To investigate the efficacy and safety of glucocorticoids combined with cyclophosphamide (CTX) and rituximab (RTX) in elderly patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with renal involvement.

BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

Objective:To evaluate the efficacy and safety of rituximab (RTX) in the treatment of idiopathic membranous nephropathy (IMN), explore the influencing factors of the therapeutic effect and construct a nomogram model for predicting the therapeutic effect.Methods:A single retrospective study was conducted in IMN patients in the First Affiliated Hospital of Zhejiang University School of Medicine from January 2017 to December 2022. All patients received monotherapy with RTX and were followed up for at least 12 months. RTX regimen adopted a B-cell guided regimen to achieve 0 cells/μl of peripheral blood CD19+ B cells through multiple administrations, followed by monitoring every 2?3 months and adding doses as needed to maintain this state. The complete response rate, partial response rate, and composite response rate at 6 months, 12 months and the end of follow up were analyzed. Logistic stepwise regression and R language were applied to construct a nomogram model for efficacy prediction. The receiver operating characteristic (ROC) curve, calibration curve and Hosmer-Lemeshow test were used to internally validate the nomogram model.Results:A total of 147 IMN patients were included in the study, with age of 56 (47, 65) years, 99 (67.4%) males. There were 69 (46.9%) newly treated patients, 78 (53.1%) retreatment patients. The follow-up time was 14.4 (12.0, 15.0) months. The total RTX dose was 1 800 (1 200, 2 400) mg. The composite response rates at 6 months, 12 months and the end of the follow-up were 36.7% (54/147), 59.9% (88/147) and 63.3% (93/147), respectively. The complete remission rates at 6 months, 12 months and the end of the follow-up were 6.1% (9/147), 13.6% (20/147) and 19.7% (29/147), respectively. Logistic stepwise regression analysis showed that age ≥ 65 years ( OR=0.335, 95% CI 0.135?0.833), retreatment ( OR=0.333, 95% CI 0.144?0.771), high cholesterol ( OR=0.716, 95% CI 0.577?0.888), high serum creatinine ( OR=0.978, 95% CI 0.963?0.993) and B-cell reconstruction within 6 months ( OR=0.273, 95% CI 0.115?0.645) were independent correlated factors affecting composite remission. Based on these factors, a nomogram model for predicting the therapeutic effect of RTX in IMN patients was constructed. The ROC curve indicated that the accuracy of this model in predicting composite remission was good ( AUC=0.814, 95% CI 0.744-0.883). The calibration curve showed that the predicted composite response rate had a good fit with the actual response rate (Hosmer-Lemeshow test χ2=11.917, P=0.155). Conclusions:RTX has good efficacy and safety as a monotherapy for IMN patients. The constructed nomogram prediction model has high discrimination and accuracy to predict the efficacy of RTX treatment for IMN.

BACKGROUND:In the process of intervening in the development of osteoarthritis,platelet-rich plasma plays an important role by intervening in autophagy,apoptotic cytokines and signal transduction pathways.OBJECTIVE:To summarize the structure of cytokines and signaling pathways involved in the diagnosis of osteoarthritis by platelet-rich plasma in recent years,as well as its correlation with chondrocyte apoptosis and autophagy,in order to provide effective targets for the future treatment of osteoarthritis.METHODS:Literature search was conducted in CNKI,WanFang Data,VIP,PubMed,Web of Science,and Medline databases using "platelet-rich plasma,chondrocyte,apoptosis,autophagy,osteoarthritis,cytokines,signaling pathway" as Chinese and English search terms.A systematic summary and induction were made for the 66 included articles.RESULTS AND CONCLUSION:Current research has shown that platelet-rich plasma can promote cartilage repair and assist bone tissue healing through various pathways,mainly divided into three aspects:(1) Platelet-rich plasma regulates the extension,closure,and maturation of microautophagosomes,promotes chondrocyte megaautophagy and molecular chaperone-mediated cell autophagy under specific conditions,enhances the expression of autophagy-related factors such as LC3Ⅱ/Ⅰ and Beclin1,inhibits the expression of P62/SQSTM1.Currently,there is no clear research directly exploring the specific effect of platelet-rich plasma on heat shock proteins,and further research is needed in this field in the future.(2) The various growth factors released by platelet-rich plasma inhibit the expression of pro-apoptotic factors Caspase,interleukin-1β,and tumor necrosis factor alpha,promote the expression of anti-apoptotic factor Bcl-2,and prevent chondrocyte apoptosis and degeneration.(3) By activating the PI3K/AKT/mTOR signaling pathway,NF-κB signal transduction pathway,death receptor pathway,mitochondrial stress pathway and other pathways,platelet-rich plasma inhibits the expression of Bax and Caspase,and prevents the release of cytochrome c,thereby inhibiting the death and necrotic apoptosis of chondrocytes.In general,platelet-rich plasma promotes cartilage repair,supports cartilage regeneration,and plays an anti-inflammatory role,and its biological effect in chondrocytes usually depends on the regulation of autophagy and apoptosis-related cytokines and signaling pathways.

