The intestinal flora and gut barrier function are of great significance for gut function and human health. When the intestinal flora is disrupted and the gut barrier structure is disrupted, it can lead to bacterial translocation, endotoxin influx into the bloodstream, and the production of pro-inflammatory factors, leading to various tissue damage in the body. Tongfu method in TCM can affect the intestinal environment by regulating intestinal permeability and immune response, restoring normal intestinal movement, and regulating the structure and metabolites of intestinal flora, thereby maintaining intestinal homeostasis and body health. The research on regulating intestinal flora and improving intestinal barrier function by Tongfu method can provide reference for further research on the relationship between TCM and intestinal microecology, and provide ideas for clinical treatment.

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Objective:This study collected a real-world data on survival and efficacy of gemcitabine-containing therapy in advanced breast cancer. Aimed to find the main reasons of affecting the duration of gemcitabine-base therapy in advanced breast cancer patients.Methods:Advanced breast cancer patients who received gemcitabine-base therapy from January 2017 to January 2019 were enrolled(10 hospitals). The clinicopathological data, the number of chemotherapy cycles and the reasons for treatment termination were collected and analyzed. To identify the reasons related with continuous treatment for advanced breast cancer and the factors which affect the survival and efficacy.Results:A total of 224 patients with advanced breast cancer were enrolled in this study, with a median age of 52 years (26-77 years), 55.4%(124/224) was postmenopausal. Luminal type were 83 cases, TNBC were 97 cases, and human epidermal growth factor receptor 2 (HER's-2) overexpression were 44. At the analysis, 224 patients who received the gemcitabine-based regimens were evaluated, included 5 complete reponse (CR), 77 partial response (PR), 112 stable disease (SD) and 27 progressive disease (PD). The objective response rate (ORR) was 36.6%(82/224). Seventy patients had serious adverse diseases, including leukopenia (9), neutrophilia (49), thrombocytopenia (15), and elevated transaminase (2). The median follow-up time was 41 months (26~61 months), and the median PFS was 5.6 months. The reasons of termination treatment were listed: disease progression were 90 patients; personal reasons were 51 patients; adverse drug reactions were 18 patients; completed treatment were 65 patients. It was found that progression-free survival (PFS) was significantly longer in patients receiving >6 cycles than that in patients with ≤6 cycles (8.2 months vs 5.4 months, HR=2.474, 95% CI: 1.730-3.538, P＜0.001). Conclusions:Gemcitabine-based regimen is generally well tolerated in the Chinese population and has relatively ideal clinical efficacy in the real world. The median PFS is significantly prolonged when the number of treatment cycles are appropriately increased.

Objective:This study collected a real-world data on survival and efficacy of gemcitabine-containing therapy in advanced breast cancer. Aimed to find the main reasons of affecting the duration of gemcitabine-base therapy in advanced breast cancer patients.Methods:Advanced breast cancer patients who received gemcitabine-base therapy from January 2017 to January 2019 were enrolled(10 hospitals). The clinicopathological data, the number of chemotherapy cycles and the reasons for treatment termination were collected and analyzed. To identify the reasons related with continuous treatment for advanced breast cancer and the factors which affect the survival and efficacy.Results:A total of 224 patients with advanced breast cancer were enrolled in this study, with a median age of 52 years (26-77 years), 55.4%(124/224) was postmenopausal. Luminal type were 83 cases, TNBC were 97 cases, and human epidermal growth factor receptor 2 (HER's-2) overexpression were 44. At the analysis, 224 patients who received the gemcitabine-based regimens were evaluated, included 5 complete reponse (CR), 77 partial response (PR), 112 stable disease (SD) and 27 progressive disease (PD). The objective response rate (ORR) was 36.6%(82/224). Seventy patients had serious adverse diseases, including leukopenia (9), neutrophilia (49), thrombocytopenia (15), and elevated transaminase (2). The median follow-up time was 41 months (26~61 months), and the median PFS was 5.6 months. The reasons of termination treatment were listed: disease progression were 90 patients; personal reasons were 51 patients; adverse drug reactions were 18 patients; completed treatment were 65 patients. It was found that progression-free survival (PFS) was significantly longer in patients receiving >6 cycles than that in patients with ≤6 cycles (8.2 months vs 5.4 months, HR=2.474, 95% CI: 1.730-3.538, P＜0.001). Conclusions:Gemcitabine-based regimen is generally well tolerated in the Chinese population and has relatively ideal clinical efficacy in the real world. The median PFS is significantly prolonged when the number of treatment cycles are appropriately increased.

