Objective To study adverse drug events(ADEs)of busulfan the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS),and to mine the potential ADE signals,so as to provide reference for the safe drug use in clinical practice.Methods Data from the first quarter of 2004 to the first quarter of 2023 were retrieved from the FAERS database,and ADE records for busulfan as a primary suspect drug were obtained through data cleaning and standardization of target drug names.Risk signals for busulfan ADEs were mined based on the reporting odds ratio method,the proportional reporting ratio method,and Medicines and Healthcare Products Regulatory Agency method.The information component method was used to assess the intense of the risk signals.The ADEs were systematically classified according to Medical Dictionary for Regulatory Activities(MedDRA),and two ranking sequence of busulfan ADEs were generated by signal occurrence frequency and signal intense,respectively.Results A total of 20 326 ADE records were collected,involving 5 615 patients with 556 related ADE signals,of which 117 were newly reported as compared to those in the drug instruction of busulfan.Male patients accounted for a higher proportion than female patients(40.71％vs.30.74％).The main population of patients were younger than 18 years old(31.56％).The reports were most reported by physicians(33.71％)and other health professionals(24.35％)as well as pharmacists(23.86％),mainly from the United States(29.69％),Japan(15.78％),and France(11.79％).The top five ADEs in terms of occurrence frequency were busulfan use in unapproved indications,hepatic veno-occlusive disease(HVOD),mucosal inflammation,cytomegalovirus infection,and graft versus host disease.The top five ADEs in terms of signal intense were HVOD,acute graft versus host disease,veno-occlusive disease,graft versus host disease,and chronic graft versus host disease.The ADE signals involves 23 system organ classes.The top three SOCs in terms of the number of ADE signals were infections/infestations,investigations and neoplasms benign/malignant/unspecified(include cysts and polyps).Conclusion When busulfan is used in clinic,attention should be paid to its adverse events in hepatic veno-occlusive disease,infections,graft versus host disease,neurotoxicity,and venous thromboembolism,which are likely to cause serious consequences.The clinical pharmacists can assist clinicians to make prevention plans in case of busulfan ADEs,so as to improve the safety of busulfan use in clinic.

Pathological mechanism of ulcerative colitis(UC)is not fully clear,which may be the result of Th17/Treg immune imbalance and the interaction of multiple complex factors.Numerous studies have found that classical TCM prescriptions,experienced formulas and TCM active components could regulate Th17/Treg balance by intervening in cytokines,transcription factors,and signaling pathways,restore intestinal mucosal immune function,suppress intestinal mucosal inflammatory response,and repair intestinal mucosal barrier damage.Based on the research status of UC,Th17/Treg balance and TCM treatment,this article reviewed the relationship between Th17/Treg balance and UC,and explained the key role of Th17/Treg balance in the occurrence and development of UC.At the same time,the Chinese materia medica targeting to regulate the balance of Th17/Treg in the treatment of UC in recent years was summarized,in order to provide reference for the treatment of UC.

Sishen Pills is a classic prescription for the treatment of spleen and kidney diarrhea,which has the effect of warming the kidney and the spleen,astringent intestine and antidiarrheal.In modern clinical application,the modified prescriptions based on Sishen Pills,combined with other treatments of TCM and integrated traditional Chinese and Western medicine are often used to treat ulcerative colitis with spleen-kidney yang deficiency syndrome,and the curative effect is remarkable.Experimental pharmacological studies have shown that Sishen Pills may achieve the purpose of ulcerative colitis by regulating the expression of related signaling pathway proteins,regulating inflammatory factors,inhibiting inflammatory response,regulating autophagy,regulating intestinal flora,improving intestinal mucosal permeability,repairing intestinal mucosal barrier,regulating cellular energy metabolism,anti-oxidative stress,regulating cellular immune function,etc.In this article,the research status of Sishen Pills in the treatment of ulcerative colitis was sorted out and summarized,in order to provide reference for further study of its mechanism and clinical application.