Objective:To investigate the protective effect of Akebia saponin D(ASD)on non-alcoholic fatty liver disease(NAFLD)in rats by regulating IL-6/STAT3 axis.Methods:Fifty SD rats were separated into control group,model group,low dose ASD group(ASD 20 mg/kg),high dose ASD group(ASD 40 mg/kg)and inhibitor group(ASD 40 mg/kg+IL-6/STAT3 signal pathway inhibitor LMT-28 3 mg/kg),with 10 rats in each group.Rats in control group were fed with standard diet,while the other four groups were fed with high fat and high sugar diet.All rats were fed for 6 consecutive weeks,and the corresponding dose of drugs was injected intraperitoneally from the 7th week,which were given drugs for 8 consecutive weeks.All rats were weighed to calculate liver index;levels of serum total cholesterol(TC),alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)were mea-sured by automatic biochemical analyzer;HE staining was used to observe pathological changes of rats liver;oil red staining was used to observe lipid accumulation in rats liver;expressions of IL-6,JAK1,STAT3 in rats liver were detected by qRT-PCR;Western blot was used to detect expressions of IL-6,JAK1,p-JAK1,STAT3 and p-STAT3 proteins.Results:Compared with control group,hepatocytes in liver tissue of model group were swollen,accompanied by many ballooning changes,severe cytoplasmic vacuolization,the structure of hepatic lobule was unclear,and accompanied by inflammatory cell infiltration,and obvious red granular lipid droplets occupied most of the cytoplasm,body mass,liver index,levels of serum TC,ALT,AST,TG,expressions of IL-6,JAK1,STAT3 mRNAs,and IL-6,p-JAK1/JAK1,p-STAT3/STAT3 proteins in liver tissue of rats were obviously increased(P<0.05);compared with model group,damage of hepatic lobule structure in low and high doses ASD groups were reduced,swelling and vacuolization of liver cells were reduced,and accumulation of lipid droplets in liver tissue was obviously reduced.Body mass,liver index,levels of serum TC,ALT,AST and TG in rats were obviously decreased(P<0.05),while expressions of IL-6,JAK1,STAT3 mRNAs and IL-6,p-JAK1/JAK1,p-STAT3/STAT3 proteins in liver tissue were further increased(P<0.05);LMT-28,an inhibitor of IL-6/STAT3 signaling pathway,attenuated the liver protective effect of ASD on NAFLD rats.Conclusion:ASD can protect liver of NAFLD rats by activating IL-6/STAT3 signaling pathway.

