Objective Mendelian randomization(MR)analysis was used to explore the genetic link between immunophenotype and breast cancer(BC)risk and how cerebrospinal fluid(CSF)metabolites play a part in mediating this.Methods We used MR to assess the genetic associations between immune cells and BC risk and their possible mediators.Genetic statistics for immune cells and CSF metabolites were obtained from the Genome-Wide Association Study(GWAS)catalog,whereas those for BC were obtained from the Japan Biobank,the UK Biobank,and FinnGen's cross-ethnic meta-analysis.We performed a two-sample MR analysis using inverse variance weighting(IVW)to investigate the genetic association between immunoepidemiology and BC.We also analyzed CSF metabolites as mediators between them.Heterogeneity was tested using the Cochran's Q statistic,horizontal pleiotropy was tested using the MR Egger intercept,and sensitivity analysis was performed using the"leave-one-out"method.Results MR analysis by the IVW method showed that HLA DR+CD4+T cells were associated with a reduced risk of BC(OR=0.972,95％ CI:0.955-0.990,P=0.003),and there was a negative genetic association between HLA DR+CD4+T cells and methylsuccinimidyl carnitine level(OR=0.922,95％ CI:0.861-0.986,P=0.018),but there was a positive genetic association between the latter and BC risk(OR=1.029,95％ CI:1.012-1.047,P＜0.001).Mediation analysis showed that the direct effect remained significant after correction for CSF methylsuccinylcarnitine level(β=-0.026,SE=0.008,P=0.002).And the indirect effect(β=-0.002,Delta Method SE=0.001)suggested that this CSF metabolite might mediate 8.36％of the association in the protective effect of immune cells against BC risk(95％ CI:-12.4％-29.1％).Conclusion Genetically predicted HLA DR+CD4+T cells may reduce the risk of BC development by modulating the level of methylsuccinylcarnitine,the CSF metabolite.

Objective Mendelian randomization(MR)analysis was used to explore the genetic link between immunophenotype and breast cancer(BC)risk and how cerebrospinal fluid(CSF)metabolites play a part in mediating this.Methods We used MR to assess the genetic associations between immune cells and BC risk and their possible mediators.Genetic statistics for immune cells and CSF metabolites were obtained from the Genome-Wide Association Study(GWAS)catalog,whereas those for BC were obtained from the Japan Biobank,the UK Biobank,and FinnGen's cross-ethnic meta-analysis.We performed a two-sample MR analysis using inverse variance weighting(IVW)to investigate the genetic association between immunoepidemiology and BC.We also analyzed CSF metabolites as mediators between them.Heterogeneity was tested using the Cochran's Q statistic,horizontal pleiotropy was tested using the MR Egger intercept,and sensitivity analysis was performed using the"leave-one-out"method.Results MR analysis by the IVW method showed that HLA DR+CD4+T cells were associated with a reduced risk of BC(OR=0.972,95％ CI:0.955-0.990,P=0.003),and there was a negative genetic association between HLA DR+CD4+T cells and methylsuccinimidyl carnitine level(OR=0.922,95％ CI:0.861-0.986,P=0.018),but there was a positive genetic association between the latter and BC risk(OR=1.029,95％ CI:1.012-1.047,P＜0.001).Mediation analysis showed that the direct effect remained significant after correction for CSF methylsuccinylcarnitine level(β=-0.026,SE=0.008,P=0.002).And the indirect effect(β=-0.002,Delta Method SE=0.001)suggested that this CSF metabolite might mediate 8.36％of the association in the protective effect of immune cells against BC risk(95％ CI:-12.4％-29.1％).Conclusion Genetically predicted HLA DR+CD4+T cells may reduce the risk of BC development by modulating the level of methylsuccinylcarnitine,the CSF metabolite.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective:To re-evaluate the systematic evaluation and meta-analysis of safety of statins in pregnancy and provide reference for the safe use of statins in pregnant women.Methods:The systematic reviews/meta-analysis on the safety of statins during pregnancy were retrieved from databases (up to October 8, 2023). The preferred reporting items for systematic reviews and meta-analyse (PRISMA) were used to evaluate the quality of the included literature, a measure tool to assess systematic reviews 2 (AMSTAR 2) scale was used to evaluate the methodological quality of the included literature, and the grading of recommendations assessment, development, and evaluation (GRADE) tool was used to evaluate the evidence quality of the included literature. The results of quantitative analysis of outcome indicators were expressed by relative risk, odds ratio, mean difference and their 95% confidence interval.Results:A total of 12 systematic reviews/meta-analysis were included. There were 5, 4 and 3 documents with high quality, medium quality, and low quality, respectively, which were evaluated by PRISMA. There were 2 and 10 documents with high and very low quality, which were evaluated by AMSTAR 2 scale. The GRADE tool evidence quality evaluation results showed that among the 48 evidence bodies, 4 were of intermediate quality (8.3%), 37 were of low quality (77.1%), and 7 were of very low quality (14.6%). The re-evaluation results of systematic review/meta-analysis showed that statins exposure during pregnancy did not increase the risk of fetal birth defects and premature delivery, but increased the risk of spontaneous abortion. Pravastatin might reduce the incidence of preeclampsia with uteroplacental insufficiency and neonatal intensive care unit occupancy in patients. There were inconsistent results of statin exposure on fetal cardiac abnormalities and the risk of artificial abortion.Conclusion:Statins exposure during pregnancy does not increase the risks of fetal birth defects and premature birth, but increases the risk of spontaneous abortion.

