Objective To evaluate the efficacy,safety and economy of inclisiran in the treatment of dyslipidemia by rapid health technology assessment,and to provide evidence-based basis for clinical treatment.Methods PubMed,Web of Science,Embase,Cochrane Library,CNKI,WanFang Data,VIP,SinoMed databases,and official websites of health technology assessment(HTA)institutions were systematically searched to collect HTA reports,systematic reviews/Meta-analysis and pharmacoeconomic studies on inclisiran for the treatment of dyslipidemia from inception to December 31,2024.Two researchers independently screened the literature,extracted information and performed quality assessment of the included literature,and then qualitative synthesis and analysis of the findings were conducted.Results A total of 8 studies were included,comprising 7 systematic reviews/Meta-analysis and 1 pharmacoeconomic study.In terms of efficacy,inclisiran significantly reduced low-density lipoprotein cholesterol,apolipoprotein B,total cholesterol,triglycerides and non-high-density lipoprotein cholesterol levels in patients with dyslipidemia compared to placebo.In terms of safety,the incidence of adverse drug reactions associated with inclisiran did not differ significantly from that of placebo,with the most common adverse drug reactions being mild injection site reactions.In terms of cost-effectiveness,the current price of inclisiran made its combination therapy with statins economically unfavorable compared to statin monotherapy.Conclusion The efficacy and safety of inclisiran in the treatment of dyslipidemia are good.However,due to its current pricing,the combination therapy of inclisiran with statins is not yet cost-advantageous compared to statin monotherapy in clinical practice.

BACKGROUND:Adipose tissue-derived mesenchymal stem cells release a large amount of exosomes to participate in various pathophysiological processes,but the impact and precise mechanism of exosomes derived from adipose tissue-derived mesenchymal stem cells on autophagy of hepatic stellate cells have not been fully elucidated.OBJECTIVE:To explore the targeted regulatory effect and molecular mechanism of adipose tissue-derived mesenchymal stem cell-derived exosomes on autophagy of hepatic stellate cells through miR-15a-5p.METHODS:Adipose tissue was collected from inguinal region of 8-week male C57BL/6 mice.Adipose tissue-derived mesenchymal stem cells were extracted by collagenase digestion.Adipose tissue-derived mesenchymal stem cell-derived exosomes were extracted by ultracentrifugation.Mouse liver tissue was obtained,and hepatic stellate cells were isolated and extracted using collagenase perfusion digestion and density gradient centrifugation.The experiment was divided into two groups.In control group,hepatic stellate cells were cultured alone for 48 hours.In the exosome group,hepatic stellate cells were co-cultured with adipose tissue-derived mesenchymal stem cell-derived exosomes for 48 hours.The effects of exosomes on hepatic stellate cell proliferation,activation,autophagy,and expression of fibrosis markers were detected by western blot assay,RT-qPCR,and immunofluorescence staining.RT-qPCR and western blot assay were used to detect the effect of exosomes on the mRNA and protein expression of miR-15a-5p and the downstream signaling pathway Bcl-2,Beclin-1,and Rubicon in hepatic stellate cells.RESULTS AND CONCLUSION:(1)Compared with the control group,the ratio of autophagy markers LC3-Ⅱ expression decreased,the number of autophagosome was also significantly decreased,and the intracellular lipid droplets were regenerated,simultaneously,cell volume diminished with the weakening of proliferation in hepatic stellate cells of the exosome group,indicated that the hepatic stellate cell activation was significantly inhibited.(2)Compared with the control group,the expressions of α-smooth actin and type Ⅰ collagen were significantly decreased(P＜0.01),and the expression of miR-15a-5p was significantly increased in hepatic stellate cells of the exosome group(P＜0.01).At the same time,the expression of its downstream target gene Bcl-2 was significantly decreased(P＜0.01),while the expressions of autophagy genes Beclin-1 and Rubicon were significantly increased in hepatic stellate cells of the exosome group(P＜0.01).The results indicate that adipose tissue-derived mesenchymal stem cell-derived exosomes inhibits the expression of Bcl-2 in hepatic stellate cells by targeting miR-15a-5p and increases the expression of downstream autophagy genes Beclin-1 and Rubicon,thereby inhibiting the autophagy of hepatic stellate cells.

