BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

OBJECTIVE To evaluate the anticoagulant efficacy and safety of nafamostat mesylate （NM） in the treatment of uremic patients at high risk of bleeding undergoing continuous veno-venous hemofiltration （CVVH） with different methods （pre- dilution and post-dilution）. METHODS A total of 130 uremic patients at high risk of bleeding who underwent CVVH treatment in the nephrology department of Chongqing University Three Gorges Hospital from July 2023 to September 2024 were selected. They were divided into pre-dilution group and post-dilution group according to the random number table method， with 65 cases in each group. Both groups of patients received CVVH treatment under NM anticoagulation. The pre-dilution group adopted the pre-dilution replacement method， while the post-dilution group adopted the post-dilution replacement method. The coagulation， pressure， and usage duration of the filter and dialysis circuit venous reservoirs were compared between the two groups. The changes in prothrombin time （PT）， prothrombin time-international normalized ratio （PT-INR）， activated partial thromboplastin time （APTT）， and fibrinogen （FIB） in the peripheral venous blood before the heparin pump and after the filter at 1， 4 and 7 h of CVVH treatment， as well as 20 min after the end of treatment， were compared between the two groups. The single-compartment urea clearance rate （spKt/V）， β2-microglobulin （β2-MG） clearance rate and the incidence of adverse reactions were duni2007@foxmail.com compared between the two groups. RESULTS Both the pre-dilution and post-dilution groups had 60 patients who completed the study. The incidence of grade Ⅱ-Ⅲ coagulation of the filter and venous reservoirs， as well as the number of patients with transmembrane and venous pressure alarm intervention in the post- dilution group were significantly higher or more than those in the pre-dilution group （P＜0.05）， while usage time of the filter and the pipeline in the post-dilution group was significantly shorter than that in the pre-dilution group （P＜0.05）. The APTT values before the heparin pump as well as PT and APTT values after the filter at 1 h， 4 h， and 7 h of CVVH treatment in the post-dilution group were significantly higher than those in the pre-dilution group （P＜0.001）. There were no significant differences in PT， PT- INR， APTT and FIB between the two groups of patients 20 min after the end of treatment （P＞0.05）. The spKt/v and β2-MG clearance rates in the post-dilution group were significantly higher than those in the pre-dilution group （P＜0.001）. There was no significant difference in the incidence of adverse reactions between the two groups （P＞0.05）. CONCLUSIONS When NM is used as an anticoagulant in the CVVH treatment of uremic patients at high risk of bleeding， compared with the pre-dilution treatment method， the post-dilution treatment method has a higher incidence of filter and dialysis tubing venous reservoir， a shorter usage time of the filter and pipeline， and a greater impact on extracorporeal coagulation， but has a higher solute clearance rate. Clinically， different dilution methods can be selected according to the different treatment needs of patients.

AIM:To investigate the effect of ranibizumab on blood flow density in different regions of the macula in patients with macular edema(ME)secondary to ischemic and non-ischemic branch retinal vein occlusion(BRVO).METHODS:This retrospective study enrolled patients with BRVO-ME who were treated at the hospital from September 2019 to March 2021. Patients were divided into ischemic and non-ischemic groups based on fundus findings. All patients received intravitreal injections of ranibizumab once monthly for three consecutive months. Best corrected visual acuity(BCVA), central macular thickness(CMT), and macular blood flow density were measured before treatment and at 1 d, 1 wk, 1 and 3 mo after treatment.RESULTS: A total of 46 patients(46 eyes)with BRVO-ME were included, comprising 21 eyes in the ischemic group(7 males, 14 females; mean age 55.81±10.36 y)and 25 eyes in the non-ischemic group(11 males, 14 females; mean age 54.84±9.81 y). At 3 mo after treatment, BCVA(LogMAR)in the non-ischemic group was superior to that in the ischemic group(0.19±0.19 vs 0.38±0.27, P=0.009). Analysis of CMT changes showed that the reduction amplitude in the ischemic group was significantly greater than that in the non-ischemic group at both 1 and 3 mo after treatment(all P<0.05). Blood flow densities in the whole, parafoveal, and perifoveal regions of the superficial capillary plexus(SCP), as well as in the whole and perifoveal regions of the deep capillary plexus(DCP), were significantly lower in ischemic patients than in non-ischemic patients, while blood flow density in the foveal region of DCP was significantly higher in the ischemic group(all P<0.05).CONCLUSION: Ranibizumab is effective for both types of patients. Non-ischemic patients have a better long-term visual prognosis, and the advantage may be related to better blood flow perfusion patterns in specific areas 3 mo after treatment. Monitoring changes in blood flow density in these areas can help provide personalized treatment for patients.