Objective To investigate the expression of Midkine(MDK)in cholangiocarcinoma(CCA)and its value in predicting the prognosis of CCA,as well as the potential mechanism of the effect of MDK on the progression of CCA.Methods The data of CCA samples were obtained from TCGA database to analyze the difference in the expression of MDK between cancer tissue and paracancerous tissue and its association with clinical features,and the data collected from GEO database and 11 CCA patients who underwent surgical resection in The Fifth Medical Center of Chinese PLA General Hospital from June 2018 to September 2021 were used for validation.STRING and Cytoscape were used to construct a protein-protein interaction network,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were used to investigate the biological functions and tumor-related pathways involving MDK-related genes.In addition,TIMER and TISIDB databases were used to analyze the correlation between MDK expression and immune cell infiltration in CCA tissue.The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the Fisher's exact test was used for comparison of categorical data between two groups.The Kaplan-Meier method was used to plot survival curves,and the Log-rank test was used for comparison between groups.The Spearman correlation analysis was used to investigate the correlation between two variables.Results The expression level of MDK in cancer tissue and paracancerous tissue of CCA patients was compared based on TCGA database,and the results of the non-paired and paired analyses showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in paracancerous tissue(P<0.001).Transcriptome sequencing was performed for the tumor tissue and its corresponding paracancerous tissue from 11 CCA patients,and the results showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in corresponding paracancerous tissue(P<0.01).High expression of MDK was associated with lymph node metastasis(P=0.045)and vascular invasion(P=0.044).Survival analysis showed that compared with the CCA patients with low MDK expression,the CCA patients with high MDK expression had significantly shorter overall survival time(χ2=5.30,P=0.028)and disease-specific survival time(χ2=6.25,P=0.019).The GO and KEGG enrichment analyses showed that the 30 MDK-related genes were closely associated with ubiquitin-mediated proteolysis and affected the prognosis of CCA patients.The TIMER analysis showed that the expression level of MDK was positively correlated with the infiltration of B cells(r=0.356,P=0.035 6)and dendritic cells(r=0.409,P=0.014 7)in tumor microenvironment of CCA;the TISIDB analysis showed that the expression level of MDK was positively correlated with CXCL16(r=0.465,P=0.004 67)and was negatively correlated with CXCL12(r=-0.389,P=0.019 7)and CXCR5(r=-0.393,P=0.018 5),and it was also negatively correlated with the immune checkpoint regulators VTCN1(r=-0.393,P=0.018 3),LTA(r=-0.380,P=0.022 7),and PVR(r=-0.350,P=0.037 3).Conclusion High expression of MDK is associated with poor prognosis in CCA patients,and MDK has the potential of being used as a molecular marker for predicting the prognosis of CCA.MDK may promote the development and progression of CCA by regulating ubiquitin-mediated proteolysis and the infiltration of B cells and dendritic cells.

Objective:To explore the effects of pelvic-abdominal mechanics exercises during pregnancy on improving pelvic floor function in primiparous women during the perinatal period.Methods:A single-center prospective study selected 200 primipara of singleton pregnancies with prenatal care and delivery established at Shanghai Tongren hospital from June 2022 to June 2023 as the study subjects. Participants were divided into two groups: the exercise group (100 cases) and the control group (100 cases) by using a random number table method, five participants dropped out of the study due to reasons such as follow-up failure. Ultimately, the exercise group consisted of 97 cases, while the control group consisted of 98 cases. Participants who engaged in pelvic-abdominal mechanics exercises for at least 3 months, exercising once a week, were included in the exercise group. Those who did not engage in exercise were included in control group. Comparing the two groups in terms of pregnancy discomfort symptoms, delivery outcomes, postpartum pelvic floor electromyography results, postpartum quality of life, and pelvic floor disease incidence. The statistical methods utilized included independent t-test, Pearson chi-square test, Fisher′s exact test, and Mann-Whitney U test. Results:In the late stage of pregnancy, the VAS score for low back pain was 5.05±1.22 in the exercise group and 5.47±1.55 in the control group, with a statistically significant difference ( t=2.090, P<0.05). The PFDI-20 score was 23.33±8.41 in the exercise group and 25.76±8.34 in the control group, with a statistically significant difference ( t=2.026, P<0.05). The PFIQ-7 score was 19.21±7.69 in the exercise group and 26.66±6.19 in the control group, with a statistically significant difference ( t=6.851, P<0.05). There was no statistically significant difference in sleep quality and incidence of urinary incontinence between the two groups in late pregnancy ( t=1.252, P=0.396, P>0.05). In terms of childbirth outcomes, the exercise group had a vaginal delivery rate of 81.44% (79 cases), while the control group had a rate of 64.28% (63 cases), with a statistically significant difference (χ 2=9.022, P<0.05). The duration of the second stage of labor was (42.68±21.38) minutes in the exercise group and (50.54±21.33) minutes in the control group, with a statistically significant difference ( t=2.178, P<0.05). At 42 days postpartum, the evaluation of pelvic floor function showed that the vaginal pressure in the exercise group was 62.19±10.04, while in the control group it was 52.68±15.55, with a statistically significant difference ( t=-5.074, P<0.05). The MOS grading in the exercise group was 3.82±1.26, whereas in the control group it was 2.34±1.55, with a statistically significant difference ( t=-7.355, P<0.05). In terms of the incidence of postpartum pelvic floor disorders, the occurrence of pelvic organ prolapse was 7.22% in the exercise group and 12.24% in the control group, with no statistically significant difference (χ 2=1.402, P>0.05). The occurrence rate of stress urinary incontinence was 13.4% in the exercise group and 30.61% in the control group, with a statistically significant difference ( P=0.015, P<0.05). Conclusion:Pelvic-abdominal mechanics exercises may have some advantages in reducing symptoms related to perinatal pelvic floor dysfunction, enhancing pelvic floor function, and preventing the occurrence of pelvic floor disease.

