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

OBJECTIVES: To explore the mechanism of Circ-MYOCD back-splicing and its regulatory role in myocardial hypertrophy. METHODS: Sanger sequencing and RNase R assays were performed to verify the circularity and stability of Circ-MYOCD, whose subcellular distribution was determined by nuclear-cytoplasmic fractionation. Bioinformatics analysis and mass spectrometry from pull-down assays were conducted to predict the RNA-binding proteins (RBPs) interacting with Circ-MYOCD. In rat cardiomyocytes H9C2 cells, the effects of HNRNPH1 and HNRNPL knockdown and overexpression on Circ-MYOCD back-splicing were evaluated. In a H9C2 cell model of angiotensin II (Ang II)-induced myocardial hypertrophy, the expression of HNRNPH1 was detected, the effects of HNRNPH1 knockdown and overexpression on progression of myocardial hypertrophy were assessed, and the regulatory effect of HNRNPH1 on Circ-MYOCD back-splicing was analyzed. RESULTS: Sanger sequencing confirmed that the junction primers could amplify the correct Circ-MYOCD sequence. RNase R and nuclear-cytoplasmic fractionation assays showed that Circ-MYOCD was stable and predominantly localized in the cytoplasm. Bioinformatics analysis and mass spectrometry from the Circ-MYOCD pull-down assay identified HNRNPH1 and HNRNPL as the RBPs interacting with Circ-MYOCD. In H9C2 cells, HNRNPH1 knockdown significantly enhanced while its overexpression inhibited Circ-MYOCD back-splicing; HNRNPH1 overexpression obviously increased the expressions of myocardial hypertrophy markers ANP and BNP, while its knockdown produced the opposite effect. In Ang II-induced H9C2 cells, which exhibited a significant increase of HNRNPH1 expression and increased expressions of ANP and BNP, HNRNPH1 knockdown obviously increased Circ-MYOCD expression, decreased MYOCD expression and lowered both ANP and BNP expressions. CONCLUSIONS HNRNPH1 regulates Circ-MYOCD back-splicing to influence the progression of myocardial hypertrophy.
Animals ; Rats ; RNA, Circular/genetics* ; Cardiomegaly/metabolism* ; Myocytes, Cardiac/metabolism* ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism* ; Cell Line ; RNA Splicing ; Angiotensin II ; RNA-Binding Proteins

Objective:To analyze the influence of midwifeled accompanyon the psychological status and delivery outcomes of gestational diabetes patients, and to provide reference for the implementation of clinical intervention programs for gestational diabetes patients.Methods:A semi-randomized controlled trial was adopted.Convenience sampling method was used to select 120 gestational diabetes patients admitted to Langfang People′s Hospital from March 2021 to September 2023, and they were divided into control group and experimental group according to the admission order. Both groups were given intraspinal delivery analgesia, while the control group was combined with routine midwifery management, and the experimental group was combined with a midwife led accompany. Intervention lasted until 2 h postpartum in both groups, and follow-up for 1 month. The delivery indicators, psychological status, delivery outcome and satisfaction of the two groups were compared.Results:Finally, 120 gestational diabetes patients were included, 60 patients in the control group, aged (28.73 ± 2.79) years, and 60 patients in the experimental group, aged (27.98 ± 1.09) years. The first and second stages of labor in the experimental group were (416.35 ± 29.87) and (60.95 ± 7.44) min, respectively, which were shorter than (501.33 ± 37.59) and (80.28 ± 8.95) min in the control group, and the differences were statistically significant ( t = 13.71, 12.87, both P<0.05). The blood glucose during delivery and 2 h postpartum hemorrhage was (6.81 ± 0.10) mmol/L and (236.18 ± 37.58) ml, respectively, lower than (7.48 ± 0.45) mmol/L and (325.70 ± 59.88) ml in the control group, the differences were statistically significant ( t = 11.26, 9.81, both P<0.05). After 1 month of follow-up, the scores of Self-rating Anxiety Scale and Self-rating Depression Scale of the experimental group were (30.86 ± 2.55) and (21.45 ± 2.67) points, which were lower than (42.19 ± 3.86) and (42.97 ± 3.15) points in the control group, and the scores of Psychological Resilience Scale were (71.22 ± 6.54) points, which was higher than that of the control group (55.38 ± 6.06) points, the differences were statistically significant ( t = 18.97, 40.37, 13.76, all P<0.05). After intervention, the incidence rates of lateral resection and postpartum hemorrhage in the experimental group were 28.3%(17/60) and 5.0%(3/60), respectively, lower than 48.3%(29/60) and 18.3%(11/60) in the control group, and the total satisfaction rate of the experimental group was 93.3%(56/60), higher than 80.0% (48/60) of the control group. The differences were statistically significant ( χ2 = 5.08, 5.18, 4.62, all P<0.05). Conclusions:The midwife led accompany could shorten the labor process of gestational diabetes patients, reduce their blood glucose during delivery and the amount of blood 2 h postpartum, and improve their psychological status and delivery outcomes, which was conducive to improving patient satisfaction.

