Aim To design the pyrimidoindole deriva-tive N-butyl-9H-pyrimido[4,5-b]indole-2-carboxamide(BFPI)and synthesize it to investigate whether it in-hibits macrophage pyroptosis and foaming effects through the NLRP3/Caspase-1 pathway.Methods BFPI was synthesized using 2,4,6-triethoxycarbonyl-l,3,5-triazine and 2-aminoindole as starting materials and structurally characterized by 1H NMR,13C NMR,and ESI-MS.The in vitro cultured mouse monocyte macro-phage cell line RAW264.7 was divided into blank,model(PA)and therapeutic(BFPI)groups,and the cells in each group were treated with the corresponding culture medium for 24 h.The proliferative viability was detected by MTT assay,and the formation of intracel-lular lipid droplets was detected by oil red O staining,and NLRP3 was detected by Western-blot and RT-qPCR,caspase-1 and MCP-1 mRNA and protein ex-pression levels by Western blot and RT-qPCR.Results Compared with the blank group,the proliferation vi-ability of cells in the model group significantly de-creased and the formation of lipid droplets significantly increased;compared with the model group,the prolif-eration viability of cells in the treatment group signifi-cantly increased and the formation of lipid droplets sig-nificantly decreased,and the differences were statisti-cally significant(P＜0.01);compared with the blank group,the cellular NLRP3,caspase-1 and MCP-1 mR-NA and protein expression levels of cells in the model group significantly increased;compared with the model group,the expression levels of the above indexes of the cells in the treatment group significantly decreased,and the difference was statistically significant(P＜0.01).Conclusions BFPI contributes to delaying macrophage-derived foam cell formation during athero-genesis by inhibiting macrophage NLRP3,caspase-1,and MCP-1 expression and thereby promoting their pro-liferation and inhibiting lipid phagocytosis.

Aim To compare the pharmacokinetics of pemirolast potassium tablets in healthy subjects in Chi-na under single fasting and postprandial conditions,and to evaluate the bioequivalence of the test prepara-tion(T)and the reference preparation(R).Methods A randomized,open-ended,single-dose,two-cycle,double-cross bioequivalence trial design was adopted,and 26 and 30 subjects were enrolled in the fasting group and the postprandial group,respectively,and 10 mg of the test preparation and the reference preparation were taken in the fasting or postprandial state each cy-cle,and venous blood was collected at the designed time points before and after the administration cycle.The concentration of pemirolast potassium in plasma was determined by LC-MS/MS method,and the phar-macokinetic parameters were calculated with PhoenixTM WinNonlin ?(8.3)software,and the bioequivalence analysis of the two preparations was performed.Re-sults The t1/2 of the test preparation and the reference preparation was(4.44±0.91)h and(4.49±0.93)h,respectively;the median tmax was(1.96±1.29)h and(2.18±1.25)h,respectively;the Cmax was(867.12±205.56)μg·L-1 and(863.35±172.03)μg·L-1,respectively;the AUC0-t was(5 513.23±1463.67)h·μg·L-1 and(5 661.32±1 628.65)h·μg·L-1,respectively;AUC0_∞ was(5 699.81±1477.68)h·μg·L-1 and(5 849.44±1 644.75)h·μg·L-1,respectively.The statistical results of the 90％confidence intervals of the main pharmacokinetic parameters Cmax,AUC0-t,and AUC0-∞ was 92.49％～107.53％,94.71％～100.67％and 95.28％～100.27％,respectively,all of which were within the range of 80.00％～125.00％,and the safety of the tested preparation and the reference preparation was good when taken orally on an empty stomach.The t1/2 of single oral administration after prandial administra-tion of the tested preparation and the reference prepara-tion was(4.46±0.78)and(4.51±0.84)h,respec-tively;the median tmax was(3.08±1.36)h and(3.28±1.28)h,respectively;the Cmax was(683.83±111.87)μg·L-1 and(689.77±110.24)μg·L-1,respectively;the AUC0-t was(5 695.99±1566.05)h·μg·L-1 and(5 773.60±1 551.04)h·μg·L-1,respectively;the AUC0-∞ was(5 914.06±1 551.86)h·μg·L-1 and(5 967.30±1552.89)h·μg·L-1,respectively.The 90％confi-dence interval of Cmax,AUC0-t,and AUC0-∞ was 93.56％～104.69％,96.43％～100.83％,and 97.29％～101.14％,respectively,which was in the range of 80.00％～125.00％,and the safety of the tested preparation and the reference preparation was good after meals.Conclusion In the state of fasting and postprandial single oral administration,the two kinds of pemirolast potassium tablets have good bio-equivalence.

