1.Flavonoids Intervene in Diabetic Nephropathy by Regulating TGF-β/Smad Signaling Pathway: A Review
Qihui QIU ; Chang LIU ; Xiaotong YAN ; Jinwei HAN ; Hui SUN ; Fengting YIN ; Yuhang WANG ; Mengmeng WANG ; Xijun WANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(7):300-309
Diabetic nephropathy (DKD), as a common microvascular complication of diabetes mellitus (DM), is a major cause of end-stage renal disease (ESRD). Its clinical manifestations include increased urinary protein excretion, thickening of the glomerular basement membrane, and renal tubulointerstitial fibrosis. The pathogenesis of DKD is complex and involves multiple factors, including disordered glucose metabolism, hemodynamic alterations, and oxidative stress. Although modern medical approaches can alleviate certain symptoms, they still have limitations such as insufficient therapeutic targeting and prominent adverse effects. The transforming growth factor-β/Smad (TGF-β/Smad) signaling pathway is not only a tissue fibrosis pathway that has attracted considerable attention in recent years, but also regulates multiple protein molecules, including the glomerular podocyte slit diaphragm protein Podocin, interleukin-1β (IL-1β), and superoxide dismutase (SOD), thereby participating in various pathological processes and ultimately mediating renal injury. Flavonoid compounds, owing to their sustained pharmacological effects, broad spectrum of action, and high safety profile, have become ideal candidates for targeted therapy research in DKD. Existing studies have shown that these compounds can exert inhibitory effects on renal fibrosis, alleviate inflammatory responses, protect podocytes, and reduce oxidative stress by regulating the interactions between the TGF-β/Smad signaling pathway and the aforementioned protein molecules, thereby maintaining renal structure and function, reducing proteinuria, and significantly improving DKD lesions. This review briefly outlines the composition and functions of the TGF-β/Smad signaling pathway, elucidates the mechanisms by which this pathway regulates DKD, and focuses on summarizing major studies from the past decade on flavonoid-based interventions in DKD through targeted inhibition of the TGF-β/Smad signaling pathway. Furthermore, it discusses the considerable therapeutic potential of flavonoids in the treatment of this disease, aiming to provide a scientific basis for future clinical prevention and treatment of DKD and to promote the development of targeted drugs.
2.Research progress in chemical constituents and pharmacological activities of Abelmoschi Corolla and prediction of its quality markers.
Shi-Han GUAN ; Chang LIU ; Xiao-Tong YAN ; Jin-Wei HAN ; Feng-Ting YIN ; Hui SUN ; Guang-Li YAN ; Ling KONG ; Ying HAN ; Xi-Jun WANG
China Journal of Chinese Materia Medica 2025;50(4):908-921
Abelmoschi Corolla, the dried corolla of Abelmoschus manihot, has anti-inflammatory, antioxidant, and anti-fibrosis activities. Its chemical constituents mainly include flavonoids, organic acids, steroids, and polysaccharides. This study reviewed the research progress in the chemical constituents and pharmacological activities of Abelmoschi Corolla in recent 20 years. According to the concept of quality marker(Q-marker), the Q-markers of Abelmoschi Corolla were predicted from plant phylogeny, chemical constituent specificity, traditional efficacy, chemical constituent measurability, and absorbed constituents. The primary Q-markers for Abelmoschi Corolla were anticipated to include quercetin-3'-O-β-D-glucopyranoside, gossypetin-8-O-β-D-glucuronide, isoquercetin, myricetin,quercetin, and hyperoside, with the aim of providing reference data for improving the quality evaluation system of Abelmoschi Corolla.
Abelmoschus/chemistry*
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Drugs, Chinese Herbal/pharmacology*
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Flowers/chemistry*
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Humans
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Animals
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Quality Control
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Flavonoids/chemistry*
3.Glucocorticoid Discontinuation in Patients with Rheumatoid Arthritis under Background of Chinese Medicine: Challenges and Potentials Coexist.
Chuan-Hui YAO ; Chi ZHANG ; Meng-Ge SONG ; Cong-Min XIA ; Tian CHANG ; Xie-Li MA ; Wei-Xiang LIU ; Zi-Xia LIU ; Jia-Meng LIU ; Xiao-Po TANG ; Ying LIU ; Jian LIU ; Jiang-Yun PENG ; Dong-Yi HE ; Qing-Chun HUANG ; Ming-Li GAO ; Jian-Ping YU ; Wei LIU ; Jian-Yong ZHANG ; Yue-Lan ZHU ; Xiu-Juan HOU ; Hai-Dong WANG ; Yong-Fei FANG ; Yue WANG ; Yin SU ; Xin-Ping TIAN ; Ai-Ping LYU ; Xun GONG ; Quan JIANG
Chinese journal of integrative medicine 2025;31(7):581-589
OBJECTIVE:
To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM).