A 62-year-old male patient received antiplatelet aggregation, lipid-lowering and hypoglycemic therapy due to cerebral infarction complicated with hypertension and diabetes.After 9 days, linagliptin (5 mg orally once daily) and ertugliflozin (5 mg orally once daily) were added due to the poor blood glucose control. The next day after taking the 2 drugs, he developed a scattered rash on the chest, which gradually worsened. A large number of circular target-like erythema appeared on the trunk andproximal limbs, accompanied by pain but no obvious itching. On the 8th day after taking the 2 drugs, the dermatologist consulted and the patient was diagnosed with drug-induced rash, which was considered to be induced by linagliptin. Then linagliptin and ertugliflozin were discontinued. The patient received intravenous infusion of methylprednisolone 40 mg once daily, along with symptomatic treatments such as antihistamines. On the 4th day of treatments, the rash on his chest and back merged into a large area, accompanied by significant flaking; the dosage of methylprednisolone was increased to 80 mg by intravenous injection once daily. On the 7th day of treatments, the rash slightly subsided, and the dosage of methylprednisolone was reduced to 60 mg by intravenous injection once daily. On the 10th day of treatments, the rash was improved significantly. Corticosteroids and antihistamines were gradually discontinued. At a two-week follow-up, the patient′s rash disappeared.

Objective:To re-evaluate the systematic evaluation and meta-analysis of safety of statins in pregnancy and provide reference for the safe use of statins in pregnant women.Methods:The systematic reviews/meta-analysis on the safety of statins during pregnancy were retrieved from databases (up to October 8, 2023). The preferred reporting items for systematic reviews and meta-analyse (PRISMA) were used to evaluate the quality of the included literature, a measure tool to assess systematic reviews 2 (AMSTAR 2) scale was used to evaluate the methodological quality of the included literature, and the grading of recommendations assessment, development, and evaluation (GRADE) tool was used to evaluate the evidence quality of the included literature. The results of quantitative analysis of outcome indicators were expressed by relative risk, odds ratio, mean difference and their 95% confidence interval.Results:A total of 12 systematic reviews/meta-analysis were included. There were 5, 4 and 3 documents with high quality, medium quality, and low quality, respectively, which were evaluated by PRISMA. There were 2 and 10 documents with high and very low quality, which were evaluated by AMSTAR 2 scale. The GRADE tool evidence quality evaluation results showed that among the 48 evidence bodies, 4 were of intermediate quality (8.3%), 37 were of low quality (77.1%), and 7 were of very low quality (14.6%). The re-evaluation results of systematic review/meta-analysis showed that statins exposure during pregnancy did not increase the risk of fetal birth defects and premature delivery, but increased the risk of spontaneous abortion. Pravastatin might reduce the incidence of preeclampsia with uteroplacental insufficiency and neonatal intensive care unit occupancy in patients. There were inconsistent results of statin exposure on fetal cardiac abnormalities and the risk of artificial abortion.Conclusion:Statins exposure during pregnancy does not increase the risks of fetal birth defects and premature birth, but increases the risk of spontaneous abortion.