Septic cardiomyopathy(SIC)is an organ dysfunction frequently observed in sepsis and characterized by high mortality and poor prognosis.Understanding the complex pathogenesis of SIC and developing effective therapeutic tools are critical issues that require attention.Previous studies have demonstrated the significant role of mitochondrial dysfunction in the development of SIC.In the presence of SIC,and the mitochondrial dysfunction that result,the aberrant regulation of the mitochondrial quality control system(MQC)can exacerbate cardiomyocyte injury.Recent studies have demonstrated that the MQC maintains the dynamics of mitochondrial homeostasis through its regulation of mitochondrial biogenesis,fusion/fission,and autophagy.This article provides an overview of the role of MQC in SIC pathogenesis,reviews the latest studies in the field,and analyzes MQC's potential as a therapeutic target.

BACKGROUND:Irreducible femoral neck fracture was difficult to obtain anatomic reduction.As a new type of internal fixation,the femoral neck system is still blank for the treatment of non-anatomical reduced femoral neck fractures. OBJECTIVE:To explore the biomechanical stability of femoral neck system internal fixation under nonanatomical reduction in the treatment of femoral neck fractures based on finite element analysis. METHODS:CT data of the hip joint of a healthy female adult were obtained.Anatomical reduction of femoral neck fracture models with Pauwels angles of 30°,50°,and 70° were established using Mimics 21.0,Geomagic Wrap 2021,and SolidWorks 2020.The fracture proximal ends of the three anatomical reduction models were shifted upward by 2 mm along the fracture line,and three positive buttress models with different Pauwels angles were obtained.In the same way,three negative buttress models were acquired by shifting downward by 2 mm.SolidWorks 2020 was used to make the femoral neck system internal fixation,and the nine femoral neck fracture models were assembled with the femoral neck system.Then Ansys 19.0 was used for finite element analysis.The displacement distribution and maximum displacement,stress distribution and maximum stress of the femur and femoral neck system were recorded under 2100 N stress. RESULTS AND CONCLUSION:(1)When Pauwels angles were 30°,50°,and 70°,the maximum stresses of the femoral neck system appeared to be concentrated at the junction of the sliding hip screw and anti-rotation screw.The maximum femur stresses appeared to be concentrated in the medial cortex of the femur.The maximum displacement was concentrated at the upper of the femoral head and femoral neck system.(2)When Pauwels angles were 30° and 50°,the maximum displacement and maximum stress of the femoral neck system and femur were:negative buttress>anatomical reduction>positive buttress.(3)When Pauwels angle was 70°,the maximum displacement and maximum stress of the femoral neck system were:negative buttress>anatomical reduction>positive buttress;the maximum displacement and maximum stress of the femur were:negative buttress>positive buttress>anatomical reduction.(4)With the increase of Pauwels angle,the biomechanical advantage of the positive buttress was weakening.However,it was better than a negative buttress.When Pauwels angle was 30°,positive buttress was more stable than anatomical reduction.When Pauwels angle was 50°,the biomechanical difference between positive buttress and anatomical reduction became smaller.When Pauwels angle was 70°,the stability of anatomical reduction was slightly better than positive buttress.(5)If it was difficult to achieve anatomical reduction of femoral neck fracture during operation,but the positive buttress had been displaced within 2 mm,the femoral neck system could be used to offer stable mechanical fixation.It is necessary to avoid negative buttress reduction.

