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.

Purpose To explore the clinicopathological features of cholangitis lenta.Methods The clinical data of 12 patients with cholangitis Lenta were collected,HE staining,his-tochemical staining and immunohistochemistry were used to de-tect the clinicopathological changes in 12 cases of cholangitis lenta,and the relevant literature was reviewed.Results All the 12 patients with cholangitis Lenta had acute history and ab-normal liver function,9 cases(75.0％)had abnormal white blood cell count,11 cases(91.7％)had abdominal infection,8 cases(66.7％)had systemic inflammatory response syndrome(SIRS)and 8 cases(66.7％)were diagnosed as sepsis.The common pathological manifestations included spotty necrosis(100％),piecemeal necrosis(100％),confluent necrosis(75.0％),bridging necrosis(66.7％),hepatocyte and capil-lary cholestasis(75.0％),and mild edema in portal area(33.3％).12 cases showed proliferation of bile ductules around the portal area,inspissated bile in dilated bile ductules and no cholestasis in interlobular bile ducts.12 cases had the basis of primary liver disease.2 patients(16.7％)died after being transferred to another hospital for treatment,and 10 patients(83.3％)survived,which lasted for 7 to 55 months.Conclu-sion Cholangitis Lenta shows unique clinical manifestations and morphological features,it is often accompanied by underly-ing diseases.The pathological manifestation of cholangitis Lenta in liver biopsy suggests that patients may have sepsis and/or ab-dominal infection,and therefore its diagnosis should be com-bined with clinical features,laboratory examination and imaging manifestations.

OBJECTIVE To provide a reference for improving the drug patent linkage system. METHODS Data on drug names， drug types， abbreviated new drug application （ANDA） acceptance numbers， registration classifications， and applicant names were obtained from the patent certifications and patent information disclosure modules of China’s patent information registration platform for marketed drugs. The data collection period was from July 4， 2021， to September 30， 2023. The analysis focused on the annual distribution of patent certifications for the ANDA varieties included in the statistics， the proportion of different registration classifications， the details of the type Ⅳ certifications， the remaining validity periods of the corresponding patents for the type Ⅲ certifications， and the number of manufacturers for the same variety. RESULTS Among the ANDA varieties analyzed， type Ⅰ certifications predominated （accounting for 86.53%）， while types Ⅱ， Ⅲ and Ⅳ certifications each accounted for approximately 4% to 5%. In the three registration classifications， type Ⅰ certifications in registration classification 3 accounted for as high as 98.55%， and in registration classification 4， type Ⅰ certifications accounted for 79.65%， while types Ⅱ， Ⅲ and Ⅳ certifications each accounted for around 7%. In terms of the detailed type of the Ⅳ certifications， type Ⅳ of article 2 certifications had a large proportion （79.23%） and showed a slight upward trend， whereas the challenges of type Ⅳ of article 1 certifications were few. The remaining validity period of the patents corresponding to type Ⅲ certifications was excessively long， with a median of 18 months. The proportion of the same variety with fewer than 5 manufacturers was 36.44%， while those with more than or equal to 20 manufacturers accounted for 14.75%. CONCLUSIONS The ANDA system in China has been orderly integrated with the drug patent linkage system in practice. It is recommended to optimize aspects such as patent certifications registration and objection mechanisms， the effective approval dates for ANDA with type Ⅲ certifications， and incentive measures for type Ⅳ of article 1 certifications， thereby further standardizing the ANDA process and guiding the high-quality development of generic drugs.

