Objective: To investigate the mechanism of Yishen Tongluo Formula in ameliorating renal pyroptosis in diabetic nephropathy mice by regulating the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. Methods: Sixty C57BL/6 male mice were randomly divided into control (10 mice) and intervention groups (50 mice) using random number table method. The diabetes nephropathy model was established by intraperitoneally injecting streptozotocin(50 mg/kg). After modeling, the intervention group was further divided into model, semaglutide (40 μg/kg), and high-, medium-, and low-dose Yishen Tongluo Formula groups (15.6, 7.8, and 3.9 g/kg, respectively) using random number table method. The high-, medium-, and low-dose Yishen Tongluo Formula groups were administered corresponding doses of medication by gavage, the semaglutide group received a subcutaneous injection of semaglutide injection, and the control group and model groups were administered distilled water by gavage for 12 consecutive weeks. Random blood glucose levels of mice in each group were monitored, and the 24-h urinary protein content was measured using biochemical method every 4 weeks; after treatment, the serum creatinine and urea nitrogen levels were measured using biochemical method. The weight of the kidneys was measured, and the renal index was calculated. Hematoxylin and eosin, periodic acid-Schiff, periodic Schiff-methenamine, and Masson staining were used to observe the pathological changes in renal tissue. An enzyme-linked immunosorbent assay was used to detect urinary β2-microglobulin (β2-MG), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) levels. Western blotting and real-time fluorescence PCR were used to detect the relative protein and mRNA expression levels of nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3), Caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18) in renal tissue. Immunohistochemistry was used to detect the proportion of protein staining area of the TLR4, MyD88, and NF-κB in renal tissue. Results: Compared with the control group, the random blood glucose, 24-h urinary protein, serum creatinine, urea nitrogen, and renal index of the model group increased, and the urine β2-MG, NGAL, and KIM-1 levels increased. The relative protein and mRNA expression levels of NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18 in renal tissue increased, and the proportion of TLR4, MyD88, and NF-κB protein positive staining areas increased (P<0.05). Pathological changes such as glomerular hypertrophy were observed in the renal tissue of the model group. Compared with the model group, the Yishen Tongluo Formula high-dose group showed a decrease in random blood glucose after 12 weeks of treatment (P<0.05). The Yishen Tongluo Formula high- and medium-dose groups showed a decrease in 24-h urinary protein, creatinine, urea nitrogen, and renal index, as well as decreased β2-MG, NGAL, and KIM-1 levels. NLRP3, Caspase-1, GSDMD, IL-1 β, and IL-18 relative protein and mRNA expression levels were also reduced, and the proportion of TLR4, MyD88, and NF-κB protein positive staining areas was reduced (P<0.05). Pathological damage to renal tissue was ameliorated. Conclusion Yishen Tongluo Formula may exert protective renal effects by inhibiting renal pyroptosis and alleviating tubular interstitial injury in diabetic nephropathy mice by regulating the TLR4/MyD88/NF-κB signaling pathway.

