BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

ObjectiveTo investigate the protective effect of α-ketoglutarate （α-KG） on hepatic lipid deposition in offspring caused by arsenic exposure during pregnancy. Methods8-week-old institute of cancer research （ICR） mice were mated in a ratio of 2∶1 between females and males， and the detection of vaginal plugs confirmed pregnant. A total of 32 pregnant mice were randomly divided into four groups： control group， arsenic group， α-KG group， arsenic+α-KG group. On gestational day 0-16 （GD0-GD16）， the arsenic and arsenic+α-KG groups were exposed to sodium arsenite （NaAsO₂ ，15 mg/L） in drinking water everyday， and the α-KG and arsenic+α-KG groups were gavaged with α-KG （2 g/kg） everyday. On GD16， pregnant mice were euthanized to collect fetal liver， and fetal body weight and crown-rump length were measured. Gene expression differences between the control group and the arsenic group were analyzed by transcriptome. The total triglycerides （TGs） and subtypes in fetal liver were detected by liquid chromatography tandem mass spectrometry （LC-MS/MS）. Oil red O staining was used to observe the histopathological changes in the liver. Quantitative polymerase chain reaction （qPCR） was used to detect the expression level of genes related to lipid synthesis， transport， and degradation， and phosphatidylinositol 3' -kinase/ protein kinase B （PI3K/AKT） in the liver of fetus. ResultsTranscriptomics analysis showed that 2 144 genes were downregulated and 1 675 genes were upregulated in the arsenic exposed fetal liver； body weight and crown-rump length were reduced （P_TuKey<0.05）； the level of hepatic TGs was elevated in arsenic group （P_TuKey<0.05）； oil-red O staining showed a significant increase in lipid droplets in arsenic group （P_TuKey<0.01）； the expression of lipid synthesis-related genes were significantly upregulated （P_TuKey<0.05）； the expression of β-oxidation-related genes and lipid degradation-related genes were downregulated （P_TuKey<0.05）； the expression of PI3K， AKT decreased（P_TuKey<0.05）. Compared with the arsenic group， the body weight and crown-rump length of fetus increased in the arsenic+α-KG group （P_TuKey<0.05）； the level of hepatic TGs decreased in the arsenic+α-KG group （P_TuKey<0.05）； oil red O staining showed lipid droplets significantly decreased （P_TuKey<0.01）； the expression of lipid synthesis-related genes were downregulated （P_TuKey<0.05）， the expression of β-oxidation-related genes and lipid degradation-related genes were upregulated （P_TuKey<0.05）； the expression levels of PI3K and AKT increased （P_TuKey<0.05）. Conclusionα-KG alleviated hepatic lipid deposition in offspring exposed to arsenic during pregnancy through activating PI3K/AKT signaling pathway.

BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

ObjectiveTo explore the vascular endothelial injury in male mice caused by exposure to polystyrene microplastics （PS-MPs） and the intervention effect of luteolin on vascular remodeling. Additionally， to investigate the mechanism through the oxidative system and metabolomics. MethodsThirty-two C57BL/6 mice （6-8 weeks old） were randomly divided into the saline group （saline group）， the 0.1 mg/kg PS-MPs exposure group （0.1PS-MPs group）， the 1 mg/kg PS-MPs exposure group （1PS-MPs group）， and the 1 mg/kg PS-MPs + luteolin treatment group （1PS-MPs + Lut group）， with 8 mice in each group. After 8 weeks of intervention， the body weight， blood pressure， aortic organ coefficient， and aortic histopathological changes of mice in each group were detected； the total cholesterol （TC）， triglyceride （TG）， and high-density lipoprotein cholesterol （HDL-C） lipid metabolism-related indicators in the aorta of mice were detected； the reactive oxygen species （ROS）， glutathione （GSH）， and malondialdehyde （MDA） oxidative stress-related indicators were detected； the endothelin （ET-1）， nitric oxide （NO）， vascular endothelial growth factor A （VEGF-A）， vascular cell adhesion molecule-1 （VCAM-1/CD106）， and intercellular adhesion molecule-1 （ICAM-1/CD54） endothelial function-related indicators and serum metabolomics were detected. ResultsCompared to the saline group， exposure to PS-MPs resulted in pathological thickening of the mouse aorta， increased aortic organ coefficient， and elevated blood pressure. Lipid metabolism-related indicators， including TC and TG， were elevated， while HDL-C was reduced， indicating lipid metabolism disorder in mice. Oxidative stress markers such as ROS and MDA increased， whereas GSH decreased， demonstrating oxidative damage. Vascular endothelial inflammation and injury markers， including ET-1， VEGF-A， VCAM-1， and ICAM-1， were upregulated， while the vasodilatory substance NO was downregulated， confirming endothelial injury. Furthermore， serum metabolomics results revealed that PS-MPs exposure induced endothelial damage by disrupting metabolic pathways such as the citrate cycle. Compared to the PS-MPs group， luteolin significantly reversed these effects， attenuating oxidative stress and lipid metabolism disorders， and effectively repairing endothelial injury. ConclusionPS-MPs induce vascular toxicity through oxidative stress and lipid metabolism. Luteolin effectively alleviates endothelial damage and vascular remodeling.

