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 investigate the inhibitory effect of astragaloside Ⅳ(AS-Ⅳ)on cisplatin(CDDP)-induced liver injury in the mice,and to elucidate its possible mechanism.Methods:Forty male C57BL/6 mice with body weights of 18-22 g were randomly divided into control group,model group,AS-Ⅳ group and adenosine 5'-monophosphate-activated protein kinase(AMPK)inhibitor(Compound C)+AS-Ⅳ group.The mice in control group and model group were gavaged with the same volume of normal saline,and the drug was administered continuously for 9 d.The mice in AS-Ⅳ group and Compound C+AS-Ⅳ group were given AS-Ⅳ aqueous solution(150 mg·kg-1·d-1),respectively.On the 6th day of experiment,the mice in Compound C+AS-Ⅳ group were intraperitoneally injected with Compound C(20 mg·kg-1),and on the 7th day,except for control group,the mice in other groups were intraperitoneally injected with 20 mg·kg-1 CDDP to establish the mouse liver injury models,and the mice were sacrificed 48 h later.Serum and liver tissues were collected,and the levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)in the serum of the mice,as well as the activities of superoxide dismutase(SOD)and catalase(CAT)and the levels of malondialdehyde(MDA)in the liver tissue of the mice in various groups were detected by kits.The pathomorphology of liver tissue of the mice in various groups were detected by HE staining.The expression levels of glutathione peroxidase 4(GPX4),ferritin heavy chain 1(FTH1)and ferroptosis inhibitory protein 1(FSP1)proteins in liver tissue of the mice in various groups were detected by immunohistochemical staining,and the expression levels of nuclear factor-E2-related factor 2(Nrf2),heme oxygenase-1(HO-1)and AMPK proteins in liver tissue of the mice in various groups were detected by Western blotting method.Results:Compared with control group,the levels of AST and ALT in serum of the mice in model group were increased(P＜0.01),the activities of SOD and CAT in the liver tissue were significantly decreased(P＜0.01),and the MDA level was increased(P＜0.01);compared with model group,the levels of AST and ALT in serum of the mice in AS-Ⅳ group were decreased(P＜0.01),the MDA level in the liver tissue was decreased(P＜0.01),and the activities of SOD and CAT were increased(P＜0.01);compared with AS-Ⅳ group(P＜0.01),the levels of AST and ALT in serum of the mice in Compound C+AS-Ⅳ group were increased(P＜0.01),the level of MDA in liver tissue was increased(P＜0.05),and the activities SOD and CAT were decreased(P＜0.01).The HE staining results showed that compared with control group,the liver damage degree of the mice in model group was enhanced,the hepatocyte arrangement was disordered,and some hepatocyte edema were increased;compared with model group,the liver morphology of the mice in AS-Ⅳ group returned to normal;compared with AS-Ⅳ group,the hepatocyte arrangement of the mice in Compound C+AS-Ⅳ group was disordered and the edges were blurred.The immunohistochemistry results showed that compared with control group,the expression levels of GPX4,FTH1 and FSP1 proteins in liver tissue of the mice in model group were decreased(P＜0.05);compared with model group,the expression levels of GPX4,FTH1 and FSP1 proteins in liver tissue of the mice in AS-Ⅳ group were increased(P＜0.05);compared with AS-Ⅳ group,the expression levels of GPX4,FTH1 and FSP1 proteins in liver tissue of the mice in Compound C+AS-Ⅳ group were decreased(P＜0.05 or P＜0.01).The Western blotting results showed that compared with control group,the expression levels of Nrf2,HO-1 and AMPK proteins in liver tissue of the mice in model group were decreased(P＜0.01);compared with model group,the expression levels of Nrf2,HO-1 and AMPK proteins in liver tissue of the mice in AS-Ⅳgroup were increased(P＜0.01);compared with AS-Ⅳ group,the expression levels of Nrf2,HO-1 and AMPK proteins in liver tissue of the mice in Compound C+AS-Ⅳ group were decreased(P＜0.01).Conclusion:AS-Ⅳ can alleviate the CDDP-induced liver injury,and its mechanism may be related to the regulation of AMPK/Nrf2/HO-1 signal pathway and ferroptosis by AS-Ⅳ.

