OBJECTIVE To explore the mechanism of improvement effect of Chanbao zhichuang suppository （CBZCS） on hemorrhoids in rats through network pharmacology and metabolomics. METHODS A hemorrhoid model was established by subcutaneous injection of rhododendron oil to induce anal swelling. SD rats were divided into blank group （NC group， 0.32 g/kg vaseline）， model group （Model group， 0.32 g/kg vaseline）， CBZCS low-， medium-， and high-dose groups （CBZCS-L， CBZCS- M， CBZCS-H groups， with dosages of 0.16， 0.32， and 0.64 g/kg respectively）， and Mayinglong musk hemorrhoids suppository group （Positive group， 0.32 g/kg）， with 9 rats in each group. Anal administration was performed at 6， 12， 24， 48， and 72 hours after modeling. After the last administration， the pathological changes of the anal tissues in rats were observed， and the serum levels of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in rats were detected. Differential metabolite analysis and enrichment analysis were conducted by metabolomics methods， and the target proteins of CBZCS in treating hemorrhoids were obtained by network pharmacology. The core metabolic pathways were screened by interaction and enrichment analysis of differential metabolites and proteins， and the core proteins were experimentally verified. RESULTS Compared with the NC group， the anal tissues of the Model group showed obvious lesions， and the levels of IL-6 and TNF- α in the serum were significantly increased （P＜0.05）； compared with the Model group， the pathological damage of the anal tissues in the treatment groups was alleviated to varying degrees， and serum levels of IL-6 in CBZCS-H group， CBZCS-M group， and Positive group as well as serum levels of TNF-α in CBZCS-H group were significantly reduced （P＜0.05）. The metabolomics results showed that 34 differential metabolites were screened from the anal tissues of rats， and 22 of them showed a return after CBZCS administration. The differential metabolites mainly enriched in arachidonic acid metabolism， histidine metabolism， and glycerophospholipid metabolism. Through the network pharmacology， 138 intersection genes of CBZCS against hemorrhoids were determined. The analysis results showed that differential metabolites and target proteins were mainly enriched in the arachidonic acid metabolism pathway， and the regulation of this pathway might be related to cyclooxygenase-2 （COX-2）， Myc proto-oncogene protein （c-MYC）， cytochrome P450 1B1 （CYP1B1）， interleukin-1β （IL-1β）， and IL-6 protein expression. The experimental verification results showed that the expression levels of key proteins （COX-2， c-MYC， CYP1B1， IL-6， IL-1β） in the anal tissues of the Model group were significantly higher than those in the NC group （P＜0.05）， and the levels of the above proteins in the anal tissues of CBZCS-H group and Positive group were significantly lower than those in the Model group （P＜0.05）. CONCLUSIONS The mechanism of CBZCS in treating hemorrhoids may be to inhibit the expression of COX-2， c-MYC and CYP1B1 proteins， thereby inhibiting arachidonic acid metabolism and reducing the release of inflammatory factors IL-6 and IL-1β.

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

Objective To observe the regulatory mechanism of drug-containing serum of Jinghou Zengzhi Prescription based on qi and blood replenishing method on the expression of growth and differentiation factor 9(GDF9)and apoptosis of ovarian granulosa cells in rats with controlled ovarian hyperstimulation(COH).Methods Serum of COH rats(blank serum)and serum of COH rats gavaged by the Jinghou Zengzhi Prescription were prepared.A COH rat model was established and ovarian granulosa cells were collected.The experiment was divided into 5 groups:blank serum group,drug-containing serum group,drug-containing serum+SB203580[p38 mitogen-activated protein kinase(p38MAPK)inhibitor]group,drug-containing serum + PDTC[nuclear transcription factor κB(NF-κB)inhibitor]group,drug-containing serum + SB203580 + PDTC group.The mRNA expression levels of p38MAPK,casein kinase 2(CK2),nuclear transcription factor κB inhibitor α(IκBα),NF-κB and GDF9 were detected by real-time quantitative polymerase chain reaction(qRT-PCR),and GDF9 protein expression level was detected by Western Blot,and ovarian granulosa cell apoptosis was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL).Results The drug-containing serum of Jinghou Zengzhi Prescription decreased the mRNA expressions of p38MAPK and NF-κB,elevated the mRNA expressions of CK2 and IκBα,increased the mRNA and protein expression levels of GDF9,and decreased the apoptosis rate of ovarian granulosa cells in COH rats.The addition of p38MAPK inhibitor SB203580 alone and the addition of NF-κB inhibitor PDTC alone both promoted the mRNA and protein expressions of GDF9 and reduced the apoptosis rate of granulosa cells.Conclusion The drug-containing serum of Jinghou Zengzhi Prescription based on qi and blood replenishing method can promote the expression of GDF9 and inhibit the apoptosis of ovarian granulosa cells in rats with COH,and its mechanism may be related to the regulation of the expression of genes of the dual signaling pathways of p38MAPK and NF-κB.

