Cirrhotic portal hypertension is a clinical syndrome caused by persistently elevated portal venous pressure due to liver cirrhosis and can lead to a series of complications， among which esophagogastric variceal bleeding has become one of the most severe complications due to sudden onset and a high mortality rate. Since the release of Expert consensus on diagnosis and treatment of esophagogastric variceal bleeding in cirrhotic portal hypertension （2019 edition）， significant advances have been achieved in this field in China and globally. In order to formulate an expert consensus aligned with the situation of China， Chinese Society of Surgery， Chinese Medical Association organized and compiled Expert Consensus on diagnosis and treatment of esophagogastric variceal bleeding in cirrhotic portal hypertension （2025 edition）. This article elaborates on the key updates in the new edition and explores the major differences between the old and new editions， in order to enhance the understanding of the new edition among clinicians and provide a reference for clinicians in clinical work.

Antibody drug conjugates (ADC) have emerged as a cutting-edge technology in anti-tumor treatment, making significant strides in recent years. ADC couple a highly active small molecule toxin payload to highly specific antibodies through a linker, enabling precise targeting of tumor cells while reducing systemic toxicity, thereby expanding the therapeutic window. However, due to the complexity of ADC molecule design, its efficacy and safety are influenced by various factors. Model-informed drug development (MIDD) is a powerful tool that utilizes various mathematical models for modeling and simulation to conduct quantitative analysis, guiding drug development and decision-making. By integrating multi-faceted data and information using mathematical models, it is possible to gain insights into the complex mechanisms, pharmacokinetics, and pharmacodynamics of ADC, providing unique perspectives for optimizing ADC development processes and clinical translation decisions. This review will introduce the basic concepts of MIDD and ADC and discuss application cases of MIDD in different stages of ADC development, aiming to provide beneficial references for the advancement of ADC.

Objective : To verify the role of vascular endothelial growth factor B(VEGFB) in maintenance of skeletal muscle mass under chow-fed and high-fat diet, and to investigate the role of crosstalk between VEGFB and fibroblast growth factor(FGF) signaling pathways in the process. Methods : Four experimental groups were designed: VEGFB+/+chow-fed diet group, VEGFB-/-chow-fed diet group, VEGFB+/+high-fat diet group, VEGFB-/-high-fat diet group. Skeletal muscles from 24 weeks mice were isolated and weighed. Gene expression association analysis and qPCR experiments were conducted to assess FGFs expression levels. Results : Under both dietary conditions, VEGFB ablation resulted in reduced muscle mass. Under chow-fed diet condition, 8 FGFs level reduced including 6 paracrine FGFs in the skeletal muscle from VEGFB-/-mice. Under high-fat diet condition, 11 FGFs level decreased including 8 paracrine FGFs in VEGFB-/-mice. Conclusion VEGFB may participate in regulating skeletal muscle mass through FGF networks in the skeletal muscles.