BACKGROUND:In the process of intervening in the development of osteoarthritis,platelet-rich plasma plays an important role by intervening in autophagy,apoptotic cytokines and signal transduction pathways.OBJECTIVE:To summarize the structure of cytokines and signaling pathways involved in the diagnosis of osteoarthritis by platelet-rich plasma in recent years,as well as its correlation with chondrocyte apoptosis and autophagy,in order to provide effective targets for the future treatment of osteoarthritis.METHODS:Literature search was conducted in CNKI,WanFang Data,VIP,PubMed,Web of Science,and Medline databases using "platelet-rich plasma,chondrocyte,apoptosis,autophagy,osteoarthritis,cytokines,signaling pathway" as Chinese and English search terms.A systematic summary and induction were made for the 66 included articles.RESULTS AND CONCLUSION:Current research has shown that platelet-rich plasma can promote cartilage repair and assist bone tissue healing through various pathways,mainly divided into three aspects:(1) Platelet-rich plasma regulates the extension,closure,and maturation of microautophagosomes,promotes chondrocyte megaautophagy and molecular chaperone-mediated cell autophagy under specific conditions,enhances the expression of autophagy-related factors such as LC3Ⅱ/Ⅰ and Beclin1,inhibits the expression of P62/SQSTM1.Currently,there is no clear research directly exploring the specific effect of platelet-rich plasma on heat shock proteins,and further research is needed in this field in the future.(2) The various growth factors released by platelet-rich plasma inhibit the expression of pro-apoptotic factors Caspase,interleukin-1β,and tumor necrosis factor alpha,promote the expression of anti-apoptotic factor Bcl-2,and prevent chondrocyte apoptosis and degeneration.(3) By activating the PI3K/AKT/mTOR signaling pathway,NF-κB signal transduction pathway,death receptor pathway,mitochondrial stress pathway and other pathways,platelet-rich plasma inhibits the expression of Bax and Caspase,and prevents the release of cytochrome c,thereby inhibiting the death and necrotic apoptosis of chondrocytes.In general,platelet-rich plasma promotes cartilage repair,supports cartilage regeneration,and plays an anti-inflammatory role,and its biological effect in chondrocytes usually depends on the regulation of autophagy and apoptosis-related cytokines and signaling pathways.

Objective:To investigate the protective effect of Akebia saponin D(ASD)on non-alcoholic fatty liver disease(NAFLD)in rats by regulating IL-6/STAT3 axis.Methods:Fifty SD rats were separated into control group,model group,low dose ASD group(ASD 20 mg/kg),high dose ASD group(ASD 40 mg/kg)and inhibitor group(ASD 40 mg/kg+IL-6/STAT3 signal pathway inhibitor LMT-28 3 mg/kg),with 10 rats in each group.Rats in control group were fed with standard diet,while the other four groups were fed with high fat and high sugar diet.All rats were fed for 6 consecutive weeks,and the corresponding dose of drugs was injected intraperitoneally from the 7th week,which were given drugs for 8 consecutive weeks.All rats were weighed to calculate liver index;levels of serum total cholesterol(TC),alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)were mea-sured by automatic biochemical analyzer;HE staining was used to observe pathological changes of rats liver;oil red staining was used to observe lipid accumulation in rats liver;expressions of IL-6,JAK1,STAT3 in rats liver were detected by qRT-PCR;Western blot was used to detect expressions of IL-6,JAK1,p-JAK1,STAT3 and p-STAT3 proteins.Results:Compared with control group,hepatocytes in liver tissue of model group were swollen,accompanied by many ballooning changes,severe cytoplasmic vacuolization,the structure of hepatic lobule was unclear,and accompanied by inflammatory cell infiltration,and obvious red granular lipid droplets occupied most of the cytoplasm,body mass,liver index,levels of serum TC,ALT,AST,TG,expressions of IL-6,JAK1,STAT3 mRNAs,and IL-6,p-JAK1/JAK1,p-STAT3/STAT3 proteins in liver tissue of rats were obviously increased(P<0.05);compared with model group,damage of hepatic lobule structure in low and high doses ASD groups were reduced,swelling and vacuolization of liver cells were reduced,and accumulation of lipid droplets in liver tissue was obviously reduced.Body mass,liver index,levels of serum TC,ALT,AST and TG in rats were obviously decreased(P<0.05),while expressions of IL-6,JAK1,STAT3 mRNAs and IL-6,p-JAK1/JAK1,p-STAT3/STAT3 proteins in liver tissue were further increased(P<0.05);LMT-28,an inhibitor of IL-6/STAT3 signaling pathway,attenuated the liver protective effect of ASD on NAFLD rats.Conclusion:ASD can protect liver of NAFLD rats by activating IL-6/STAT3 signaling pathway.