METHODS:
This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis.
RESULTS:
Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings.
CONCLUSIONS
RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult
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Aged
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Female
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Humans
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Male
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Middle Aged
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Arthritis, Rheumatoid/drug therapy*
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Glucocorticoids/therapeutic use*
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Medicine, Chinese Traditional
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Retrospective Studies
4.Suanzaoren Decoction Alleviates Anxiety- and Depression-Like Behaviors Induced by Chronic Restraint Stress via Regulating Pyramidal Neuron Activity in Basolateral Amygdala of Mice.
Chang-Feng CHEN ; Yin-Huan GAO ; Qin FANG ; Yong-Feng ZHOU ; Yong LIU ; Jian WU ; Hao CHEN ; Lie-Cheng WANG ; Lei CHEN
Chinese journal of integrative medicine 2025;31(11):982-990
OBJECTIVE:
To elucidate the modulation mechanism of Suanzaoren Decoction (SZRD) on basolateral amygdala (BLA) neuronal activity to alleviate chronic restraint stress (CRS)-related behavioral deficits.
METHODS:
The male C57BL/6J mice were assigned to 4 groups using the complete randomization method, including control (CON, n=19), CRS (n=19), SZRD (n=21), and fluoxetine (Flu, n=22) groups. Mice were restrained for 6 h per day, over a 21-d period to establish CRS models. The CON group remained in their cages without food or water during the 6-h matching period. SZRD and Flu groups received intragastric administration of SZRD (4.68 g/kg) and Flu (20 mg/kg) daily, respectively, 30 min before restraint for 21 consecutive days. The therapeutic effects of SZRD were evaluated using behavioral tests including the tail suspension test, elevated plus maze test, and forced swimming test. The cellular Fletcher B. Judson murine osteosarcoma proto-oncogene (c-Fos) expression in the BLA was measured using immunofluorescence, while action potential (AP) firing and synaptic transmission in BLA pyramidal neurons were evaluated using whole-cell patch-clamp recordings.
RESULTS:
SZRD administration significantly increased time spent in the open arms and open-arm entries while reducing immobility time (P<0.05 or P<0.01). It downregulated CRS-induced c-Fos expression and AP firing of pyramidal neurons in the BLA (P<0.01). Additionally, SZRD selectively attenuated excitatory (P<0.01), but not inhibitory, synaptic transmission onto BLA pyramidal neurons.
CONCLUSION
SZRD alleviated CRS-induced anxiety- and depression-like behaviors in mice by modulating the excitability and synaptic transmission of BLA pyramidal neurons.
Animals
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Drugs, Chinese Herbal/therapeutic use*
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Depression/complications*
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Pyramidal Cells/pathology*
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Male
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Mice, Inbred C57BL
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Basolateral Nuclear Complex/pathology*
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Restraint, Physical
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Anxiety/complications*
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Behavior, Animal/drug effects*
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Stress, Psychological/physiopathology*
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Mice
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Proto-Oncogene Proteins c-fos/metabolism*
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Action Potentials/drug effects*
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Synaptic Transmission/drug effects*
5.Evidence-based clinical practice guideline for bone cement-augmented pedicle screw technique (version 2025)
Sihao HE ; Junchao XING ; Tongwei CHU ; Zhengqi CHANG ; Xigao CHENG ; Fei DAI ; Xiaobing JIANG ; Jie HAO ; Jiang HU ; Jinghui HUANG ; Tianyong HOU ; Fei LUO ; Bo LIAO ; Changqing LI ; Lei LIU ; Guodong LIU ; Peng LIU ; Sheng LU ; Weishi LI ; Yang LIU ; Zhen LIU ; Wei MEI ; Peifu TANG ; Bing WANG ; Bing WANG ; Ce WANG ; Hongli WANG ; Liang WANG ; Shengru WANG ; Xiaobin WANG ; Yang WANG ; Yingfeng WANG ; Zheng WANG ; Jianzhong XU ; Guoyong YIN ; Haiyang YU ; Qiang YANG ; Zhaoming YE ; Bin ZHANG ; Chengmin ZHANG ; Jun ZOU ; Qiang ZHOU ; Min ZHAO ; Rui ZHOU ; Xiaojun ZHANG ; Yongfei ZHAO ; Zhongrong ZHANG ; Zehua ZHANG ; Yingze ZHANG
Chinese Journal of Trauma 2025;41(11):1035-1047