Objective:To evaluate the efficacy of remimazolam-based anesthesia in daytime laparoscopic cholecystectomy.Methods:In this multicenter, non-inferiority, randomized controlled trial, 300 American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ patients of either sex, aged 18-60 yr, with body mass index of 18-28 kg/m 2, who underwent daytime laparoscopic cholecystectomy under general anesthesia with tracheal intubation at Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou First People′s Hospital Affiliated to Westlake University School of Medicine, Ningbo No. 2 Hospital, and the Second Affiliated Hospital of Nanchang University from August 2021 to August 2023, were selected and divided into 2 groups ( n=150 each) using a random number table method: remimazolam group (R group) and propofol group (P group). Anesthesia was induced as follows: Sufentanil was intravenously injected at a rate of 0.5 μg/kg, remimazolam was intravenously injected at a rate of 0.3 mg/kg in group R, propofol was intravenously injected at a rate of 2.0-2.5 mg/kg in group P, and cisatracurium besilate was intravenously injected at a rate of 0.2 mg/kg after loss of consciousness in two groups. The patients were mechanically ventilated after tracheal intubation. Anesthesia was maintained as follows: Remimazolam was intravenously injected at a rate of 0.5-1.0 mg·kg -1·h -1 in group R, propofol was intravenously injected at a rate of 4-10 mg·kg -1·h -1 in group P, and remifentanil was intravenously infused at a rate of 0.25-2.00 μg·kg -1·min -1, maintaining intraoperative bispectral index value of 40-60. The success rate of sedation was recorded, and non-inferiority tests were conducted. The time to loss of consciousness, emergence time, extubation time, recovery time of orientation, time of stay in post-anesthesia care unit and occurrence of delayed emergence were recorded. Liver function and renal function were measured before operation and within 24 h after operation. The occurrence of abnormal alanine transaminase, abnormal aspartate transaminase, abnormal creatinine and abnormal urea was recorded. The occurrence of adverse reactions during and after operation was recorded. Results:The success rates of sedation were 98.6% and 99.3% in group R and group P, respectively, there was no statistically significant difference in the success rate of sedation between the two groups ( P>0.05), and the difference in the success rates of sedation between the two groups was -0.007 (95% confidence interval-0.0301-0.0161), which met the pre-set non-inferiority criteria(95% confidence interval >-0.055). Compared with group P, the time to loss of consciousness and recovery time of orientation were significantly prolonged, and the incidence of delayed emergence was increased ( P<0.05), and no statistically significant changes were found in the emergence time, extubation time, time of stay in post-anesthesia care unit and severity of postoperative nausea and vomiting in group R ( P>0.05). There was no statistically significant difference in the abnormal rates of alanine transaminase, aspartate transaminase, creatinine and urea before and after operation between the two groups ( P>0.05). Conclusions:The efficacy of remimazolam-based anesthesia in daytime laparoscopic cholecystectomy is not inferior to that of propofol-based anesthesia.

Objective To evaluate the efficacy,safety and economy of inclisiran in the treatment of dyslipidemia by rapid health technology assessment,and to provide evidence-based basis for clinical treatment.Methods PubMed,Web of Science,Embase,Cochrane Library,CNKI,WanFang Data,VIP,SinoMed databases,and official websites of health technology assessment(HTA)institutions were systematically searched to collect HTA reports,systematic reviews/Meta-analysis and pharmacoeconomic studies on inclisiran for the treatment of dyslipidemia from inception to December 31,2024.Two researchers independently screened the literature,extracted information and performed quality assessment of the included literature,and then qualitative synthesis and analysis of the findings were conducted.Results A total of 8 studies were included,comprising 7 systematic reviews/Meta-analysis and 1 pharmacoeconomic study.In terms of efficacy,inclisiran significantly reduced low-density lipoprotein cholesterol,apolipoprotein B,total cholesterol,triglycerides and non-high-density lipoprotein cholesterol levels in patients with dyslipidemia compared to placebo.In terms of safety,the incidence of adverse drug reactions associated with inclisiran did not differ significantly from that of placebo,with the most common adverse drug reactions being mild injection site reactions.In terms of cost-effectiveness,the current price of inclisiran made its combination therapy with statins economically unfavorable compared to statin monotherapy.Conclusion The efficacy and safety of inclisiran in the treatment of dyslipidemia are good.However,due to its current pricing,the combination therapy of inclisiran with statins is not yet cost-advantageous compared to statin monotherapy in clinical practice.

