Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective To investigate influencing factors of textbook outcome(TO)in patients with pancreatic ductal adenocarcinoma undergoing minimally invasive pancreaticoduodenectomy(MIPD).Methods A retrospective analysis was conducted on the clinical data of 101 cases of pancreatic ductal adenocarcinoma treated with MIPD in our hospital from January 2020 to December 2022.According to the inclusion and exclusion criteria,89 cases were ultimately included in this study,of which 61 cases reached TO(TO group)and 28 cases did not reach TO(non-TO group).Variables with P<0.05 in univariate analysis were included in multivariate logistic regression analysis to identify independent prognostic factors of TO.Results Univariate analysis showed that there were significant differences in pancreatic duct dilation>3 mm,preoperative neutrophil lymphocyte ratio(NLR),extended hospital stay,postoperative hospitalstay,and drain fluid amylase(DFA)>1100 U/L at1-3 d aftersurgery(P<0.05).Multivariate logistic regression analysis showed that the independent prognostic factors affecting TO were:pancreatic duct dilation>3 mm(OR=7.290,95%CI:1.485-35.786,P=0.014),postoperative hospital stay(OR=0.862,95%CI:0.751-0.989,P=0.034),and the DFA on the first postoperative day>1100 U/L(OR=0.052,95%CI:0.005-0.545,P=0.014).Conclusions The outcome of TO in patients after MIPD is not related to the surgical approach(robot assisted minimally invasive pancreaticoduodenectomy or laparoscopic pancreaticoduodenectomy).Pancreatic duct dilation>3 mm,postoperative hospital stay,and DFA on the first postoperative day>1100 U/L are independent prognostic factors of TO after MIPD in patients with pancreatic ductal adenocarcinoma.

Objective To investigate influencing factors of textbook outcome(TO)in patients with pancreatic ductal adenocarcinoma undergoing minimally invasive pancreaticoduodenectomy(MIPD).Methods A retrospective analysis was conducted on the clinical data of 101 cases of pancreatic ductal adenocarcinoma treated with MIPD in our hospital from January 2020 to December 2022.According to the inclusion and exclusion criteria,89 cases were ultimately included in this study,of which 61 cases reached TO(TO group)and 28 cases did not reach TO(non-TO group).Variables with P<0.05 in univariate analysis were included in multivariate logistic regression analysis to identify independent prognostic factors of TO.Results Univariate analysis showed that there were significant differences in pancreatic duct dilation>3 mm,preoperative neutrophil lymphocyte ratio(NLR),extended hospital stay,postoperative hospitalstay,and drain fluid amylase(DFA)>1100 U/L at1-3 d aftersurgery(P<0.05).Multivariate logistic regression analysis showed that the independent prognostic factors affecting TO were:pancreatic duct dilation>3 mm(OR=7.290,95%CI:1.485-35.786,P=0.014),postoperative hospital stay(OR=0.862,95%CI:0.751-0.989,P=0.034),and the DFA on the first postoperative day>1100 U/L(OR=0.052,95%CI:0.005-0.545,P=0.014).Conclusions The outcome of TO in patients after MIPD is not related to the surgical approach(robot assisted minimally invasive pancreaticoduodenectomy or laparoscopic pancreaticoduodenectomy).Pancreatic duct dilation>3 mm,postoperative hospital stay,and DFA on the first postoperative day>1100 U/L are independent prognostic factors of TO after MIPD in patients with pancreatic ductal adenocarcinoma.

Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective To optimize the preparation process of Swertia patens,Burk.standard decoction and establish its quality standard by using the quality by design(QbD)concept.Methods Critical Quality Attributes(CQAs)were predicted and analyzed according to the quality marker(Q-marker)theory of traditional Chinese medicine;Failure mode and effects analysis(FMEA)was used to screen critical process parameters(CPPs);The measurement method of key quality attributes was established;The extraction process was optimized by Box Behnken test after the preliminary range was determined according to the single factor test;The entropy method was used for comprehensive scoring;The design space was established and the optimal operation space for process validation was selected;Standard decoction of Swertia patens Burk in fifteen batches with different habitats were prepared with the best technology,and the quality standards for the extraction rate,extract,thin layer chromatography,fingerprint,content,and the content transfer rate were established finally.Results The key quality attributes were swertiamarin content,gentiopicrin content,and paste yield;The key process parameters were soaking time,water amount,and decocting time;The established model had statistical significance;The optimum conditions were as follows:soaking time 90 min,adding water 15 times,decocting time 30 min(second decocting 20 min);The paste yield was 21.13％-30.73％;The extract was 82.00％-88.00％;The spot of swertiamarin was clear in TLC;The similarity between each samples in 15 batches and reference atlas were＞0.85％;The content of swertiamarin was 250.64-385.21 mg·g-1,and the transfer rate was 43.76％-77.73％;The content of gentiopicrin was 0.69-2.70 mg·g-1,and the transfer rate was 56.02％-105.29％.Conclusion Based on the above methods and techniques,the preparation process of Swertia patens Burk.The standard decoction was screened,which provides a reference for the preparation development and quality control of its formula granules.