Objective:To evaluate the effect of nursing specialist nurses′ assistance on the ability of nursing home nurses to maintain venous catheter under the vision of combination of medical care and nursing care, providing reference for carrying out specialized nursing assistance work in grassroots hospitals.Methods:This study was an experimental study. According to Miller′s pyramid theory, a model of specialist nurse assistance was established with specialized technology as the core. From January to December 2021, three nursing hospitals in Suzhou were assisted. Convenience sampling method was used to investigate the ability of intravenous catheter maintenance, the incidence of central venous catheter maintenance defects, the incidence of central venous catheter complications and unplanned extubation, and the satisfaction of doctors and patients before and after help.Results:Totally 86 nurses were included, aged (33.17 ± 2.31) years old. After the help, the theoretical and operational skill scores of nurses in the nursing home were (89.77 ± 2.11) and (92.75 ± 1.62) points, respectively, which were significantly higher than those before the help (60.84 ± 2.71) and (79.81 ± 1.68) points, and the differences were statistically significant ( t=-84.96, -52.12, both P<0.05). Among the maintenance defects of central venous catheter in nursing homes, incomplete labeling, film wrapping, blood seepage, catheter discounting, non-standard film fixing, and incomplete information of extended care were 9.95% (21/211), 8.53% (18/211), 2.84% (6/211), 6.16% (13/211), 4.74% (10/211), 2.37% (5/211) after help, all lower than 50.57% (89/176), 43.18% (76/176), 14.20% (25/176), 25.57% (45/176), 18.18% (32/176), 11.93% (21/176) before help. The differences were statistically significant ( χ2 values were 14.00 to 77.81, all P<0.05). The incidence of medical adhesive related skin injury, catheter obstruction complications and unplanned extubation were 4.44% (4/90), 3.33% (3/90) and 2.22% (2/90), respectively, which were lower than 20.51% (16/78), 15.38% (12/78) and 11.54% (9/78) before help. The differences were statistically significant ( χ2=8.81, 6.06, 4.50, all P<0.05). Doctors′ satisfaction with nurses and patients′ satisfaction with nursing work were 96.43%(27/28) and 93.75%(45/48), respectively, both higher than 71.43%(20/28) and 72.73%(32/44) before help, and the differences were statistically significant respectively ( χ2=4.77, 5.97, both P<0.05). Conclusions:From the perspective of combination of medical care and nursing care, the maintenance and assistance of intravenous catheters by the team of intravenous therapy nurses in nursing hospitals can effectively reduce the incidence of central venous catheter complications and unplanned extubation, improve the maintenance ability of intravenous catheters of nurses in nursing hospitals, and help to improve the quality of nursing care in nursing hospitals.

ObjectiveTo observe the spontaneous testicular tumors in interferon receptor-deficient mice (AG129) and provide a basis for further research using this mouse strain. MethodsThe AG129 mouse population was bred in an SPF barrier environment and reproduced normally. Among the 3-week-old weaned mice, we found that one male mouse had an abnormally enlarged testis, while none of the other mice in the same litter exhibited a similar condition. The spontaneous testicular tumor in this mouse was continuously monitored. The mouse was euthanized and dissected at 9 weeks of age. The gross morphology of the tumor was observed, and the tissue was then embedded in paraffin and sectioned for hematoxylin and eosin (HE) staining. ResultsAfter several weeks of observation, the tumor tissue gradually increased in size as the mice aged. Upon dissection, the tumor tissue was encapsulated in a smooth capsule. After opening the capsule, the tumor tissue was irregular in shape, with some areas being hard and others soft. The results of HE staining showed that the tumor tissue developed from tissues derived from multiple germ layers, with nerve tissue, bone tissue, muscle tissue, and adipose tissue inside, exhibiting an irregular morphological structure. ConclusionBased on the tumor development, gross morphological structure, and the HE staining results of the pathological sections, the tumor in this mouse was preliminarily diagnosed as an immature teratoma.

