OBJECTIVE To form an expert consensus on the clinical application of parenteral direct thrombin inhibitors （DTIs） in patients during the perioperative period. METHODS Led by Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital （the Affiliated Hospital of UESTC）， a multidisciplinary working group was established. Through literature review and the Delphi method， clinical questions related to the rational perioperative use of parenteral DTIs were identified. A structured design was adopted using the “Population-Intervention-Comparison-Outcome” framework； systematic searches were conducted in CNKI， Medline， Embase and other databases. Relevant evidence from randomized controlled trials and cohort studies was included and synthesized. Evidence quality was assessed using the Grades of Recommendations Assessment，Development and Evaluation （GRADE） approach， and recommendations were formulated through multiple rounds of Delphi surveys and expert consensus meetings. RESULTS &CONCLUSIONS Seven recommendations （each with an expert consensus rate exceeding 90%） on the use of parenteral DTIs in perioperative patients were developed. These recommendations specify drug selection， dosing ranges， key monitoring points， and safety management strategies for parenteral DTIs in various scenarios， including the perioperative period of ventricular assist device implantation， the perioperative period of cardiac surgery， perioperative patients with lower-extremity atherosclerotic disease， the perioperative period of percutaneous coronary intervention in patients with acute coronary syndrome， the perioperative period of carotid artery stenting in patients with carotid stenosis， the perioperative period of patients with right heart thrombosis， and patients who develop related thrombosis and dysfunction after a central venous catheter insertion. In addition， warning and management pathways for perioperative bleeding and thrombotic events were proposed. This expert consensus， which is formulated based on the best available evidence， provides evidence-based guidance for standardized and individualized use of parenteral DTIs in perioperative period.

OBJECTIVE: To assess the association of microribonucleic acid (miRNA) gene polymorphisms with the risk and clinicopathological characteristics of Crohn's disease (CD) and the influence of miRNA gene variants on the response to ustekinumab (UST) treatment among CD patients. METHODS: From January 2018 to February 2025, 312 patients diagnosed with CD and 527 gender- and age-matched normal controls were selected as the study subjects at the Department of Gastroenterology of the Second Affiliated Hospital of Wenzhou Medical University. Genotypes of miR-155 (rs767649), miR-21 (rs13137), miR-124 (rs531564) and miR-146a (rs57095329, rs2431697) were determined with multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. The patients were divided into different subgroups according to the Montreal Classification Criteria for CD. Harvey-Bradshaw index (HBI) and simplified endoscopic score for CD were respectively applied to assess the clinical and endoscopic disease activity of CD. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between the two groups, as well as their influence on the clinicopathological characteristics of CD patients. Among them, 185 CD patients received first-line UST treatment, with the first sufficient dose of UST (6 mg/kg) administered intravenously. Based on the changes in HBI at week 8, the response of patients to UST treatment was evaluated. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between clinically responsive group (the decline of HBI ≥ 3 scores compared to week 0) and non-responsive group. All of the P values were adjusted by Bonferroni correction. This study has been approved by the Medical Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (Ethics No.: 2025-K-12-01). RESULTS: No significant difference was found in the distribution of miRNA gene polymorphisms between the two groups (all P > 0.05). The variant genotype (TC+CC) of rs2431697 was more common among patients with terminal ileal-type and ileocolic-type CD than those with the colonic-type CD (OR = 4.98, 95%CI: 1.49~16.68, P = 0.009, adjusted P = 0.045). However, the opposite conclusion was drawn for the homozygous variant genotype (TT) of rs13137 and variant genotype (GC+CC) of rs531564 (OR = 0.37, 95%CI: 0.18~0.76, P = 0.007, adjusted P = 0.035; OR = 0.36, 95%CI: 0.18~0.73, P = 0.004, adjusted P = 0.020). Compared to patients with non-stricturing and penetrating CD, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common in those with stricturing and penetrating CD (OR = 4.06, 95%CI: 2.46~6.71, P < 0.001, adjusted P < 0.005; OR = 3.12, 95%CI: 2.06~4.73, P < 0.001, adjusted P < 0.005). However, the frequencies of variant genotype (AT+TT) and variant allele (T) of rs13137 were lower among patients with stricturing and penetrating CD than in those without (OR = 0.25, 95%CI: 0.15~0.41, P < 0.001, adjusted P < 0.005; OR = 0.45, 95%CI: 0.33~0.63, P < 0.001, adjusted P < 0.005). Additionally, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common among those with moderately to severely endoscopic activity than those with mildly endoscopic activity (OR = 2.01, 95%CI: 1.19~3.42, P = 0.009, adjusted P = 0.045; OR = 2.04, 95%CI: 1.28~3.25, P = 0.003, adjusted P = 0.015). In total 117 cases had shown clinical response by week 8, while 68 cases showed no response. Compared with t he clinically non-responsive group, the variant genotype (TC+CC) and variant allele (C) of rs2431697 were more common in the clinically responsive group (OR = 3.86, 95%CI: 1.80~8.32, P = 0.001, adjusted P = 0.005; OR = 2.60, 95%CI: 1.34~5.06, P = 0.005, adjusted P = 0.025). However, the variant genotype (TA+AA) of rs767649 was less frequent in the clinically responsive group than the non-responsive group (OR = 0.40, 95%CI: 0.21~0.74, P = 0.004, adjusted P = 0.020). The same conclusion was drawn for the variant genotype (AT+TT) and variant allele (T) of rs13137 when the clinically responsive group was compared with the non-responsive group (OR = 0.30, 95%CI: 0.14~0.63, P = 0.002, adjusted P = 0.010; OR = 0.54, 95%CI: 0.35~0.82, P = 0.005, adjusted P = 0.025). CONCLUSION Genetic polymorphisms of miRNAs are not associated with the risk of developing CD. The miR-146a (rs57095329) variant may increase the endoscopic activity of CD and the risk for stenosis or penetration. However, the miR-146a (rs2431697) variant may increase the risk of ileal involvement. The miR-21 (rs13137) variant may reduce the risk of ileal involvement and the risk of stenosis or penetration. The miR-124 (rs531564) variant may reduce the risk of ileal involvement. Among patients receiving UST treatment, the miR-146a (rs2431697) variant may increase the clinical response by week 8. However, both the miR-155 (rs767649) and miR-21 (rs13137) variants may decrease the clinical response by week 8.
Humans ; MicroRNAs/genetics* ; Crohn Disease/pathology* ; Male ; Female ; Adult ; Polymorphism, Single Nucleotide ; Middle Aged ; Asian People/genetics* ; Genetic Predisposition to Disease ; Genotype ; Young Adult ; Case-Control Studies ; Adolescent ; East Asian People

