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: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

Objective To explore the expression and prognostic value of microRNA-145-5p(miR-145-5p)and fascin actin-bundling protein-1(FSCN1)in gastric cancer tissues.Methods The study participants were selected from 103 gastric cancer patients treated at The First Hospital of Handan from August 2019 to August 2021.The expression levels of miR-145-5p and FSCN1 mRNA in the cancer tissues and adjacent non-cancerous tissues of gastric cancer patients were measured.Pearson correlation analysis was used to assess the relationship between the expression of miR-145-5p and FSCN1 mRNA.The area under curve(AUC)was used to evaluate the prognostic value of miR-145-5p and FSCN1 mRNA for gastric cancer patients.The Cox proportional hazards regression model was used to analyze factors influencing adverse prognosis,and Kaplan-Meier method was employed for survival analysis.Results The expression level of miR-145-5p was lower in cancer tissues compared to adjacent tissues(P<0.05),while the expression level of FSCN1 mRNA was higher in cancer tissues compared to adjacent tissues(P<0.05).The expression level of miR-145-5p was lower in cancer tissues of the patients with moderate-to-poor differentiation,tumor stage Ⅲ +Ⅳ,invasion depth T3-T4,lymph node metastasis,or maximum tumor diameter≥5 cm,compared to those with high differentiation,tumor stage Ⅰ+Ⅱ,invasion depth T1-T2,no lymph node metastasis,or maximum tumor diameter<5 cm,whereas the expression level of FSCN1 mRNA was higher(P<0.05).Pearson analysis revealed a negative correlation between miR-145-5p and FSCN1 mRNA expression in cancer tissues(r=-0.617,P=0.000).COX multivariate regression analysis indicated that moderate-to-poor differentiation,tumor stage Ⅲ +Ⅳ,maximum tumor diameter≥5 cm,invasion depth T3-T4,low miR-145-5p expression,high FSCN1 mRNA expression,and lymph node metastasis were risk factors for poor prognosis in gastric cancer(P<0.05).Kaplan-Meier survival curves demonstrated a statistically significant difference in the 3-year overall survival rate between the low and high miR-145-5p expression groups(P<0.05).Similarly,a statistically significant difference was observed between the low and high FSCN1 mRNA expression groups(P<0.05).ROC curve analysis showed that the combined detection of miR-145-5p and FSCN1 mRNA yielded an AUC of 0.947 and a sensitivity of 92.3％,both of which were significantly higher than those of individual indicators(P<0.05).Conclusion MiR-145-5p and FSCN1 are closely related to the clinical pathological characteristics of gastric cancer patients and are effective prognostic indicators for survival.

L-citrulline is a nonprotein amino acid that plays an important role in human health and has great market demand. Although microbial cell factories have been widely used for biosynthesis, there are still challenges such as genetic instability and low efficiency in the biosynthesis of L-citrulline. In this study, an efficient, plasmid-free, non-inducible L-citrulline-producing strain of Escherichia coli BL21(DE3) was engineered by combined strategies. Firstly, a chassis strain capable of synthesizing L-citrulline was constructed by block of L-citrulline degradation and removal of feedback inhibition, with the L-citrulline titer of 0.43 g/L. Secondly, a push-pull-restrain strategy was employed to enhance the L-citrulline biosynthesis, which realized the L-citrulline titer of 6.0 g/L. Thirdly, the NADPH synthesis and L-citrulline transport were strengthened to promote the synthesis efficiency, which achieved the L-citrulline titer of 11.6 g/L. Finally, fed-batch fermentation was performed with the engineered strain in a 3 L fermenter, in which the L-citrulline titer reached 44.9 g/L. This study lays the foundation for the industrial production of L-citrulline and provides insights for the modification of other amino acid metabolic networks.
Citrulline/biosynthesis* ; Escherichia coli/genetics* ; Metabolic Engineering/methods* ; Fermentation ; NADP/biosynthesis*