Objective:To explore the application value of right-opening single flap valvuloplasty based on tubular stomach in gastrointestinal reconstruction after laparoscopic proximal gastrectomy.Method:Use a linear cutting stapler to make a parallel curve from the angle of the stomach to the junction of the gastric fundus to remove the lesser curvature of the stomach, and detach the gastric body about 5 cm away from the tumor to create a tubular stomach. Use a marker pen to draw a C-shaped seromuscular flap area with a width of 2.5 cm and a height of 3.5 cm 1.5 cm below the residual stomach closure nail, and create a free muscle flap in the gap between the plasma muscle layer and the submucosal layer. Make a transverse incision of 3 cm at the lower edge of the mucosal bed, and intermittently suture the entire lower edge of the gastric wall with 3 stitches. Under laparoscopy, use 4-0 barbed wire to suture the 1 cm wide muscular layer at the top of the tubular stomach and the posterior wall of the esophagus about 5 cm away from the esophageal stump with 3 stitches. Push the upper end of the tubular stomach into the mediastinum, and then tighten the barbed wire to ensure a tight fit between the stomach and the posterior wall of the esophagus. Use an ultrasonic scalpel to remove the esophageal stump, suture the entire posterior wall of the esophagus with the gastric mucosa, and use barbed wire to suture the anterior wall from left to right. The anastomotic site is completely covered with a free muscle flap, and the barbed line is used to continuously suture the muscle flap along the C-shaped line to the gastric pulp muscle layer at the edge of the mucosal bed, embedding the anastomotic site and completing the reconstruction of the digestive tract.Results:Clinical data of 23 patients (18 from the First Affiliated Hospital of Wenzhou Medical University and 5 from the Quzhou Hospital affiliated with Wenzhou Medical University) who underwent laparoscopic proximal gastrectomy, tubular gastroesophageal anastomosis, and pure manual right flap reconstruction surgery for esophagogastric junction adenocarcinoma and proximal gastric cancer from October 2023 to August 2024. There were 15 males and 8 females, with an age of (65.3±7.7) years, the BMI was (22.9±2.8) kg/m 2. All patients in the group successfully completed the surgery, with a surgery time of (218.5±38.1) minutes, including (73.5±19.2) minutes for anastomosis, intraoperative blood loss of (64.5±15.4) ml, postoperative passage of gas on (3.4±0.5) days, first consumption of liquid food after surgery of (3.9±1.1) days, and postoperative hospital stay of (9.1±0.8) days. One patient developed anastomotic stenosis (grade I) after surgery, presenting with mild swallowing obstruction, which returned to normal after dietary adjustment, and there were no cases of secondary surgery. The median follow-up time for the entire group was 4.0 (0.7-7.0) months, during which there were no deaths or tumor recurrence or metastasis, no complications such as anastomotic stenosis or gastric emptying disorders, and no complaints of acid reflux or heartburn. At one month of postoperative follow-up, the reflux symptom index (RSI) score was (3.1±2.9) points, and at three months, the RSI score was (2.4±1.4) points. Conclusions:The application of right-opening single flap valvuloplasty based on tubular stomach for gastrointestinal reconstruction after laparoscopic proximal gastrectomy is safe,feasible,and has satisfactory short-term efficacy.