Objective:To introduce the surgical method of Ortho-Bridge system (OBS) in the treatment of distal femoral fractures in elderly patients and investigate its clinical effect.Methods:From January 2018 to July 2021, 24 elderly patients who suffered distal femoral fractures were treated with bilateral OBS. There were 8 males and 16 females aging from 62 to 87 years, with an average age of 72.6 years. It included 15 cases of simple distal femoral fractures. According to AO classification, there were one case of A1, two of A2, five of A3, two of C1, three of C2 and two of C3. Nine cases of femoral periprosthetic fractures after total knee arthroplasty (TKA) were classified as type II according to rorabeck's classification. After operation, all patients were guided to perform knee joint functional exercise and to measure the range of motion of the knee joint. Then imaging examinations were used to evaluate the fracture healing and measure the femoral-tibial and femoral angles. The American Hospital for Special Surgery (HSS) knee joint scoring system was used to evaluate the knee function.Results:All 24 patients successfully completed the operation. The operation time was 84-115 min, with an average of 96.6 min; the intraoperative blood loss was 150-335 ml, with an average of 240 ml. All patients were followed up for 8-17 months, with an average of 13.6 months. Except for 1 case of nonunion due to few primary bone grafts, which required secondary bone grafting, the other 23 cases achieved bone union. The healing time was 3.5-6 months, with an average of 4.6 months. At 1, 3, and 6 months after operation and at the last follow-up, the flexion angles of knee were 92.2°±10.2°, 98.6°±13.3°, 106.4°±13.7°, 115.7°±15.3°, and the extension angles were -4.7°±4.1°, -1.2°±4.2°, 0.7°±4.5°, 1.8°±4.6°, respectively; and all differences were statistically significant ( F=17.03 and 12.68, P<0.001). The knee flexion and extension angles at the last follow-up were greater than 1, 3, and 6 months after operation, and the differences were statistically significant ( P<0.001). The femoral-tibial angle was 171.2°±2.4° and 170.7°±3.2°, and the femoral angle was 80.3°±1.7° and 79.6°±2.1°, respectively, at the immediate postoperative and last follow-up, with no significant difference. The HSS scores at 1, 3, 6 months after operation and at the last follow-up were 71.5±7.5, 74.6± 9.3, 78.9±10.4 and 84.7±9.4 respectively, with significant difference ( F=9.17, P<0.001). At the last follow-up, the HSS score was higher than that at 1, 3, and 6 months after the operation, and the differences were statistically significant ( P<0.001), and the knee function was evaluated according to the HSS scoring system: excellent in 12 cases, good in 9, fair in 3, with an excellent and good rate of 88% (21/24). There was no OBS crack or fixation failure in all patients, and no prosthetic loosening and instability occurred in patients with periprosthetic femoral fractures after TKA. Statistical analysis of the data at the last follow-up between the distal femoral fracture group and the periprosthetic femoral fracture group after TKA showed that the knee flexion function and HSS score of the periprosthetic femoral fracture group after TKA (126.8°±3.7°, 92.2±4.1) were both better than the simple distal femur fracture group (108.9°±15.7°, 80.2±8.8). The difference was statistically significant ( t=4.22, 4.52, P<0.05). One patient had incision fat liquefaction and healed after debridement; bone nonunion occurred in 1 case, which healed after iliac bone grafting. Conclusion:Double OBS has a good clinical effect in the treatment of distal femoral fractures in the elderly, especially in patients with periprosthetic femoral fractures after TKA.

