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 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 discuss the ameliorative effect of total flavonoids from corn silk(TFCS)on kidney injury in the rats with urate nephropathy,and to clarify the possible mechanism.Methods:Sixty male Wistar rats were randomly divided into control group,model group,positive control group[benzbromarone(BZM)group,5 mg·kg-1·d-1],low dose of TFCS group(20 mg·kg-1·d-1),medium dose of TFCS group(40 mg·kg-1·d-1),and high dose of TFCS group(80 mg·kg-1·d-1),and there were 10 rats in each group.Except for control group,the rats in the other groups were administered potassium oxonate(350 mg·kg-1)and adenine(70 mg·kg-1)by gavage for 4 weeks to establish the hyperuricemic nephropthy models.The rats in different doses of TFCS groups were treated with TFCS for 2 weeks.Speckle blood flow imager was used to detect the renal blood perfusion of the rats in various groups and the kidney coefficients of the rats in various groups were caculated;HE staining and Masson staining were used to observe the pathomorphology and fibrosis degrees of kidney tissue of the rats in various groups and enzyme-linked immunosorbent assay(ELISA)method was used to detect the levels of uric acid(UA),creatinine(Cr),blood urea nitrogen(BUN),interleukin-6(IL-6),and tumor necrosis factor-α(TNF-α)in the serum and levels of β2-microglobulin(β2-MG)and microalbumin(ALB)in the urine of the rats in various groups;Western blotting method was used to detect the expression levels of urate transporter 1(URAT1),glucose transporter 9(GLUT9),and ATP-binding cassette transporter G2(ABCG2)proteins in kidney tissue of the rats in various groups.Results:Compared with control group,the renal blood perfusion volume of the rats in model group was significantly decreased(P<0.01).Compared with model group,the renal blood perfusion volumes of the rats in BZM group and low,medium,and high doses of TFCS groups were significantly increased(P<0.05 or P<0.01).Compared with control group,the kidney weight of the rats in model group was increased,with visible white granular spots on the surface,absence of blood color,and kidney volume was increased.Compared with model group,the kidney volumes of the rats in BZM group and medium and high doses of TFCS groups were decreased,with color tending toward that in control group,and the white granular spots on the surface were significantly reduced.Compared with model group,the kidney coefficients of the rats in BZM group and medium and high doses of TFCS groups were decreased(P<0.01).The HE staining results showed there were no abnormalities in kidney tissue structure in control group,while there were a small amount of brown-yellow urate crystal deposition and interstitial connective tissue hyperplasia in model group;compared with model group,the kidney tissue damage and inflammatory infiltration were alleviated to varying degrees in BZM group and different doses of TFCS groups.The Masson staining results revealed no obvious collagen fiber deposition in control group,whereas significant blue collagen fiber deposition in kidney tissue of the rats was found in model group,and the collagen volume fraction(CVF)was increased compared with control group(P<0.01);compared with model group,the CVFs of the rats in BZM group and different doses of TFCS groups were decreased(P<0.01).The ELISA results showed that compared with control group,the levels of UA,Cr,BUN,IL-6,and TNF-α in serum of the rats in model group were increased(P<0.01);compared with model group,the levels of UA,Cr,BUN,IL-6,and TNF-α in serum of the rats in BZM group and medium and high doses of TFCS groups were decreased(P<0.01).Compared with control group,the levels of β2-MG and ALB in urinary in model group were increased(P<0.01);compared with model group,the levels of β2-MG and ALB in urinary of the rats in different doses of TFCS groups were decreased(P<0.05 or P<0.01).The Western blotting results showed that compared with control group,the expression levels of URAT1 and GLUT9 proteins in kidney tissue of the rats in BZM group and model group were increased(P<0.01),while the expression level of ABCG2 protein was decreased(P<0.01).Compared with model group,the expression levels of URAT1 and GLUT9 proteins in kidney tissue of the rats in different doses of TFCS groups were decreased(P<0.05 or P<0.01),and the expression level of ABCG2 protein was increased(P<0.01).Conclusion:TFCS can significantly alleviate the kidney injury in the rats with urate nephropathy model,and its mechanism may be related to the downregulation of expression of URAT1 and GLUT9 proteins and upregulation of ABCG2 protein expression in kidney tissue.