Objective:To explore the relevant factors affecting the efficacy of microscopic spermatic cord surgery and build a predictive model for postoperative pain relief.Methods:A retrospective analysis was conducted on the clinical data of 324 patients with spermatic cord pain who visited the Department of Urology at Peking University People's Hospital between October 2015 and April 2023.This cohort included 212 patients with varicocele-related spermatic cord pain and 112 patients with idiopathic sper-matic cord pain.All the patients underwent microsurgical procedures:varicocele-related pain was treated with microsurgical varicocelectomy,and idiopathic pain was treated with microsurgical denervation of the spermatic cord.The patients were categorized into effective and ineffective groups based on whether their pain had decreased by more than 50％six months post-surgery compared with pre-surgery levels.Base-line data were preliminarily screened for clinical indicators using t tests and univariate analysis.Clinical predictor variables[age,duration of pain,diameter of varicocele,patient health questionnaire-9(PHQ-9)score,generalized anxiety disorder-7(GAD-7)score]were selected using Lasso regression.Aclini-cal prediction model for effective pain relief following microscopic spermatic cord surgery was constructed using Logistic regression and presented as a nomogram.The model's internal validation was performed using the bootstrap method.Its predictive power and clinical utility were evaluated through the concor-dance index,the area under the receiver operating characteristic curve,and calibration plots.Results:Post-microscopic varicocele ligation,156 patients(73.58％)experienced significant pain relief,as did 94 patients(83.93％)following microscopic denervation.Independent predictors for postoperative out-comes included age,PHQ-9 score,GAD-7 score,chronic pain duration,and varicocele diameter,diffe-ring slightly between varicocele-related and idiopathic pain groups.The models demonstrated excellent predictive ability,with areas under the curve of 0.909 and 0.913 for varicocele and idiopathic groups,respectively,and high concordance indices.Conclusion:The postoperative efficacy prediction model based on age,pain duration,PHQ-9 score,GAD-7 score,and varicocele diameter has good predictive ability and clinical applicability,and can be used in clinical practice.

Objective:To discuss the protective effect of polygonatum odoratum polysaccharide(POP)on the mice with cisplatin-induced acute kidney injury(AKI),and to clarify its possible mechanism.Methods:Forty male C57BL/6 mice were randomly divided into control group,model group,POP group,and ferroptosis inducer Erastin combined with POP(Erastin+POP)group,and there were 10 mice in each group.The mice in POP group and Erastin+POP group were given intragastric administration of POP(400 mg·kg-1),and on the 7th day,the mice in model group,POP group,and Erastin+POP group were intraperitoneally injected with cisplatin(20 mg·kg-1)to establish the AKI models,the mice in control group were injected with the same volume of normal saline,and the mice in Erastin+POP group were intraperitoneally injected with Erastin(40 mg·kg-1)one day in advance(on the 6th day of the experiment).After 9 d,the mice were killed and the serum and kidney tissue were collected,and the levels of serum creatinine(Scr)and blood urea nitrogen(BUN)and the levels of malondialdehyde(MDA)and glutathione(GSH)in kidney tissue of the mice in various groups were detected by kit;HE staining was used to observe the pathomorphology of kidney tissue of the mice in various groups;the expression levels of ferroptosis suppressor protein 1(FSP1),ferritin heavy chain 1(FTH1),and glutathione peroxidase 4(GPX4)proteins in kidney tissue of the mice in various groups were detected by immunohistochemistry;Western blotting method was used to detect the expression levels of nuclear factor-E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)proteins in kidney tissue of the mice in various groups.Results:Compared with control group,the levels of Scr and BUN of the mice in model group were significantly increased(P＜0.01),the level of MDA in kidney tissue was significantly increased(P＜0.01),and the level of GSH was significantly decreased(P＜0.01);most kidney tubules were dilated,the epithelial cells were swollen,the vacuolar degeneration and epithelial cells fell off,and the protein-like tubules could be seen in the lumen;the expression levels of FSP1,FTH1,GPX4,Nrf2,and HO-1 proteins in kidney tissue were decreased significantly(P＜0.05 or P＜0.01).Compared with model group,the levels of Scr and BUN of the mice in POP group were significantly decreased(P＜0.01),the level of MDA in kidney tissue was significantly decreased(P＜0.01),and the level of GSH was significantly increased(P＜0.01);the dilatation of kidney tubular lumen,epithelial cell swelling,vacuolar degeneration,and epithelial cell exfoliation were decreased;the expression levels of FSP1,FTH1,GPX4,Nrf2,and HO-1 proteins in kidney tissue of the mice in POP group were significantly increased(P＜0.05 or P＜0.01).Compared with POP group,the levels of Scr and BUN of the mice in Erastin+POP group were significantly increased(P＜0.01),the level of MDA in kidney tissue was increased(P＜0.05),and the level of GSH was significantly decreased(P＜0.01);the pathological injury of kidney tissue was aggravated obviously;the expression levels of FSP1,FTH1,GPX4,Nrf2,and HO-1 proteins in kidney tissue were significantly decreased(P＜0.05 or P＜0.01).Conclusion:POP can reduce the AKI in the mice induced by cisplatin,and its mechanism may be related to the inhibitory effect of POP on the ferroptosis induced by cisplatin.