ObjectiveTo investigate the risk factors for early tumor recurrence after laparoscopic pancreaticoduodenectomy （LPD） in patients with pancreatic ductal adenocarcinoma （PDAC）， and to establish a predictive model. MethodsA retrospective analysis was performed for the clinical data of 240 PDAC patients who underwent LPD in The First Hospital of Jilin University from April 2016 to July 2022， with early postoperative tumor recurrence （time to recurrence ≤12 months） as the study outcome. The patients were randomly divided into training group with 168 patients and validation group with 72 patients at a ratio of 7∶3. In the training group， there were 70 patients （41.67%） with early postoperative recurrence and 98 （58.33%） without early recurrence， and in the validation group， there were 32 （44.44%） with early postoperative recurrence and 40 （55.56%） without early recurrence. The chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups； a logistic regression analysis was used to investigate the risk factors for early postoperative recurrence； the receiver operating characteristic （ROC） curve and the area under the ROC curve （AUC） were used to evaluate the discriminatory ability of the model， with AUC>0.75 indicating that the model had adequate discriminatory ability. The Bootstrap resampling method was used for validation after 1 000 times of random sampling， and the model was validated again in the validation group. The calibration curve and the Hosmer-Lemeshow goodness-of-fit test were used to evaluate the degree of calibration， and the decision curve analysis was used to evaluate clinical practicability. ResultsThe univariate and multivariate analyses showed that preoperative CA19-9 level≥37 U/mL （odds ratio ［OR］=6.265， 95% confidence interval ［CI］： 1.938‍ ‍—‍ ‍20.249， P<0.05）， maximum tumor diameter >3 cm （OR=10.878， 95%CI： 4.090‍ ‍—‍ ‍28.932， P<0.05）， poor tumor differentiation （OR=3.679， 95%CI： 1.435‍ ‍—‍ ‍9.433， P<0.05）， lymph node metastasis （OR=0.209， 95%CI： 0.080‍ ‍—‍ ‍0.551， P<0.05）， and absence of adjuvant chemotherapy after surgery （OR=0.167， 95%CI： 0.058‍ ‍—‍ ‍0.480， P<0.05）. A nomogram model was constructed based on these factors； the ROC curve analysis showed that the model had an AUC of 0.895 （95%CI： 0.846‍ ‍—‍ ‍0.943， P<0.001）， and the calibration curve and the Hosmer-Lemeshow test showed that the model had a good degree of calibration （P=0.173）. The decision curve analysis showed that the nomogram had a good clinical application value. ConclusionPreoperative CA19-9 level ≥37 U/mL， maximum tumor diameter >3 cm， poor tumor differentiation， lymph node metastasis， and absence of adjuvant chemotherapy after surgery are independent risk factors for the early recurrence of PDAC after LPD， and the nomogram model established based on these factors can effectively predict early postoperative recurrence.

Objective To evaluate the bioequivalence of the vardenafil hydrochloride tablets in fasting and fed conditions in healthy Chinese adult subjects with the test and reference formulations.Methods A randomized,open,single-dose,two-preparation,two-sequence,two-period,crossover design was used,and 40 healthy male subjects enrolled in the fasting state and 66 healthy male subjects enrolled in the fed state.The trial was conducted in two cycles,with 20 mg of either the subject formulation or the reference formulation,vardenafil hydrochloride tablets,being administered in each cycle.The drug concentration of vardenafil in plasma was determined by the liquid chromatography-tandem mass spectrometry(LC/MS-MS)method.Pharmacokinetic parameters were calculated using the non-compartment model,and the safety evaluation indexes were statistically analyzed using SAS 9.4 or above version program data statistical software.Results Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of vardenafil hydrochloride tablets and the reference formulation in the fasting state:Cmaxwere(34.94±18.33)and(36.69±19.45)ng·mL-1;AUC0-t were(74.38±34.11)and(74.25±33.37)ng·mL-1·h;AUC0-∞ were(76.70±34.36)and(76.46±33.84)ng·mL-1·h,respectively.Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of vardenafil hydrochloride tablets and the reference formulation in the fed state:Cmax were(22.84±12.48)and(21.68±11.12)ng·mL-1;AUC0_twere(70.82±35.88)and(72.71±34.63)ng·mL-1·h;AUC0-∞ were(73.48±36.44)and(75.29±35.12)ng·mL-1·h,respectively.The 90％confidence intervals for the geometric mean ratios of the main pharmacokinetic parameters such as Cmax,AUC0-t and AUC0-∞ of the prototype drug vardenafil in plasma after oral administration of 20 mg of the test and reference formulations of vardenafil tablets to the subjects in fasting and postprandial states fell within the equivalence interval of 80.00％to 125.00％.Conclusion The subject formulation of vardenafil hydrochloride tablets was bioequivalent to the reference formulation in fasting and fed conditions in healthy Chinese subjects.

Gegen Qinlian decoction has a wide range of clinical applications. However, there is a lack of systematic quality evaluation methods to ensure the safety and effectiveness of Gegen Qinlian decoction in clinical use. The UHPLC fingerprint and multi-component determination method of Gegen Qinlian decoction were established to provide scientific basis for the quality control and evaluation of Gegen Qinlian decoction. The chromatography was performed on a ZORBAX Eclipse Plus-C₁₈ column (150 mm × 4.6 mm, 3.5 μm) with mobile phase consisted of acetonitrile (A) - 20 mmol·L^-1 ammonium acetate (containing 0.8% acetic acid and 0.5% triethylamine) (B) and gradient elution at a flow rate of 1.0 mL·min^-1. The column temperature was 25 ℃, the detection wavelength was 260 nm, the fingerprint of 10 batches of Gegen Qinlian decoction was determined, and the similarity evaluation system of TCM chromatographic fingerprint was used for comprehensive analysis, and 9 components were quantitatively analyzed. In the fingerprint study of Gegen Qinlian decoction, a total of 18 peaks were obtained, 12 of which were identified by reference substances. Moreover, the similarity of 10 batches of Gegen Qinlian decoction was good, and all of them were greater than 0.99. In the multi-component quantitative analysis, the linear relationship between the nine components and the peak area was good (r ≥ 0.999) in the corresponding mass concentration range. The average recovery rate was 94.4%-100.3%, and the RSD was 0.1%-1.4%. The fingerprint of Gegen Qinlian decoction was studied under the same wavelength, and the content of 9 main components were determined by our established method. The method has high sensitivity and strong specificity, which provided a comprehensive scientific basis for the comprehensive evaluation of the quality of Gegen Qinlian decoction.