OBJECTIVE: To investigate the clinical and genetic characteristics of a Chinese pedigree affected with Neurodevelopmental disorder with absent language and variable seizures (NEDALVS) due to variant of WASF1 gene, and to review the literature on NEDALVS associated with WASF1 gene variants. METHODS: A 4-year-and-8-month-old boy with NEDALVS diagnosed at Linyi People's Hospital in July 2024 due to "discovering language development delay for more than 2 years" and his family members were selected as the study subjects. Clinical data of the family members were collected. Peripheral venous blood samples were collected from family members. Whole-exome sequencing (WES) was performed, and candidate variants were verified, by Sanger sequencing. Pathogenicity of candidate variant was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG). Using the MUpro website, SWISS-MODEL, PyMOL, Clustal X, PolyPhen-2, and Mutation Taster software, bioinformatics analysis of protein three-dimensional structure modeling for gene mutations, cross-species conservation of mutant amino acids, and pathogenicity prediction of mutation sites. Relevant literature was retrieved from databases such as CNKI, Wanfang Data Knowledge Service Platform, and PubMed, and the clinical phenotypes and genotypes of patients with WASF1 gene mutations reported in the literature were summarized and analyzed. This study was approved by the Medical Ethics Committee of Linyi People's Hospital (Ethics No.: YX200303). RESULTS: The proband, a 4-year and 8-month-old male, mainly presented with delayed language and motor development, accompanied by autistic behaviors; the proband's younger brother was 2 years and 7 months old at the time of consultation, mainly presented with delayed language and motor development, accompanied by short stature; the proband's mother mainly presents with limited language expression and poor interpersonal interaction; the proband's maternal grandmother mainly presents with soliloquizing?behavior. The results of WES showed that the proband carried a heterozygous mutation c.214C>T (p.Arg72Cys) in the WASF1 gene, and this site has not been recorded in the database. Sanger sequencing confirmed that the proband's younger brother, mother, and maternal grandmother had harbored the same variant. Based on the guidelines from the ACMG, this variant was rated as likely pathogenic (PM2_Supporting+PP1+PP3+PP4). Through SWISS-MODEL homology modeling and PyMOL structure visualization analysis, it was further confirmed that this variant can lead to a decrease in protein stability. Amino acid sequence conservation analysis of the WASF1 protein using Clustal X software suggested that the c.214C>T (p.Arg72Cys) variant has caused replacement of a highly conserved amino acid. According to the results of PolyPhen-2 and Mutation Taster, the p.Arg72Cys variant was predicted to be a hazardous. By following the retrieval strategy set in this study, a total of 5 research articles regarding to patients with NEDALVS caused by WASF1 gene mutations were retrieved, which involved 15 patients. Combining the proband and their family members discovered in this study, there were a total of 19 NEDALVS patients. The main clinical features included: motor developmental delay (100%, 17/17), language/intellectual developmental delay (100%, 17/17), epilepsy (64.7%, 11/17), autistic behavior (76.5%, 13/17), hypotonia (70.6%, 12/17), abnormal electroencephalogram (64.7%, 11/17), and short stature (17.6%, 3/17). All 19 patients had heterozygous mutations, with 8 mutation sites. Missense mutations were the most common, accounting for 84.2% (16/19). CONCLUSION A pathogenic variant of the WASF1 gene was identified in a pedigree affected with NEDALVS. Discovery of the novel variant has, expanded the mutational spectrum of the WASF1 gene.
Child, Preschool ; Female ; Humans ; Infant ; Male ; China ; Exome Sequencing ; Mutation ; Neurodevelopmental Disorders/genetics* ; Pedigree ; Seizures/genetics* ; East Asian People/genetics*