ObjectiveTo investigate the effect and mechanism of Yishen Tongluo prescription in protecting mice from oxidative stress injury in diabetic kidney disease （DKD） via the nuclear factor erythroid 2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1）/NAD（P）H quinone oxidoreductase 1 （NQO1） signaling pathway. MethodsSpecific pathogen-free （SPF） male C57BL/6 mice were assigned into a control group （n=10） and a modeling group （n=50）. The DKD model was established by intraperitoneal injection of streptozotocin. The mice in the modeling group were randomized into a model group， a semaglutide （40 μg·kg^-1） group， and high-， medium-， and low-dose （18.2， 9.1， 4.55 g·kg^-1， respectively） Yishen Tongluo prescription groups， with 10 mice in each group. The treatment lasted for 12 weeks. Blood glucose and 24-h urine protein levels were measured， and the kidney index （KI） was calculated. Serum levels of creatinine （SCr）， blood urea nitrogen （BUN）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） were assessed. The pathological changes in the renal tissue were evaluated by hematoxylin-eosin， periodic acid-Schiff， periodic acid-silver methenamine， and Masson’s trichrome staining. Enzyme-linked immunosorbent assay kits were used to measure the levels of β2-microglobulin （β2-MG）， neutrophil gelatinase-associated lipocalin （NGAL）， kidney injury molecule-1 （KIM-1）， liver fatty acid-binding protein （L-FABP）， nitric oxide synthase （NOS）， glutathione （GSH）， total antioxidant capacity （T-AOC）， and 8-hydroxy-2'-deoxyguanosine （8-OHdG）. Immunohistochemical staining was performed to examine the expression of Kelch-like ECH-associated protein 1 （Keap1） and malondialdehyde （MDA）. Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR） and Western blot were employed to determine the mRNA and protein levels， respectively， of factors in the Nrf2/HO-1/NQO1 signaling pathway. ResultsCompared with the control group， the DKD model group showed rises in blood glucose， 24-h urine protein， KI， SCr， BUN， and ALT levels， along with glomerular hypertrophy， renal tubular dilation， thickened basement membrane， mesangial expansion， and collagen deposition. Additionally， the model group showed elevated levels of β2-MG， NGAL， KIM-1， L-FABP， NOS， and 8-OHdG， lowered levels of GSH and T-AOC， up-regulated expression of MDA and Keap1， and down-regulated expression of Nrf2， HO-1， NQO1， and glutamate-cysteine ligase catalytic subunit （GCLC） （P<0.05）. Compared with the model group， the semaglutide group and the medium- and high-dose Yishen Tongluo prescription groups showed reductions in blood glucose， 24-h urine protein， KI， SCr， BUN， and ALT levels， along with alleviated pathological injuries in the renal tissue. In addition， the three groups showed lowered levels of β2-MG， NGAL， KIM-1， L-FABP， NOS， and 8-OHdG， elevated levels of GSH and T-AOC， down-regulated expression of MDA and Keap1， and up-regulated expression of Nrf2， HO-1， NQO1， and GCLC （P<0.05）. ConclusionYishen Tongluo prescription exerts renoprotective effects in the mouse model of DKD by modulating the Nrf2/HO-1/NQO1 signaling pathway， mitigating oxidative stress， and reducing renal tubular injuries.

ObjectiveTo improve the accuracy of discrete element method in simulating the processing of traditional Chinese medicine（TCM） powder system under low shear conditions. MethodsIn this study， extract powders of Tongsaimai tablets and Qige granules were used as the research objects， the angle of repose（AOR） and effective angle of internal friction of the two materials were determined by AOR test method and shear cell test method. Based on the Hertz-Mindlin with JKR V2 contact model and particle scaling theory， taking the particle-particle restitution coefficient（A）， particle-particle static friction coefficient（B）， particle-particle rolling friction coefficient（C）， particle-steel restitution coefficient（D）， particle-steel static friction coefficient（E）， particle-steel rolling friction coefficient（F） and Johnson-Kendall-Roberts（JKR） surface energy（G） as test factors， the simulated contact parameters of Tongsaimai tablets extract powder were first calibrated with a single reference value using AOR as the reference value， and then the simulated contact parameters of Tongsaimai tablets extract powder as well as Qige granules extract powder were co-calibrated with AOR and effective angle of internal friction as the joint reference value， respectively. Then， Plackett-Burman design was used to screen the critical contact parameters that have a significant effect on the simulated reference value， and the steepest ascent design was used to determine the optimal range of the critical contact parameters， finally， the regression model between the critical contact parameters and the simulated reference values was established through the design of the response surface test， and the critical contact parameters were calibrated based on the regression model and the desirability function approach. ResultsThe optimal combination of discrete elemental contact parameters A-G for Tongsaimai tablets extract powder under a single reference value was 0.100， 0.718， 0.616， 0.100， 0.400， 0.250 and 0.075 J·m^-2， which was validated to have relative errors of 0.10% and -8.64% for the simulated AOR and the simulated effective angle of internal friction， respectively. And the optimal combination of discrete elemental contact parameters A-G for Tongsaimai tablets extract powder at the joint reference values was 0.100， 0.682， 0.598， 0.100， 0.521， 0.294 and 0.075 J·m^-2， which was verified to have relative errors of 0.10% and -0.18% for the simulated AOR and the simulated effective angle of internal friction， respectively. The optimal combination of discrete elemental contact parameters A-G for Qige granules extract powder at the joint reference values was 0.150， 0.370， 0.330， 0.150， 0.500， 0.500 and 0.100 J·m^-2， which was verified to have relative errors of 2.70% and -1.30% for the simulated AOR and the simulated effective angle of internal friction， respectively. Compared with the single reference value method， the joint calibration method not only increased the number of the critical contact parameters for characterizing particle-device interactions， but also was more accurate and reliable. ConclusionCompared with the results of single reference value calibration， the results obtained by the method of joint calibration of discrete element simulation contact parameters with AOR and effective angle of internal friction as the reference values are more accurate， which can provide more accurate and reliable simulation physical property data for the simulation experiments of TCM extract powder under low shear process conditions.