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 explore the characteristics of brain functional connectivity changes associated with repetitive transcranial magnetic stimulation (rTMS) in adolescents with anhedonia symptoms, and to develop a predictive model of treatment efficacy based on baseline functional connectivity.Methods:A total of 88 adolescents (aged 13-18 years) with major depressive disorder and comorbid anhedonia, diagnosed according to the Diagnostic And Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), were enrolled in a randomized, double-blind, block-design trial. Participants received either active rTMS ( n=44) or sham stimulation ( n=44) for 15 consecutive days with individualized targeting. Resting-state functional magnetic resonance imaging (fMRI) data and clinical assessments were collected before and after the intervention. Brain regions were parcellated using the Brainnetome Atlas to construct whole-brain functional connectivity matrices. Linear mixed-effects models were used to identify functional connections showing significant group×time interaction effects. The percentage change in Snaith-Hamilton Pleasure Scale (SHAPS) scores (ΔSHAPS) served as the dependent variable in multiple regression analyses to examine the explanatory power of connectivity changes for treatment response. A connectome-based predictive modeling (CPM) approach was employed to predict individual treatment responses based on baseline functional connectivity with permutation testing used to validate model robustness. Results:Thirty-one functional connections showing significant group×time interaction ( F=6.67-15.69, all P<0.01) were identified between the active and sham stimulation groups, primarily involving the subcortical network (SCN), dorsal attention network (DAN), limbic network (LN), and default mode network (DMN). Changes in these connections accounted for 53% of the variance in ΔSHAPS (adjusted R2=0.53, F=4.574, P=0.001). The CPM model based on baseline connectivity showed strong predictive performance (10-fold cross-validation: r=0.65, R2=0.40, MAE=0.095, permutation P<0.001; leave-one-out cross-validation: r=0.74, R2=0.52, MAE=0.013, permutation P<0.001). Among the 59 predictive features, those originating from the LN contributed most substantially, particularly cross-network connections with the DMN and SCN. Correlation analyses revealed widespread associations between baseline predictive features and rTMS-induced connectivity changes, including significant negative correlations between baseline LN-DMN connectivity and post-treatment changes in DAN and subcortical connectivity. Conclusion:rTMS significantly alleviates anhedonia symptoms in adolescents with depression and induces widespread reconfiguration of functional connectivity across multiple brain networks. The CPM model based on baseline connectivity features effectively predicts rTMS treatment efficacy for anhedonia, providing new insights for individualized treatment strategies in adolescent depression.

Objective To investigate the labeling of dialysis-related information in the instructions of drugs for systemic use in patients with end-stage renal disease undergoing hemodialysis,and to provide reference for further standardization and im-provement of drug instructions.Methods Collected the information on pharmacokinetics and drug dose adjustment in hemodi-alysis patients with end-stage renal disease from the instructions of chemicals and biologics used systemically in XuanWu hospital's formulary from January to March 2023.Classified and compared the labeling rates of the corresponding information of the originally developed drugs and generic drugs,imported drugs and domestic drugs;Drugs eliminated by non-renal route,or with mo-lecular weight≥5 000,or binding rate of plasma protein ≥ 60％,or drug distribution volume＞360L were classified as"non-dialysis group",and other drugs were classified as"dialysis group",compared the labeling rate of corresponding information of drugs in"dialysis group"and"non-dialysis group";and compared the labeling rate and content with relevant information in Lexicomp and Micromedex.Results Among the 930 drug instructions,the labeling rates of drug dialysis clearance,drug adjustment,and ex-plicit drug adjustment plan were 16.67％,25.16％,and 24.52％.There was no significant difference in the labeling rate of dialysis-related information between original and generic drugs,and imported and domestic drugs.There was a significant difference in the labeling rate of dialysis-related information between the"dialyzable group"and the"non-dialyzable group"(P＜0.01).The differ-ence in the labeling rate of dialysis related information between the investigated drug instructions and the corresponding drugs in Lexicomp or Micromedex was statistically significant(P＜0.01).Conclusion Attention should be paid to the lack of informa-tion and unclear labeling of hemodialysis patients with end-stage renal disease in the drug instructions by relevant departments.