Objective To investigate the relationship between cystatin C(CysC)/prealbumin(PAB)ratio and lung function and chronic obstructive pulmonary disease(COPD)assessment test(CAT)score in patients with COPD.Methods A total of 216 COPD patients admitted to the hospital from February 2021 to February 2024 were selected as the study group,and 150 healthy subjects were selected as the control group during the same period.CysC and PAB levels were detected by immunoturbidimetry,CysC/PAB ratio was calculated,lung function was detected and CAT scores were recorded.Pearson correlation was used to analyze the rela-tionship between CysC/PAB ratio,lung function and CAT score in COPD patients.Results The CysC and CysC/PAB ratio in the study group was significantly higher than that in the control group,and the level of PAB was significantly lower than that in the control group,with statistical significance(P＜0.05).The forced expiratory volume in the first second as a percentage of predicted value(FEV1％pred),the percentage of pre-dicted forced vital capacity(FVC％pred)and the ratio of the first second forced expiratory volume to forced vital capacity(FEV1/FVC)of the study group were lower than those of the control group,and the CAT score of the study group was higher than that of the control group,with statistical significance(P＜0.05).The Cy-sC/PAB ratio and CAT score of COPD patients with the global initiative for chronic obstructive lung disease(GOLD)grade 4 were significantly higher than those with GOLD grade 3,GOLD grade 2 and GOLD grade 1,and the difference was statistically significant(P＜0.05).The ratio of CysC/PAB in very severely affected pa-tients was higher than that in severely affected,moderately affected and mildly affected patients,while the ra-tio of FEV1％pred,FVC％pred and FEV1/FVC was lower than that in severely affected,moderately affected and mildly affected patients,and the difference was statistically significant(P＜0.05).In COPD patients,Cy-sC/PAB ratio was negatively correlated with FEV1％pred,FVC％pred,FEV1/FVC,and positively correlated with CAT score(P＜0.05).Conclusion CysC/PAB ratio is highly expressed in COPD patients,and its level is related to lung function and CAT score,which can reflect the degree of disease and quality of life in COPD patients to a certain extent.

Objective To construct a hybrid decision-making model that integrates knowledge-driven and data-driven approaches,and to apply it to the etiological diagnosis of ventricular tachycardia(VT).Methods Clinical practice guidelines,expert consensus documents,and medical literature in the field of ar-rhythmia diseases from 2018 to 2023 were retrieved as knowledge sources.Retrospective electronic medical re-cord data of VT patients from Fuwai Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College,from 2013 to 2023 were collected as the dataset.A knowledge-driven model was constructed using a knowledge-rule-based approach to establish clinical pathways.A three-class machine learning model for VT eti-ology diagnosis was developed based on real-world data,and the best-performing model was selected as the rep-resentative of the data-driven approach.The machine learning model was embedded into the decision nodes of the clinical pathway in the form of custom operators,forming the hybrid model.The precision,recall,and F1 score of the three models were evaluated.Results Three clinical practice guidelines were included as knowl-edge sources for the knowledge-driven model.A total of 1305 patient records were collected as the dataset,and five machine learning models were constructed,with the XGBoost model performing the best.The hybrid model adopted a knowledge-driven decision-making framework,embedding the XGBoost model into the decision nodes of a two-level classification.The precision,recall,and F1 scores of the three models were as follows:the knowledge-driven model achieved 80.4％,79.1％,and 79.7％;the data-driven model achieved 88.4％,88.5％,and 88.4％;and the hybrid model achieved 90.4％,90.2％,and 90.3％.Conclusions The hybrid model integrating knowledge-driven and data-driven approaches demonstrated higher accuracy,and all its deci-sion outcomes were based on evidence-based practices,aligning more closely with the actual diagnostic reason-ing of clinicians.Further rigorous validation is needed to assess the feasibility of widely applying the hybrid model in the medical field.

Objective To analyze the hotspots and developments in the field of language model-assisted artificial intelli-gence(Al)for antibody design and optimization in order to provide reference for research on development of antibodies.Methods By using CiteSpace software,hotspots of research were analyzed based on literature retrieved from the Web of Science,PubMed,and Scopus databases,focusing on three pivotal areas of research related to antibody design and optimization:the construction of pre-trained language models for antibodies,the generation of antibody sequences,and the prediction of three-dimensional structures of antibodies.In addition,this analysis reviewed the major advances in each of the specified research tasks,focusing on the delineation of similarities and differences across studies and dominating challenges in this field.Results From 2019(10 publications)to 2023(89 publications),the scale of and interest in this field kept increasing.Hotspots involved leveraging language models to assist the design or optimization of humanized,high-affinity,and highly specific antibodies.Within each research,methods were characterized by the diversity of model architectures,consistency of training data,and variations in training strategies.Challenges to the field included sparse antigen data,computational power limitations,and insufficient integration of wet and dry lab experiments.Conclusion Research in language model-assisted Al antibody design and optimization is gaining momentum and proves fruitful.However,researchers should be alert to the inadequate attention to antigen-antibody interactions and insufficient integration of experimental and computational validation,conduct more in-depth research and expand applications.