Objective To investigate the rate of germline variants in patients with pancreatic cancer and clinical characteristics related with germline variants.Methods A total of 271 patients diagnosed with pancreatic cancer were enrolled in this study.Germline variants of 21 tumor susceptibility genes were detected by next-generation sequencing,and the relationship between germline variants and clinical factors such as age of onset,family history and personal history was analyzed.Results The rate of germline P/LP variants was 6.3%in unselected pancreatic cancer patients,but was high as 17.1%in genetic high-risk group patients(those with a family or personal history of cancer,or early-onset).Genes with higher frequency of germline variants in pancreatic cancer patients were PALB2,BRCA2,and ATM.Conclusion The rate of germline variants in overall pancreatic cancer patients is not high,but it increases significantly in genetic high-risk group,proving the importance of clinical factors in the screening of hereditary pancreatic cancer.

Objective To explore the eradication rate of human papillomavirus(HPV)and gestational outcome of patients with high-grade squamous intraepithelial disease of the cervix(HSIL)after loop electrosurgical excision procedure(LEEP)by transvaginal dissection of the vesicorectal form the cervix.Methods A total of 53 patients treated with LEEP by transvaginal dissection of the vesicorectal form the cervix in Obstetrics and Gynecology Hospital,Fudan University from Jan to Dec,2019 were investigated.Clinical information of cervical cytological examination,HPV test and cervical biopsy under colposcopy were followed up for 6,12 and 24 months post-LEEP were collected.HPV infection in these 53 patients were compared before and after LEEP surgery.The rate of successful fertility of the cohort,the HPV conversion rate of patients with hysterectomy and LEEP done were compared.The association between the pathological type and positive surgical margin and the association between HPV infection type and positive surgical margin were analyzed.Results HPV infection rate of was 94.3%(50/53)and the proportion of HPV16 and/or 18 infection was 75.5%(40/53).Mono-HPV infection rate(69.8%,37/53)was significantly higher than mixed HPV infection rate(22.7%,13/53).Thirty-eight patients(71.7%)were found with positive surgical margin in previous LEEP operation.Fifteen patients had recurrence(28.3%)and 40 patients(75.5%)successfully delivered baby after surgery.Postoperative pathology was mainly HSIL,accounting for 66%(30/53),and 28.3%patients(15/53)had no pathological change.Forty cases had satisfying fertility-conservative operation outcome with negative surgical margin,and 38 patients eradicated HPV infection after LEEP,which took up 95%of patients with satisfying fertility-conservative operation.There was no significant difference of positive resection margin rate in between groups of HPV16/18 infection and other types.Five cases had successful delivery(12.5%,5/40)with 1 case of vaginal delivery and 4 cases of cesarean section.Among these 5 cases,3 cases undertook preventive cervical cerclage,with 1 case of vaginal delivery and 2 cases of cesarean sections.Conclusion HPV eradication rate and surgical outcome could be significantly improved by LEEP with transvaginal dissection of the vesicorectal from the cervix,which satisfied the fertility preservation of females at reproductive age.

AIM: To establish a method for quantitation of cefepime and avibactam in M-H broth, and applicated in the in vitro dynamic PK/PD model. METHODS: The cefepime was also determined using the high-performance liquid chromatography method (HPLC), the avibactam was also determined using the liquid chromatography-mass spectrometry (LC-MS/MS), an in vitro dynamic PK/PD model was established to study the PK/PD relationship of cefepime/avibactam against carbapenem resistant Klebsiella pneumoniae (CRKP). RESULTS: The linear ranges of cefepime and avibactam were good at (0.5-20) and (0.1-25) μg/mL (r=0.999), and the lower limit concentrations were 0.5 and 0.1 μg/mL. The extraction recoveries of cefepime and avibactam in M-H broth were 88.0%-101.7% and 90.9%-95.2%, the relative standard deviation of intra-day precision and inter-day precision were less than 5.2%. The concentration-time curves were well simulated by the PK/PD model. All observed concentrations in each experiment were in the range of 20% of the targeted values. For the CRKP of MIC=8 μg/mL and MIC=16 μg/mL, the colony decreased to 2.783Log10 CFU/mL and 1.325Log10 CFU/mL at the cefepime/avibactam 2.5 g q8 h administration after 24 h. CONCLUSION: The determination method of cefepime and avibactam in broth established in this study has high sensitivity and good stability. For the CRKP with MIC≤8 μg/mL,cefepime/avibactam showed that good anti-CRKP activity under routine administration in vitro dynamic PK/PD model.

