ObjectiveTo evaluate the clinical effectiveness and safety of Bairui Granules （百蕊颗粒） in the treatment of acute pharyngitis with wind-heat syndrome. MethodsA multicenter， double-blind， double-simulation， randomised controlled trial was conducted， in which 162 patients with acute pharyngitis and wind-heat syndrome from 7 centers were recruited， and each center was divided into trial group and control group on the ratio of 2∶1. In the trial group， 108 cases were orally administered with Bairui Granules plus Reyanning Granules （热炎宁颗粒） simulant， and in the control group， 54 cases were orally administered with Reyanning Granules plus Bairui Granules simulant for 5 days， with a follow-up visit on the 6th day. Full analysis set （FAS） analysis and per protocol set （PPS） were used for analysis， respectively. The primary efficacy index was the disappearance rate of sore throat after 5-day treatment； the secondary efficacy indexes were the disappearance rate of sore throat after 3-day treatment， as well as the visual analogue score （VAS） of sore throat before treatment， every day during the treatment， and follow-up on day 6， and the traditional Chinese medicine （TCM） syndrome score was performed before treatment and at the follow-up on day 6. The effectiveness on TCM syndrome was evaluated at the follow-up on day 6， and the changes of vital signs， blood routine， urine routine， liver functions， kidney function， the adverse events before and after the treatment were recorded， and safety analysis set （SS） was analysed. Results162 patients entered the FAS and SS analyses， and 158 cases （105 cases in the trial group and 53 cases in the control group） entered the PPS analysis. FAS analysis showed that the disappearance rate of sore throat after 5-day treatment was 80.56% （87/108） in the trial group and 64.81% （35/54） in the control group， and the difference between groups was statistically significant （χ² = 5.10， P = 0.0239）. PPS analysis showed that the disappearance rate of sore throat after 5-day treatment was 80.00% （84/105） in the trial group and 64.15% （34/53） in the control group， and the difference between groups was statistically significant （χ² =4.85， P = 0.0277）. FAS and SS analyses both showed that the difference in disappearance rate of sore throat between groups on 3-day treatment was not statistically significant （P＞0.05）. Compared with those before treatment， the VAS scores of sore throat were lower in both groups during treatment on day 2， 3， 4， 5， and follow-up on day 6 （P＜0.01）， but the difference between groups at each time point was not statistically significant （P＞0.05）. TCM syndrome scores of both groups at the follow-up were lower than that before treatment， and those of the trial group were lower than those of the control group （P＜0.01）. The cure rate and effective rate of TCM syndrome of the trial group were significantly higher than those of the control group （P＜0.01）. There was no significant difference in blood routine， urine routine， liver function， kidney function between groups before and after treatment （P＞0.05）， and no serious adverse events occured in both groups. ConclusionBairui Granules showed clinical effectiveness in the treatment of acute pharyngitis of wind-heat syndrome， and it could significantly improve the clinical symptoms， accelerate the disappearance time of sore throat with good safety.