Objective:To compare the biomechanical parameters of Ortho-Bridge system (OBS) and locking compression plate+locking attachment plate (LCP+LAP) in the fixation of femoral periprosthetic type B1 fracture.Methods:The same periprosthetic type B1 fracture of human femur were made, including simple fracture model and comminuted fracture model, 12 in each. And the simple fracture models were randomly divided into 6 pieces of OBS system fixation group and 6 pieces of LCP+LAP system fixation group, and the complex fracture models were also randomly divided into 6 pieces of OBS system fixation group and 6 pieces of LCP + LAP system fixation group. Then the four groups of models were tested by axial compression and torsion tests, and the stiffness of the models under axial compression and torsion angle of the models under torsion test were collected. The axial compression failure test was carried out to collect the vertical load of the ultimate failure test. The axial stiffness, torsion angle and axial failure load of OBS and LCP+LAP fixed simple and comminuted fractures were statistically analyzed by t test. Results:For the test of fixed simple fracture, there was no significant difference ( t=0.535, P=0.522) in the axial stiffness between the OBS group (868.87±157.14 N) and the LCP+LAP group (904.53±44.76 N), whereas the results of torsion test showed that the LCP+LAP group had a higher torsion angle 7.17°±0.52° than the OBS group 5.45°±0.44° ( t=5.616, P<0.001); When fixing comminuted fractures, the OBS group had a higher axial stiffness (145.33±10.34 N) than the LCP+LAP group (84.15±8.94 N) ( t=10.961, P<0.001), but the LCP+LAP group had a higher torsion angle 7.75°±1.17° than the OBS group 5.23°±0.31° ( t=4.652, P=0.001). Ultimate failure test data showed that the failure pressure of OBS fixed group (4 967.49±132.88 N) was higher than LCP+LAP group (3 967.41±145.16 N) ( t=12.447, P<0.001). In the LCP+LAP group, there was destruction of the contact cortex at the fracture site, while in the OBS group, there was destruction of the contact cortex at the fracture site as well as fractures around the proximal fixation screw. Conclusion:OBS group has similar axial compression resistance to LCP+LAP group, but better torsion resistance than LCP+LAP group when it is used to fix B1 simple fracture around femoral prosthesis. When comminuted fracture is fixed, the axial compression resistance and torsion resistance of OBS group are better than LCP+LAP group. The stress is dispersed during OBS fixation, which can better avoid the failure of internal fixation during early functional exercise.

OBJECTIVE： To mine and evaluate the post-marketing safety alert signals of pegaspargase （PEG-ASP） and L-asparaginase （L-ASP），and compare the safety differences between them ，so as to provide reference for clinical safe and rational drug use. METHODS ： The adverse drug event （ADE） reports of PEG-ASP and L-ASP issued by FDA adverse event reporting system from Jan. 1st，2004-Jun. 30th，2020 were retrieved. BCPNN method was used to mine the safety signals of these two drugs under the condition that the lower limit of information component （IC－2SD）＞0 and the number of events ≥3. The medium and strong signals of two drugs with IC －2SD≥1.5 were evaluated and compared in 8 system organ class，such as gastrointestinal system ，hepatobiliary system ，blood and lymphatic system ，blood vessels and lymphatic vessels ， nervous system ，immune system ，metabolism and nutrition ，various examinations. IC value of specific ADE signal and its 95％ confidence interval were analyzed by time scanning spectrum. RESULTS & CONCLUSIONS ：The reports of PEG-ASP and L-ASP as suspected drugs were 2 324 and 3 824；67 and 68 medium and strong signals were included ，respectively. In gastrointestinal system，the common strong signal of PEG-ASP and L-ASP was necrotic pancreatitis. In hepatobiliary system ，both of them showed strong signal in venoocclusive liver disease ，and this ADE was not included in the drug instruction. In blood and lymphatic system ， common strong signals of the two drugs were febrile neutropenia ，coagulation disorder ，neutropenia and febrile bone marrow regeneration disorder ；in blood vessels and lymphatic vessels ，in addition to haemodynamic instability ，IC values of other signals of L-ASP were higher than those of PEG-ASP. In nervous system ，IC values of other signals of L-ASP were higher than those of PEG-ASP except for intracranial haemorrhage. In immune system ，anaphylactic reaction was a medium signal for L-ASP but was a strong signal for PEG-ASP. In metabolism and nutritional diseases ，except for tumor lysis syndrome ，IC values of other signals of L-ASP were higher than those of PEG-ASP. The results of time scanning spectrum showed that the signals of necrotic pancreatitis and coagulation disorder of PEG-ASP were stable ，while the signals of veno occlusive liver disease and hypersensitivity were unstable and needed to be observed ；above four signals of L-ASP were stable signals. When using PEG-ASP or L-ASP clinically ， close attention should be paid to the safety problems such as hypersensitivity ，coagulation disorder ，thrombosis，necrotic pancreatitis，venoocclusive liver disease and hypoproteinemia.