Objective: To provide high-quality clinical evidence of the efficacy of Tibetan medicine Honghua Ruyi (HHRY) pills for endometriosis-associated dysmenorrhea. Methods: This study constitutes a multicenter, randomized, double-blind, placebo-controlled trial encompassing a three-menstrual cycle intervention followed by a three-menstrual cycle follow-up period. A total of 164 eligible females with endometriosis-associated dysmenorrhea were randomly divided into HHRY pills and placebo groups in a 1:1 ratio. The primary outcome included dysmenorrhea symptoms assessed using Visual Analog Scale (VAS) scores and quality of life, whereas the secondary outcome measures included the maximum VAS for non-menstrual pelvic pain, duration of pain episodes (in days), frequency and quantity of the consumption of ibuprofen sustained-release capsules (or other non-steroidal anti-inflammatory drugs), and days off work/study for staff/student due to dysmenorrhea, ovarian cyst, and/or pelvic nodule size. The safety was monitored throughout the treatment period. All the analyses were based on the intention-to-treat principle. For continuous outcomes, simple or multiple linear regressions were used to estimate the differences between the HHRY pills and placebo groups, with categorical data expressed as the number and percentage of occurrences. Differences were compared using the chi-square test or Fisher's exact test. The predefined analysis was adjusted for concomitant treatment, a variable considered to be associated with outcomes but unaffected by treatment allocation. Estimates of treatment effects were reported with 95% confidence intervals. Two-tailed P values ≤ .05 were considered statistically significant. Conclusion Positive results from this trial, upon completion would provide robust evidence for the efficacy and safety of HHRY pills in treating dysmenorrhea in patients with endometriosis.

Objective To investigate the effects of linoleic acid(LA)on the diversity and structure of intestinal flora in mice.Methods Twelve SPF grade male C57BL/6J mice at 7 weeks were randomly divided into control group(CTRL group)and linoleic acid group(LA group).One day before the linoleic acid diet was supplemented,the normal food was removed from the LA group and the mice in the LA group were fasted for one night,so that the LA diet was more acceptable to the mice in the LA group,and LA was given on the day of the experiment recording,and the feed was updated at any time to ensure that the mice could eat freely until the end of modeling.After 12 weeks of modeling,mouse feces were collected,and mixed samples were collected for every two mice feces,and then 16sRNA high-throughput sequencing was performed to analyze intestinal flora structure,Alpha and Beta diversity.Results 16sRNA high-throughput sequencing showed that LA intervention damaged the richness and diversity of intestinal flora.The results of principal component analysis showed that the composition of flora in CTRL group was different from that in LA group.At gate level,the relative abundance of Actinobacteria in LA group increased(P＜0.01).At the genus level,the relative abundance of L.Duchennei in the LA group decreased(P＜0.05),but the relative abundance of Bifidobacterium,Faecalibaculum and Erysipelotrichaceae in the LA group increased(all P＜0.01).Conclusion LA intervention could reduce the richness and diversity of intestinal flora in mice,and adjust the structure of intestinal flora.There were significant differences between beneficial bacteria and pathogenic bacte-ria in intestinal flora after LA intervention,which provided certain basis for the treatment of bioactive compounds of linoleic acid and the therapeutic adjustment of intestinal microorganisms as targets.

To construct a recombinant expression system for a single-domain antibody targeting the urease of Helicobacter pylori(Hp),this study employed several strategies.First,using artificial intelligence(AI)auxiliary tools such as Pymol,I-TASSER,and ClussPro2,the molecular interactions between different antibodies and Hp urease subunit B(UreB)were analyzed.The fully humanized single-domain antibody UreBAb was identified as the primary research target.Next,the UreBAb gene sequence was optimized based on Escherichia coli codon preferences,and was inserted into expression vectors such as pET28a and pE-SUMO.The resulting recombinant expression strains were obtained by transforming Escherichia coli Rosetta(DE3).Recombinant antibody proteins were prepared through IPTG induction,and its activity was detected using extracted Hp urease as the antigen.SDS-PAGE analysis confirmed the correct expression of both UreBAb and SUMO-UreBAb,with protein yields of 0.34 mg/mL and 0.41 mg/mL,respectively.Unidirectional immunodiffusion experiments further confirmed that both recombinant antibodies exhibited strong affinity for Hp UreB antigen,with inhibition rates of 51.27%and 74.07%,respectively.Additionally,leveraging artificial intelligence tools such as AlphaFold2,cluspro2,mCSM-AB,OSPREY,and FoldX,the study evaluated and analyzed key binding sites and mutational strategies affecting the stability of the antigen-antibody complex.Subsequently,nine UreBAb evolution mutants were constructed,and their binding activities with the antigen were enhanced.Among these,the I107W mutant showed the most significant improvement,achieving a 24.95%increase compared to the wild-type UreBAb.This research lays a solid foundation for the development of fully humanized single-domain antibodies against Hp.