The pharmaceutical industry faces challenges in quality digitization for complex multi-stage processes, especially in small-sample systems. Here, an intelligent quality prediction and diagnostic (IQPD) framework was developed and applied to Tong Ren Tang's Niuhuang Qingxin Pills, utilizing four years of data collected from four production units, covering the entire process from raw materials to finished products. In this framework, a novel path-enhanced double ensemble quality prediction model (PeDGAT) is proposed, which combines a graph attention network and path information to encode inter-unit long-range and sequential dependencies. Additionally, the double ensemble strategy enhances model stability in small samples. Compared to global traditional models, PeDGAT achieves state-of-the-art results, with an average improvement of 13.18% and 87.67% in prediction accuracy and stability on three indicators. Additionally, a more in-depth diagnostic model leveraging grey correlation analysis and expert knowledge reduces reliance on large samples, offering a panoramic view of attribute relationships across units and improving process transparency. Finally, the IQPD framework integrates into a Human-Cyber-Physical system, enabling faster decision-making and real-time quality adjustments for Tong Ren Tang's Niuhuang Qingxin Pills, a product with annual sales exceeding 100 million CNY. This facilitates the transition from experience-driven to data-driven manufacturing.

Objective To investigate associations between three-dimensional(3D)morphology of cervical vertebrae and skeletal mat-uration by cone-beam computed tomography(CBCT)and establish corresponding regression models for quantitatively evaluating cervical vertebral maturation(CVM).Methods The analyzed sample consisted of 358 CBCT images(175 male,183 female),of which 277 images were randomly selected as the model development group and 81 as the performance test group.Twenty-one 3D morphological pa-rameters were defined and measured,incorporating all parts of the cervical vertebrae,including the cervical vertebral bodies,transverse processes,spinous processes,pedicles,lamina,and articular processes.The cervical vertebral maturation index(CVMI)was determined by experienced orthodontists as reference standard.Spearman's rank correlation coefficient and multivariable stepwise regression analysis were used to identify the associations and build regression models.The performance test group was employed to ex-amine each model's reliability.Paired-samples Wilcoxon signed-rank test compared the CVMI of the model prediction with the reference standard.Results Three-dimensional morphological changes in various parts of the cervical vertebrae correlated with CVMI(P＜0.05).Six 3D morphometric parameters were each recognized for male and female models,three of which were identical.The adjusted R2 was 0.899 for males and 0.902 for females,with corresponding accuracies of 85.0%and 85.4%,respectively.These models showed no difference as compared with the reference standard(P＞0.05).Con-clusion New associations were found between 3D morphology of cer-vical vertebrae and skeletal maturation.The 3D-driven morphometric CVM assessment method and corresponding regression models exhibited good credibility and high consistency with experts.