BACKGROUND:Skeletal muscle insulin resistance is the key pathological link of type 2 diabetes.Static exercise can effectively improve skeletal muscle insulin resistance,but the mechanism remains unclear. OBJECTIVE:To explore the mechanism of static exercise on insulin resistance in the skeletal muscle of type 2 diabetic mice based on the phosphatidyl inositol 3-kinase(PI3K)/protein kinase B(AKT)/glucose transporter(GLUT4)signaling pathway. METHODS:After 1 week of adaptive feeding,7 out of 40 C57BL/6 mice were randomly selected as blank group and fed common diet,while the other mice were fed high-fat diet and taken to prepare type 2 diabetes models through the low-dose streptozotocin intraperitoneal injection.Twenty-four mice were successfully modeled and they were randomly divided into model group(n=8),metformin group(n=8)and static exercise group(n=8),which continued to be fed high-fat diet.The metformin group was given 200 mg/kg metformin dissolved in normal saline(2 ml/kg)by gavage,once a day,for 6 weeks.The static exercise group was given normal saline daily by gavage and carried out static exercise,30 minutes a day,6 days per week.The model group was given the same dose of normal saline daily by gavage without exercise intervention.After the intervention,the fasting blood glucose of each group was detected,the intraperitoneal glucose tolerance test was performed,and the area under the glycemic curve was calculated.Glycosylated hemoglobin,serum insulin,insulin resistance index were detected by ELISA.Total cholesterol,triglyceride,high-density lipoprotein,low-density lipoprotein were detected using biochemical methods.The mRNA expression levels of PI3K,AKT and GLUT4 in the gastrocnemius of mice were detected by real-time quantitative PCR.Morphological changes of the gastrocnemius were observed by hematoxylin-eosin staining,and the cross-sectional area of muscle fibers was calculated. RESULTS AND CONCLUSION:Compared with the blank group,fasting blood glucose,glycosylated hemoglobin,area under the glycemic curve,insulin resistance index,total cholesterol,triglyceride and low-density lipoprotein levels were significantly increased in the model group(P<0.01,P<0.05).Whereas,these indicators were significantly lower in the static exercise and metformin group than the model group(P<0.01,P<0.05).Compared with the blank group,serum insulin and high-density lipoprotein levels were significantly declined in the model group(P<0.01)and the mRNA expression of PI3K,AKT and GLUT4 in the gastrocnemius of mice were also significantly reduced(P<0.01).These indicators were significantly elevated in the metformin group and static exercise group compared with the blank group(P<0.01).Compared with the blank group,the muscle fibers in the model group were disordered,and the muscle cells atrophied and the muscle fiber gap widened.The cross-sectional area of muscle fibers was significantly decreased in the model group compared with the blank group(P<0.01).Compared with the model group,atrophy of the gastrocnemius fibers and muscle fiber space were improved in the static exercise group and the metformin group,and the cross-sectional area of muscle fiber was significantly increased in both groups(P<0.01).These findings indicate that static resistance training may promote glucose uptake and utilization by up-regulating the expression of PI3K,AKT and GLUT4 mRNA in skeletal muscle tissue,thereby improving the morphology and function of skeletal muscle tissue,alleviating insulin resistance and regulating glucose homeostasis.

Objective To investigate the therapeutic effect of Euryale ferox seed shell extract on oral ulcer in rats and its underlying mechanism. Methods The contents of polyphenols and flavonoids in Euryale ferox seed shells were determined by Folin-phenol assay and aluminum nitrate colorimetry, respectively. DPPH · , ABTS+· , · OH and · O2- scavenging experiments were performed to evaluate the antioxidant activities of Euryale ferox seed shell extract in vitro. In a rat model of oral ulcer induced by burning with glacial acetic acid, the therapeutic effect of Euryale ferox seed shell extract was assessed by detecting changes in serum levels of oxidative factors by enzyme-linked immunosorbent assay (ELISA) and observing pathological changes of the ulcerous mucosa using HE staining; the therapeutic mechanism of the extract was explored by detecting the expression levels of Keap1, Nrf2, Nes-Nrf2 and HO-1 proteins in ulcerous mucosa using Western blotting. Results The ethyl acetate extract of Euryale ferox seed shells contained 306.74±1.04 mg/g polyphenols and 23.43±0.61 mg/g flavonoids and had IC50 values for scavenging DPPH · and ABTS+· free radicals of 3.42 ± 0.97 μg/mL and 3.32 ± 0.90 μg/mL, respectively. In the rat models, the ethyl acetate extract significantly ameliorated oral mucosal ulcer, increased serum CAT level, and decreased serum MDA level. The protein expression levels of Nes-Nrf2 and HO-1 were increased and Keap1 protein expression was lowered significantly in the ulcerous mucosa of the rats after treatment with the extract (P<0.05 or 0.01). Conclusion The therapeutic effect of Euryale ferox seed shell extract on oral ulcers in rats is mediated probably by activation of the Keap1/Nrf2/HO-1 signaling pathway.

