrations of hydrocarbon compounds. Additionally, the long-term variation characteristics in groundwater levels showed that the relatively stable hydrodynamic field conditions enabled the simulation of the natural attenuation processes of chlorinated hydrocarbons. The simulation which also considered the biodegradation processes showed that the use of TMVOC and hydro-chemical parameters may better describe natural attenuation processes. Over 3 years (from 2017 to 2019), the average percentage of biodegradation in the total natural attenuation was estimated to be 88.35%. Similarly, Trichloromethane and 1,1,2-Trichlorethane are forecasted to have no health hazards in 10 and 15 years, respectively. The contribution rates of biodegradation to HCO 3 - and Cl - in the fractured karst aquifer varied with the concentrations of chlorinated hydrocarbons. Overall, the findings and methods in this work have significant contributions for advancing remediation developments of petroleum hydrocarbons, especially in karst environments that are highly susceptible to contamination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: None.

Echinacoside (ECH), acteoside (ACT), and isoacteoside (ISAT), the typical phenylethanoid glycosides (PhGs) in cistanches herba, have various pharmacological activities. However, the ECH, ACT and ISAT have extremely low oral bioavailability, which is related to their metabolism under the intestinal flora. Previous studies showed that intestinal metabolites were the hepatoprotective substances in vivo, but the research on whether PhGs has effects without intestinal bacteria has not been studied. In this paper, ECH, ACT and ISAT were incubated with human or rat intestinal bacteria for 36 h. After incubating with human bacteria for 36 h, three prototype compounds were not detected and were mainly biotransformed to 3-HPP and HT. In the network pharmacology, a total of 6 common targets were obtained by analysing the prototypes, the metabolites and the liver injury. It was found that the combinations of three metabolites and common targets were more stable than those of the prototypes and common targets by molecular docking. Meanwhile, hepatocellular apoptosis, proliferation, inflammation and oxidative responses might play important roles in the mechanisms of the metabolites exerting hepatoprotective activities. Then normal and pseudo-sterile mice experiments were adopted to further compare the hepatoprotective activities of prototypes and metabolites. Animal experiment results showed that the prototypes and the metabolites in the normal mice had significantly hepatoprotective activity. Interestingly, in the pseudo-germfree mice, the metabolites showed significant hepatoprotective effect, but the prototypes had not effect. It indicated that the prototype cannot exert liver protective activity without the effect of intestinal bacteria., (© 2021. The Japanese Society of Pharmacognosy.)

Objective/hypothesis: To evaluate the efficacy of initial sirolimus therapy in the treatment of intractable head and neck lymphatic malformations (LMs) in children., Study Design: Prospective open-label study., Methods: In this study, Twenty-seven children diagnosed with LMs were given oral sirolimus as primary treatment over a minimum 6-month trial. The major parameter to evaluate therapeutic outcome was percentage of lesion volume change compared with baseline. Average serum sirolimus concentrations, and adverse side effects, were monitored throughout the study period., Results: Fifteen girls and twelve boys, average age 27 months (16 days-171 months), constitute the study group. Treatment was deemed effective for twenty-three participants, judged as fair in seven, good in nine, and excellent in seven. Two patients had minimal improvement, and two had increased volume to some degree. Effectiveness differed among LMs subtypes with responsiveness of macrocystic LMs exceeding that of microcystic LMs (P < .05). Adverse drug reactions totaled 27 events in ten patients, the majority being mild with upper respiratory infections being most common., Conclusions: Sirolimus as initial therapy is effective in decreasing lesion volume in intractable LMs in head and neck region, especially in macrocystic subtypes. Although most cases cannot be completely cured, side effects are few and tolerable., Level of Evidence: 4 Laryngoscope, 131:1902-1908, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case., Materials and Methods: One family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line., Results: A novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings' mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant., Conclusion: In summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Chen, Qin, Jin, Zhang, Yang, Wang, Fu, Hong, Yu, Lu, Chang, Ni, Xu, Shi and Guo.)

Objectives: The objectives of this study were to explore the clinical heterogeneity of differentiated thyroid cancer (DTC) between prepubertal children and adolescents and guide clinical treatment., Methods: A retrospective study included patients with DTC aged ≤19 years in Beijing Children's Hospital from June 2014 to June 2019. All patients were enrolled and divided into 2 subgroups based on the threshold age of 10 years, namely the childhood group (CG) (≤10 years old); and the adolescent group (AG) (between 10 and 19 years old). The χ 2 test and Fisher's exact test were used to estimate the effect of risk factors in the 2 age groups. Multivariate binary logistic regression models were conducted to assess the recurrent risk factors., Results: Seventy cases of DTC were included with an average age of 9.94 ± 2.88 years, including 35 in CG and 35 in AG. The most common clinical manifestation was a painless mass in the neck, accounting for 77.1% (54/70) of patients. Compared with the AG, the CG was more likely to have lymph node metastasis ( p = 0.022) and distant metastasis ( p = 0.041). The CG was more likely to have extrathyroidal extension ( p = 0.012) and had a significantly higher recurrence rate than the AG ( p = 0.040). Age was an independent variable predictive of recurrence ( p = 0.0347)., Conclusion: Regional invasiveness, cervical lymph node metastasis, and distant metastasis of DTC were more likely to occur in children ≤10 years old. Meanwhile, children ≤10 years old with DTC were more likely to have recurrence than adolescent's postsurgical treatment. Thus, children younger than 10 years of age with DTC should be treated more aggressively., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 by S. Karger AG, Basel.)