Objective:To develop and evaluate a rapid and sensitive point-of-care chemiluminescent assay(POC-CLIA)for β-human chorionic gonadotropin(β-HCG).Methods:POC-CLIA was constructed based on alkaline phosphatase(Alp)-AMPPD lumi-nescence system and magnetic particles(Mps)carrier.Performance of POC-CLIA,including sensitivity,precision,accuracy,linear dilution,specificity,stability,hook effect and clinical application were evaluated.Results:Detection limit of β-HCG was 0.71 mU/ml,linear detection range was 0.710～1.092×104 mU/ml,and was no hook effect up to 1.7×105 mU/ml.Intra and inter batch coefficients of variation were less than 10％,and could be stored stably at 37℃ for 10 days.Accuracy deviation was within±10％,so results were reliable.There was no cross-reactivity between interfering substances and anti-β-HCG antibdies.For detecting β-HCG in 100 clinical serum samples,results were highly correlated with those that were tested by clinical standard methods(R2=0.997 0).Turnaround time for single sample was less than 15 min and throughput could reach 200 T/h.Conclusion:This method is adequate that can be widely used in grassroots communities to help large-scale screening of pregnancy and related diseases.

Objective:To discuss the inhibitory effect of chelerythrine(CHE)on the migration,invasion,and epithelial-mesenchymal transition(EMT)of the human ovarian cancer SKOV3 cells,and to clarify the associated mechanism.Methods:The SKOV3 cells were cultured in vitro and divided into control group and 2.5,5.0,10.0,20.0,and 40.0 μmol·L-1 CHE groups.Methylthiazolydiphenyl-tetrazolium(MTT)assay was used to detect the inhibitory rates of proliferation of the cells in various groups.The SKOV3 cells were cultured in vitro and divided into control group,transforming growth factor-β1(TGF-β1)group,TGF-β1+5 μmol·L-1 CHE group,and TGF-β1+10 μmol·L-1 CHE group.Cell scratch assay was used to detect the migration rates of the cells in various groups;Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups;Western blotting method was used to detect the expression levels of E-cadherin,N-cadherin,and Vimentin proteins in the cells in various groups;immunofluorescence staining method was used to detect the fluorescence intensities of E-cadherin and N-cadherin in the cells in various groups.Results:The MTT assay results showed that compared with control group,the inhibitory rates of proliferation of the cells in 5.0,10.0,20.0,and 40.0 μmol·L-1 CHE groups were significantly increased(P<0.05 or P<0.01).The cell scratch assay results showed that compared with control group,the migration rate of the cells in TGF-β1 group was increased(P<0.01);compared with TGF-β1 group,the migration rates of the cells in TGF-β1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly decreased(P<0.01).The Transwell chamber assay results showed that compared with control group,the numbers of migration and invasion cells in TGF-β1 group were significantly increased(P<0.05);compared with TGF-β1 group,the numbers of migration and invasion cells in TGF-β1+5 μmo·l L-1 CHE group and TGF-β1+10 μmo·l L-1 CHE group were significantly decreased(P<0.01).The Western blotting results showed that compared with control group,the expression level of E-cadherin protein in the cells in TGF-β1 group was significantly decreased(P<0.01),while the expression levels of N-cadherin and Vimentin proteins were increased(P<0.05 or P<0.01);compared with TGF-β1 group,the expression levels of E-cadherin protein in the cells in TGF-β1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly increased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins were significantly decreased(P<0.01).The immunofluorescence staining results showed that compared with control group,the fluorescence intensity of E-cadherin in the cells in TGF-β1 group was decreased,and the fluorescence intensity of N-cadherin was increased;compared with TGF-β1 group,the fluorescence intensities of E-cadherin in the cells in TGF-β 1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly increased,and the fluorescence intensities of N-cadherin were decreased.Conclusion:CHE can inhibit the proliferation,migration,invasion,and EMT of the human ovarian cancer SKOV3 cells.

Premature ejaculation (PE), a common ejaculatory dysfunction in men with high prevalence, is a frequent cause of low sexual satisfaction for both patients and their partners.The etiology of PE is complex, including psychological, anatomical, neurobiological, and behavioral medicine factors, making it difficult to cure.Currently, treatments of PE include psychological interventions, local anesthetics, medications such as dapoxetine, and surgical treatments.Hyaluronic acid (HA) gel injection is an alternative treatment method.By subcutaneously injecting HA gel into the glans penis, the sensory input from nerve endings can be blocked, thereby reducing glans sensitivity.This approach can significantly extend the intravaginal ejaculatory latency time (IELT) and improve patient satisfaction.Moreover, it has advantages such as safety and high tolerability, making it a promising treatment option.In this paper, the technique, efficacy and safety of HA injection therapy for PE are introduced in detail on the basis of exploring other therapies for PE.

Bone Transplantation/adverse effects* ; Transplantation, Autologous/adverse effects*

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H₂O₂-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H⁺ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H₂O₂-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.