Objective:To explore the effects of pelvic-abdominal mechanics exercises during pregnancy on improving pelvic floor function in primiparous women during the perinatal period.Methods:A single-center prospective study selected 200 primipara of singleton pregnancies with prenatal care and delivery established at Shanghai Tongren hospital from June 2022 to June 2023 as the study subjects. Participants were divided into two groups: the exercise group (100 cases) and the control group (100 cases) by using a random number table method, five participants dropped out of the study due to reasons such as follow-up failure. Ultimately, the exercise group consisted of 97 cases, while the control group consisted of 98 cases. Participants who engaged in pelvic-abdominal mechanics exercises for at least 3 months, exercising once a week, were included in the exercise group. Those who did not engage in exercise were included in control group. Comparing the two groups in terms of pregnancy discomfort symptoms, delivery outcomes, postpartum pelvic floor electromyography results, postpartum quality of life, and pelvic floor disease incidence. The statistical methods utilized included independent t-test, Pearson chi-square test, Fisher′s exact test, and Mann-Whitney U test. Results:In the late stage of pregnancy, the VAS score for low back pain was 5.05±1.22 in the exercise group and 5.47±1.55 in the control group, with a statistically significant difference ( t=2.090, P<0.05). The PFDI-20 score was 23.33±8.41 in the exercise group and 25.76±8.34 in the control group, with a statistically significant difference ( t=2.026, P<0.05). The PFIQ-7 score was 19.21±7.69 in the exercise group and 26.66±6.19 in the control group, with a statistically significant difference ( t=6.851, P<0.05). There was no statistically significant difference in sleep quality and incidence of urinary incontinence between the two groups in late pregnancy ( t=1.252, P=0.396, P>0.05). In terms of childbirth outcomes, the exercise group had a vaginal delivery rate of 81.44% (79 cases), while the control group had a rate of 64.28% (63 cases), with a statistically significant difference (χ 2=9.022, P<0.05). The duration of the second stage of labor was (42.68±21.38) minutes in the exercise group and (50.54±21.33) minutes in the control group, with a statistically significant difference ( t=2.178, P<0.05). At 42 days postpartum, the evaluation of pelvic floor function showed that the vaginal pressure in the exercise group was 62.19±10.04, while in the control group it was 52.68±15.55, with a statistically significant difference ( t=-5.074, P<0.05). The MOS grading in the exercise group was 3.82±1.26, whereas in the control group it was 2.34±1.55, with a statistically significant difference ( t=-7.355, P<0.05). In terms of the incidence of postpartum pelvic floor disorders, the occurrence of pelvic organ prolapse was 7.22% in the exercise group and 12.24% in the control group, with no statistically significant difference (χ 2=1.402, P>0.05). The occurrence rate of stress urinary incontinence was 13.4% in the exercise group and 30.61% in the control group, with a statistically significant difference ( P=0.015, P<0.05). Conclusion:Pelvic-abdominal mechanics exercises may have some advantages in reducing symptoms related to perinatal pelvic floor dysfunction, enhancing pelvic floor function, and preventing the occurrence of pelvic floor disease.

