OBJECTIVE To investigate the mechanism of Xibining Ⅱ formula in alleviating synovial inflammation and fibrosis in knee osteoarthritis （KOA） rats based on Janus kinase 2 （JAK2）/signal transducer and activator of transcription 3 （STAT3） pathway. METHODS Seventy-five male SD rats were randomly divided into sham operation group （Sham group）， KOA group， Xibining Ⅱ low-dose group （XBNⅡ-L group， 4 g/kg）， Xibining Ⅱ high-dose group （XBNⅡ-H group， 8 g/kg）， and Xibining Ⅱ high-dose combined with STAT3 activator Colivelin trifluoroacetate （C-TFA） group [C-TFA group， 8 g/kg Xibining Ⅱ+ 1.0 mg/（kg·d） C-TFA]， with 15 rats in each group. Except for the Sham group， the KOA model was established by anterior cruciate ligament transection in the other groups. After successful modeling， each group was given corresponding drugs by intragastric administration and （or） intraperitoneal injection once daily for 28 consecutive days. After the last medication， the pathological changes of synovial tissue of knee joint in each group were evaluated and the indicators were calculated. The levels of serum inflammatory factors were detected. The positive expressions of phosphorylated JAK2 （p-JAK2） and phosphorylated STAT3 （p-STAT3） in synovial tissue of the knee joint were detected. The expressions of JAK2/STAT3 pathway-related proteins and mRNAs in synovial tissue were detected. RESULTS Compared with the Sham group， the synovial lining cells in the KOA group showed significant proliferation and disordered arrangement； the Krenn score， fibrosis ratio， positive area percentage of p-JAK2 and p-STAT3， p-JAK2/JAK2 and p-STAT3/STAT3， protein expression of Collagen-Ⅰ and α -smooth muscle actin， the mRNA expression of JAK2， STAT3， Collagen-Ⅰ and α -smooth muscle actin， as well as serum levels of interleukin-1β and interleukin-18 were significantly increased （ P ＜0.05）. Compared with the KOA group， the above pathological changes were significantly improved in each dose group of Xibining Ⅱ formula， and all indicators were significantly decreased （ P ＜0.05）， with the XBNⅡ-H group showing better effects than the XBNⅡ-L group （ P ＜0.05）. Compared with the XBNⅡ-H group， the above pathological damages were aggravated in the C-TFA group， and all indicators were significantly worsened （ P ＜0.05）. CONCLUSIONS Xibining Ⅱ formula can alleviate synovial inflammation and fibrosis in KOA rats， and its mechanism may be related to inhibiting the activation of JAK2/STAT3 pathway.

ObjectiveTo establish and evaluate different disease-syndrome combination mice models of knee osteoarthritis （KOA） with cold-dampness obstruction syndrome， and to identify the optimal modeling method. MethodsEighty mice were randomly divided into a control group， a treadmill plus climate chamber group， an anterior cruciate ligament transection （ACLT） plus climate chamber group， an ACLT group， a destabilization of the medial meniscus （DMM） plus climate chamber group， a DMM group， an intra-articular injection plus climate chamber group， and an intra-articular injection group， with 10 mice in each group. Mice in the ACLT group underwent surgical transection of the knee anterior cruciate ligament to establish the model， while those in the DMM underwent surgical transection of the medial meniscal tibial ligament of the knee， and those in the intra-articular injection group were modeled by an intra-articular injection of 50 μl of normal saline containing 1mg of monosodium iodoacetate （MIA） into the medial side of the patellar ligament. Mice in the ACLT plus climate chamber， DMM plus climate chamber， and intra-articular injection plus climate chamber groups were placed in an artificial climate chamber （relative humidity 60%， temperature 4 ℃， wind speed 6 m/s） simultaneously with aforementioned interventions， once daily for 2 h each time， for 14 consecutive days. Mice in the control group underwent sham surgery， involving only the incision of the skin and subcutaneous tissue at the knee joint to expose the articular cavity， followed by layer-by-layer suturing. Mice in the treadmill plus climate chamber group were placed on an animal treadmill starting on the 4th day after the sham operation， undergoing high-intensity treadmill exercise at a speed of 20 m/min， an inclination of 5°， for 30min per session， 5 times per week for 28 consecutive days， while being housed in the artificial climate chamber. Cold pain thresholds of the mice in each group were compared using the cold plate test and the acetone low-temperature test before and after modeling. Following modeling， knee joint pathological changes were observed using HE and Safranin O-Fast Green staining， and quantified using Mankin and Osteoarthritis Research Society International （OARSI） scores. Serum levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were measured by ELISA. Protein and mRNA expression levels of pain-related markers， including calcitonin gene-related peptide （CGRP）， protein gene product 9.5 （PGP9.5）， and cellular proto-oncogene Fos （c-Fos）， and the cold hyperalgesia-related markers including transient receptor potential ankyrin 1 （TRPA1） and transient receptor potential melastatin 8 （TRPM8） in the dorsal root ganglion （DRG） tissues were detected by Western Blot and qPCR. TRPA1 and TRPM8 fluorescent intensity in the DRG was detected by immunofluorescence assay. ResultsCompared to the control group， the remaining groups showed decreased cold pain thresholds in the cold plate tese， increased cold pain thresholds in the acetone low-temperature test， elevated Mankin and OARSI scores， and increased serum TNF-α and IL-1β levels， upregulated protein and mRNA expression levels of CGRP， PGP9.5， c-Fos， TRPA1， and TRPM8 in the DRG， and increased immunofluorescence intensities of TRPA1 and TRPM8 in the DRG tissue （P＜0.05 or P＜0.01）， along with severe pathological damage and cartilage degeneration in the knee joints. Compared to the ACLT， DMM， and intra-articular injection groups， the ACLT plus climate chamber， DMM plus climate chamber， and intra-articular injection plus climate chamber groups exhibited more significant changes in all the aforementioned indicators （P＜0.01）. Furthermore， changes in the aforementioned indicators were more pronounced in the ACLT plus climate chamber group compared to the Treadmill plus climate chamber group， DMM plus climate chamber and intra-articular injection plus climate chamber group （P＜0.01）， exhibiting the most severe degree of pathological damage and cartilage degeneration. ConclusionThe combination of an artificial climate chamber can successfully establish a disease-syndrome combined animal model of KOA with cold-damp obstruction syndrome， with the ACLT combined with the artificial climate chamber being the optimal modeling approach.