Objective To evaluate the impact of flash glucose monitoring(FGM)system on glycemic control and adverse pregnancy outcome in pregnant women with type 2 diabetes mellitus(T2DM).Methods This prospective,open-label,randomized,controlled clinical trial involved 109 women with T2DM at 16～18 weeks of gestation who visited Liaocheng People's hospital and Liaocheng Women and Children Hospital from June 2018 to June 2022.They were randomly assigned to FGM group(54 cases)and control group(55 cases).The FGM group wore FGM at 20,24,28 and 32 weeks of pregnancy respectively.The Con group underwent self-monitoring of blood glucose(SMBG).Both groups adjusted insulin doses based on blood glucose monitoring results.HbA1c was measured at 18 weeks and 36 weeks of pregnancy.Information related to adverse pregnancy outcomes was compared between the two groups.Results Fasting and postprandial glucose and HbA1c were significantly lower in FGM group compared with con group(P<0.05).Neonatal hypoglycemia was significantly lower in FGM group(P<0.05).There was no difference between the two groups in terms of BMI,insulin dose,gestational week of delivery,Apgar score,neonatal weight and the incidence of preeclampsia,premature delivery,polyhydramnios,cesarean section,SGA,macrosomia and postpartum hemorrhage(P>0.05).Time in range(TIR),time below range(TBR),time above range(TAR),and mean amplitude of glucose excursion(MAGE)were significantly improved at 32 weeks compared to 20 weeks in FGM group(P<0.05).Conclusions Repeated intermittent use of FGM in pregnant women with T2DM could reduce the blood glucose level and the incidence of neonatal hypoglycemia.

Objective To explore the mechanism by which diazepam alleviates lipopolysaccharide(LPS)-induced pyroptosis and inflammation to delay the progression of pulmonary fibrosis.Methods MRC-5 cells challenged with LPS were treated with diazepam and transfected with a let-7a-5p mimic alone or co-transfected with pc-DNA-MYD88.The changes in cellular expressions of inflammatory factors were analyzed with ELISA,and the expressions of fibrosis-and pyroptosis-related proteins were detected using Western blotting.In the animal experiment,C57BL/6 mice were randomized for treatment with LPS,LPS+diazepam,LPS+diazepam+let-7a-5p mimic,LPS+diazepam+ST2825(a MYD88 inhibitor),or LPS+diazepam+let-7a-5p mimic+pc-DNA-MYD88,and pulmonary fibrosis and pulmonary expression of α-SMA were examined using Masson staining and immunofluorescence staining,respectively.Results LPS exposure of MRC-5 cells significantly downregulated let-7a-5p expression,up-regulated MYD88 expression,increased the levels of IL-4,IL-6,TGF-β and TNF-α,and enhanced the expressions of fibrosis-related proteins(Col-I,Col-III,and α-SMA)and pyroptosis-related proteins(NLRP3,caspase-1,ASC,and GSDMD-N).Diazepam treatment of LPS-stimulated cells effectively inhibited the expressions of inflammation-related factors and the fibrosis-and pyroptosis-related proteins.In C57BL/6 mice,diazepam treatment obviously alleviated LPS-induced pulmonary fibrosis and reduced and pulmonary expression of α-SMA,and these effects were further enhanced by treatment with let-7a-5p mimic or ST2825,but the effect of let-7a-5p mimic was significantly attenuated by MYD88 over-expression.Conclusion Diazepam can negatively regulate MYD88 by upregulating the expression of let-7a-5p to inhibit LPS-induced pyroptosis and inflammatory response,thereby alleviating lung fibrosis in mice.