Critical care medicine-related treatment is an interdisciplinary and multi-professional process,often leading to secondary or concomitant mental disorders in clinical practice.Currently,there is no consensus on the pharmacological treatment of related mental illnesses in China.The Chinese Society of Psychosomatic Medicine collaborated with the Critical Care Medicine expert group to form a consensus writing expert group.After a systematic review of relevant literature,summarizing published domestic and foreign literature,and extensive discussions,the consensus was developed.The consensus elaborates on the principles and processes of the standardized use of psychotropic drugs in critical care medicine,as well as the clinical indications,precautions,and specific drug selection of various psychiatric medications,providing feasible suggestions and guidance for the clinical application of psychiatric medications in the intensive care unit.

Objective:To explore the neuroprotective effect and molecular mechanism of sulforaphane (SFN) on acute carbon monoxide poisoning (ACOP) in rats.Methods:A total of 135 healthy adult male Sprague-Dawley (SD) rats were randomly divided into normal control group, ACOP model group, and SFN intervention group, with 45 rats in each group. The ACOP animal model was reproduced using carbon monoxide (CO) inhalation in a hyperbaric oxygen chamber, while the normal control group was allowed to breathe fresh air freely. The rats in the SFN intervention group received intraperitoneal injection of SFN at a dose of 20 mg/kg once daily starting 2 hours after CO poisoning and continuing until euthanasia. The normal control group and the ACOP model group received equivalent volume of saline injection. Three rats from each group were sacrificed 1 day after intervention to observe the changes in the ultrastructure of neuronal mitochondria in brain tissues under transmission electron microscopy. Six rats from each group were evaluated for cognitive function using neurobehavioral test 7 days after intervention. Brain tissues of 6 rats in each group were collected 1, 3, and 7 days after intervention, and the expressions of phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1) were detected using immunohistochemistry staining and Western blotting. Linear regression analysis was performed to assess the correlations between the expression levels of above proteins.Results:In the normal control group, the rats did not exhibit any abnormalities in cognitive function or the ultrastructure of neuronal mitochondria in brain tissues. ACOP induced cognitive impairment and ultrastructural injury to neuronal mitochondria in rats. However, SFN significantly improved cognitive function in poisoned rats and mitigated the extent of neuronal mitochondrial damage. Over poisoning time, the expression levels of p-AMPK and MFN2 in the brain tissues of ACOP rats were gradually decreased, while the expression level of DRP1 was gradually increased. Compared with the normal control group, the ACOP model group showed significant differences in the expressions of p-AMPK, MFN2, and DRP1. After SFN intervention, the expression levels of above proteins were significantly reversed. Compared with the ACOP model group, the SFN intervention group exhibited a marked increase in the expressions of p-AMPK and MFN2 [p-AMPK positive expression ( A value): 0.226±0.003 vs. 0.177±0.033, p-AMPK protein (p-AMPK/GAPDH): 1.41±0.05 vs. 0.89±0.05, MFN2 positive expression ( A value): 0.241±0.004 vs. 0.165±0.007, MFN2 protein (MFN2/GAPDH): 1.33±0.04 vs. 0.79±0.03, all P < 0.05], along with a significant decrease in DRP1 expression [DRP1 positive expression ( A value): 0.103±0.002 vs. 0.214±0.011, DRP1 protein (DRP1/GAPDH): 1.00±0.03 vs. 1.50±0.03, both P < 0.05]. Linear regression analysis revealed a strong negative linear correlation between DRP1 protein expression and MFN2, p-AMPK protein expressions ( R2 values were 0.977 and 0.971, both P < 0.01), and a positive linear correlation between p-AMPK protein expression and MFN2 protein expression ( R2 = 0.985, P < 0.01). Conclusion:SFN can help maintain neuronal mitochondrial homeostasis by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby alleviating neuronal injury caused by ACOP.

Purpose: This study aims to evaluate the efficacy and safety of trastuzumab biosimilar (HLX02) in combination with pertuzumab and chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) after progression of trastuzumab. Materials and Methods: In this prospective, single-arm, phase II study, patients with HER2-positive MBC after progression of trastuzumab received pertuzuamb, HLX02, and chemotherapy in Beijing Cancer Hospital from March 2020 to December 2022. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov (NCT05188495). Results: A total of 45 patients were included in this study. Twelve patients (26.7%) were treated in second-line and 33 patients (73.3%) were in third-line and later setting. Eighty percent and 15.5% patients had previously received pyrotinib/lapatinib and T-DM1, respectively. With a median follow-up of 24.4 months (range, 1.2 to 43.9 months), the median PFS was 7.6 months (95% confidence interval, 4.3 to 10.9), OS was not reached, the ORR was 31.1%, and DCR was 91.1%. The treatment was well tolerated. Conclusion The combination of trastuzumab biosimilar HLX02, pertuzumab, and chemotherapy exhibited promising efficacy and a favorable safety profile as second- and beyond-line treatment in HER2-positive MBC.