Objective:To evaluate the efficacy and safety of rituximab (RTX) in the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN).Methods:This was a single-center, retrospective and single-arm study. The clinical data of AAGN patients who received RTX induction therapy at the First Affiliated Hospital of Zhejiang University School of Medicine from April 2016 to July 2021 and had a follow-up period of more than 6 months were collected. The follow-up was up to June 2022. The Birmingham Vasculitis Activity Score (BVAS) from 2003 was used to assess vasculitis activity. The treatment regimen for RTX was once every 1 to 2 weeks, with 375 mg/m 2 each time. For some patients, the dose was adjusted according to the immune status before medication. The clinical outcomes, renal remission, recurrence and safety was analyzed. Kaplan-Meier method was used to analyze the cumulative renal remission rate. Results:A total of 43 AAGN patients were included in the study, with age of (57.6±16.6) years, 19 males (44.2%) and 34 (79.1%) newly treated patients. There were 34 patients (79.1%) with positive myeloperoxidase-ANCA and 8 patients (18.6%) with positive proteinase 3-ANCA. The dosage of RTX used at the 12-month follow-up was 600 (500, 1 200) mg. At 6 months of follow-up, 32 patients (74.4%) achieved renal remission, and renal remission time was 5.0 (3.3, 5.8) months. Three patients (7.0%) progressed to end-stage renal disease, and two patients (4.7%) died. Compared with patients without renal remission, patients with renal remission had lower baseline serum creatinine ( Z=-2.853, P=0.004), serum uric acid ( t=-2.861, P=0.007), urine protein/urine creatinine ratio ( Z=-2.130, P=0.033) and proportion of methylprednisolone pulse therapy ( χ 2=5.002, P=0.025), and higher estimated glomerular filtration rate ( Z=-2.728, P=0.006). At 12 months of follow-up, 33 patients (76.7%) achieved renal remission, and the cumulative renal remission rate was 82.4%. Two patients (4.7%) had renal recurrence, 5 patients (11.6%) progressed to end-stage renal disease, and 3 patients (7.0%) died. Infection (4 patients, including 2 severe infections) was the main adverse event, all of which occurred within 6 months of RTX treatment. Conclusions:The clinical remission rate and safety of RTX in the treatment of AAGN are both relatively high.

Objective:To compare the differences of long-term survival rates between hemodialysis (HD) and peritoneal dialysis (PD) in the oldest old end-stage renal disease (ESRD) patients, and analyze the influencing factors of mortality.Methods:It was a retrospective cohort study. The clinical data from the oldest old patients (≥80 years old) who underwent HD or PD for the first time and maintained dialysis treatment for ≥3 months in the Zhejiang Dialysis Registration System from January 1, 2008 to December 31, 2021 were collected. The follow-up endpoint was until the patients' death or December 31, 2022. The propensity score matching method was used to match groups. Kaplan-Meier method and log-rank test were used to compare the differences of long-term survival rates between the two groups. Cox regression analysis was used to analyze the risk factors of mortality.Results:A total of 5 880 the oldest old dialysis patients were included in this study, with 5 363 patients in the initial HD group and 517 patients in the initial PD group. After matching, there were 517 patients in the HD group and 517 patients in the PD group. The median survival time of HD group before matching was 39.9 months, with 1-year, 3-year, and 5-year survival rates of 85.4%, 54.9%, and 30.0%, respectively. The median survival time of PD group was 32.9 months, with 1-year, 3-year, and 5-year survival rates of 82.5%, 47.1%, and 22.3%, respectively. After matching, the median survival time of HD group was 40.3 months, and the 1-year, 3-year, and 5-year survival rates were 86.1%, 57.8%, and 29.1%, respectively. The survival rate of PD group remained unchanged. The difference of 1-year survival rate between the two groups was not statistically significant, but the 2-year, 3-year, 4-year, 5-year, and overall survival rates in HD group were higher than those in PD group (Log‐rank test, χ2=4.897, P=0.027; χ2=9.693, P=0.002; χ2=10.194, P=0.001; χ2=7.868, P=0.005; χ2=12.510, P<0.001). Multivariate Cox regression analysis showed that HD (HD/PD, HR=0.794, 95% CI 0.669-0.943, P=0.009), increasing age ( HR=1.069, 95% CI 1.038-1.110, P<0.001), comorbidity with chronic obstructive pulmonary disease ( HR=1.510, 95% CI 1.065-2.139, P=0.021) and serum albumin <35 g/L ( HR=1.393, 95% CI 1.165-1.665, P<0.001) were independent correlated factors of mortality. Conclusions:There is no significant difference in the 1-year survival rate between HD and PD groups. The survival rate for more than 1 year in HD patients is higher than that in PD patients. HD is an independent protective factor of survival, and increasing age, comorbidities of chronic obstructive pulmonary disease, and serum albumin <35 g/L are independent risk factors affecting the survival in the oldest old dialysis patients.