Objective To explore whether adiponectin receptor 1/2(AdipoR1/R2)mediates berberine to alleviate renal lipid toxicity in mice with diabetic kidney disease.Methods C57BLKS/J db/db mice and db/m mice were selected and divided into 4 groups,with 8 in each group.db/db mice and db/m mice were given berberine(150 mg·kg-1·d-)or placebo by gavage for 12 weeks,respectively.After intervention,blood glucose,blood lipids,urinary microalbumin/creatinine ratio and urinary albumin excretion rate were determined.Kidney tissues were taken for pathological examination,and oil red O staining,immunohistochemistry,ELISA and Western blotting were used to examine lipid deposition,AdipoRl/R2 expression and fibrosis markers expressions,etc.,respectively.The human glomerular endothelial cell line(HGEC)was used to verify the role of AdipoR1/R2 in berberine alleviating renal lipid toxicity.Results After berberine intervention,the body weight,blood glucose,lipids,proteinuria,renal lipid deposition,and renal pathological changes decreased in db/db mice(P＜0.05);the expressions of AdipoR1 and AdipoR2 increased,expressions of TGF-β1 and Col-Ⅳ decreased,and the expressions of PPAR-α and p-AMPK increased in kidney tissue of db/db mice(P＜0.05).In high-fat cultured HGEC cells treated with berberine-treated db/db mouse serum,the expressions of TGF-β1 and Col-Ⅳ decreased,while the expressions of PPAR-α and p-AMPK increased(P＜0.05);after AdipoR1/R2 on HGEC cells were silenced,the expressions of TGF-β1 and Col-Ⅳ increased,while the expressions of PPAR-α and p-AMPK decreased(P＜0.05).Conclusions Berberine can reduce renal lipid toxicity in diabetic nephropathy mice,and adiponectin receptor may mediate this effect of berberine.

ObjectiveTo explore the possible peripheral analgesic mechanism of electroacupuncture （EA） at promimal and distal acupoints in treatment of myofascial pain syndrome （MPS）. MethodsTwenty-four SD rats were randomly divided into blank group， model group， proximal group， and distal group， with six rats in each group. MPS model was prepared by “strike combined with centrifugal exercise” in all groups except for the blank group. After modeling， the rats in the proximal group received EA at the local myofascial trigger points （MTrPs）， namely the Ashi points， with dilatational waves of frequency of 2/100 HZ and voltage of 2-4 V， current intensity depending on a slight trembling of the left lower limbs， once a day， 15min each time，for 14 days. The rats in the distal group received EA at “Yanglingquan” （GB 34） and “Yinlingquan” （SP 9）， with the same operations as the proximal group. The rats in the blank group and the model group were only grasped and hedged， without other interventions. After intervention， the paw withdrawl mechanical threshold （PWMT） was measured， and variability between the left and right hind paws was calculated. Musculoskeletal ultrasound imaging and electromyography monitoring were performed on the left lower extremity vastus medialis. The morphological changes of vastus medialis muscle of the left lower extremity were observed by HE staining. The positive expression of substance P （SP）， calcitonin gene-related peptide （CGRP）， CD68 and CD206 in muscle tissue was detected by immunohistochemistry. Abdominal aortic serum interleukin-1β （IL-1β）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， interleukin-10 （IL-10）， and interleukin-8 （interleukin-8） were detected by ELISA. ResultsCompared to those in the blank group， the fibers of the vastus medial muscle of the rats in the model group were broken and distorted with thickness in variation， and the myofascia was broken， with fibrillation potential， enlarged muscle cells， inward moved nucleus， and widened muscle space； the variability of PWMT between the left and right hind paws significantly increased， as well as the levels of SP， CGRP， CD68， and CD206 in the vastus medialis muscle （P＜0.01）， and the serum IL-8 and TNF-αlevels were significantly elevated （P＜0.05 or P＜0.01）. Compared to those in the model group， the muscle fibers in the proximal and distal group were complete in shape and arranged in an orderly manner， with continued non-broken myofascia， regular shape of muscle cells， and significantly reduced level of IL-8 （P＜0.01）； the amplitude and frequency of spontaneous discharge in the proximal group significantly decreased， as well as the variability of PWMT between the left and right hind paws， and the levels of SP， CGRP， and CD68 in the vastus medialis muscle， while the CD206 level increased significantly （P＜0.05 or P＜0.01 ）； there was complex discharges in the distal group， with significantly decreased level of CD68 in the vastus medialis muscle and increased level of CD206 （P＜0.01）. Compared to the proximal group， the level of IL-8 in the distal group was significantly higher （P＜0.05）. ConclusionsEA at proximal acupoints can significantly improve the pain threshold and local muscle tissue morpho-logy in rats， and its mechanism may be related to reducing the levels of pain-causing substances and related inflammatory factors and promoting the polarization of macrophages. The analgesic effect of EA at distal acupoints is not obvious， and the mechanism is still unclear.