"Shaoyang as the pivot"is one of the important concepts in the theory of traditional Chinese medicine.It is believed that shaoyang is located between half exterior and half interior,which reaches the muscular striae and the exterior and connects with the internal organs,and plays the role of promoting qi movement,regulating water channel and distributing ministerial fire.The dysfunction of shaoyang pivot leads to the disorder of qi movement,abnormal water metabolism,and stagnation or hyperactivity of ministerial fire.Cholinergic urticaria is a special type of urticaria caused by the disorder of cholinergic nerve conduction,which has a long course of disease and is difficult to be cured.According to the clinical characteristics of the disease,Professor SUI Dao-Shun believes that the dysfunction of shaoyang pivot is the core pathogenesis of cholinergic urticaria.Emotional disorders lead to the dysfunction of pivot,and then cause the disordered flow of qi and fluid and internal disturbance of hyperactive ministerial fire,which induce the disharmony between nutritive qi and defensive qi,and the failure of being against the pathogens.Finally,wind pathogen attacks the skin and muscular striae and becomes latent,and results in cholinergic urticaria.For the treatment of cholinergic urticaria,Chaihu Guizhi Decoction can be used as the basic prescription to harmonize shaoyang,expel pathogens and release exterior.Corresponding modification of herbal medicines should be performed for various syndromes caused by the dysfunction of shaoyang pivot such as qi stagnation,dampness retention and heat stagnation during the clinical application.The prevention and treatment of cholinergic urticaria based on the theory of shaoyang as the pivot can provide thoughts for the clinical treatment of cholinergic urticaria.

Objective To investigate the therapeutic effect of transcutaneous auricular vagus nerve stimulation(taVNS)on overweight/obesity patients,and to explore its central mechanism.Methods Twenty-six overweight/obesity patients were randomly divided into two groups,12 cases in the taVNS test group(shortened as the taVNS group)and 14 cases in the lifestyle intervention control group(shortened as the control group).The patients in the control group were treated with online lifestyle intervention of calorie-restricted diet(CRD),and the patients in the taVNS group were treated with taVNS on the basis of the intervention for the control group.The taVNS was performed on unilateral acupoints of spleen and endocrine,twice(in the morning and at evening)per day,for five days a week.The treatment for the two groups covered four weeks.The obesity indicators such as body weight,body mass index(BMI)and waist circumference of the patients in the two groups were observed before and after treatment.Moreover,the resting-state cerebral functional magnetic resonance imaging(fMRI)data of the patients were collected after treatment,and then the regulatory effect of taVNS on the regional homogeneity(ReHo)of local cerebral area of the patients was observed.Results(1)During the trial,one case in each group dropped off,and a total of 24 patients(including 13 cases in the control group and 11 cases in the taVNS group)were finally included in the statistical analysis of the observation indicators.(2)After treatment,the body weight,BMI and waist circumference of patients in the taVNS group were decreased compared with those before treatment(P＜0.05),while the obesity indicators in the control group only showed a downward trend compared with those before treatment,the differences being not statistically significant(P＞0.05).The improvement of the obesity indicators of body weight,BMI,and waist circumference in the taVNS group was significantly superior to that in the control group,and there were statistically significant differences in the post-treatment indicators and in the pre-and post-treatment difference values of the indicators between the two groups(P＜0.05 or P＜0.01).(3)After treatment,the taVNS group had greater ReHo values in the left prefrontal lobe and medial frontal gyrus than the control group,and the control group had greater ReHo value in the right parietal lobe than the taVNS group,which indicated that compared with the control group,the ReHo of the left prefrontal lobe and medial frontal gyrus in the taVNS group was increased and the ReHo of the right parietal lobe was decreased(Pvoxel＜0.001,Pcluster＜0.05,corrected by FWE level).Conclusion As a non-invasive treatment method,taVNS exerts certain efficacy for the treatment of overweight/obesity patients.The central response mechanism for treatment of obesity is probably related with the modulation of taVNS on the functional areas of left prefrontal lobe,medial frontal gyrus,and right parietal lobe of the patients.

Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.