BACKGROUND:Studies have shown that gut microbiota may affect the progression of rheumatoid arthritis.However,the causal relationship between the two is unknown.Mendelian randomization analysis of the two using published Genome Wide Association Study(GWAS)data can explore the causal relationship between gut microbiota and rheumatoid arthritis,helping to develop targeted microbial therapies and provide methods and strategies for the prevention and treatment of rheumatoid arthritis.OBJECTIVE:To explore the potential causal relationship between gut microbiota and rheumatoid arthritis using two-sample two-way Mendelian randomization method.METHODS:Gut microbiota GWAS data from the MiBio-Gen consortium and rheumatoid arthritis GWAS data from the IEU Open GWAS database(a large gene-phenotype association database developed at the MRC Integrative Epidemiology Unit(IEU)at the University of Bristol,UK)were used.Inverse variance weighting was used as the main analysis method,and MR-Egger regression method,weighted median method,weighted model and simple model method were used as supplements to study the causal relationship between gut microbiota and rheumatoid arthritis.Heterogeneity was assessed using Cochran's Q test,horizontal pleiotropy was assessed using MR-PRESSO and MR-Egger intercept tests,robustness of results was tested using leave-one method,and reverse Mendelian randomization analysis was used to assess the presence or absence of reverse causality.RESULTS AND CONCLUSION:(1)There was a causal relationship between five kinds of enteric bacteria and rheumatoid arthritis.Ruminococcus gauvreauii group(β=0.262,odds ratio[OR]=1.300,P=0.013)and Butyricimonas(β=0.001,OR=1.001,P=0.014)increased the risk of rheumatoid arthritis,while Anaerostipes(β=-0.225,OR=0.798,P=0.025),Lachnospiraceae-UCG010(β=-0.177,OR=0.838,P=0.026)and Oxalobacter(β=-0.171,OR=0.843,P=0.001)reduced the risk of rheumatoid arthritis.Sensitivity analyses showed no significant heterogeneity or horizontal pleiotropy(all P＞0.05),and leave-one-out testing confirmed the robustness of the results,while the addition of the remaining four methods other than the inverse variance weighting method further validated the reliability and stability of the results.(2)Reverse Mendelian randomization analysis did not find a causal association between rheumatoid arthritis and the five kinds of enteric bacteria identified by Mendelian randomization analysis.These findings indicate that Ruminococcus gauvreauii group and Butyricimonas may be the risk factors of rheumatoid arthritis,while Anaerostipes,Lachnospiraceae-UCG010 and Oxalobacter may be the protective factors of rheumatoid arthritis.Gut microbiota may play an important role in the pathogenesis of rheumatoid arthritis,and provide new biomarkers for the prevention and treatment of rheumatoid arthritis.In addition,for the field of biomedical research in China,we can learn from international experience and gradually establish and improve a multi-center large-scale genetic database,so as to deeply explore the relationship between gut microbiota and disease risk,and promote the development of precision medicine and personalized treatment in China.