For middle-aged and elderly patients with conditions such as spinal fractures and degenerative spinal diseases, spinal internal fixation is a core surgical procedure for reconstructing spinal stability, heavily relying on the biomechanical stability provided by pedicle screw systems. Whereas, these patients are often complicated by osteoporosis that can significantly compromise the stability of the bone-pedicle screw interface, leading to a marked increase in pedicle screw loosening and surgical failure rates. The bone cement-augmented pedicle screw technique, which involves injecting bone cement into the vertebral body or screw trajectory to optimize the mechanical properties of the bone-pedicle screw composite, has been proven to significantly enhance fixation strength and effectively prevent screw-related failures, thereby reducing the incidence of internal fixation failure in high-risk populations undergoing spinal fusion. However, the widespread clinical application of this technique has faced challenges such as inaccurate clinical decision-making (indication and contraindication selection), non-standardized operative practices, and insufficient awareness of complication prevention, resulting in considerable variability in clinical outcomes and even severe complications. To address this, Prof. Luo Fei from First Affiliated Hospital of Army Medical University initiated the project and the Chinese Association Orthopaedic Surgeons organized relevant experts to develop the Evidence-based clinical practice guideline for bone cement-augmented pedicle screw technique ( version 2025), based on current evidence. The guidelines put forward 8 recommendations regarding the clinical value, scope of application, and operational standards of the technique, aiming to provide evidence-based medical support and technical standardization for clinical decision-making.
6.Effect of side-to-end anastomosis on postoperative bowel function in rectal cancer surgery: a prospective single-center randomized controlled trial
Chang WANG ; Fan LIU ; Sen HOU ; Zhanlong SHEN ; Mujun YIN ; Xiaodong YANG ; Kewei JIANG ; Qiwei XIE ; Bin LIANG ; Kai SHEN ; Zhidong GAO ; Yingjiang YE
Chinese Journal of Gastrointestinal Surgery 2025;28(6):644-652
Objective:To compare bowel function 12 months after surgery between side-to-end anastomosis (SEA) and end-to-end anastomosis (EEA) groups of patients who had undergone rectal cancer resection.Methods:This single-center, prospective, open-label, phase III randomized controlled trial was approved by the Ethics Committee of Peking University People's Hospital (2018PHB040-01) and registered at ClinicalTrials. org (NCT03669237). Inclusion criteria were as follows: (1) histologically confirmed rectal adenocarcinoma; (2) tumor located 0 to 12 cm from the anal verge; (3) age≥18 years; and (4) planned R0 resection with primary reconstruction. Exclusion criteria included: (1) emergency surgery; (2) cognitive impairment; (3) non-primary anastomosis; (4) history of left-sided colonic or anorectal surgery; and (5) preexisting chronic defecation dysfunction. Eligible rectal cancer patients scheduled for elective sphincter-preserving surgery at Peking University People's Hospital were prospectively enrolled between October 2018 and March 2021 and randomly assigned to either the EEA group or the SEA group via computer-generated numbers prior to entering the operating room. All patients underwent standard radical tumor resection. Bowel function was evaluated by the low anterior resection syndrome (LARS) questionnaire. It consists of five single-choice questions and yields a total score ranging from 0 to 42. Defecation function is categorized into three levels: no LARS (0-20 points), minor LARS (21-29 points), and major LARS (30-42 points). The primary endpoint was the LARS score 12 months after surgery. Secondary endpoints included LARS scores from 1 to 11 months and during long-term follow-up(>12 months). The final follow-up was completed in July 2022. All randomized patients were included in the intention-to-treat set (ITTS). The full analysis set (FAS) was defined as ITTS patients with valid outcome data. All primary statistical analyses were performed in the FAS, and results were further compared in the per-protocol set (PPS) based on the actual treatment received.Results:A total of 323 patients underwent eligibility assessment, of whom 71 did not meet the inclusion criteria and 52 declined to participate. Ultimately, 200 patients were randomized. Median age was 64 years and 85 were women. The SEA and EEA groups comprised 102 and 98 patients, respectively. A total of 181 patients (90.5%) were included in the FAS, and 170 (85.0%) were included in the PPS. Among these, the 12-month LARS score was evaluated in 178 patients (98.3%) in the FAS and in 167 (98.2%) in the PPS. Median LARS score at 1–12 months were significantly lower in the SEA group in both the FAS dataset [12 months:8 (interquartile range [IQR], 0–22) vs. 14 (IQR, 8–29); Z=2.687, P=0.007] and the PPS dataset [12 months: 8 (IQR, 0–22) vs. 14 (IQR, 6–29); Z=2.543, P=0.011]. During long-term follow-up, the median LARS score was also significantly lower in the SEA group in the FAS dataset [2 (IQR, 0–4) vs. 11 (IQR, 2–23); Z=2.968, P=0.003] and the PPS dataset [2 (IQR, 0–14) vs. 11 (2, 27); Z=2.687, P=0.007]. Conclusion:Compared with the EEA group, bowel function was superior in the SEA group 1 year after surgery and during long-term follow-up.