OBJECTIVE To compare the efficacy and safety of new oral anticoagulants （NOACs） and warfarin in the treatment of left ventricular thrombus （LVT）， and to provide evidenced-based reference for rational drug use in clinic. METHODS Retrieved from PubMed， Cochrane Library， Embase， Ovid Medline， CNKI， Wanfang and VIP during the inceptions to March 2022， after screening the literature and extracting data， the quality of randomized controlled trials （RCTs） was evaluated by using bias risk evaluation tool recommended by Cochrane systematic evaluator manual. Newcastle Ottawa Scale was used to evaluate the quality of cohort studies， and RevMan 5.3 software was used for meta-analysis and bias risk analysis. RESULTS A total of 13 studies were included in the analysis， including 2 RCTs， 11 cohort studies and 2 261 patients； results of meta-analysis showed that there was no statistical significance in the incidence of complete LVT resolution [OR＝1.05， 95%CI（0.81，1.37）， P＝0.71]， the incidence of stroke/systemic embolism [OR＝0.89， 95%CI（0.67，1.18）， P＝0.42]， the incidence of massive haemorrhage [OR＝ 0.61， 95%CI（0.19，1.97）， P＝0.41]， the incidence of rehospitalization [OR＝0.84， 95%CI（0.49，1.46）， P＝0.54] or all-cause mortality [OR＝0.93， 95%CI（0.56，1.56）， P＝0.79] between 2 groups. The incidence of any bleeding event in trial group was significantly lower than that control group[OR＝ 025-80863493。0.65， 95%CI（0.45，0.93）， P＝0.02]. Subgroup analysis showed that complete LVT resolution of patients with follow-up ≤6 months in trial group was significantly higher than control group， and the incidence of any bleeding event was significantly lower in patients with follow-up ＞6 months and in the European region than control group （P＜0.05）. There was no statistically significant difference in the rate of complete LVT resolution in patients with follow-up＞6 months， the incidence of any bleeding event in patients from Asia and America， or the incidence of any bleeding event in the two groups included in the RCT or the cohort study （P＞0.05）. The publication bias analysis showed that publication bias was less likely in the rate of complete LVT resolution but more likely in the incidence of any bleeding event. CONCLUSIONS NOACs can eliminate thrombus faster in the early stage， but with the prolongation of anticoagulation time， the efficacy of NOACs is comparable to warfarin， and the safety of NOACs in any bleeding event is better than warfarin.

Objective:To investigate the effects of persistent isolated hypothyroxinemia in the first and second trimester of pregnancy on complications and adverse outcomes of pregnancy.Methods:A retrospective analysis was conducted in 784 pregnant women including 111 cases of persistent isolated hypothyroxinemia in the first and second trimester of pregnancy and 673 pregnant women with normal thyroid function as control group. All women were registered and delivered in the Department of Obstetrics of our hospital from April 2016 to April 2017. The complications and adverse outcomes of pregnancy in the two groups were analyzed.Results:Age, body weight before pregnancy, body mass index(BMI), 1 h plasma glucose and 2 h plasma glucose during oral glucose tolerance test in persistent isolated hypothyroxinemia group were higher than those in control group( P<0.05), with increased incidence of anemia during pregnancy( P<0.05). However, there were no significant differences in the incidences of gestational diabetes mellitus and gestational hypertension between the two groups( P>0.05). No significant statistical differences were found in macrosomia, stillbirth, neonatal malformation, postpartum hemorrhage, acute delivery, premature delivery, fetal intrauterine development delay, and small full-term infants between the two groups( P>0.05). Logistic regression analysis showed that age( OR=1.1, 95% CI 1.0-1.1, P=0.002) and pre-pregnancy body weight( OR=1.0, 95% CI 1.0-1.1, P=0.046) were risk factors for the occurrence of persistent isolated hypothyroxinemia in the first and second trimesters of pregnancy. Persistent isolated hypothyroxinemia in the first and second trimesters was associated with anemia during pregnancy( OR=1.9, 95% CI 1.1-3.2, P=0.024). Conclusions:Pregnant women who are older and heavier before pregnancy should pay more attention to their thyroid function. Pregnant women with persistent isolated hypothyroxinemia in the first and second trimesters should be concerned for anemia.