ObjectiveTo establish and evaluate different disease-syndrome combination mice models of knee osteoarthritis （KOA） with cold-dampness obstruction syndrome， and to identify the optimal modeling method. MethodsEighty mice were randomly divided into a control group， a treadmill plus climate chamber group， an anterior cruciate ligament transection （ACLT） plus climate chamber group， an ACLT group， a destabilization of the medial meniscus （DMM） plus climate chamber group， a DMM group， an intra-articular injection plus climate chamber group， and an intra-articular injection group， with 10 mice in each group. Mice in the ACLT group underwent surgical transection of the knee anterior cruciate ligament to establish the model， while those in the DMM underwent surgical transection of the medial meniscal tibial ligament of the knee， and those in the intra-articular injection group were modeled by an intra-articular injection of 50 μl of normal saline containing 1mg of monosodium iodoacetate （MIA） into the medial side of the patellar ligament. Mice in the ACLT plus climate chamber， DMM plus climate chamber， and intra-articular injection plus climate chamber groups were placed in an artificial climate chamber （relative humidity 60%， temperature 4 ℃， wind speed 6 m/s） simultaneously with aforementioned interventions， once daily for 2 h each time， for 14 consecutive days. Mice in the control group underwent sham surgery， involving only the incision of the skin and subcutaneous tissue at the knee joint to expose the articular cavity， followed by layer-by-layer suturing. Mice in the treadmill plus climate chamber group were placed on an animal treadmill starting on the 4th day after the sham operation， undergoing high-intensity treadmill exercise at a speed of 20 m/min， an inclination of 5°， for 30min per session， 5 times per week for 28 consecutive days， while being housed in the artificial climate chamber. Cold pain thresholds of the mice in each group were compared using the cold plate test and the acetone low-temperature test before and after modeling. Following modeling， knee joint pathological changes were observed using HE and Safranin O-Fast Green staining， and quantified using Mankin and Osteoarthritis Research Society International （OARSI） scores. Serum levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were measured by ELISA. Protein and mRNA expression levels of pain-related markers， including calcitonin gene-related peptide （CGRP）， protein gene product 9.5 （PGP9.5）， and cellular proto-oncogene Fos （c-Fos）， and the cold hyperalgesia-related markers including transient receptor potential ankyrin 1 （TRPA1） and transient receptor potential melastatin 8 （TRPM8） in the dorsal root ganglion （DRG） tissues were detected by Western Blot and qPCR. TRPA1 and TRPM8 fluorescent intensity in the DRG was detected by immunofluorescence assay. ResultsCompared to the control group， the remaining groups showed decreased cold pain thresholds in the cold plate tese， increased cold pain thresholds in the acetone low-temperature test， elevated Mankin and OARSI scores， and increased serum TNF-α and IL-1β levels， upregulated protein and mRNA expression levels of CGRP， PGP9.5， c-Fos， TRPA1， and TRPM8 in the DRG， and increased immunofluorescence intensities of TRPA1 and TRPM8 in the DRG tissue （P＜0.05 or P＜0.01）， along with severe pathological damage and cartilage degeneration in the knee joints. Compared to the ACLT， DMM， and intra-articular injection groups， the ACLT plus climate chamber， DMM plus climate chamber， and intra-articular injection plus climate chamber groups exhibited more significant changes in all the aforementioned indicators （P＜0.01）. Furthermore， changes in the aforementioned indicators were more pronounced in the ACLT plus climate chamber group compared to the Treadmill plus climate chamber group， DMM plus climate chamber and intra-articular injection plus climate chamber group （P＜0.01）， exhibiting the most severe degree of pathological damage and cartilage degeneration. ConclusionThe combination of an artificial climate chamber can successfully establish a disease-syndrome combined animal model of KOA with cold-damp obstruction syndrome， with the ACLT combined with the artificial climate chamber being the optimal modeling approach.