Objective:To evaluate the efficacy and safety of rituximab (RTX) in the treatment of idiopathic membranous nephropathy (IMN), explore the influencing factors of the therapeutic effect and construct a nomogram model for predicting the therapeutic effect.Methods:A single retrospective study was conducted in IMN patients in the First Affiliated Hospital of Zhejiang University School of Medicine from January 2017 to December 2022. All patients received monotherapy with RTX and were followed up for at least 12 months. RTX regimen adopted a B-cell guided regimen to achieve 0 cells/μl of peripheral blood CD19+ B cells through multiple administrations, followed by monitoring every 2?3 months and adding doses as needed to maintain this state. The complete response rate, partial response rate, and composite response rate at 6 months, 12 months and the end of follow up were analyzed. Logistic stepwise regression and R language were applied to construct a nomogram model for efficacy prediction. The receiver operating characteristic (ROC) curve, calibration curve and Hosmer-Lemeshow test were used to internally validate the nomogram model.Results:A total of 147 IMN patients were included in the study, with age of 56 (47, 65) years, 99 (67.4%) males. There were 69 (46.9%) newly treated patients, 78 (53.1%) retreatment patients. The follow-up time was 14.4 (12.0, 15.0) months. The total RTX dose was 1 800 (1 200, 2 400) mg. The composite response rates at 6 months, 12 months and the end of the follow-up were 36.7% (54/147), 59.9% (88/147) and 63.3% (93/147), respectively. The complete remission rates at 6 months, 12 months and the end of the follow-up were 6.1% (9/147), 13.6% (20/147) and 19.7% (29/147), respectively. Logistic stepwise regression analysis showed that age ≥ 65 years ( OR=0.335, 95% CI 0.135?0.833), retreatment ( OR=0.333, 95% CI 0.144?0.771), high cholesterol ( OR=0.716, 95% CI 0.577?0.888), high serum creatinine ( OR=0.978, 95% CI 0.963?0.993) and B-cell reconstruction within 6 months ( OR=0.273, 95% CI 0.115?0.645) were independent correlated factors affecting composite remission. Based on these factors, a nomogram model for predicting the therapeutic effect of RTX in IMN patients was constructed. The ROC curve indicated that the accuracy of this model in predicting composite remission was good ( AUC=0.814, 95% CI 0.744-0.883). The calibration curve showed that the predicted composite response rate had a good fit with the actual response rate (Hosmer-Lemeshow test χ2=11.917, P=0.155). Conclusions:RTX has good efficacy and safety as a monotherapy for IMN patients. The constructed nomogram prediction model has high discrimination and accuracy to predict the efficacy of RTX treatment for IMN.

Objective·To investigate the current situation and distribution characteristics of chronic comorbidities,and to provide reference for further improving the self-management of comorbidities and implementing the whole course and all-round management of comorbidity.Methods·Two thousand and forty-five inpatients in the Department of Geriatrics,Renji Hospital,Shanghai Jiao Tong University School of Medicine were enrolled in this study from December 2020 to February 2023.The general vital signs,routine laboratory examination and disease status were collected.The epidemiological distribution characteristics of chronic diseases and comorbidities were analyzed.Results·The incidence of chronic diseases in the surveyed population was 99.6％,and the incidence of comorbidities was 94.2％.The top 5 chronic diseases were hypertension(43.68％),diabetes mellitus(24.81％),malignant tumor(21.48％),hyperlipidemia(18.38％)and coronary heart disease(11.99％).The detection rates of hypertension,diabetes mellitus,coronary heart disease,chronic obstructive pulmonary disease,stoke and chronic kidney disease in males were significantly higher than those in females(P＜0.05).The proportion of patients with 5 chronic diseases was the highest(11.99％),followed by 7 chronic diseases(10.26％)and 6 chronic diseases(10.04％).Among the patients of different ages,the comorbidity rate was the highest in the patients aged 50-59 years(27.78％).In different age groups,patients aged 50 to 59 with 2 chronic diseases had the highest incidence of comorbidity,which was as high as 40.82％.Although the overall proportion of comorbidities among male patients(95.37％)was higher than that among females(93.77％),there was no statistically significant difference(P=0.125).However,the proportions of male patients with 2 and 5 chronic diseases were 70.41％and 60.63％,respectively,which were significantly higher than those of female patients(29.59％and 39.37％).The correlations between coronary heart disease and diabetes mellitus,hypertension and coronary heart disease,hypertension and diabetes mellitus were higher(r=0.24,r=0.27,r=0.35,all P＜0.05).Conclusion·The prevalence of chronic diseases and comorbidities is high in the middle-aged and elderly population,and the number of comorbidities increases significantly with the increase of age.