Objective To investigate the therapeutic effect of Euryale ferox seed shell extract on oral ulcer in rats and its underlying mechanism. Methods The contents of polyphenols and flavonoids in Euryale ferox seed shells were determined by Folin-phenol assay and aluminum nitrate colorimetry, respectively. DPPH · , ABTS+· , · OH and · O2- scavenging experiments were performed to evaluate the antioxidant activities of Euryale ferox seed shell extract in vitro. In a rat model of oral ulcer induced by burning with glacial acetic acid, the therapeutic effect of Euryale ferox seed shell extract was assessed by detecting changes in serum levels of oxidative factors by enzyme-linked immunosorbent assay (ELISA) and observing pathological changes of the ulcerous mucosa using HE staining; the therapeutic mechanism of the extract was explored by detecting the expression levels of Keap1, Nrf2, Nes-Nrf2 and HO-1 proteins in ulcerous mucosa using Western blotting. Results The ethyl acetate extract of Euryale ferox seed shells contained 306.74±1.04 mg/g polyphenols and 23.43±0.61 mg/g flavonoids and had IC50 values for scavenging DPPH · and ABTS+· free radicals of 3.42 ± 0.97 μg/mL and 3.32 ± 0.90 μg/mL, respectively. In the rat models, the ethyl acetate extract significantly ameliorated oral mucosal ulcer, increased serum CAT level, and decreased serum MDA level. The protein expression levels of Nes-Nrf2 and HO-1 were increased and Keap1 protein expression was lowered significantly in the ulcerous mucosa of the rats after treatment with the extract (P<0.05 or 0.01). Conclusion The therapeutic effect of Euryale ferox seed shell extract on oral ulcers in rats is mediated probably by activation of the Keap1/Nrf2/HO-1 signaling pathway.

Objective To propose strategies for developing clinical predictive models,aiming to assist researchers in conducting standardized clinical prediction model studies.Methods Literature review was conducted to summarize the operational steps and content for developing clinical predictive models.Then,a methodological framework was summarized and refined through expert consultation.Results The 11-step methodological framework for developing clinical predictive models was obtained by synthesizing the experience of 456 clinical predictive modeling studies and expert consultation,and the details were analyzed and elaborated.Conclusions This study presents methodological strategies and recommendations for the development of clinical predictive models,intended to serve as a guide for researchers.

Objective:To analyze the distribution and drug resistance of pathogens of bacterial bloodstream infection in patients with hematological diseases in the Department of Hematology of Tianjin Medical University General Hospital, and to provide etiological data for clinical empirical anti-infection treatment.Methods:A retrospective analysis was conducted on the general clinical information, pathogenic bacteria and drug susceptibility test results of patients with hematological diseases diagnosed with bacterial bloodstream infection by menstrual blood culture in our center from January 2016 to December 2022.Results:Patients included 498 inpatients, with a total of 639 bacterial strains. Among the patients, 86.9% patients had malignancies, and 76.7% had agranulocytosis. Symptoms of concurrent infections, including those of the respiratory tract, oral mucosa, skin and soft tissues, and abdominal sources were observed in 68.3% patients. Gram-negative bacteria (G -) accounted for 79.0% of the isolated bacteria, and gram-positive bacteria (G +) accounted for 21.0%. The top five isolated pathogens were Klebsiella pneumoniae (22.5%), Escherichia coli (20.8%), Pseudomonas aeruginosa (15.0%), Enterococcus faecium (5.5%), and Stenotrophomonas maltophilum (5.0%). Escherichia coli exhibited a decreasing trend of resistance to quinolones, cephalosporins, and carbapenems. Klebsiella pneumoniae exhibited increasing rates of resistance to quinolones and cephalosporins between 2016 and 2018, but the rated decreased after 2019. The resistance rate to carbapenems exhibited by Pseudomonas aeruginosa was approximately 20%. Carbapenem-resistant strains of Pseudomonas aeruginosa strains were first detected in 2017, with a peak resistance rate of 35.7%, detected in 2019. A 60.0% resistance rate to methicillin was observed in methicillin-resistant coagulase-negative staphylococci (MRCNS), and one case of linezolid-resistant MRCNS was detected. Conclusions:Pathogenic bacteria of bacterial bloodstream infections were widely distributed in our center, and precautions are warranted against carbapenem resistant P. aeruginosa and Klebsiella pneumoniae.