Objective To investigate the vasodilatory effect of luteolin on isolated denuded-endothelium rat thoracic aorta(DRTA)vascular rings,and the mechanistic role of the Kv7 ion channel.Methods The tension of DRTA vascular rings was measured using an ex vivo tissue perfusion muscle-tone detection system.DRTA vascular rings were pre-contracted with 60 mmol/L KCl or 0.3 μmol/L U46619,and the effect of luteolin on vascular-ring relaxation was observed at 1,3,10,30,100 and 300 μmol/L.The effects of 4-AP,XE-991,and ML213 on luteolin-induced vasodilation were also observed.The effect of luteolin on KCNQ1-KCNQ5 expression in the thoracic aorta was detected by real-time fluorescence quantitative polymerase chain reaction.Expression levels of Kv7.1 and Kv7.4 proteins in the DRTA were detected by Western blot.Results(1)The luteolin-induced maximum vasodilation rates in DRTA pre-contracted with 60 mmol/L KCl and 0.3 μmol/L U46619 were(97.67±8.51)％and(98.42±9.76)％,respectively.The vasodilation effect was concentration-dependent(P＜0.05).(2)4-AP(3 mmol/L)significantly reduced the vasodilatory effect of luteolin on DRTA vascular rings at 10,30,and 100 μmol/L(P＜0.05),and XE-991(3 μmol/L)significantly reduced the effect of luteolin at 30 and 100 μmol/L(P＜0.05),while ML213(1 μmol/L)significantly enhanced the vasodilatory effect of luteolin at 3,10,and 30 μmol/L(P＜0.05).(3)The relative gene expression levels of each subtype of Kv7 channel in normal DRTA were KCNQ1＞KCNQ5＞KCNQ4＞KCNQ3＞KCNQ2,with KCNQ1 being the most highly expressed.(4)Luteolin significantly enhanced the expression levels of KCNQ1 at 3,10,30,and 100 μmol/L,KCNQ2 at 1,3,10,30,and 100 μmol/L(P＜0.05),KCNQ3 at 3,10,30,and 100 μmol/L,and KCNQ4 at 10,30,and 100 μmol/L(P＜0.05),but did not significantly enhance the expression of KCNQ5 at 1,3,10,30,or 100 μmol/L(P＞0.05).(5)Luteolin significantly increased the expression of Kv7.1 protein in DRTA at 3,10,30,and 100 μmol/L(P＜0.05)and the expression of Kv7.4 at 10,30,and 100 μmol/L(P＜0.05).Conclusions Luteolin-induced dilation of DRTA vascular rings may be related to the enhanced gene expression of KCNQ1-4 and increased expression of Kv7.1 and Kv7.4 channel proteins.

Purpose To analyze and discuss the clinicopathological,molecular pathological characteristics,as well as diagnostic and prognostic features of pleomorphic xanthoastrocytoma(PXA)according to the new WHO classifi-cation.Methods 79 cases of PXA were collected to analyze their pathological and clinical data.Immunohistochemis-try using the EnVision method was employed to detect the expression of CD34,ATRX,Rb,Olig-2,H3K27M,H3K27me3,IDH1 R132H,BRAF VE1 and Ki67.Sanger sequencing was used to detect mutations in H3F3A and IDH1/2.Fluorescence quantitative PCR was used to detect the BRAF V600E mutation and TERT promoter region al-terations.Fluorescence in situ hybridization(FISH)was used to detect CDKN2A and EGFR alterations.The relation-ship between clinical,pathological,molecular genetics data,and prognosis was analyzed.Results The patients'ages ranged from 9 to 69 years,with an average age of 36.4 years.Most tumors were located in the temporal lobe,frontal lobe and parietal lobe.Among the 79 cases,42 were classified as grade 2 PXA and 37 as grade 3 PXA.The tumor cells exhibited pleomorphic changes,with perivascular lymphocytic sheaths and eosinophilic bodies frequently ob-served.Grade 3 PXA exhibited more mitotic figures(average of 11.8/10 HPF),and was usually accompanied by nec-rosis,focal marginal infiltration and microvascular proliferation.Immunohistochemistry and molecular characteristics revealed frequent positivity for CD34,BRAF V600E mutation(68.1％),and CDKN2A homozygous deletion(36.8％)in PXA.Some cases showed TERT gene mutation and absent Rb expression.Univariate survival analysis in-dicated that necrosis,focal marginal infiltration,and CNS WHO grade were related to overall survival,while focal infil-tration and CNS WHO grade were the independent risk factors.Conclusion The prognosis of CNS WHO grade 3 PXA is wrose than that of grade 2 PXA.Accurate diagnosis of PXA requires the combination of the morphological features,immunohistochemical staining,and multiple molecular tests.