Objective:To investigate the relationship between the polymorphism of endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene and the occurrence of pre-eclampsia (PE).Methods:A case-control study was conducted in Beijing Obstetrics and Gynecology Hospital from October 2018 to October 2021. A total of 51 PE pregnant women with onset gestational age<34 weeks were selected as the PE group, and 48 normal pregnant women during the same period were selected as the control group. Venous blood samples were collected from the pregnant women before delivery and umbilical cord within 5 minutes after delivery. Single nucleotide polymorphisms (SNP) of ERAP-1 gene in the pregnant women and their fetus were detected by next-generation sequencing. Univariate analysis and multivariate logistic regression analysis were used to analyze all the SNP loci and alleles detected in the two groups, and the significant SNP were screened.Results:(1) A total of 13 target SNP loci of maternal ERAP-1 gene were selected by univariate analysis. Among them, the frequency distribution of genotypes at 96096828, 96121524, 96121715, 96122260 and 96122281 showed statistically significant differences between PE group and control group (all P<0.05). Multivariate logistic regression analysis showed that the risk of PE in pregnant women with TC genotype at locus 96121524 was 2.002 times higher than those with TT genotype (95% CI: 0.687-5.831, P=0.020). (2) A total of 4 target SNP loci of ERAP-1 gene in fetal were selected by univariate analysis, and there was no statistical significance in gene polymorphism of the 4 loci between PE group and control group (all P>0.05). Multivariate logistic regression analysis showed that the risk of PE in fetus with genotype AA at locus 96121406 was 0.236 times that of fetus with genotype GG (95% CI: 0.055-1.025, P=0.016). Conclusion:ERAP-1 gene with TC genotype at 96121524 in the mother and GG genotype at 96121406 in the fetus might be related to the incidence of PE.

Vascular calcification refers to the process of calcium salt deposition in the blood vessel wall,leading to vascular stiffening and loss of elasticity.It commonly occurs in middle-aged and elderly individuals,especially those with chronic conditions such as atherosclerosis,hypertension,diabetes,and chronic kidney disease.Vascular calcification is an active process,and one of the key events is the transdifferentiation of smooth muscle cells into osteoblast-like cells.These cells release calcium ions during the calcification process,leading to calcium salt deposition and the formation of cal-cified plaques.Vascular calcification is regulated by various factors,including high levels of phosphate and calcium,oxi-dative stress,and mechanical stress.Traditional Chinese medicine research has shown potential in attenuating vascular calcification,with substances such as Ganoderma lucidum spore powder and its derivatives,Panax notoginseng,baicalin,geniposide,and triptolide.These studies provide important evidence for further understanding and intervention in vascular calcification and reveal potential inhibitory factors that could be explored for future treatments.

The uniqueness of the location of large general hospitals in urban areas determines that the contradiction between space constraints and medical expansion has become a problem of management bottleneck.The situation that expert visits are too concentrated on a certain working day morning has been significantly improved by carrying out peak load shifting in the visiting arrangements and visiting units of large general hospitals through the Total Quality Management theory and continuous improvement of work mode,greatly alleviating public transportation congestion around the hospital.Through the internal construction of the quality of outpatient clinics,it can effectively improve the patients'sense of access to health care.

The uniqueness of the location of large general hospitals in urban areas determines that the contradiction between space constraints and medical expansion has become a problem of management bottleneck.The situation that expert visits are too concentrated on a certain working day morning has been significantly improved by carrying out peak load shifting in the visiting arrangements and visiting units of large general hospitals through the Total Quality Management theory and continuous improvement of work mode,greatly alleviating public transportation congestion around the hospital.Through the internal construction of the quality of outpatient clinics,it can effectively improve the patients'sense of access to health care.

The uniqueness of the location of large general hospitals in urban areas determines that the contradiction between space constraints and medical expansion has become a problem of management bottleneck.The situation that expert visits are too concentrated on a certain working day morning has been significantly improved by carrying out peak load shifting in the visiting arrangements and visiting units of large general hospitals through the Total Quality Management theory and continuous improvement of work mode,greatly alleviating public transportation congestion around the hospital.Through the internal construction of the quality of outpatient clinics,it can effectively improve the patients'sense of access to health care.