OBJECTIVE: Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. Huachansu (Cinobufacini) is active extract isolated from the dry skin of Bufo Bufo gargarizans. It has now been widely used in clinical treatment of cancer, this study is to clarify the material basis of down-regulation of thymidylate synthase (TYMS) induced by Huachansu. METHODS: Our study utilized UPLC-MS/MS to identify major bioactive components from Huachansu. Cell Counting Kit 8 (CCK-8) assay and clone formation assay were used to examine the cell viability of tumor cells. TYMS and γ-H2AX level were detected by using quantitative real-time RT-PCR and/or western blotting. Small interfering RNA (siRNA) transfection was used to explore whether inhibition of TYMS could enhance the suppressive effect of Huachansu on cell growth of HCC cells. RESULTS: In our study, firstly, we identify 21 major bioactive components from Huachansu. CCK-8 assay results showed that Huachansu and its bioactive bufadienolides (Bufalin, Bufotalin, Cinobufotalin, Desacetylcinobufagin, Arenobufagin, Telocinobufagin, and Resibufogenin) significantly inhibited the proliferation of HepG2 and SK-HEP-1 cells in a dose- and time-dependent manner. Further molecular mechanistic investigation demonstrates that Huachansu significantly suppresses thymidylate synthase (TYMS), the enzyme which provides the sole de novo source of thymidylate for DNA synthesis. The inhibition of TYMS could lead to cell-cycle block and DNA damage of HCC cells. Furthermore, we identified that Huachansu markedly increased γ-H2AX expression, which indicated the presence of DNA damage. Moreover, we confirmed that transfection of cells with small interfering RNA specific to TYMS could increase the suppressive effects of Huachansu on the HCC cells proliferation. Quantitative RT-PCR analysis showed that Huachansu treatment had no effect on the transcription level of TYMS. Furthermore, proteasomal inhibitor MG132 could block TYMS inhibition induced by Huachansu, and concomitant administration of protein synthesis inhibitor cycloheximide (CHX) with Huachansu could further suppress the protein level of TYMS, indicating that Huachansu promotes proteasome-dependent degradation of TYMS in liver cancer cells. More importantly, the bioactive bufadienolides of Huachansu such as Bufalin, Bufotalin, Cinobufotalin, Desacetylcinobufagin, Arenobufagin, Telocinobufagin, and Resibufogenin could also significantly restrain the protein level of TYMS, revealing the material basis of inhibition of TYMS exposed to Huachansu. 5-Fluorouracil (5-FU) is a TYMS inhibitor, we also evaluate the effects of the combined treatment of Huachansu with 5-FU, the results show that interactions between Huachansu and 5-FU are synergistic or antagonistic. Thus, in clinical, attention should be paid to the dosage of Huachansu in combination with 5-FU. CONCLUSION Huachansu inhibits the growth and induces DNA damage of human HCC cells through proteasome-dependent degradation of TYMS, bioactive bufadienolides are the material basis of down-regulation of TYMS induced by Huachansu.

OBJECTIVE: To compare the difference in forefoot width between minimally invasive extra-articular osteotomy via small incision and traditional Chevron osteotomy in the treatment of hallux valgus. METHODS: A retrospective analysis was conducted on the clinical data of 45 patients with hallux valgus between April 2019 and July 2022. Among them, 22 cases underwent minimally invasive extra-articular osteotomy via small incision (minimally invasive group), and 23 cases underwent traditional Chevron osteotomy (traditional group). There was no significant difference in the baseline data between the two groups ( P>0.05), including gender, age, affected side, Mann classification of hallux valgus, disease duration, and preoperative intermetatarsal angle (IMA), hallux valgus angle (HVA), distal metatarsal articular angle (DMAA), bony forefoot width, soft tissue forefoot width, osteophyte width, and American Orthopaedic Foot and Ankle Society (AOFAS) score. The osteotomy healing time and the occurrence of complications in the two groups were recorded. The differences between pre- and post-operation (changes) in various imaging indicators and AOFAS scores in the two groups were calculated. And the bony forefoot width and soft tissue forefoot width at 1, 6, and 12 months after operation were also recorded and compared between the two groups. RESULTS: One case of skin injury occurred during operation in the minimally invasive group, while 3 cases of poor wound healing occurred after operation in the traditional group. None of the patients experienced infections, nerve injuries, or other complications. All patients were followed up 12-31 months (mean, 22.5 months). The osteotomy healed in the two groups and no significant difference in healing time between the two groups was found ( P>0.05). The IMA, HVA, DMAA, osteophyte width, and AOFAS score at 12 months after operation significantly improved compared to those before operation ( P<0.05). There was no significant difference between the two groups in the changes of IMA, HVA, and osteophyte width ( P>0.05). However, the differences in the changes of AOFAS score and DMAA were significant ( P<0.05). There was no significant difference between the two groups in bony and soft tissue forefoot widths at different time points after operation ( P>0.05). However, there were significant differences in the two groups between the pre- and post-operation ( P<0.05). CONCLUSION The minimally invasive extra-articular osteotomy via small incision for hallux valgus, despite not removing the medial osteophyte of the first metatarsal, can still effectively improve the forefoot width and osteophyte width. While correcting the IMA and HVA, it can more effectively restore the DMAA, resulting in better AOFAS scores.
Humans ; Hallux Valgus/surgery* ; Osteotomy/methods* ; Male ; Female ; Minimally Invasive Surgical Procedures/methods* ; Retrospective Studies ; Middle Aged ; Forefoot, Human/pathology* ; Adult ; Treatment Outcome ; Aged