Objective To investigate the risk factors for postoperative recurrence and metastasis in patients with T1 stageⅢ/Ⅳ clear cell renal cell carcinoma(ccRCC), and to analyze the influence of surgical methods on prognosis, so as to provide prognostic evaluation and treatment guidance for clinical practice. Methods A retrospective analysis was conducted on 398 patients diagnosed with T1 stage Ⅲ/Ⅳ ccRCC who underwent either partial nephrectomy(PN)or radical nephrectomy(RN)at Jiangsu Province Hospital during Jan. 2008 and Sep. 2022. The patients were divided into recurrence group(n=49)and non-recurrence group(n=349)according to whether the tumor recurred during the follow-up period. The general, clinical data and prognosis were compared between the two groups. Univariate and multivariate Cox regression analyses were used to explore the factors influencing disease-free survival(DFS)and overall survival(OS)after surgery. Subgroup analysis using Kaplan-Meier curves was performed for T1a and T1b patients. Results During the median follow-up of 67(42, 98)months, the recurrence group was characterized by older age, larger tumor diameter, higher proportion of T1b stage, and more complex tumor anatomy. Univariate and multivariate Cox regression analyses showed that age ≥55 years and R.E.N.A.L. score ≥7 were independent risk factors for poorer DFS and OS(P＜0.05). Subgroup analysis revealed that PN or RN did not significantly affect DFS or OS in T1a patients and OS in T1b patients, while RN significantly improved DFS in T1b patients(P＜0.05). Conclusion Age ≥55 years and R.E.N.A.L. score ≥7 are independent risk factors for poor DFS and OS in highgrade T1 ccRCC patients. For T1b patients, RN may improve DFS.

Objective To explore the association between the ratio of red blood cell distribution width to albumin level(RAR)and the risk of non-valvular atrial fibrillation(NVAF)in patients with hyperuricemia.Methods A total of 8 277 patients with hyperuricemia who underwent physi-cal examinations at the Physical Examination Center of Northern Jiangsu People's Hospital from January 2021 to June 2024 were enrolled.From them,185 patients with AF were assigned into a case group,and 740 patients without AF were into a control group in a ratio of 1∶4 with propen-sity score matching(PSM).Logistic regression analysis,restricted cubic spline analysis,and sub-group analysis were employed to investigate the association between RAR and the risk of NVAF in hyperuricemic patients.Results The case group had significantly larger ratio of smoking,high-er levels of red blood cell distribution width,total bilirubin,hematocrit,and RAR index,but lower albumin,low-density lipoprotein cholesterol(LDL-C)and triglyceride(TG)levels,and smaller ra-tio of fatty liver than the control group(P＜0.01).Multivariate logistic regression analysis showed that the patients at Q2,Q3,and Q4 quartiles of RAR index have higher risk for AF than those at Q1 quartile(OR=2.843,OR=4.263,OR=7.801,P＜0.01).The effect of RAR index was significant when below the breakpoint of 2.85(OR=1.492,95％CI:1.151-1.993,P=0.004).Subgroup analysis indicated significant interactions between RAR index and age as well as smok-ing(P interaction＜0.05).The area under curve value of RAR index in predicting NVAF occurrence in male hyperuricemic patients was 0.679(95％CI:0.632-0.725).Conclusion In patients with hyperuricemia,a higher RAR index is associated with an increased risk of NVAF.RAR index has guiding significance for diagnosing male hyperuricemic patients complicated with AF.