Objective To verify the consistency of the reference intervals of thyroid hormone estimated in this investigation with the reference interval in the manual of the currently used reagent and industrial standard(WS/T 404.10-2022),and select the reference interval of thyroid hormone suitable for the healthy subjects at this hospital.Methods The indirect sampling technique was used to ret-rospectively analyze the results of thyroid hormone tests of healthy subjects in the Clinical Testing Center of Suzhou Dushu Lake Hospi-tal from December 2022 to August 2023.Nonparametric method was used to estimate thyroid hormone P2.5-P97.5 reference intervals and 95％confidence intervals of the testing subjects with different genders and ages,and to explore the significant differences in the data distribution among different gender and age groups.The differences were compared with the reference intervals recommended by the in-dustrial standard(WS/T 404.10-2022)and Roche reagent specification.Results There were significant differences in TSH,FT3,FT4 and TT3 between sexes(P＜0.001,Z＞Z*),but there was no significant difference in TT4 between sexes(P=0.998,Z＜Z*).In terms of TSH levels,the women were divided into 20 to 60-year-old group(reference interval:0.62-6.40 mIU/L)and≥61-year-old group(reference interval:0.85-7.47 mIU/L).There was significant difference between the 2 groups(P＜0.001),but there was no sig-nificant difference of TSH levels among the male groups with different age(reference interval:0.79-5.64 mIU/L).In terms of FT3 lev-els,the males were divided into 20 to 40-year-old group(reference interval:4.37-6.36 pmol/L)and ≥41-year-old group(reference interval:4.02-6.34 pmol/L).There was significant difference between the 2 groups(P＜0.001),but there was no significant difference in the female among various age groups(reference interval:3.44-5.63 pmol/L).In terms of FT4 level,the males were divided into 20 to 50-year-old group(reference interval:13.7-21.4 pmol/L)and ≥51-year-old group(reference interval:12.0-20.4 pmol/L),and the females were divided into 20 to 50-year-old group(reference interval:12.5-20.25 pmol/L)and≥51-year-old group(reference interval:11.34-19.18 pmol/L).There was all significant difference between various age groups in both male and female(P＜0.001).In terms of TT3 level,no difference was found between male and female regardless of age(male[reference interval:1.18-2.18 nmol/L]and female[reference interval:1.10-2.23 nmol/L]).In terms of TT4 level,there was no significant difference between sex and age(reference interval:64.1-127 nmol/L).There was no significant difference between the reference interval recommended by Roche reagent manual and the laboratory estimated FT4 reference interval,but there were significant differences in reference interval of TSH,FT3,TT3 and TT4.There was no significant difference between the industrial standard recommended reference interval and the laboratory estimated reference interval.Conclusion There were differences of TSH,FT3 and FT4 levels for gender and age,but no differences of TT4 levels for sex and age.There was gender difference of TT3 levels but no differences for age.The estimated reference interval verified by the laboratory was consistent with the industrial standard recommendation of WS/T 404.10-2022,but it was differ-ent from the recommendation of current Roche reagent manual.

Objective:To analyze the risk factors for central lymph node metastasis (CLNM) in patients with papillary thyroid cancer (PTC) aged 55 years and above, and to construct a predictive model with columnar graph.Methods:This retrospective study included 406 PTC patients aged 55 and above, treated at the First Affiliated Hospital of Zhengzhou University from Nov. 2019 to Feb. 2022. Data on demographic characteristics, disease features, and laboratory test results were collected. Univariate and multivariate logistic regression analyses were used to identify risk factors for CLNM and develop a clinical prediction model and nomogram.Results:The study involved 406 patients, divided into a modeling group (285 patients) and a validation group (121 patients). The predictive model identified independent risk factors for CLNM. In the modeling group, the model demonstrated a ROC AUC of 0.769, with 82.6% sensitivity, 63.0% specificity, and 67.7% accuracy. The validation group showed 66.7% sensitivity, 74.5% specificity, and 72.7% accuracy, with an AUC of 0.760. Hosmer-Lemeshow tests indicated good fit in both groups. Decision curve analysis confirmed the model's clinical decision-making value, showing better performance than traditional strategies and good generalizability and reliability.Conclusions:Sex, maximum tumor diameter, bilateral involvement of thyroid lobes, clinically evident cervical lymph nodes, and local invasion are independent predictive factors for CLNM in patients over 55 with papillary thyroid carcinoma (PTC). A clinical risk stratification nomogram model based on these risk factors demonstrates good predictive performance.