Aim To investigate the pharmacological mechanism of Ebselenin(Ebselen,EbSe)in the treat-ment of Escherichia coli(E.coli)infection,which had no significant inhibitory effect on Gram-negative bacte-ria,based on previous studies.Methods After EbSe intervention in E.coli infected Raw264.7 cells,the via-bility of Raw264.7 cells was determined by CCK-8 method,the morphology and structure of Raw264.7 cells were observed by electron microscope,and the in-tracellular bacterial load of Raw264.7 cells was calcu-lated by coated plate method.Polarization status of peritoneal macrophages,Raw264.7 intracellular NO and ROS content and intracellular HO-1 expression in Raw264.7 and E.coli acutely infected mice after E.co-li infection by flow cytometry.qPCR was used to detect the expression of related mRNAs in Raw264.7 cells.qPCR was used to detect the intracellular GSH content in Raw264.7 cells by spectrophotometric assay,and the state of cytoskeletal proteins was observed by immuno-fluorescence.Western blot assay was performed to de-tect the intracellular Txnrd1 expression level.Results Microtiter method,CCK-8,and electron microscopy observations showed that EbSe had no effect on the growth of E.coli and Raw264.7 cells in vitro.The re-sults of smear plate counting showed that EbSe reduced the intracellular bacterial load of Raw264.7 in the in-fected group.Flow cytometry results showed that EbSe upregulated the number of M2-type macrophages.The EbSe-treated infected group had reduced intracellular NO and ROS levels and increased GSH levels.The qPCR results showed that the expression of IL-6,IL-1β,and iNOS was decreased,and the expression of HO-1,Txnrd1,and Glut1 was increased in DHB4-in-fected Raw264.7 cells after EbSe treatment.Cytoskel-etal staining showed that the morphology of the EbSe-treated infected cells was similar to that of oxPAPC-in-duced cells.Western blot results showed the expres-sion of Txnrd1 protein in EbSe-treated infected cells in-creased.Conclusion EbSe exerts anti-E.coli acute infection effect by regulating macrophage polarization and inhibiting macrophage excessive inflammatory state.

Meniere's disease represents an idiopathic inner ear disorder characterized by endolymphatic hy-drops.Currently,the research methods for identifying genes associated with this disease mainly involve first-genera-tion sequencing and second-generation sequencing.This article reviews research on the genetic study of Meniere's disease,mainly summarizing the candidate genes with repeated pedigree validation in familial Meniere's disease,as well as those frequently reported in sporadic Meniere's disease.

Aim To investigate the pharmacological mechanism of Ebselenin(Ebselen,EbSe)in the treat-ment of Escherichia coli(E.coli)infection,which had no significant inhibitory effect on Gram-negative bacte-ria,based on previous studies.Methods After EbSe intervention in E.coli infected Raw264.7 cells,the via-bility of Raw264.7 cells was determined by CCK-8 method,the morphology and structure of Raw264.7 cells were observed by electron microscope,and the in-tracellular bacterial load of Raw264.7 cells was calcu-lated by coated plate method.Polarization status of peritoneal macrophages,Raw264.7 intracellular NO and ROS content and intracellular HO-1 expression in Raw264.7 and E.coli acutely infected mice after E.co-li infection by flow cytometry.qPCR was used to detect the expression of related mRNAs in Raw264.7 cells.qPCR was used to detect the intracellular GSH content in Raw264.7 cells by spectrophotometric assay,and the state of cytoskeletal proteins was observed by immuno-fluorescence.Western blot assay was performed to de-tect the intracellular Txnrd1 expression level.Results Microtiter method,CCK-8,and electron microscopy observations showed that EbSe had no effect on the growth of E.coli and Raw264.7 cells in vitro.The re-sults of smear plate counting showed that EbSe reduced the intracellular bacterial load of Raw264.7 in the in-fected group.Flow cytometry results showed that EbSe upregulated the number of M2-type macrophages.The EbSe-treated infected group had reduced intracellular NO and ROS levels and increased GSH levels.The qPCR results showed that the expression of IL-6,IL-1β,and iNOS was decreased,and the expression of HO-1,Txnrd1,and Glut1 was increased in DHB4-in-fected Raw264.7 cells after EbSe treatment.Cytoskel-etal staining showed that the morphology of the EbSe-treated infected cells was similar to that of oxPAPC-in-duced cells.Western blot results showed the expres-sion of Txnrd1 protein in EbSe-treated infected cells in-creased.Conclusion EbSe exerts anti-E.coli acute infection effect by regulating macrophage polarization and inhibiting macrophage excessive inflammatory state.