Objective:To explore therapeutic effect of cardiac rehabilitation based on traditional exercise on heart failure(HF).Methods:We searched databases including CNKI,Wanfang,VIP,Pubmed and Cochrane library for literature about application of cardiac rehabilitation exercise based on traditional exercises in HF patients before Mar 2023.Literature were screened according to inclusion and exclusion criteria,while article quality assessment and da-ta extraction were performed,and RevMan 5.3 software was used to perform Meta analysis.Results:Meta analysis indicated that compared with control group,there were significant increase in LVEF[MD=4.51,95％CI(1.70,7.33),P=0.002]and 6 min walking distance[6MWD,MD=51.90,95％CI(39.24,64.57),P=0.001],and sig-nificant reductions in left ventricular end-systolic diameter[MD=-1.64,95％CI(-3.18,-0.11),P=0.040],left ventricular end-diastolic diameter[MD=-2.49,95％C1(-3.28,-1.69),P=0.001],score of Minnesota living with heart failure questionnaire[MD=-6.89,95％CI(-8.64,-5.33),P=0.001]and level of N-ter-minal pro-brain natriuretic peptide[MD=-151.46,95％CI(-208.21,-94.70),P=0.001]in observation group.Conclusion:Cardiac rehabilitation based on traditional exercise can significantly improve heart function,in-crease 6 min walking distance and improve quality of life in patients with heart failure.

Continuing medical education for general practitioners is an important measure to upgrade the quality of primary health care services in China, which is still facing various challenges and need to be further developed and improved. This article analyzes the status quo and existing problems of continuing medical education for general practitioners in China, and proposes suggestions based on the concept of people centered and integrated health care (PCIC), including faculty development, training contents, assessment methods, and experience learning, to provide references for the improvement of continuing medical education for general practitioners.

【Objective】 To explore the diagnosis, treatment, prognosis and long-term follow-up of urogenital solitary fibrous tumor (SFT) and to differentiate the characteristics between benign and malignant SFT. 【Methods】 Clinical data of 20 patients with urogenital SFT treated in our hospital during Jan.2004 and Aug.2021 were respectively analyzed, including the general characteristics, clinical symptoms, imaging results, treatment methods, pathological results, and long-term follow-up results. 【Results】 Of the 20 cases, 9 cases had tumor in kidney, 7 in pelvic cavity, 3 in bladder and 1 in prostate.Six patients showed non-specific clinical symptoms, including lower extremity weakness, urodynia, dysuria, frequent urination with changes in stool habits, low back pain, and abdominal wall mass with abdominal pain, and the other 14 cases were asymptomatic.The median diameter of SFT was 5.2 cm (range:1.7-15.0 cm).All patients received surgical treatment, including robotic-assisted surgery in 8 cases, open surgery in 5 cases, laparoscopic surgery in 5 cases, and transurethral resection of tumor in 2 cases.CT plain scan showed high, low and mixed density soft tissue masses, and enhanced CT showed enhanced results.Pathology results revealed frequent nuclear divisions, morphological variations and necrosis in malignant SFT, which had higher expression of Ki-67 than benign SFT.The results of the modified Demicco prognostic risk stratification model showed that all malignant SFT cases were at intermediate risk. The DFS of the SFT radical tumor resection group was slightly longer than that of the simple tumor resection group but the difference was not statistically significant (P=0.203). 【Conclusion】 Markers such as CD34, Bcl2, STAT6 and CD99 are used to diagnose SFT, while Ki-67 and tumor necrosis are used to differentiate benign and malignant SFT.The modified Demicco prognostic risk stratification model plays an important role in predicting the prognosis of SFT.Surgical resection is the most common treatment with excellent prognosis.In addition, benign SFT has much better prognosis than malignant case.

Background::Oral anti-coagulants (OAC) are the intervention for the prevention of stroke, which consistently improve clinical outcomes and survival among patients with atrial fibrillation (AF). The main purpose of this study is to identify problems in OAC utilization among hospitalized patients with AF in China.Methods::Using data from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) registry, guideline-recommended OAC use in eligible patients was assessed.Results::A total of 52,530 patients with non-valvular AF were enrolled from February 2015 to December 2019, of whom 38,203 were at a high risk of stroke, 9717 were at a moderate risk, and 4610 were at a low risk. On admission, only 20.0% (6075/30,420) of patients with a diagnosed AF and a high risk of stroke were taking OAC. The use of pre-hospital OAC on admission was associated with a lower risk of new-onset ischemic stroke/transient ischemic attack among the diagnosed AF population (adjusted odds ratio: 0.54, 95% confidence interval: 0.43–0.68; P <0.001). At discharge, the prescription rate of OAC was 45.2% (16,757/37,087) in eligible patients with high stroke risk and 60.7% (2778/4578) in eligible patients with low stroke risk. OAC utilization in patients with high stroke risk on admission or at discharge both increased largely over time (all P <0.001). Multivariate analysis showed that OAC utilization at discharge was positively associated with in-hospital rhythm control strategies, including catheter ablation (adjusted odds ratio [OR] 11.63, 95% confidence interval [CI] 10.04–13.47; P <0.001), electronic cardioversion (adjusted OR 2.41, 95% CI 1.65–3.51; P <0.001), and anti-arrhythmic drug use (adjusted OR 1.45, 95% CI 1.38–1.53; P <0.001). Conclusions::In hospitals participated in the CCC-AF project, >70% of AF patients were at a high risk of stroke. Although poor performance on guideline-recommended OAC use was found in this study, over time the CCC-AF project has made progress in stroke prevention in the Chinese AF population.Registration::ClinicalTrials.gov, NCT02309398.