Objective:To identify which induced the symptoms/signs and laboratory abnormal findings occurred in patients with novel coronavirus pneumonia, by disease itself or by ribavirin and interferon-alpha treatments, through mining the adverse events (AEs) signals of the 2 antivirus agents.Methods:According to the symptoms/signs and laboratory abnormal findings of novel coronavirus pneumonia mentioned in the literature and "Diagnosis and Treatment scheme of Novel Coronavirus Pneumonia (trial version 5)" , AEs in this study were selected. Related data were collected from the U.S. FDA Adverse Events Reporting System (FARES) from Jan 1, 2004 to Dec 31, 2019, and the reporting odds ratio ( ROR) method was used for signals detection for the above-mentioned 2 drugs. Results:A total of 7 582 463 AEs related to drugs were reported in the FAERS database, of which 31 775 related to ribavirin and 2 345 related to interferon-alpha. The results showed that AEs related to ribavirin in respiratory, thoracic, and mediastinal disorders were nasal congestion, cough, laryngeal pain, pharyngeal oedema, productive cough, and dyspnoea; AEs related to interferon-alpha were laryngeal pain and haemoptysis. In other system organ class, AEs related to above 2 drugs were pyrexia, feeling cold, pyrexia, nausea, vomiting, diarrhoea, headache, arthralgia, myalgia, and rash. AEs of laboratory abnormal results related to ribavirin were white blood cell/platelet count decrease and aspartate/alanine aminotransferase increase; AEs related to interferon-alpha were white blood cell/platelet count decrease, aspartate/alanine aminotransferase increase, and lymphocyte count decrease.Conclusion:Some AEs induced by ribavirin and interferon-alpha were similar to symptoms/signs and laboratory abnormal findings of novel coronavirus pneumonia, which should be distinguished in the clinical practice.

Objective:To identify which induced the symptoms/signs and laboratory abnormal findings occurred in patients with novel coronavirus pneumonia, by disease itself or by ribavirin and interferon-alpha treatments, through mining the adverse events (AEs) signals of the 2 antivirus agents.Methods:According to the symptoms/signs and laboratory abnormal findings of novel coronavirus pneumonia mentioned in the literature and "Diagnosis and Treatment scheme of Novel Coronavirus Pneumonia (trial version 5)" , AEs in this study were selected. Related data were collected from the U.S. FDA Adverse Events Reporting System (FARES) from Jan 1, 2004 to Dec 31, 2019, and the reporting odds ratio ( ROR) method was used for signals detection for the above-mentioned 2 drugs. Results:A total of 7 582 463 AEs related to drugs were reported in the FAERS database, of which 31 775 related to ribavirin and 2 345 related to interferon-alpha. The results showed that AEs related to ribavirin in respiratory, thoracic, and mediastinal disorders were nasal congestion, cough, laryngeal pain, pharyngeal oedema, productive cough, and dyspnoea; AEs related to interferon-alpha were laryngeal pain and haemoptysis. In other system organ class, AEs related to above 2 drugs were pyrexia, feeling cold, pyrexia, nausea, vomiting, diarrhoea, headache, arthralgia, myalgia, and rash. AEs of laboratory abnormal results related to ribavirin were white blood cell/platelet count decrease and aspartate/alanine aminotransferase increase; AEs related to interferon-alpha were white blood cell/platelet count decrease, aspartate/alanine aminotransferase increase, and lymphocyte count decrease.Conclusion:Some AEs induced by ribavirin and interferon-alpha were similar to symptoms/signs and laboratory abnormal findings of novel coronavirus pneumonia, which should be distinguished in the clinical practice.