BACKGROUND:Adipose tissue-derived mesenchymal stem cells release a large amount of exosomes to participate in various pathophysiological processes,but the impact and precise mechanism of exosomes derived from adipose tissue-derived mesenchymal stem cells on autophagy of hepatic stellate cells have not been fully elucidated.OBJECTIVE:To explore the targeted regulatory effect and molecular mechanism of adipose tissue-derived mesenchymal stem cell-derived exosomes on autophagy of hepatic stellate cells through miR-15a-5p.METHODS:Adipose tissue was collected from inguinal region of 8-week male C57BL/6 mice.Adipose tissue-derived mesenchymal stem cells were extracted by collagenase digestion.Adipose tissue-derived mesenchymal stem cell-derived exosomes were extracted by ultracentrifugation.Mouse liver tissue was obtained,and hepatic stellate cells were isolated and extracted using collagenase perfusion digestion and density gradient centrifugation.The experiment was divided into two groups.In control group,hepatic stellate cells were cultured alone for 48 hours.In the exosome group,hepatic stellate cells were co-cultured with adipose tissue-derived mesenchymal stem cell-derived exosomes for 48 hours.The effects of exosomes on hepatic stellate cell proliferation,activation,autophagy,and expression of fibrosis markers were detected by western blot assay,RT-qPCR,and immunofluorescence staining.RT-qPCR and western blot assay were used to detect the effect of exosomes on the mRNA and protein expression of miR-15a-5p and the downstream signaling pathway Bcl-2,Beclin-1,and Rubicon in hepatic stellate cells.RESULTS AND CONCLUSION:(1)Compared with the control group,the ratio of autophagy markers LC3-Ⅱ expression decreased,the number of autophagosome was also significantly decreased,and the intracellular lipid droplets were regenerated,simultaneously,cell volume diminished with the weakening of proliferation in hepatic stellate cells of the exosome group,indicated that the hepatic stellate cell activation was significantly inhibited.(2)Compared with the control group,the expressions of α-smooth actin and type Ⅰ collagen were significantly decreased(P＜0.01),and the expression of miR-15a-5p was significantly increased in hepatic stellate cells of the exosome group(P＜0.01).At the same time,the expression of its downstream target gene Bcl-2 was significantly decreased(P＜0.01),while the expressions of autophagy genes Beclin-1 and Rubicon were significantly increased in hepatic stellate cells of the exosome group(P＜0.01).The results indicate that adipose tissue-derived mesenchymal stem cell-derived exosomes inhibits the expression of Bcl-2 in hepatic stellate cells by targeting miR-15a-5p and increases the expression of downstream autophagy genes Beclin-1 and Rubicon,thereby inhibiting the autophagy of hepatic stellate cells.

Purpose To analyze and discuss the clinicopathological,molecular pathological characteristics,as well as diagnostic and prognostic features of pleomorphic xanthoastrocytoma(PXA)according to the new WHO classifi-cation.Methods 79 cases of PXA were collected to analyze their pathological and clinical data.Immunohistochemis-try using the EnVision method was employed to detect the expression of CD34,ATRX,Rb,Olig-2,H3K27M,H3K27me3,IDH1 R132H,BRAF VE1 and Ki67.Sanger sequencing was used to detect mutations in H3F3A and IDH1/2.Fluorescence quantitative PCR was used to detect the BRAF V600E mutation and TERT promoter region al-terations.Fluorescence in situ hybridization(FISH)was used to detect CDKN2A and EGFR alterations.The relation-ship between clinical,pathological,molecular genetics data,and prognosis was analyzed.Results The patients'ages ranged from 9 to 69 years,with an average age of 36.4 years.Most tumors were located in the temporal lobe,frontal lobe and parietal lobe.Among the 79 cases,42 were classified as grade 2 PXA and 37 as grade 3 PXA.The tumor cells exhibited pleomorphic changes,with perivascular lymphocytic sheaths and eosinophilic bodies frequently ob-served.Grade 3 PXA exhibited more mitotic figures(average of 11.8/10 HPF),and was usually accompanied by nec-rosis,focal marginal infiltration and microvascular proliferation.Immunohistochemistry and molecular characteristics revealed frequent positivity for CD34,BRAF V600E mutation(68.1％),and CDKN2A homozygous deletion(36.8％)in PXA.Some cases showed TERT gene mutation and absent Rb expression.Univariate survival analysis in-dicated that necrosis,focal marginal infiltration,and CNS WHO grade were related to overall survival,while focal infil-tration and CNS WHO grade were the independent risk factors.Conclusion The prognosis of CNS WHO grade 3 PXA is wrose than that of grade 2 PXA.Accurate diagnosis of PXA requires the combination of the morphological features,immunohistochemical staining,and multiple molecular tests.