Bacterial meningitis shows a higher incidence in children than adults, but signs may be scarce. Although some pathogenic microorganisms of meningitis from cerebrospinal fluid (CSF) have been reported, the signature of the representative microbiota in CSF and blood samples from patients remains incompletely revealed. To extend the understanding of the microbiome in patients, we recruited 32 children with bacterial meningitis, 30 undiagnosed infectious children, and 10 matched healthy individuals, which was followed by untargeted metagenomic next-generation sequencing (mNGS) and bioinformatic analysis. Our results showed that children with bacterial meningitis exhibited different microbiome signatures in their CSF and blood compared with undiagnosed and healthy children, and patients could be divided into varied subsets according to these signatures, including Escherichia coli, Klebsiella pneumoniae, Thermothelomyces thermophila, Lactobacillus acidophilus, and Staphylococcus haemolyticus. To further explore their potential role in patients' conditions, we examined their correlation with clinical parameters. Importantly, microbiome signatures with compositional changes were correlated with the C-reactive protein (CRP) level in blood and granulocyte percentage in CSF. Moreover, the blood in subsets of patients with a predominance of Klebsiella pneumoniae could replace CSF as the main specimen for clinical monitoring. IMPORTANCE This study revealed the microbial compositions in children with bacterial meningitis who were treated with antibiotics and made a comprehensive comparison between blood and CSF specimens for the risk and prognosis assessment. We found that microbiome signatures could distinguish patient subsets in the children and were correlated with the CRP level in blood and granulocyte percentage in CSF. The compositional changes in representative microbiota constituents could provide guidance for clinical monitoring and antibiotic intervention.

Importance: First branchial cleft anomalies (FBCAs) are rare congenital malformations, accounting for < 8% of all branchial cleft anomalies. However, little is currently known about the cause of FBCAs at the molecular level., Objective: To identify genomic alterations related to the genetic etiology of FBCAs in Chinese children., Methods: We performed whole-exome sequencing of samples from 10 pediatric patients with FBCAs. Data analysis was carried out using the Burrow-Wheeler Alignment software package, and the dbSNP database for comparisons. Rare variants were further validated by Sanger sequencing. Insertion/deletions (indels) were examined using the Genome Analysis Toolkit., Results: We identified 14 non-synonymous mutations in seven potential FBCA-susceptibility genes ( TRAPPC12 , NRP2 , NPNT , SH3RF2 , RHPN1 , TENM4 , and ARMCX4 ). We also detected 133 shared small indels in 125 genes. Gene Ontology analysis indicated that most of the identified genes played critical roles in development and differentiation pathways involved in regulating organ development., Interpretation: We characterized the mutational landscape in pathways involved in development and differentiation in Chinese children with FBCA. The results identified potential pathogenic genes and mutations related to FBCA, and provide molecular-level support for the branchial theory of FBCA pathogenesis., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2021 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Importance: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. More than 90% of cases are classified as embryonic RMS (ERMS) or alveolar RMS (ARMS). ERMS has a worse prognosis than ARMS. Early differential diagnosis is of paramount importance for optimization of treatment., Objective: To identify genes that are differentially expressed between ARMS and ERMS, which can be used for accurate rhabdomyosarcoma classification., Methods: Three Gene Expression Omnibus datasets composed of ARMS and ERMS samples were screened and 35 differentially expressed genes (DEGs) were identified. Receiver operating characteristic curve analysis and area under the curve analysis was performed for these 35 DEGs and seven candidate genes with the best differential expression scores between ARMS and ERMS were determined. The expression of these seven candidate genes was validated by immunohistochemical analysis of pre-chemotherapy ARMS and ERMS specimens., Results: The levels of DCX and CRABP2 were confirmed to be remarkably different between paraffin-embedded ARMS and ERMS tissues, while EGFR abundance was only marginally different between these two RMS subtypes., Interpretation: DCX and CRABP2 are potential biomarkers for distinguishing ARMS from ERMS in pre-chemotherapy pediatric patients., Competing Interests: None., (© 2021 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Neuroblastoma (NB) is one of the most common malignant tumors in children, with variable clinical behaviors and a 15% death rate of all malignancies in childhood. However, genetic susceptibility to sporadic NB in Han Chinese patients is largely unknown. To identify genetic risk factors for NB, we performed an association study on 357 NB patients and 738 control subjects among Han Chinese children. We focused on DEAD box 1 (DDX1), a putative RNA helicase, which is involved in NB carcinogenesis. The potential association of DDX1 polymorphisms with NB has not been discovered. Our results demonstrate that rs72780850 (NM&#95;004939.2:c.-1555T>C) located in the DDX1 promoter region is significantly associated with higher expression of DDX1 transcript and increased NB risk (odds ratio=1.64, 95% confidence interval=1.03%-2.60%, P=0.004), especially in aggressive NB compared with ganglioneuroma and ganglioneuroblastoma in a dominant model (TC+CC vs. TT). Furthermore, the MYC-associated protein X (MAX) transcription factor showed stronger binding affinity to the DDX1 rs 72780850 CC allele compared with the TT allele, explaining the molecular mechanism of the increased NB risk caused by the rs72780850 polymorphism. Our results highlight the involvement of regulatory genetic variants of DDX1 in NB.