Traditional treatment for type 1 diabetes mellitus （T1DM） primarily involves insulin replacement， yet some patients encounter issues such as significant blood glucose fluctuations， high risk of hypoglycemia， and weight gain. In recent years， the adjuvant therapeutic role of non-insulin hypoglycemic drugs in T1DM has gradually gained attention. This article reviews the mechanisms of action and clinical research progress of five types of non-insulin hypoglycemic drugs in the treatment of T1DM： amylin analogues （pramlintide）， biguanides （metformin）， sodium-glucose co-transporter 2 inhibitor， dipeptidyl peptidase-4 inhibitor， and glucagon-like peptide-1 receptor agonist. It is found that these drugs can enhance clinical benefits for T1DM patients by improving insulin sensitivity， delaying gastric emptying， promoting urinary glucose excretion， and regulating incretin levels， thereby reducing glycated hemoglobin levels， decreasing insulin dosage， and managing body weight. Simultaneously， these drugs also present limitations such as low patient compliance due to complex dosing regimens， increased risk of diabetic ketoacidosis， and heterogeneity in glycemic control. Future research could focus on developing individualized treatment strategies， combining pharmacogenomics with novel biomarkers to precisely identify subpopulations of patients who may benefit， and delving into the potential value of these drugs in delaying diabetic vascular complications and improving patients’ quality of life.

Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective:To analyze the levels of thrombin generation and activated protein C resistance (APC-R) in lupus anticoagulant (LA)-positive patients, and to assess their effectiveness in predicting thrombotic risk in these patients.Methods:Retrospective case-control study. A total of 185 patients with positve LA [91 males, 94 females; age (47.59±19.14) years] in Ruijin Hospital of Shanghai Jiaotong University School of Medicine from November 1st, 2024 to March 31st, 2025 were included. Patients were stratified into thrombotic ( n=91) and non-thrombotic groups ( n=94) based on clinical diagnosis and imaging evidence of thrombosis. The basic characteristics and routine laboratory coagulation levels of LA-positive patients were analyzed. Post-test plasma samples were collected from 43 cases with positive or strongly positive LA, categorized into thrombotic ( n=23) and non-thrombotic ( n=20) groups. Additionally, plasma was collected from 80 healthy controls [40 males and 40 females, age (38.37±15.74) years]. Using simple random sampling method, plasma samples from 10 selected males and 10 selected females were mixed to make 1 group of healthy control, thus accordingly resulted in a total of 4 healthy control groups. Thrombin generation assays (TGA) were then employed to measure prothrombin generation and activated protein C resistance (APC-R) levels in the healthy control, non-thrombotic, and thrombotic groups. One-way analysis of variance was utilized to compare thrombin generation and APC-R levels across these groups. Results:Among the routine laboratory coagulation indexes, the median levels of activated partial thromboplastin time (APTT), fibrin degradation product (FDP) and protein C (PC) in thrombotic group were 30.9 (28.8, 35.5) s, 2.5 (1.3, 2.8) mg/L, and 107.0 (93.0, 127.0)%, respectively, which were significantly higher compared with the non-thrombosis group (all P<0.05). However, between the thrombotic and non-thrombotic group, no statistically significant differences were observed for the levels of prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), or D-dimer (D-D) ( P>0.05). The TGA results showed that the total thrombin generation, the maximal thrombin generation and APC-R levels of patients in the thrombotic group were (1 118.72±387.34) nmol/L·min, (106.01±59.00) nmol/L and (0.33±0.22), respectively, which were significantly higher compared with those in the non-thrombotic group (all P<0.05). Conclusion:Significantly increased thrombin generation and enhanced APC-R were present in the LA-positive patients with thrombosis, indicating the important values of thrombin generation and APC-R in assessing thrombosis risk among this population.

Objective:To compare the accuracy of one-stage clotting assay and chromogenic substrate assay for testing an extended half-life recombinant FⅧ and to explore standardized conversion models between methods.Methods:Observational study. FⅧ activity (FⅧ:C) in plasma samples with theoretical values of 1 000, 800, 600, 500, 400, and 300 IU/L was measured using both one-stage clotting assay (employing Siemens Actin FSL reagent, Werfen SynthASil reagent, Stago PTT-A reagent) and the chromogenic substrate assay from Hyphen Biomed. Differences in FⅧ:C measured by the various methods were compared using the SNK test. Recovery rates were calculated to evaluate the accuracy of each assay. Sample activity was verified using the thrombin generation assay (TGA). Correlations between activities determined by the different assay systems were assessed using linear regression analysis.Results:Observational study. FⅧ activity (FⅧ:C) in diluted plasma samples with theoretical values of 1 000, 800, 600, 500, 400, and 300 IU/L was measured using both one-stage clotting assay (employing Siemens Actin FSL reagent, Werfen SynthASil reagent, Stago PTT-A reagent) and the chromogenic substrate assay from Hyphen Biomed. Differences in FⅧ:C measured by the various methods were compared using the SNK test. Recovery rates were calculated to evaluate the accuracy of each assay. Sample activity was verified using the thrombin generation assay (TGA). Correlations between activities determined by the different assay systems were assessed using linear regression analysis.Conclusion:Some marked one-stage clotting assay system has limitations in the clinical detection of extended half-life recombinant FⅧ. While the chromogenic substrate assay provides more accurate results. The one-stage clotting assay values can undergo cross-assay correction for FⅧ:C using a standardized conversion coefficient, which can further elevate the accuracy of monitoring hemophilia treatment efficacy.