Objective To explore the impact of vascular calcification on patency rate of arteriovenous fistula(AVF)after ultrasound-guided percutaneous transluminal angioplasty(UG-PTA)for stenosis.Methods Forty-eight chronic kidney disease patients who underwent maintenance hemodialysis(HD)and received UG-PTA since autologous or artificial AVF stenosis were retrospectively enrolled.The patients were divided into calcification group(n=21)and non-calcification group(n=27)according to ultrasonic findings of AVF calcification or not.The technical success rate of UG-PTA,the clinical success rate and UG-PTA related adverse events were recorded.Ultrasound was performed to evaluate the patency of AVF 3,6,9,12,24 and 36 months after UG-PTA,and the primary and secondary patency rates were calculated.Kaplan-Meier survival curves were used to analyze the patency rates of AVF.Results UG-PTA was successfully performed in all 48 cases.All patients completed more than 3 times effective HD,the technical and clinical success rate both of 100%(48/48).No serious adverse event occurred.In calcification group,the primary patency rate 3,6,9,12,24 and 36 months after UG-PTA was 75.89%,37.95%,37.95%,27.10%,14.46%and 0,and the secondary patency rate was 95.24%,95.24%,95.24%,89.95%,83.03%and 83.03%,respectively,while in non-calcification group the primary patency rate was 92.31%,73.08%,57.69%,53.85%,36.15%and 36.15%,and the secondary patency rate was 100%,100%,100%,100%,95.24%and 95.24%,respectively.After UG-PTA,the primary patency rate in calcification group was lower than that in non-calcification group(P＜0.05),but there was no significant difference of the secondary patency rate between groups(P＞0.05).Conclusion Calcification was a risk factor for primary patency rate of AVF after UG-PTA for stenosis,but had no significant impact on the secondary patency rate.

Diabetic kidney disease(DKD)is the leading cause of end-stage renal disease.Chinese materia medica shows unique advantages in intervening DKD.Silent information regulator 1(SIRT1)protein plays a vital role in the occurrence and development of DKD.This article was about the SIRT1 signaling pathway and the main molecular regulatory mechanisms to sort out the role of Chinese materia medica in regulating SIRT1 in podocytes,oxidative stress and inflammatory response.It was found that Chinese materia medica monomers and compounds were capable of regulating the PGC-1 α signaling pathway,Nrf2/ARE signaling pathway,AMPK signaling pathway,NF-κB p65 signaling pathway,and PI3K/AKT/FoxO1 signaling pathway by targeting SIRT1,exerting pharmacological effects such as inhibiting cell apoptosis,improving mitophagy,inhibiting inflammatory response,etc.,thus intervening in DKD,which can provide reference for relevant research.