Objective To investigate the role of the GPR120 gene in the progression of sepsis,explore the molecular mechanisms through which GPR120 gene regulates NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)inflammasome activation and macrophage polarization.Methods The blood and pleural fluid samples were collected from the sepsis patients and the control group.The expression of inflammatory factors and the associated proteins were detected by flow cytometry and ELISA.C57BL/6 mice and monocyte-macrophage cell line(Raw264.7)were treated with lipopolysaccharide(LPS)to construct the sepsis models.After the intervention of GPR120 agonist TUG891,the expression of GPR120 gene,NLRP3 inflammasome protein and macrophage polarization protein were detected between the control group and the sepsis group.Results The expression of inflammatory factors,such as IL-1β in the serum of septic patients,significantly increased compared with the control(P<0.001).And the expression of inflammasome proteins such as NLRP3,Caspase-1 and IL-1β in the pleural fluid also increased(all P<0.05).In vivo,LPS could induce severe inflammation in lung tissue,the GPR120 gene expression decreased in lung tissue,and inflammatory factors were up-regulated in mouse serum(P<0.01).The inflammasome-associated protein and M1 type polarization of macrophages were enhanced,the TUG891 could reduce the inflammatory response,inhibit the NLRP3 inflammasome activating,and promote the M2 polarization of macrophages(P<0.01).In vitro,LPS could inhibit the intracellular GPR120 expression.The inflammatory factors secreted more in LPS-induced sepsis cells.TUG891 could promote the up-regulation of GPR120 protein and alleviate the secretion of inflammatory factors(P<0.05).Conclusion In sepsis,GPR120 gene activation could inhibit the NLRP3 inflammasome activation,promote macrophage polarization,and reduce the inflammatory damage,thereby delay the rapid progression of sepsis.

Objective To explore the relationship between insulin resistance and idiopathic central precocious puberty(ICPP)in girls and the diagnostic value of insulin resistance.Methods Clinical data of 245 girls aged 4 to 7.5 years with low luteinizing hormone(LH)levels(0.2-0.83 IU/L),normal body weight(body mass index standard deviation score between-2 and+2),and early breast development who visited the Department of Pediatric Endocrinology,Henan Provincial Maternal and Child Health Hospital from January 2022 to March 2025 were retrospectively analyzed.According to the Expert Consensus on the Diagnosis and Treatment of Central Precocious Puberty(2022),patients were assigned to an ICPP group(n=123)or a control group(n=122).Correlations between the homeostasis model assessment of insulin resistance(HOMA-IR)and selected indices were assessed.Multivariable logistic regression was used to evaluate the association between HOMA-IR and ICPP,and the diagnostic performance of various indices for ICPP was evaluated.Results HOMA-IR was higher in the ICPP group than in the control group(P<0.001)and was positively correlated with LH peak(rs=0.467,P<0.05)and the LH peak/FSH peak ratio(rs=0.444,P<0.05).The multivariable logistic regression model including age,BMI,and basal LH showed that HOMA-IR was closely associated with ICPP(OR=2.756,95%CI:1.940-3.913).Receiver operating characteristic curve analysis showed that the areas under the curve for basal LH,HOMA-IR,and their combination in diagnosing ICPP were 0.735,0.735,and 0.805,respectively(P<0.05),and the combined model had a greater area under the curve than either basal LH or HOMA-IR alone(both P<0.05).Conclusions HOMA-IR is closely associated with ICPP in girls with low LH and normal body weight,and combining HOMA-IR with basal LH improves early identification and diagnostic efficiency in this population.

Objective To explore the relationship between insulin resistance and idiopathic central precocious puberty(ICPP)in girls and the diagnostic value of insulin resistance.Methods Clinical data of 245 girls aged 4 to 7.5 years with low luteinizing hormone(LH)levels(0.2-0.83 IU/L),normal body weight(body mass index standard deviation score between-2 and+2),and early breast development who visited the Department of Pediatric Endocrinology,Henan Provincial Maternal and Child Health Hospital from January 2022 to March 2025 were retrospectively analyzed.According to the Expert Consensus on the Diagnosis and Treatment of Central Precocious Puberty(2022),patients were assigned to an ICPP group(n=123)or a control group(n=122).Correlations between the homeostasis model assessment of insulin resistance(HOMA-IR)and selected indices were assessed.Multivariable logistic regression was used to evaluate the association between HOMA-IR and ICPP,and the diagnostic performance of various indices for ICPP was evaluated.Results HOMA-IR was higher in the ICPP group than in the control group(P<0.001)and was positively correlated with LH peak(rs=0.467,P<0.05)and the LH peak/FSH peak ratio(rs=0.444,P<0.05).The multivariable logistic regression model including age,BMI,and basal LH showed that HOMA-IR was closely associated with ICPP(OR=2.756,95%CI:1.940-3.913).Receiver operating characteristic curve analysis showed that the areas under the curve for basal LH,HOMA-IR,and their combination in diagnosing ICPP were 0.735,0.735,and 0.805,respectively(P<0.05),and the combined model had a greater area under the curve than either basal LH or HOMA-IR alone(both P<0.05).Conclusions HOMA-IR is closely associated with ICPP in girls with low LH and normal body weight,and combining HOMA-IR with basal LH improves early identification and diagnostic efficiency in this population.