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

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*

Objective:To investigate the effect of pre-dialysis blood pressure (Pre-BP) on all-cause and cardiovascular disease (CVD) mortality in patients on maintenance hemodialysis (MHD).Methods:This single-center, retrospective cohort study enrolled patients undergoing first-time hemodialysis between January 1, 2007, and June 30, 2021, from the dialysis registry of the First Affiliated Hospital, Zhejiang University School of Medicine. General information and laboratory parameters were collected. Pre-dialysis systolic blood pressure (Pre-SBP) and pre-dialysis diastolic blood pressure (Pre-DBP) were calculated and averaged at 4-6 months after dialysis. The mean Pre-SBP and Pre-DBP values were used as continuous variables, and restricted cubic spline (RCS) curves were used to assess the relationship between Pre-BP and mortality risk. Patients were subsequently divided into six groups for Pre-DBP and six groups for Pre-SBP combined with Pre-DBP. Survival analyses were performed using the Kaplan-Meier method. All-cause and CVD mortality were compared between groups using the log-rank test. Multivariate Cox regression models were used to analyze the associations between Pre-BP and all-cause and CVD mortality.Results:A total of 1 213 patients were enrolled. By the end of follow-up, 175 patients (14.4%) had died, of whom 62 (35.4%) died from CVD. Kaplan-Meier survival curves showed that the Pre-DBP<65 mmHg group (1 mmHg=0.133 kPa) had a significantly lower cumulative survival rate ( χ2=90.52, P<0.001) and a significantly higher CVD mortality rate ( χ2=35.54, P<0.001) than the other groups. The combined Pre-SBP and Pre-DBP analysis showed that the Pre-SBP≥150 mmHg and Pre-DBP<80 mmHg groups had a significantly lower cumulative survival rate ( χ2=45.58, P<0.001) and a significantly higher CVD mortality rate ( χ2=30.13, P<0.001) than the other groups. Multivariate Cox regression model analysis showed that compared with other groups, the risk of MHD all-cause mortality was increased in the Pre-DBP<65 mmHg group and the Pre-SBP≥150 mmHg and Pre-DBP<80 mmHg group [ HR (95% CI)=1.927 (1.195-3.109), 3.298 (1.567-6.939), both P<0.05]. Conclusion:In patients undergoing MHD, Pre-DBP<65 mmHg or Pre-SBP≥150 mmHg and Pre-DBP<80 mmHg were independent risk factors for all-cause mortality, with a low cumulative survival rate and a high risk of CVD mortality.

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 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.

Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

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.