7.Expressions and significance of NLRP3, Caspase-1 and IL-1β in patients with hemorrhagic stroke
Genwei WANG ; Keliang CHANG ; Xiaoteng GENG ; Dongtao ZHANG ; Menglei YIN ; Tengxiao KONG
Chinese Journal of Behavioral Medicine and Brain Science 2025;34(2):124-130
Objective:To explore the expressions and significance of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (Caspase-1) and interleukin-1β (IL-1β) in patients with hemorrhagic stroke.Methods:One hundred and three patients with hemorrhagic stroke who visited the Department of Neurosurgery of the Second Affiliated Hospital of Zhengzhou University from January 2022 to January 2024 were selected as the hemorrhage group.Another 90 healthy individuals who underwent physical examinations were selected as the control group.The differences in the levels of NLRP3, Caspase-1 and IL-1β in peripheral blood between the two groups were compared. The National Institutes of Health neurological deficiency score (NHISS) was used to evaluate the degree of neurological deficits of patients in the hemorrhage group. All patients were followed up for 3 months. The prognosis of patients was evaluated by modified Rankin scale (mRS). The statistical analysis was performed using SPSS 20.0 software. The relationship between peripheral blood indexes and blood loss, severity of neurological impairment was analyzed by Spearman correlation analysis. The predictive value of peripheral blood indexes for prognosis was evaluated by receiver operating characteristic (ROC) curves.Results:The expression levels of NLRP3 mRNA (2.67±0.42, 1.04±0.28), Caspase-1 mRNA (1.24±0.26, 0.75±0.14) and IL-1β protein ((24.92±4.97) pg/mL, (13.39±2.35) pg/mL) in the hemorrhage group were higher than those in the control group ( t=31.243, 15.967, 20.126, all P<0.05). When comparing the levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β in the peripheral blood of patients with different amounts of bleeding, those with massive bleeding were higher than those with moderate bleeding, and those with moderate bleeding were higher than those with mild bleeding (all P<0.05).The Spearman correlation analysis showed that the levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β in peripheral blood were positively correlated with the amount of bleeding in patients with hemorrhagic stroke ( r=0.646, 0.585, 0.604, all P<0.05). The levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β in patients with severe neurological deficits were higher than those in patients with moderate and mild neurological deficits, and those in patients with moderate neurological deficits were higher than those in patients with mild neurological deficits (all P<0.05). The results of Spearman correlation analysis showed that the levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β in peripheral blood were positively correlated with the degree of neurological deficits in patients with hemorrhagic stroke ( r=0.607, 0.522, 0.546, all P<0.05). The expression levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β in peripheral blood in the poor prognosis group were higher than those in the good prognosis group (all P<0.05). The prediction results indicated that bleeding into the cerebral ventricles, large amount of bleeding, and high expression of NLRP3, Caspase-1 and IL-1β in peripheral blood were independent risk factors for poor prognosis in patients with hemorrhagic stroke (all P<0.05). The area under the ROC curve for the combined assessment of poor prognosis in hemorrhagic stroke by the levels of NLRP3 mRNA, Caspase-1 mRNA and IL-1β was 0.856, which was larger than the areas under the curves of the three indicators detected separately (0.720, 0.703, 0.715, P<0.05). Conclusion:The expressions of peripheral blood NLRP3, Caspase-1 and IL-1β are up-regulated in patients with hemorrhagic stroke, and their high expressions are related to blood loss and the severity of neurological deficit, which also indicate poor prognosis of patients.