Intra-abdominal infection is the second common infectious disease in intensive care unit and inhospital patients, with the mortality rate of 20%-30%. Advances in medicine have not improved the outcomes of patients with intra-abdominal infection, and the increasing multi-drug resistance organism may lead to a deterioration in the prognosis of patients with intra-abdominal infection. Gut microbiota dysbiosis and abdominal cavity infections show an interdependent and mutually aggravating relationship. Intestinal microecological preparations regulate gut flora and are potential therapeutic measures for intra-abdominal infections. The authors review the changes in gut flora during intra-abdominal infection, the effect of gut flora on the prognosis of intra-abdominal infections and the role of intestinal microecological preparations in intra-abdominal infections.

Objective To investigate the effect of bone marrow mesenchymal stem cells(BMSCs)on the inflamma-tory response of lipopolysaccharide(LPS)induced acute lung injury(ALI)in mice.Methods 32 SPF KM mice,aged 4 weeks were randomly divided into four groups,control group,LPS group,dexamethasone treatment group(LPS+DEX)and BMSCs treatment group(LPS+BMSCs).The latter three groups were injected with LPS by tra-cheal puncture to establish mouse ALI model 24 h after modeling,BMSCs isolated from the femur of mice were in-jected into the caudal vein,and DEX were injected into caudal vein at the same time in LPS+DEX group for 3 consecutive days.On the 4th day after cell transplantation or 24 h after DEX injection,the survival quantity of mice was recorded,lung function was detected,and the wet/dry weight ratio(W/D)of lung was measured.Then in-flammatory cells in bronchoalveolar lavage fluid(BALF),lung pathological changes and serum inflammatory cyto-kines were collected.Green fluorescent protein(GFP)staining was used to observe the homing of BMSCs in lung tissues.The mRNA and protein expression of TLR4,MyD88 and NF-κB in lung tissues were detected by RT-PCR and Western blot assay respectively.Results Compared with the control group,LPS model group showed de-creased lung function,significantly increase in the W/D weight ratio of lung,inflammatory cytokines in serum and inflammatory cells in BALF,and severe damage in lung tissue.Compared with LPS group,LPS+DEX group and LPS+BMSCs group showed improved lung function,reduced lung tissue damage,significantly decrease in the W/D weight ratio of lung,inflammatory cytokines in serum and inflammatory cells in BALF.And the expression of TLR4-MyD88-NF-κB signaling pathway-related genes and proteins decreased,the survival quantity increased.Conclusion Homologous BMSCs transplantation can effectively treat LPS-induced acute lung injury,and the mechanism may be related to the regulation of TLR4-MyD88-NF-κB signaling pathway and the reduction of inflam-matory response.These findings provide the experimental basis for BMSCs homologous transplantation for ALI.