With high incidence, high disability rate and serious impact on patients' quality of life, advanced primary angle-closure glaucoma (PACG) with cataract is a severe eye disease in China and its main treatment method is surgery.Phacoemulsification cataract extraction and intraocular lens implantation (PEI) combined with trabeculectomy has been used to treat advanced PACG with cataract, but there are many postoperative complications.Recently, combined PEI, goniosynechialysis (GSL) and goniotomy (GT) has been proven to be a safe and effective surgical treatment for advanced PACG with cataract.At present, the combined PEI+ GSL+ GT surgery has been widely applied, but there is still a lack of uniform standards for its clinical application.Therefore, it is necessary to formulate a detailed and complete recommendation of the surgical procedures for PEI+ GSL+ GT, to standardize its application in clinical practice.Based on the analysis of the existing problems, some glaucoma experts in China have formulated detailed and complete operation norms, as well as expert recommendations on surgical indications and contraindications, anesthetic methods, surgical techniques and perioperative medication to standardize the application process of PEI+ GSL+ GT in clinical practice.

Objective:To explore independent predictors for poor outcome at 3 months in elderly patients with acute cerebral infarction(ACI)treated with intravenous thrombolysis(IVT), and to develop a nomogram-based predictive model.Methods:This was a retrospective cohort study.Clinical, laboratory and imaging data of 346 elderly patients with ACI treated with IVT from January 2016 to April 2021 in our hospital were collected.Poor outcome was defined as a modified Rankin Scale(mRS)score >2 at 3 months after the stroke.Logistic regression analysis was used to screen for independent factors predicting poor outcome in elderly ACI patients treated with IVT, and a corresponding nomogram model was developed using the R software.The ROC curve, calibration plots and decision curve analysis were used to evaluate discrimination, calibration and clinical application value of the nomogram model.Results:Among 346 candidates, 109 developed a poor outcome, representing a rate of 31.5%.Logistic regression analysis showed that symptomatic hemorrhagic transformation( OR=15.647, 95% CI: 8.913-27.454), stroke severity(moderate stroke, OR=3.322, 95% CI: 1.414-7.811; moderate-severe stroke, OR=8.169, 95% CI: 4.102-16.258; severe stroke, OR=9.653, 95% CI: 5.440-17.121), stroke-associated pneumonia( OR=2.239, 95% CI: 1.134-4.420), and heart failure( OR=2.758, 95% CI: 1.424-5.336)were independent predictors for poor outcome at 3 months in elderly ACI patients treated with intravenous thrombolysis(all P<0.05). With the area under curve(AUC-ROC)value at 0.85(95% CI: 0.80-0.89), the nomogram model, which was composed of the above four predictors, demonstrated good discrimination.On the calibration plot, the mean absolute error was 0.020, indicating that the model had good calibration.Decision curve analysis revealed that the model had good clinical application value. Conclusions:The nomogram model composed of symptomatic hemorrhagic transformation, stroke severity, stroke-associated pneumonia and heart failure may predict poor outcome at 3 months in elderly ACI patients treated with IVT, with high prediction accuracy and high clinical application value.

Objective:To investigate the value of MR subtraction images in improving the interobserver agreement for Bosniak Ⅱ, ⅡF, and Ⅲ cystic renal masses (CRMs) with Bosniak classification version 2019.Methods:From January 2009 to August 2020, 323 patients (335 CRMs) with surgical pathology results and complete preoperative MRI examination (T 2WI, T 1WI precontrast images and enhanced MRI in corticomedullary, nephrographic, and excretory phases) were retrospectively collected in the First Medical Center of PLA General Hospital. The CRMs of Bosniak Ⅱ, ⅡF, and Ⅲ were selected and classified by 2 experienced genitourinary radiologists according to the Bosniak classification version 2019. The "Subtraction" function in the American GE ADW 4.4 workstation was used to perform subtraction images reconstruction on the enhanced images in the corticomedullary, nephrographic, and excretory phases. Blinded to pathologic information, the other 2 radiologists independently classified the enrolled CRM cases with and without subtraction MR images, respectively, with an interval of 1 month. Ultimately, by using weighted Kappa value, interobserver agreement was evaluated, and the differences in weighted Kappa value were compared using the Gwet coefficient. Results:A total of 187 patients with 187 CRMs were enrolled in the study. The results of the classification of Bosniak Ⅱ, ⅡF, and Ⅲ CRMs categorized by 2 radiologists without and with subtraction images showed that 119 and 141 cases were consistent, and 68 and 46 were inconsistent, respectively. The weighted Kappa value for interobserver agreement among two radiologists without and with subtraction MR images was 0.60 (95%CI 0.53-0.68) and 0.73 (95%CI 0.66-0.80), respectively. The interobserver agreement was higher with subtraction images than that without subtraction images ( t=-2.56, P=0.011). Conclusion:According to the MRI criteria of Bosniak classification version 2019, the interobserver agreement for Bosniak Ⅱ, ⅡF, and Ⅲ CRMs could be improved using subtraction MR images, which may facilitate the popularization and application of Bosniak classification version 2019.