OBJECTIVE: To investigate the effectiveness of spring ligament repair combined with subtalar arthroereisis (STA) and the Kidner procedure for treating children's flexible flatfoot with painful accessory navicular. METHODS: A retrospective analysis was conducted on clinical data from 45 children (45 feet) aged 7-14 years with flexible flatfoot and painful accessory navicular who met the selection criteria and were treated between February 2018 and May 2022. Among them, 23 cases (23 feet) were treated with spring ligament repair combined with STA and Kidner procedure (observation group), while 22 cases (22 feet) received STA with Kidner procedure alone (control group). Comparison of baseline data between the two groups including gender, age, affected side, preoperative visual analogue scale (VAS) score, American Orthopaedic Foot & Ankle Society (AOFAS) score, talonavicular coverage angle (TCA), talus-first metatarsal angle (T1MT), talus-second metatarsal angle (T2MT), talus first plantar angle (Meary angle), calcaneal inclination angle (Pitch angle) showed no significant differences ( P>0.05). The following parameters were recorded and compared between the two groups: operation time, intraoperative blood loss, incision length, hospital stay, time to full weight-bearing, and complication rates. Foot pain and functional recovery were assessed using the VAS score and AOFAS score preoperatively and at last follow-up. Radiographic measurements including TCA, T1MT, T2MT, Meary angle, and Pitch angle were analyzed by comparing preoperative to last follow-up values. RESULTS: Both groups of patients successfully completed the surgery without any procedure-related complications such as vascular, neural, or tendon injury. The operation time in the observation group was significantly longer than that in the control group ( P<0.05). There was no significant difference between the two groups in terms of intraoperative blood loss, incision length, hospital stay, or time to full weight-bearing ( P>0.05). All patients were followed up 23-47 months (mean, 33.7 months). In the control group, 1 patient experienced discomfort during walking, attributed to screw irritation in the sinus tarsi, which resolved after 2-3 months of rehabilitation. None of the remaining patients developed complications such as sinus tarsi screw loosening, peroneal tendon contracture, or wound infection. At last follow-up, the observation group showed significantly better improvements in radiographic parameters (TCA, T1MT, T2MT, Meary angle, Pitch angle) and greater reductions in VAS and AOFAS scores compared to the control group ( P<0.05). CONCLUSION The combined procedure of spring ligament repair, STA, and Kidner procedure for children's flexible flatfoot with painful accessory navicular demonstrates significant improvements in foot appearance, arch collapse correction, and pain relief. This technique offers technical simplicity, minimal intraoperative complications, and satisfactory clinical outcomes.
Humans ; Flatfoot/surgery* ; Child ; Retrospective Studies ; Adolescent ; Male ; Female ; Treatment Outcome ; Tarsal Bones/abnormalities* ; Subtalar Joint/surgery* ; Ligaments, Articular/surgery* ; Orthopedic Procedures/methods* ; Foot Diseases

The current classification methods for traditional Chinese medicine （TCM） visceral syndrome differentiation suffer from excessive generalization， which hinders their clinical application. Based on the analysis of the pattern of "one syndrome corresponding to multiple formulas"， this paper focused on the principle of syndrome-formula correspondence， and proposed that formula-syndromes are the smallest units for refining visceral syndromes. By establishing the correspondence between formula-syndromes and visceral syndromes， this study aims to further clarify the refined categories of syndromes and their treatment patterns， providing a new perspective for the standardization and objectification of TCM syndromes.