Objective:To explore the efficacy of secondary targeted percutaneous vertebroplasty (PVP) for the treatment of refracture of injured vertebrae after vertebral augmentation for osteoporotic vertebral compression fracture (OVCF).Methods:A retrospective case series study was performed on the clinical data of 25 patients with refracture of injured vertebrae after vertebral augmentation for OVCF admitted to Honghui Hospital, Xi′an Jiaotong University from January 2019 to January 2022, including 10 males and 15 females, aged 62-86 years [(73.8±5.2)years]. The fractured segments involved T 10 in 1 patient, T 11 in 2, T 12 in 10, L 1 in 10 and L 2 in 2. All the patients were treated with secondary targeted PVP. The operation time and the amount of bone cement injected were recorded. The visual analogue scale (VAS) of lower back, Oswestry disability index (ODI), vertebral body index (VBI) and kyphotic angle (KA) were compared before surgery, at 1 day, 6 months after surgery and at the last follow-up. Odom criteria were used to evaluate the efficacy of the surgical procedure at the last follow-up. The intraoperative bone cement leakage and new vertebrae fracture during follow-up were observed. Results:All the patients were followed up for 23-59 months [(36.8±7.6)months]. The operation time was 35-60 minutes [(42.6±5.2)minutes], with the amount of bone cement injected for 3-5 ml [(3.6±0.8)ml]. The VAS scores of lower back at 1 day, 6 months after surgery and at the last follow-up were 3.1(2.0, 4.0)points, 1.7(1.0, 2.0)points and 0.6(0.0, 1.0)points respectively, significantly lower than 7.6(7.0, 9.0)points before surgery ( P<0.01), and a statistically singnificant decrease was found over follow-up time ( P<0.01). The ODI values at 1 day, 6 months after surgery and at the last follow-up were (49.5±5.9)%, (28.5±4.6)% and (19.2±4.8)% respectively, significantly lower than (78.8±6.8)% before surgery ( P<0.01), and a statistically singnificant decrease was found over follow-up time ( P<0.01). The VBI values at 1 day, 6 months after surgery and at the last follow-up were (76.6±4.5)%, (76.3±4.0)% and (76.1±3.8)% respectively, significantly higher than (58.9±5.8)% before surgery ( P<0.01), while there were no significant differences among those at 1 day, 6 months after surgery and at the last follow-up ( P>0.05). The KA values at 1 day, 6 months after surgery and at the last follow-up were (12.4±2.7)°, (12.6±2.5)° and (12.8±2.9)° respectively, significantly lower than (20.8±3.6)° before surgery ( P<0.01), while there were no significant differences among those at 1 day, 6 months after surgery and at the last follow-up ( P>0.05). According to the Odom criteria, 20 patients were rated excellent and 5 good at the last follow-up, with an excellent and good rate of 100%. Intraoperative asymptomatic bone cement leakage occurred in 3 patients (12%), including 2 with intervertebral leakage and 1 with lateral vertebral leakage. No adjacent vertebral body or other vertebral fracture was observed during the follow-up. Conclusions:For patients with refracture of injured vertebrae after vertebral augmentation for OVCF, the secondary targeted PVP has advantages of attenuation of the lower back pain, improvement of the quality of life, restoration of the height of refractured vertebrae, correction of the local kyphosis, and a low incidence of complications.

Masquelet technique has become a safe and effective treatment for chronic osteomyelitis of the long limb shaft. The vast majority of osteomyelitis can be ultimately controlled, segmental bone defects repaired and limb functions restored. Accumulation of clinical applications and development of imaging technology have led to rapid progress in determining the infection scope of chronic limb osteomyelitis, precise preoperative design for repair of soft tissue defects, evaluation of bone structure stability, and use of bone grafting materials. This article reviews the progress of Masquelet technique in the treatment of chronic limb osteomyelitis from the aspects of its theoretical foundation, key operations, and selection of fixation methods, hoping to deepen the understanding of current Masquelet technique.

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.

Cancer is a prevalent and challenging disease that is difficult to treat.Western medicine recognizes the disruption of the immune and inflammatory microenvironment as a crucial factor in the development and progression of cancer.According to traditional Chinese medicine,cancer falls into the categories of"accumulation"and"abnormal masses".Based on the attributes of cold and heat in the overall and local conditions as well as the characteristic of the struggle between the vital qi and pathogenic factors at different stages of this disease,this article proposes the concept of"body coldness and tumor heat"to describe the pathogenesis of cancer formation and progression.This pathogenesis aligns with the disruption of the immune and inflammatory microenvironment in modern medical oncology.The article suggests a treatment approach that focuses on balancing cold and heat,nourishing and protecting yang qi,warming the kidneys,and strengthening the spleen to address the"coldness of the entire body".This approach also involves promoting qi circulation,eliminating dampness,phlegm,and stasis,and detoxifying and dispersing nodules to address the"heat in the tumor locally".By addressing deficiencies,eliminating pathogenic factors,and promoting circulation to alleviate stagnation,the aim is to restore the balance of yin and yang and improve the complex state of"coldness of the entire body"and"heat in the tumor locally".These interventions can ameliorate the disorder in the microenvironment and enhance clinical efficacy.