Objective To analyze the clinical characteristics of C-TI-RADS 3 thyroid nodules with a diameter greater than 2 cm and explore their correlation with gender,nodule ingredient,contralateral cancer presence,diffuse echo changes,TPOAB and TGAB.Methods A retrospective analysis was made on the clinical and pathological information of 94 patients with thyroid nodules who were admitted to our department from September 2022 to March 2023.All the patients underwent cytological and/or histopathological examinations.The proportions of TBS I category,benign tumors,low-risk tumors,and malignant tumors were calculated.The proportion of TBS type Ⅰ,benign tumors,low-risk tumors,and malignant tumors was quantified.Subsequently,a comparative analysis was conducted among the benign,low-risk,and malignant groups in terms of clinical characteristics including gender distribution,nodule composition,contralateral cancer occurrence,diffuse echo changes presence,as well as TPOAB and TGAB levels.Results Seven cases in TBS I category were excluded.Among the remaining 87 cases with confirmed pathology results for nodules,there were 72 benign cases(38 cytology cases and 34 histology cases),5 low-risk thyroid tumors(2 cytology cases and 3 histology cases),10 malignant cases(8 PTC cases,1 FTC case,and 1 MTC case).There was a significant difference in nodule ingredient(cystic/solid)between different pathological types(x2=10.369,P=0.006).However,no statistical significance was found in terms of gender,diffuse echo changes,contralateral cancer presence,TPOAB or TGAB(P＞0.05).Further analysis showed that the proportion of solid component was higher in low-risk tumors than in benign nodules(x2=9.571,P=0.002).No statistical significance was found between malignant nodules and low-risk nodules(x2=2.143,P=0.143),or between malignant nodules and benign nodules(x2=2.165,P=0.141).Conclusion Although TI-RADS 3 nodules are generally considered as potentially benign according to various versions of thyroid imaging reporting and data system,malignant nodules still account for a certain proportion.Attention should be paid to thyroid nodules with a typical ultrasonic signs,such as cystic nodules,thyroid follicular tumors and medullary thyroid carcinoma.Ultrasound guided fine needle aspiration cytopathology is necessary for evaluating benign and malignant nodules.It is necessary to pay attention to unsatisfactory or undiagnosable specimens to improve the accuracy of diagnosis.

Objective To explore the clinical efficacy of dulaglutide combined with metformin in the treatment of obese patients with type 2 diabetes mellitus(T2DM).Methods A total of 200 obese patients with T2DM who were treated in Shanghai Jiading District Anting Hospital from January 2021 to January 2023 were randomly divided into liraglutide group(n=100)and dulaglutide group(n=100).The liraglutide group was treated with liraglutide combined with metformin,and the dulaglutide group was treated with dulaglutide combined with metformin.Both groups were treated for 3 months.The body metabolic indexes[fasting blood glucose(FBG),2 h postprandial blood glucose(2 h PBG),hemoglobin(HbA1 c),total cholesterol(TC),triglyceride(TG)],body fat composition[body fat rate,body mass index,subcutaneous fat rate of limbs,visceral fat index]and serum adipokines(adiponectin,neuropeptide Q(NPQ),asprosin,irisin)levels were compared before treatment and 3 months after treatment.The clinical efficacy and adverse reactions of the two groups were observed.Results After 3 months of treatment,FBG,2 h PBG,HbAlc,TC,TG,body fat rate,body mass index,subcutaneous fat rate of limbs,visceral fat index and asprosin in the two groups were lower than those before treatment,and those in the dulaglutide group were lower than those in the liraglutide group(P＜0.05).After 3 months of treatment,the levels of serum adiponectin,NPQ and irisin in the two groups were higher than those before treatment,and the increase in the dulaglutide group was greater than that in the liraglutide group(P＜0.05).The effective rate of dulaglutide group(98.00%)was higher than that of liraglutide group(91.00%)(P＜0.05).There was no significant difference in the incidence of adverse reactions between the two groups(11.00%,14.00%)(P＞0.05).Conclusion Dulaglutide combined with metformin could improve the metabolic status of obese T2 DM patients,regulate body fat composition and serum adipokines,with significant clinical efficacy and safety.

Thyroid cancer is the most common malignant tumor of the head and neck, among which papillary thyroid carcinoma is the most common. Papillary thyroid carcinoma with a diameter of ≤ 1.0 cm is called thyroid micropapillary carcinoma. In recent years, thermal ablation technology for the treatment of thyroid micropapillary carcinoma has developed rapidly at home and abroad. At present, many guidelines, consensus and clinical studies related to thermal ablation treatment of thyroid micropapillary carcinoma have been published at home and abroad. Based on the existing literature, guidelines and clinical studies, this article summarizes, discusses and analyzes the advantages, indications, efficacy, safety, and existing problems of thermal ablation therapy for thyroid cancer.