Objective:To investigate the association of blood lipids and body mass index (BMI) with hyperuricemia (HUA) in the elderly.Methods:It was a cross-sectional study. A total of 114 391 elderly individuals received health examinations at primary healthcare institutions in Wujin District from January to December in 2022. The health examination included questionnaire survey, physical examination and laboratory examination. The multivariate logistic regression and restricted cubic spline (RCS) plots were used to analyze the association and dose-response relationship of blood lipid and BMI with HUA. The mediating effect model was used to explore the mediation effect of BMI on the association between blood lipid and HUA.Results:Among the 112 415 subjects, 18 506 (16.46%) were checked with HUA. After adjusting for relevant confounders, total cholesterol (TC) ( OR=1.20, 95% CI: 1.16-1.23), triglyceride (TG) ( OR=1.46, 95% CI: 1.44-1.49), high density lipoprotein cholesterol (HDL-C) ( OR=0.74, 95% CI: 0.73-0.76), low density lipoprotein cholesterol (LDL-C) ( OR=1.14, 95% CI: 1.12-1.15) and BMI ( OR=1.42, 95% CI: 1.39-1.44) were all associated with HUA (all P0.05). The RCS analysis revealed that TG, HDL-C, and LDL-C each exhibited a nonlinear dose-response relationship with HUA, the inflection points was 3.00 mmol/L, 1.57 mmol/L and 2.50 mmol/L, respectively (all P-nonlinear0.001). The results of interaction showed that there were additive interaction between high TC( S=1.27 , 95% CI: 1.17-1.37), high TG( S=1.32 , 95% CI: 1.25-1.40), high LDL-C( S=1.23 , 95% CI: 1.14-1.34) and overweight/obesity with HUA (all P0.05). The results of mediation effect analysis showed that the mediation effect of BMI on the association between blood lipids (HDL-C, LDL-C, TG and TC) and HUA, from high to low, were as follows: 22.5% (95% CI: 20.8%-24.2%), 13.9% (95% CI: 12.0%-16.2%), 13.5% (95% CI: 12.7%-14.4%) and-3.9% (95% CI:-6.6%--1.8%). Conclusion:The blood lipid levels and BMI are positively correlated with HUA in the elderly.

Objective:To investigate the association of blood lipids and body mass index (BMI) with hyperuricemia (HUA) in the elderly.Methods:It was a cross-sectional study. A total of 114 391 elderly individuals received health examinations at primary healthcare institutions in Wujin District from January to December in 2022. The health examination included questionnaire survey, physical examination and laboratory examination. The multivariate logistic regression and restricted cubic spline (RCS) plots were used to analyze the association and dose-response relationship of blood lipid and BMI with HUA. The mediating effect model was used to explore the mediation effect of BMI on the association between blood lipid and HUA.Results:Among the 112 415 subjects, 18 506 (16.46%) were checked with HUA. After adjusting for relevant confounders, total cholesterol (TC) ( OR=1.20, 95% CI: 1.16-1.23), triglyceride (TG) ( OR=1.46, 95% CI: 1.44-1.49), high density lipoprotein cholesterol (HDL-C) ( OR=0.74, 95% CI: 0.73-0.76), low density lipoprotein cholesterol (LDL-C) ( OR=1.14, 95% CI: 1.12-1.15) and BMI ( OR=1.42, 95% CI: 1.39-1.44) were all associated with HUA (all P0.05). The RCS analysis revealed that TG, HDL-C, and LDL-C each exhibited a nonlinear dose-response relationship with HUA, the inflection points was 3.00 mmol/L, 1.57 mmol/L and 2.50 mmol/L, respectively (all P-nonlinear0.001). The results of interaction showed that there were additive interaction between high TC( S=1.27 , 95% CI: 1.17-1.37), high TG( S=1.32 , 95% CI: 1.25-1.40), high LDL-C( S=1.23 , 95% CI: 1.14-1.34) and overweight/obesity with HUA (all P0.05). The results of mediation effect analysis showed that the mediation effect of BMI on the association between blood lipids (HDL-C, LDL-C, TG and TC) and HUA, from high to low, were as follows: 22.5% (95% CI: 20.8%-24.2%), 13.9% (95% CI: 12.0%-16.2%), 13.5% (95% CI: 12.7%-14.4%) and-3.9% (95% CI:-6.6%--1.8%). Conclusion:The blood lipid levels and BMI are positively correlated with HUA in the elderly.