OBJECTIVE To observe the effect of biapenem combined with moxifloxacin on treatment of the elderly patients with severe pneumonia based on the expression levels of microribonucleic acid(miR)-146a,miR-124 and miR-127.METHODS A total of 112 elderly patients with severe pneumonia who were treated in Jiangnan Uni-versity Affiliated Central Hospital from Jan.2021 to Oct.2023 were recruited as the research subjects and were randomly divided into the study group and the control group,with 56 cases in each group.The control group was treated with moxifloxacin,and the study group was treated with biapenem combined with moxifloxacin,and both groups were treated for 10 consecutive days.The curative effect was compared between the two groups after the treatment for 10 days,the rehabilitation status was observed;the curative effect,expression levels of miR-146a,miR-124 and miR-127 as well as inflammatory response were compared between the two groups before and after the treatment.The adverse reactions during the treatment were analyzed.RESULTS The total effective rate of the study group was 92.86％(52/56)after the treatment for 10 days,higher than 75.00％(42/56)of the control group(x2=10.693,P=0.001).The duration of cough,lung rales,recovery of body temperature and mechanical ventilation were shorter in the study group than those in the control group(P＜0.05).The expression levels of miR-146a and miR-127 of the two groups were lower after the treatment for 10 days than those before the treat-ment,the levels of whole blood white blood cell(WBC)counts,serum interleukin-6(IL-6)and procalcitonin(PCT)were lower after the treatment for 10 days than those before the treatment;the levels of the above indexes of the study group were lower than those of the control group(P＜0.05).The expression level of serum miR-124 of the two groups was higher after the treatment for 10 days than those before the treatment,and the level of the study group was higher than that of the control group(P＜0.05).The total incidence of adverse reactions was 14.29％in the study group,10.71％in the control group,and there was no significant difference(x2=1.298,P=0.255).CONCLUSION Biapenem combined with moxifloxacin can achieve exact effect on treatment of the elderly patients with severe pneumonia,regulate the expression levels of miR-146a,miR-124 and miR-127,inhibit the in-flammatory response of the body,and promote the rehabilitation,with the safety favorable.

Objective To evaluate the clinical efficacy and safety of the daratumumab-based regimens,including daratumumab,dexamethasone,and lenalidomide(DRd),as well as daratumumab,dexamethasone,and bortezomib(DVd),in the treatment of patients with relapsed or refractory multiple myeloma(RRMM)at our center.Methods Eighty patients with RRMM were assigned to either the DRd group(42 cases)or the DVd group(38 cases)based on their treatment regimens.Both groups received a baseline treatment of daratumumab combined with dexamethasone(Dd regimen).In the DVd group,1.3 mg/m2 of bortezomib was administered subcutaneously on days 1,4,8,and 11 of each cycle,followed by a 10 day drug-free interval(days 12～21),repeated every 3 weeks until disease progression.In the DRd group,25 mg of lenalidomide was orally administered daily from day 1 to day 21 of each cycle,in addition to the Dd regimen,continuing until disease progression.The two groups were compared in terms of laboratory parameters,tumor markers,clinical efficacy,safety profiles,and long-term prognostic outcomes.Results After treatment,the overall response rate(ORR)of the DRd group and the DVd group was 78.57%(33 out of 42 cases)and 52.63%(20 out of 38 cases),respectively.The serum creatinine(SCr)levels were(92.54±14.33)and(102.07±15.41)μmol/L,respectively;the M protein contents were(19.62±2.04)and(21.08±2.23)g/L,respectively;the β2-microglobulin(β2-MG)levels were(3.49±1.12)and(4.16±1.25)mg/L,respectively;and the progression-free survival rates were 42.86%(18 out of 42 cases)and 26.32%(10 out of 38 cases),respectively.All these indicators showed statistically significant differences between the DRd group and the DVd group(all P<0.05).The incidence rates of adverse reactions in the observation group and the control group were 14.29%(6 out of 42 cases)and 13.16%(5 out of 38 cases),respectively,and the difference was not statistically significant(P>0.05).Conclusion The DRd regimen demonstrates superior efficacy compared to the DVd regimen in treating patients with RRMM,leading to improved patient prognosis with a favorable safety profile.