Congenital coagulation factor Ⅶ deficiency is a rare autosomal incomplete recessive disorder caused by a defect in the coagulation factor Ⅶ (FⅦ) gene, with an incidence of approximately 1 in 500 000. Antiphospholipid antibody syndrome is relatively common and is a common cause of acquired thrombosis. However, the combination of the latter and the former is extremely rare in clinical practice, which brings difficulties to diagnosis and treatment. This article reported the laboratory examination, diagnosis and treatment of a patient with congenital coagulation factor Ⅶ deficiency and antiphospholipid syndrome after portal vein thrombosis, and reviewed the relevant literature.

Objective To explore the time-varying pattern of potential symptoms in breast cancer patient before and after chemotherapy,and further analyze its influencing factors,aims to provide reference for clinical nursing practice.Methods 233 cases of breast cancer in a tertiary A hospital in Ningxia from June to October,2023 were selected as the research subjects.By the general information questionnaire and the Chinese version of Anderson Symptom Assessment Scale,the potential change of symptoms of breast cancer patients undergoing chemotherapy 1-3 days before the first chemotherapy(T1,233 cases)and 7-14 days after the third or fourth chemotherapy(T2,225 cases)was analyzed.Results 225 cases of breast cancer patients completed 2 surveys,and their symptom characteristics before and after chemotherapy can be divided into 2 categories:a high symptom troubled group and a low symptom troubled group.The high-symptom troubled group has strong stability,and the probability of maintaining the original group is 85.20％,while the low-symptom troubled group is more inclined to change to the high-symptom troubled group,and the transition probability is 26.60％.Logistic regression analysis showed that the mass was located on the left side,and the patients who obtained disease knowledge mainly through the Internet were more likely to change from the high symptom troubled group to the low symptom troubled group,while the patients who were employed,with unsatisfactory sleep at night,and never exercised were more likely to change from the low symptom troubled group to the high symptom troubled group.Conclusion The symptoms of breast cancer patients before and after chemotherapy are heterogeneous.Patients who are on the job,have unsatisfied sleep at night and never exercise are more likely to change from the low-symptom troubled group to the high-symptom troubled group,which suggests that medical staff should identify potential high-risk groups at an early stage,and make full use of the predictive function of symptom characteristics to carry out individualized management based on the dynamic monitoring of symptoms according to different types of population characteristics,so as to reduce the burden of symptoms and improve their quality of life.

Objective To investigate the medication law of Professor Wang Xuefeng in the treatment of transient tic disorders in children using data mining techniques;To clarify clinical thoughts and academic experience in the treatment of this disease.Methods The outpatient medical records of Professor Wang Xuefeng treated children with transient tic disorder in Affiliated Hospital of Liaoning University of Traditional Chinese Medicine from September 2021 to September 2024 were collected,and the prescriptions for patients'first visit were input after screening and sorting.Excel 2019 was used to establish the database.SPSS Modeler 18.0 was used to analyze the association rules of high-frequency drugs.SPSS Statistics 27.0 was used for clustering analysis.Gephi 0.10.1 was used for complex network analysis,and medication law was summarized.Results A total of 223 TCM prescriptions meeting the standard were included,involving 116 kinds of Chinese materia medica,with a total frequency of 3 668,and 30 high-frequency drugs were screened.The properties were mainly cold,neutral,and warm and the tastes were mainly pungent,bitter and sweet.The meridians were mainly liver,lung and heart meridians.The efficacy was mainly for suppressing hyperactive liver for calming endogenous wind,relieving surface and clearing heat;the results of association rules analysis showed that the drug combination with the highest correlation was Paeoniae Radix alba-Glycyrrhizae Radix et Rhizoma Praeparata cum Melle-Acori Tatarinowii Rhizoma;the high-frequency drugs were grouped into 9 categories by clustering analysis;a core drug combination consisting of 10 kinds of highly correlated Chinese materia medica was obtained by complex network analysis.Conclusion Professor Wang Xuefeng believes that transient tic disorders is mainly in the lung and liver,the etiology is due to the wind and phlegm,the pathogenesis is the external pathogens invading the lung,the pathogenic qi is reluctant to leave,the five viscera are disharmonious,the producing phlegm and turbid,the internal and external connection,the wind phlegm consolidation,the flowing meridians,thus causing twitching.It is necessary to take into account the whole process of disease development,with clear medication,fewer tastes,refined prescription and special efficacy.

A 64-year-old male patient with hemophilia A was scheduled for the surgical removal of a pulmonary mass. Preoperative evaluation revealed that the coagulation factor Ⅷ (FⅧ) activity was 0.5%, with an F Ⅷ inhibitor level of 32 BU/ml; the R value could not be detected on the thromboelastogram. Thoracoscopic lobectomy was successfully completed. On the day of the operation and the first day after the operation, 6 mg of recombinant activated coagulation factor Ⅶ (rFⅦa) was intravenously administered every 6 h. On postoperative day 1, the patient’s blood pressure dropped and the HGB gradually declined from 102 g/L to 65 g/L. Chest X-ray revealed a large amount of pleural effusion on the left side, and urgent thoracoscopic thoracic exploration was performed. A total of 3200 mL fresh blood was cleared, and a thoracic drainage tube was placed. On postoperative day 2, the rFⅦa dose was increased to 6 mg, which was intravenously administered every 4 h, and concentrated red cells were intermittently infused to correct anemia. Four days later, due to the inability to obtain rFⅦa, PCC (50 IU/kg every 8 hours) was administered. Additionally, treatment with methylprednisolone (40 mg/d) and cyclophosphamide (200 mg, every 2 weeks) was initiated to remove FⅧ inhibitors. The thoracic drainage tube was removed on postoperative day 9, and the patient was successfully discharged 3 weeks later.