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.
Medicine, Chinese Traditional ; Reproducibility of Results ; China ; Quality Control ; Pharmaceutical Preparations

Objective To investigate the effect of Yangxue Rougan pills on a rat model of liver fibrosis induced by multiple factors and the mechanism of action of Yangxue Rougan pills in the treatment of liver fibrosis. Methods A total of 50 male rats were randomly divided into blank control group, multi-factor model group, Fuzheng Huayu capsule group, and high-, middle-, and low-dose Yangxue Rougan pill groups. The rats in the blank control group were given normal water and feed, and those in the other groups were given modified high-fat low-protein diet and 5% alcohol, as well as subcutaneous injection of olive oil solution containing 40% carbon tetrachloride and intraperitoneal injection of pig serum 0.5 mL per rat, twice a week for 12 consecutive weeks. Since week 7, the rats in the high-, middle-, and low-dose Yangxue Rougan pill groups were given Yangxue Rougan pills at a dose of 9.5, 4.75, and 2.38 g/kg, respectively, those in the Fuzheng Huayu capsule group were given Fuzheng Huayu capsules at a dose of 0.75 g/kg, and those in the blank control group and the multi-factor model group were given an equal volume of distilled water by gavage every day for 6 consecutive weeks. The rats were treated at week 12. HE staining and Masson staining were used to observe the degree of liver fibrosis in rats, and PCR and Western blot were used to measure the expression of TGF-β1, Smad3, and Smad7 in the liver. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the Dunnett's t -test was used for further comparison between two groups. Results Compared with the blank control group, the multi-factor model group had a severely damaged lobular structure and a significantly higher degree of liver fibrosis, with the formation of pseudolobules with different sizes; compared with the multi-factor model group, the Yangxue Rougan pill groups had a significant improvement in the degree of liver fibrosis, with the most significant therapeutic effect in the high- and middle-dose Yangxue Rougan pill groups. Compared with the blank control group, the multi-factor model group had significant increases in the expression of TGF-β1 and Smad3 and a significant reduction in the expression of Smad7 in liver tissue (all P < 0.05); compared with the multi-factor model group, the Yangxue Rougan pill groups had a significant reduction in the expression of TGF-β1 and a significant increase in the expression of Smad7 (all P < 0.05); compared with the multi-factor model group, the high- and middle-dose Yangxue Rougan pill groups had a significant reduction in the expression of Smad3 (both P < 0.05). Conclusion Yangxue Rougan pills can significantly inhibit liver fibrosis in rats by downregulating the expression of TGF-β1 and Smad3 and upregulating the expression of Smad7, and therefore, the TGF-β1/Smad signaling pathway is one of the mechanisms of action of Yangxue Rougan pills in improving liver fibrosis.

To study the preventive effects of double guidewire technique combined with pancreatic duct stenting in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Patients receiving ERCP were divided into the treatment group and the control group by random number table. In the treatment group, double guidewire technique combined with pancreatic duct stenting was applied. In the control group, selective biliary intubation was applied in the conventional way. The intubation time, PEP, hyperamylasemia and bleeding incidence were analyzed between the two groups. A total of 80 patients were enrolled in this study from January 2016 to December 2018. There were 40 cases in the treatment group and 39 cases in the control group. In the treatment group, the mean intubation time was 384±102 seconds. No PEP or bleeding during and after the operation occurred, but hyperamylasemia occurred in 2 cases. In the control group, the mean intubation time was 427±115 seconds. Hyperamylasemia occurred in 6 cases, PEP occurred in 3 cases, and 1 case of intraoperative bleeding happened in the control group. The incidence of PEP [0 VS 7.7%(3/39)]and hyperamylasemia [5.0% (2/40)VS 15.4%(6/39)] were lower in the treatment group (both P<0.05). Double guidewire technique combined with pancreatic duct stenting can successfully perform selective bile duct intubation and effectively prevent PEP.