8.Expert Consensus on the Ethical Requirements for Generative AI-Assisted Academic Writing
You-Quan BU ; Yong-Fu CAO ; Zeng-Yi CHANG ; Hong-Yu CHEN ; Xiao-Wei CHEN ; Yuan-Yuan CHEN ; Zhu-Cheng CHEN ; Rui DENG ; Jie DING ; Zhong-Kai FAN ; Guo-Quan GAO ; Xu GAO ; Lan HU ; Xiao-Qing HU ; Hong-Ti JIA ; Ying KONG ; En-Min LI ; Ling LI ; Yu-Hua LI ; Jun-Rong LIU ; Zhi-Qiang LIU ; Ya-Ping LUO ; Xue-Mei LV ; Yan-Xi PEI ; Xiao-Zhong PENG ; Qi-Qun TANG ; You WAN ; Yong WANG ; Ming-Xu WANG ; Xian WANG ; Guang-Kuan XIE ; Jun XIE ; Xiao-Hua YAN ; Mei YIN ; Zhong-Shan YU ; Chun-Yan ZHOU ; Rui-Fang ZHU
Chinese Journal of Biochemistry and Molecular Biology 2025;41(6):826-832
With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.
9.Congenital tracheal agenesis in a preterm infant
Fengxia ZHAO ; Juan WANG ; Chang WANG ; Chuangao YIN ; Zeyu YANG ; Jian ZHANG ; Shaohua BI ; Yu LIU
Chinese Journal of Perinatal Medicine 2025;28(11):974-977
This report described the multidisciplinary management of a preterm infant with congenital tracheal agenesis (TA). The infant, delivered via cesarean section at 32 +5 weeks' gestation, had Apgar scores of 6 and 8 at 1 and 5 minutes, respectively. Although skin color improved after 30 seconds of bag-mask ventilation, the infant exhibited no cry, weak spontaneous breathing, and failed multiple intubation attempts. The patient was transferred to Anhui Children's Hospital of Fudan University under continuous bag-mask positive-pressure ventilation at 3 hours after birth (September 10, 2024). Combined imaging and fiberoptic bronchoscopy confirmed TA (Floyd type Ⅱ/Faro type C) with multiple anomalies, including duodenal atresia, aortic coarctation, and butterfly vertebrae. Whole-genome sequencing revealed a suspected mosaic SCN2A c.5317G>A variant (wild-type parents) and an ERCC5 c.2974C>T heterozygous variant inherited from the mother (homozygous). Following esophageal intubation, invasive mechanical ventilation, and continuous gastrointestinal decompression, respiratory distress significantly improved with a stabilized condition. The infant died 30 hours after birth following treatment withdrawal.
10.Health economic analysis and medical cost analysis of children with severe hepatitis B in China: A retrospective study from 2016 to 2022
Qijun SHAN ; Xudong MA ; Yujie CHEN ; Guanghua ZHOU ; Sifa GAO ; Jialu SUN ; Fuping GUO ; Feng ZHANG ; Dandan MA ; Guoqiang SUN ; Wen ZHU ; Xiaoyang MENG ; Guiren RUAN ; Yuelun ZHANG ; Xutong TAN ; Dawei LIU ; Yi WANG ; Chang YIN ; Xiang ZHOU
Chinese Medical Journal 2025;138(5):562-567
Background::Hepatitis B poses a heavy burden for children in China, however, the national studies on the distributional characteristics and health care costs of children with severe hepatitis B is still lacking. This study aimed to analyze the disease characteristics, health economic effects, and medical cost for children with severe hepatitis B in China.Methods::Based on patient information in the Hospital Quality Monitoring System, cases with severe hepatitis B were divided into four groups according to age, and the etiology and symptoms of each group were quantified. The cost of hospitalization was calculated for cases with different disease processes, and severity of disease. The spatial aggregation of cases and the relationship with health economic factors were analyzed by Moran’s I analysis. Results::The total number of children discharged with hepatitis B from January 2016 to April 2022 was 1603, with an average age of 10.5 years. Liver failure cases accounted for 43.48% (697/1603) of total cases and cirrhosis cases accounted for 11.23% (180/1603). According to the grouping of disease progression, there were 1292 cases without associated complications, and the median hospitalization cost was $818.12. According to the spatial analysis, the aggregation of cases was statistically significant at the prefectural and provincial levels in 2019, 2020, and 2021 (all P <0.05). The number of severe cases was negatively correlated with gross domestic product (Moran’s I <0) and percentage of urban population (Moran’s I <0), and positively correlated with the number of pediatric beds per million population (Moran’s I >0). Conclusion::The number of severe hepatitis B cases is low in areas with high gross domestic product levels and high urban population ratios, and health care costs have been declining over the years.

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