Objective To summarize the clinical characteristics and analyze prognostic factors of neuroblastoma (NB) in infants (≤12 months) at a single center. Methods A retrospective analysis was conducted on the clinical data of infant patients (≤12 months) diagnosed with NB and treated between January 2014 and December 2022. Clinical features were analyzed, and comparisons between two sample rates were performed using the χ² test. Univariate prognostic analysis was conducted using the log-rank test, and survival outcomes were analyzed using the Kaplan-Meier method. Results A total of 42 infants (≤12 months) with NB were enrolled. Low-risk patients underwent surgical resection alone; intermediate-risk patients received surgery combined with chemotherapy with or without maintenance therapy; high-risk patients were treated with surgery and chemotherapy with or without maintenance therapy or radiotherapy. The 5-year event-free survival (EFS) rate was (92.7±4.9)%, and the 5-year overall survival rate was (95.2±3.6)%. Only two patients died because of tumor recurrence or progression. Univariate analysis identified MYCN amplification and the initial lactate dehydrogenase (LDH) level ≥ five times the upper limit of the normal were significantly associated with poor prognosis (5-year EFS: 33.3% vs. 97.4% and 60.0% vs. 97.3%, P<0.0001 and P=0.0035). Conclusion Infant NB has a favorable overall prognosis. MYCN amplification and markedly elevated initial LDH are associated with poor outcomes.

Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity. Methods: Wild type and Serpina3c knockout (Serpina3c–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes. Results: Serpina3c–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation. Conclusion These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Objective To compare the dosimetric differences, plan complexity, verification pass rate, and execution efficiency of volumetric modulated arc therapy (VMAT) plans designed for post-mastectomy radiotherapy of breast cancer using Halcyon 2.0 and VitalBeam accelerators in flattening filter-free mode. Methods A retrospective analysis was conducted on imaging data from 87 female breast cancer patients aged 29 to 75 (49.9 ± 9.9) years who underwent modified radical mastectomy followed by radiotherapy. VMAT plans were designed using both VitalBeam and Halcyon accelerators in flattening filter-free mode. The dosimetric parameters, plan complexity, verification pass rate, and execution efficiency were compared between the plans designed for both accelerators, with a significance level of P<0.05. Results In terms of target volume parameters, Halcyon 2.0 plans demonstrated superior homogeneity index and conformity index. For organs at risk, the Halcyon 2.0 plans showed lower doses for the lungs (D_20% and D_mean) and heart (D_mean) compared to the VitalBeam plans (all P<0.05). Regarding plan complexity, Halcyon 2.0 plans exhibited better median average aperture area variation (0.35 ± 0.02), smaller aperture score, and larger median plan aperture area than VitalBeam plans (all P<0.05). However, VitalBeam plans had a superior median modulation complexity score (0.28 ± 0.01) compared to Halcyon 2.0 plans (P<0.05). Patient plans were assessed using the ArcCHECK phantom, revealing higher pass rates and significantly shorter execution time for Halcyon plans compared to VitalBeam plans (P<0.05). Conclusion Both Halcyon 2.0 and VitalBeam accelerators can provide high-quality VMAT plans for postoperative radiotherapy of breast cancer, with excellent verification pass rates ensuring treatment accuracy and efficacy. However, Halcyon 2.0 offers lower plan complexity, simplifies the treatment planning process, and reduces execution time, thereby achieving higher treatment efficiency and demonstrating greater advantages in clinical applications.