Objective:To investigate the clinical, genetic, and pathological features of nemaline myopathy type 8 (NEM8) caused by KLHL40 gene variation. Methods:The clinical data, gene sequencing results, and musculoskeletal pathophysiology of two cases (a pair of twins) with NEM8 admitted to our hospital in July 2022 were collected. CNKI, VIP, Wanfang, Yiigle, PubMed, Embase, and Web of Science Database were searched with the English and Chinese terms "nemaline myopathy type 8", "nemaline body myopathy type 8", and " KLHL40" from January 2007 to February 2023. The clinical, genetic, and musculoskeletal characteristics of the NEM8 cases were summarized using the descriptive statistical analysis method. Results:(1) Case report: The mother (G2P2) of the twins (Ⅳ-2 and Ⅳ-3) was conceived by IVF-embryo transfer and delivered at 37 +1 gestational weeks. The two cases were dizygotic twins whose maternal grandmother had lip and palate cleft. The first baby (Ⅳ-1) of the woman exhibited absent left pinna, contracture at the end of both fingers, talipes equinovarus in both feet and died of respiratory failure two hours after birth. Fetal edema and fetal movement delay in the twins and varus right foot in one twin were found during pregnancy. Both cases developed intrapartum asphyxia with the clinical manifestations of generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fractures. The families withdrew the treatment and the twins died after maintaining life with ventilators for 53 days after birth. Whole exome sequencing of the pedigree found c.1779G>T (p.W593C) homozygous variants of the KLHL40 gene in the twins and c.1779G>T (p.W593C) heterozygous variants of the KLHL40 gene in the parents, both were de novo. Musculoskeletal pathophysiology indicated that muscle fibers are thin and round with a fetal shape and absent rod. (2) Literature review: Among the 29 cases of NEM8, including two current cases and 27 cases retrieved from 15 papers, eight cases terminated the pregnancies, and 21 were live births; seven cases (24.1%) with positive family history; 19 cases (65.5%) were found with abnormalities during pregnancy, including abnormal fetal movements, polyhydramnios, joint contracture, and fetal edema. Of the 21 live births, 20 cases had intrapartum asphyxia, 21 had postnatal respiratory failure, 20 had generalized muscle weakness, and 19 had dysphagia. Among the 29 cases, 17 cases (58.6%) were homozygous variants of the KLHL40 gene, and 12 cases (41.4%) were compound heterozygous variants. The detection rate of c.1516A>C(p.Thr506Pro) was the highest [72.4% (21/29)], followed by c.602G>A(p.Trp201*) [17.2% (5/29)]. Out of the 15 cases who underwent musculoskeletal pathological examination, all had abnormal muscle fiber size and morphology; 10 cases had rods. Conclusions:NEM8 should be considered for those with abnormal fetal movements, polyhydramnios, joint malformation, fetal edema during the fetal period and failure to establish respiration at birth as well as postnatal generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fracture. Moreover, genetic detection should be performed as soon as possible. NEM8 can be diagnosed in ones with KLHL40 gene homozygous or compound heterozygous variants and musculoskeletal pathological results of abnormal size and shape of muscle fibers, regardless of the presence of rods.

Objective: More than 75% of ovarian cancer patients are diagnosed at advanced stages and die of tumor cell metastasis. This study aimed to identify new epigenetic and transcriptomic alterations associated with ovarian cancer metastasis. Methods: Two cell sublines with low- and high-metastasis potentials were derived from the ovarian cancer cell line A2780. Genome-wide DNA methylome and transcriptome profiling were carried out in these two sublines by Reduced Representation Bisulfite Sequencing and RNA-seq technologies. Cell-based assays were conducted to support the clinical findings. Results: There are distinct DNA methylation and gene expression patterns between the two cell sublines with low- and high-metastasis potentials. Integrated analysis identified 33 methylation-induced genes potentially involved in ovarian cancer metastasis. The DNA methylation patterns of two of them (i.e., SFRP1 and LIPG) were further validated in human specimens, indicating that they were hypermethylated and downregulated in peritoneal metastatic ovarian carcinoma compared to primary ovarian carcinoma. Patients with lower SFRP1 and LIPG expression tend to have a worse prognosis. Functionally, knockdown of SFRP1 and LIPG promoted cell growth and migration, whereas their overexpression resulted in the opposite effects. In particular, knockdown of SFRP1 could phosphorylate GSK3β and increase β-catenin expression, leading to deregulated activation of the Wnt/β-catenin signaling. Conclusion Many systemic and important epigenetic and transcriptomic alterations occur in the progression of ovarian cancer. In particular, epigenetic silencing of SFRP1 and LIPG is a potential driver event in ovarian cancer metastasis. They can be used as prognostic biomarkers and therapeutic targets for ovarian cancer patients.