Objective To investigate the mechanism by which 4-week high-intensity interval training(HIIT)regulates the mitochondrial unfolded protein response(UPRmt)in skeletal muscle and improves mitochondrial function in a rat model of chronic unpredictable mild stress(CUMS).Methods Male SPF-grade SD rats(6～8 weeks old)were divided randomly into control(C),model(M),HIIT+control(HC),and HIIT+model(HM)groups.Rats in the M and HM groups were subjected to CUMS for 8 weeks to establish a depression model,while rats in the HC and HM groups received HIIT for 5 d a week for 4 weeks.The exercise regimen consisted of 3 min high-speed(85％～90％Smax)combined with 1 min low-speed(50％～55％Smax)uninterrupted repetitive training(Smax is maximum training speed).Behavioral changes were evaluated at weeks 4 and 8.Tissue samples were taken 24 h after the last behavioral test and skeletal muscle mitochondria were examined by transmission electron microscopy.The ATP and reactive oxygen species(ROS)contents were measured by enzyme-linked immunosorbent assays and protein expression levels of activating transcription factor(ATF)4,ATF5,C/EBP homologous protein(CHOP),and heat shock protein 60(HSP60)were detected by Western blot.Results(1)The body mass,number of crossing grids,number of upright positions,sugar-water preference rate,and ATP content were significantly decreased in group M compared with group C(P＜0.01),while the number of damaged mitochondria,ROS content,ATF4,ATF5,CHOP,and HSP60 protein expression were significantly increased(P＜0.01).(2)After 4-weeks of HIIT intervention,the ATP content and ATF4 and ATF5 protein expression levels were significantly increased in the HC group compared with C group(P＜0.05,P＜0.01).The number of crossing grids,number of upright positions,sugar-water preference rate,ATP content,and ATF4 protein expression were significantly increased in the HM group compared with M group(P＜0.01),while the number of damaged mitochondria,ROS content,and ATF5,CHOP,and HSP60 protein expression levels were significantly decreased(P＜0.01).(3)After 4 weeks of HIIT intervention,the number of crossing grids in CUMS rats was significantly positively correlated with ATF4 protein expression,and ROS content was correlated with CHOP protein expression,number of damaged mitochondria,and ATF5 protein expression(|r|＞0.75,P＜0.01;|r|＞0.75,P＜0.05).Upright frequency was significantly negatively correlated with ATF5 and HSP60 protein expression,the number of crossing grids,the sugar-water preference rate,and the expression of CHOP and HSP60 proteins(|r|＜0.75,P＜0.05).Conclusions 4-week HIIT intervention can improve mitochondrial dysfunction and alleviate depressive-like behavior in CUMS rats by regulating skeletal muscle UPRmt.

Objective To explore the association between the ratio of red blood cell distribution width to albumin level(RAR)and the risk of non-valvular atrial fibrillation(NVAF)in patients with hyperuricemia.Methods A total of 8 277 patients with hyperuricemia who underwent physi-cal examinations at the Physical Examination Center of Northern Jiangsu People's Hospital from January 2021 to June 2024 were enrolled.From them,185 patients with AF were assigned into a case group,and 740 patients without AF were into a control group in a ratio of 1∶4 with propen-sity score matching(PSM).Logistic regression analysis,restricted cubic spline analysis,and sub-group analysis were employed to investigate the association between RAR and the risk of NVAF in hyperuricemic patients.Results The case group had significantly larger ratio of smoking,high-er levels of red blood cell distribution width,total bilirubin,hematocrit,and RAR index,but lower albumin,low-density lipoprotein cholesterol(LDL-C)and triglyceride(TG)levels,and smaller ra-tio of fatty liver than the control group(P＜0.01).Multivariate logistic regression analysis showed that the patients at Q2,Q3,and Q4 quartiles of RAR index have higher risk for AF than those at Q1 quartile(OR=2.843,OR=4.263,OR=7.801,P＜0.01).The effect of RAR index was significant when below the breakpoint of 2.85(OR=1.492,95％CI:1.151-1.993,P=0.004).Subgroup analysis indicated significant interactions between RAR index and age as well as smok-ing(P interaction＜0.05).The area under curve value of RAR index in predicting NVAF occurrence in male hyperuricemic patients was 0.679(95％CI:0.632-0.725).Conclusion In patients with hyperuricemia,a higher RAR index is associated with an increased risk of NVAF.RAR index has guiding significance for diagnosing male hyperuricemic patients complicated with AF.