Objective: To systematically analyze the revisions content and technological development trends of microbiological standards in the Chinese Pharmacopoeia (ChP) 2025 Edition, and explore its novel requirements in risk-based pharmaceutical product lifecycle management.
Methods: A comprehensive review was conducted on 26 microbiological-related standards to summarize the revision directions and scientific implications from perspectives including the revision overview, international harmonization of microbiological standards, risk-based quality management system, and novel tools and methods with Chinese characteristics.
Results: The ChP 2025 edition demonstrates three prominent features in microbiological-related standards: enhanced international harmonization, introduced emerging molecular biological technologies, and established a risk-based microbiological quality control system.
Conclusion: The new edition of the Pharmacopoeia has systematically constructed a microbiological standard system, which significantly improves the scientificity, standardization and applicability of the standards, providing a crucial support for advancing the microbiological quality control in pharmaceutical industries of China.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

The Masquelet technique, also known as the induced membrane technique, is a surgical technique for repairing large bone defects based on the use of a membrane generated by a foreign body reaction for bone grafting. This technique is not only simple to perform, with few complications and quick recovery, but also has excellent clinical results. To better understand the mechanisms by which this technique promotes bone defect repair and the factors that require special attention in practice, we examined and summarized the relevant research advances in this technique by searching, reading, and analysing the literature. Literature show that the Masquelet technique may promote the repair of bone defects through the physical septum and molecular barrier, vascular network, enrichment of mesenchymal stem cells, and high expression of bone-related growth factors, and the repair process is affected by the properties of spacers, the timing of bone graft, mechanical environment, intramembrane filling materials, artificial membrane, and pharmaceutical/biological agents/physical stimulation.
Humans ; Bone Transplantation/methods* ; Membranes, Artificial ; Bone Regeneration ; Animals

OBJECTIVE: To understand clinical and laboratory characteristics of acute myeloid leukemia, myelodysplasia-related (AML-MR). METHODS: Blood sample of one patient with AML-MR admitted to our hospital in September 2021 was collected and synthetically analyzed by using techniques including complete blood cell count, peripheral blood and bone marrow cell morphology, bone marrow pathology and immunohistochemistry, hematology examination, flow cytometry (FCM), chromosome karyotype analysis and molecular pathology. The clinical and laboratory characteristics of AML-MR were analyzed and summarized according to the World Health Organization (WHO) standards. RESULTS: The patient showed pancytopenia and increased proportion of blasts in smear of peripheral blood cells. Bone marrow cytology and pathological examination showed significant proliferation of hematopoietic cells. Pathological immunohistochemistry showed increased expression of CD61, CD34, and CD117, while MPO, CD13, and CD33 were positive. FCM showed that abnormal myeloid progenitor cells accounted for approximately 18.61% of the total number of nuclear cells, with expression of CD34, CD13, CD117, HLA-DR, and CD33 (small amount). Additionally, 36.34% of the cells were primitive/immature red blood cells which expressed CD36, CD71, and CD117 (small amount). Chromosome karyotype analysis and molecular pathology detected three kinds of abnormalities including -5 and two kinds of TP53 related gene mutation, respectively. CONCLUSION AML-MR patient shows pancytopenia and increased proportion of blasts in smear of peripheral blood cells. Bone marrow cytology and pathological examination show significant proliferation of hematopoietic cells. FCM can detect myeloid progenitor cells and primitive/immature red blood cells, while chromosome karyotype analysis can detect three abnormal karyotypes.
Humans ; Leukemia, Myeloid, Acute/diagnosis* ; Myelodysplastic Syndromes ; Flow Cytometry ; Karyotyping ; Male ; Middle Aged ; Mutation

Osteoarthritis (OA), the most prevalent joint disease of late life, is closely linked to cellular senescence. Previously, we found that the senescence of fibroblast-like synoviocytes (FLS) played an essential role in the degradation of cartilage. In this work, single-cell sequencing data further demonstrated that cartilage acidic protein 1 (CRTAC1) is a critical secreted factor of senescent FLS, which suppresses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression. In vivo, deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA. Oppositely, intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice. Mechanistically, we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes, which subsequently suppresses the transcription of SIRT3 in vitro. In addition, SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction, which finally contributes to the degradation of chondrocytes. To conclude, this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression, which provided a potential strategy for the OA therapy.