Background Atmospheric fine particulate matter (PM_2.5) can disrupt the metabolic homeostasis of the liver and accelerate the progression of liver diseases, but there are few studies on the effects of sub-chronic PM_2.5 exposure on the liver metabolome. Objectives To investigate the effects of sub-chronic exposure to concentrated PM_2.5 on hepatic metabolomics in mice by liquid chromatography-mass spectrometry (LC-MS), and to identify potentially affected metabolites and metabolic pathways. Methods Twelve male C57BL/6J (6 weeks old) mice were randomly divided into two groups: a concentrated PM_2.5 exposure group and a clean air exposure group. The mice were exposed to concentrated PM_2.5 using the "Shanghai Meteorological and Environmental Animal Exposure System" at Fudan University. The exposure duration was 8 h per day, 6 d per week, for a total of 8 weeks. The mice's liver tissues were collected 24 h after the completion of exposure. LC-MS was performed to assess changes in the hepatic metabolome. Orthogonal partial least squares discriminant analysis and t-test were employed to identify differentially regulated metabolites between the two groups under the conditions of variable important in projection (VIP)≥1.0 and P<0.05. Metabolic pathway enrichment analysis was performed using MetaboAnalyst 5.0 software and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results A total of 297 differentially regulated metabolites were identified between the concentrated PM_2.5 exposure group and the clean air group. Among these metabolites, 142 were upregulated and 155 were downregulated. A total of 38 metabolic pathways were altered, with 7 pathways showing significant perturbation (P<0.05). These pathways involved amino acid metabolism, glucose metabolism, nucleotide metabolism, as well as cofactor and vitamin metabolism. The 7 significant metabolic pathways were pantothenic acid and coenzyme A biosynthesis; purine metabolism; amino sugar and nucleotide sugar metabolism; arginine biosynthesis; alanine, aspartate and glutamate metabolism; aminoacyl-tRNA biosynthesis; and fructose and mannose metabolism. Conclusion The results from metabolomics analysis suggest that sub-chronic exposure to PM_2.5 may disrupt hepatic energy metabolism and induce oxidative stress damage. Aspartic acid, succinic acid, ornithine, fumaric acid, as well as purine and xanthine derivatives, were identified as potential early biomarkers of hepatic response to sub-chronic PM_2.5 exposure.

ObjectiveTo investigate the effect of community-based rehabilitation exercise and physical activity on the physical activity levels, functional states, and quality of life for people with mild and moderate disabilities in community settings, to ascertain the health benefits of their engagement in such fitness sports activities, anchoring in the WHO "Global Action Plan on Physical Activity 2018-2030: More Active People for a Healthier World" and the guidelines tailored for people with disabilities, using the theoretical framework and methodology of the International Classification of Functioning, Disability and Health (ICF). MethodsAligning with the WHO guidelines for people with disabilities and the ICF, a community-based rehabilitation exercise and physical activity program was designed for individuals with mild to moderate disabilities, featuring activities like fitness training (aerobic and resistance exercises), skill exercises (such as balance and coordination), as well as sports and recreational games (ball and games, etc.). A total of 230 people with mild and moderate disabilities were recruited from 20 communities in Shenzhen, with types of disabilities including physical, speech, intellectual, and mental. Professional rehabilitation fitness instructors implemented and supervised the program. The activities were of low to moderate intensity, 30 to 50 minutes per session, five times a month for six months. The community-based rehabilitation exercise and physical activity progress of these individuals was surveyed using the International Physical Activity Questionnaire (IPAQ), and their overall functioning was evaluated with WHODAS 2.0. The health-related quality of life was measured with WHOQOL-BREF. The health benefits from participation in community-based rehabilitation exercise and physical activity were assessed in terms of functioning, activity involvement, and quality of life. ResultsAfter the fitness activities, participation levels significantly increased in IPAQ domains of work-related, transport-related, domestic and gardening activity, and leisure time (|t| > 3.391, P < 0.001). The scores significantly decreased in the domains of cognition, activity, self-care, getting along, life activities and participation; and overall scores also decreased in WHODAS 2.0 (t > 6.639, P < 0.001). The scores significantly increased in the four dimensions of WHOQOL-BREF (|t| > 7.486, P < 0.001). ConclusionAfter participating in a six-month community-based rehabilitation exercise and physical activity program of mild to moderate intensity, individuals with mild to moderate disabilities have improved in physical activity and engagement levels, and the overall functioning and quality of life.