Objective:To investigate the inhibitory effects and mechanism of Reyanning mixture （RYN） combined with linezolid （LNZ） against methicillin-resistant Staphylococcus aureus （MRSA） and its biofilm. Method:The minimum inhibitory concentrations （MICs） of RYN and LNZ against MRSA were determined by microdilution assay. The microplate method was used to detect the changes in viable count before and after MRSA administration at four time points （0， 6， 12， 24 h） in the process of biofilm growth. The morphological changes of MRSA after 24 h were observed by scanning electron microscope. Metabonomic technique was applied to analyze the changes in terminal metabolites of endogenous small molecules from MRSA treated by the two drugs at four time points. Result:The MICs of RYN and LNZ were 1/2 of the stock solution concentration and 4 mg·L^-1， respectively. The inhibitory effect of LNZ （2 mg·L^-1） against viable bacteria at 0 h was better than that of 1/16 RYN. At 6， 12， 24 h， 1/16 RYN was superior to LNZ in inhibiting MRSA. The inhibitory effects of RYN combined with LNZ were better than those of RYN or LNZ alone at the four time points. RYN combined with LNZ caused more severe damages to the morphological structure of MRSA biofilm at 24 h than RYN or LNZ alone. Cyclic adenosine monophosphate （cAMP）， adenosine diphosphate （ADP）-D-ribose and 2-methylbutanoyl-coenzyme A （2M-CoA）， as the metabolites related to biofilm formation， were immune to LNZ， but 2M-CoA and ADP-D-ribose were influenced by RYN at 12 h and 24 h. The combined use of RYN and LNZ interfered with the three metabolites at 24 h. L-tryptophan， phenylpyruvic acid， cytidine and sebacic acid were the pharmacometabolic markers of LNZ， and the related biological pathways were phenylalanine， tyrosine and tryptophan biosynthesis and phenylalanine metabolism. Four metabolites such as L-histidine， uric acid， and L-lysine were the pharmacometabolic markers of RYN， with phenylalanine metabolism and aminoacyl-transfer ribonucleic acid （tRNA） biosynthesis confirmed as the related biological pathways. Nine metabolites such as L-tryptophan， L-lysine， and sphingosine-1-phosphate were responsible for the efficacy of RYN combined with LNZ. The related biological pathways involved aminoacyl-tRNA biosynthesis， phenylalanine， tyrosine and tryptophan biosynthesis， novobiocin biosynthesis， and tyrosine metabolism. Conclusion:RYN combined with LNZ better exerts the inhibitory effects against MRSA at each time point of its biofilm formation， which is attributed to cAMP metabolism. The synergistic effect resulted from aminoacyl-tRNA biosynthesis and phenylalanine， tyrosine and tryptophan biosynthesis. RYN combined with LNZ can serve as a potentially effective solution to MRSA infection.

Background: Cardiopulmonary resuscitation (CPR) strategies in COVID-19 patients differ from those in patients suffering from cardiogenic cardiac arrest. During CPR, both healthcare and non-healthcare workers who provide resuscitation are at risk of infection. The Working Group for Expert Consensus on Prevention and Cardiopulmonary Resuscitation for Cardiac Arrest in COVID-19 has developed this Chinese Expert Consensus to guide clinical practice of CPR in COVID-19 patients. Main recommendations: 1) A medical team should be assigned to evaluate severe and critical COVID-19 for early monitoring of cardiac-arrest warning signs. 2) Psychological counseling and treatment are highly recommended, since sympathetic and vagal abnormalities induced by psychological stress from the COVID-19 pandemic can induce cardiac arrest. 3) Healthcare workers should wear personal protective equipment (PPE). 4) Mouth-to-mouth ventilation should be avoided on patients suspected of having or diagnosed with COVID-19. 5) Hands-only chest compression and mechanical chest compression are recommended. 6) Tracheal-intubation procedures should be optimized and tracheal-intubation strategies should be implemented early. 7) CPR should be provided for 20-30 min. 8) Various factors should be taken into consideration such as the interests of patients and family members, ethics, transmission risks, and laws and regulations governing infectious disease control. Changes in management: The following changes or modifications to CPR strategy in COVID-19 patients are proposed: 1) Healthcare workers should wear PPE. 2) Hands-only chest compression and mechanical chest compression can be implemented to reduce or avoid the spread of viruses by aerosols. 3) Both the benefits to patients and the risk of infection should be considered. 4) Hhealthcare workers should be fully aware of and trained in CPR strategies and procedures specifically for patients with COVID-19.