Objective·To explore the correlation between comorbidities of chronic non-communicable diseases(chronic diseases),phase angle(PhA),and muscle mass decline associated with sarcopenia in the elderly,and the predictive value of chronic disease comorbidities and PhA in muscle mass decline in the elderly.Methods·By retrospectively screening inpatients aged≥60 years who were admitted to the Department of Geriatrics,Renji Hospital,Shanghai Jiao Tong University School of Medicine from August 1,2018 to July 31,2019,basic information and medical history of the patients(gender,age,number of medications used,number of comorbidities,presence of osteoporosis,smoking history,etc.)were collected,as well as laboratory examination indicators(hemoglobin,albumin,serum creatinine,serum uric acid,ferritin,vitamin D,triacylglycerol,total cholesterol,high-density lipoprotein,low-density lipoprotein,etc.).The age-adjusted Charlson comorbidity index(aCCI)was calculated.The InBody S10 bioelectrical impedance body composition detector was used to test the body composition.Body mass index(BMI),skeletal muscle mass index(SMI),and PhA were collected.Some patients underwent measurement of grip strength.Muscle mass decline was diagnosed by using the SMI values recommended by the 2019 Asian Working Group for Sarcopenia(AWGS)(≤7.0 kg/m2 for males and≤5.7 kg/m2 for females).According to the measured SMI values,patients were divided into a group with normal muscle mass and a group with muscle mass decline.Univariate and multivariate Logistic analyses were employed to investigate the risk factors associated with muscle mass decline related to sarcopenia in the elderly.Additionally,the receiver operator characteristic(ROC)curve and the area under the curve were utilized to predict the significance of these factors in muscle mass decline.Results·A total of 359 chronic disease patients were enrolled,including 226 males and 133 females.There were 241 cases in the normal muscle mass group and 118 cases in the muscle mass decline group.The incidence of muscle mass decline related to sarcopenia in the elderly was 32.9%.The univariate Logistic regression analysis showed that age(OR=1.036,95%CI 1.013?1.060),comorbidities(OR=1.117,95%CI 1.025?1.217),aCCI(OR=1.123,95%CI 1.031?1.222),and high-density lipoprotein(OR=3.688,95%CI 2.065?6.622)were positively correlated with the risk of muscle mass decline in the elderly.BMI(OR=0.514,95%CI 0.443?0.597),PhA(OR=0.195,95%CI 0.126?0.303),hemoglobin(OR=0.984,95%CI 0.972?0.996)and triacylglycerol(OR=0.606,95%CI 0.424?0.866)were negatively correlated with the risk of muscle mass decline in the elderly.Multivariate Logistic regression model indicated that PhA(OR=0.338,95%CI 0.119?0.959)and BMI(OR=0.634,95%CI 0.476?0.844)were negatively correlated with the risk of muscle mass decline in elderly.The area under the ROC curve for predicting muscle mass decline related to sarcopenia in elderly by using BMI and PhA was 0.893(95%CI 0.855?0.931)and 0.786(95%CI 0.736?0.837),respectively.The sensitivity was 0.724 and 0.676,respectively.The specificity was 0.916 and 0.762,respectively.When BMI combined with PhA predicted muscle mass decline in the elderly,the area under the ROC curve was 0.917(95%CI 0.883?0.951).The sensitivity was 0.867,and the specificity was 0.860.Conclusion·aCCI is correlated with muscle mass decline associated with sarcopenia in the elderly.As BMI and PhA decrease,the risk of muscle mass decline in the elderly increases.The combination of BMI and PhA has a high predictive value in muscle mass decline in the elderly.No predictive value of chronic diseases comorbidities in muscle mass decline related to sarcopenia in the elderly is found.