A 62-year-old male patient received antiplatelet aggregation, lipid-lowering and hypoglycemic therapy due to cerebral infarction complicated with hypertension and diabetes.After 9 days, linagliptin (5 mg orally once daily) and ertugliflozin (5 mg orally once daily) were added due to the poor blood glucose control. The next day after taking the 2 drugs, he developed a scattered rash on the chest, which gradually worsened. A large number of circular target-like erythema appeared on the trunk andproximal limbs, accompanied by pain but no obvious itching. On the 8th day after taking the 2 drugs, the dermatologist consulted and the patient was diagnosed with drug-induced rash, which was considered to be induced by linagliptin. Then linagliptin and ertugliflozin were discontinued. The patient received intravenous infusion of methylprednisolone 40 mg once daily, along with symptomatic treatments such as antihistamines. On the 4th day of treatments, the rash on his chest and back merged into a large area, accompanied by significant flaking; the dosage of methylprednisolone was increased to 80 mg by intravenous injection once daily. On the 7th day of treatments, the rash slightly subsided, and the dosage of methylprednisolone was reduced to 60 mg by intravenous injection once daily. On the 10th day of treatments, the rash was improved significantly. Corticosteroids and antihistamines were gradually discontinued. At a two-week follow-up, the patient′s rash disappeared.

High-risk neuroblastoma (NB) is highly aggressive and has poor prognosis. Treatment of NB mainly includes comprehensive therapies, of which radiotherapy serves as a part of consolidation therapy. For patients who receive complete resection of the primary lesion, usually an irradiation dose of 21-23.4 Gy is given; for patients with incomplete resection, further study focused on radiation dose is necessary. Recurrence is most commonly observed in the bone lesions involved at presentation. Currently, the principle of irradiation to the metastatic sites is to treat lesions where metaio-dobenzylguanidine (MIBG) uptake remains positive after induction chemotherapy, or those become negative uptake but still at high risk of recurrence. On the premise of lacking of MIBG imaging, positron emission tomography CT (PET-CT) may assist in screening for metastatic sites requiring irradiation. The late side effects of radiotherapy are mainly mild musculoskeletal abnormalities. No significant increase is observed in the incidence of second primary tumor during short-term follow-up.

OBJECTIVE To evaluate the effects of gene polymorphism on the efficacy and safety of citalopram/escitalopram， and to provide evidence-based reference for precision medication. METHODS Retrieved from PubMed， Embase， the Cochrane Library， CNKI， Wanfang data and SinoMed， clinical studies about the association of gene polymorphism with efficacy and safety of citalopram/escitalopram were collected. Meta-analysis was performed with RevMan 5.3 software after literature screening， data extraction and quality evaluation based on Newcastle-Ottawa scale. RESULTS Totally 35 pieces of literature were included， all of which were cohort studies， with a total of 9 836 patients. Meta-analysis showed that the SLC6A4 gene 5-serotonin transporter linked polymorphic region （HTTLPR） LL genotype was associated with high response rate of citalopram/escitalopram [LS/SS vs. LL： OR＝0.47， 95%CI （0.22， 0.98）， P＝0.05]； results of subgroup analysis suggested a higher correlation in white people with LL genotype and escitalopram； there was no significant correlation of HTTLPR genotype with remission rate [LS/SS vs. LL： OR＝ 0.92，95%CI（0.77， 1.10）， P＞0.05； SS vs. LL/LS：OR＝0.73， 95%CI（0.45， 1.19）， P＞0.05] or overall incidence of ADR in patients with gene SLC6A4； but high expression of rs25531 LA was significantly associated with reduced incidence of ADR（P＜ 0.05）. CYP2C19*2/*3 allele was significantly associated with slowed metabolism， higher response rate and increased incidence of ADR. CONCLUSIONS HTTLPR LL genotype is associated with the increased response rate of citalopram/escitalopram， but no significant correlation with safety is found， while CYP2C19*2/*3 allele is significantly associated with higher response rate and reduced tolerability.