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 transfer and diffusion of berberine hydrochloride(BBH), the main active component of Coptis and Phellodenticum in the system of carboxymethyl chitosan(CMCS)-sodium alginate(SA). METHODS CMCS and SA were stirred in a certain proportion, and D-gluconolactone(GDL) was added to form polyelectrolyte hydrogel. Rheometer was used to study the rheological properties of CMCS-SA hydrogel, including the elastic modulus G′ and the viscous modulus G′′. A BBH diffusion model for CMCS-SA hydrogel was designed, and the relevant rules of BBH permeation through CMCS-SA polyelectrolyte hydrogel were observed by UV-VIS. RESULTS The elastic modulus G′ of the hydrogel was measured when the ratio of CMCS to SA was 3∶1, 2∶1, 1∶1, 1∶2, and 1∶3. When the ratio of CMCS to SA was 1∶1, G′ was the highest, and the crosslinking strength of the hydrogel was the highest. The cumulative amount of BBH transfer was measured by the BBH transfer model, and the diffusion of BBH in CMCS-SA hydrogel was fitted as the skeleton dissolution by Peppas equation, indicating that BBH dissociation and the transfer efficiency increased as the amino group of CMCS decreased or the carboxyl group of SA increased. The elastic modulus G′ of CMCS-SA hydrogel increased with the increase of GDL content. The reason was that the binding force between CMCS and SA molecules gradually increased with the decrease of pH, and the crosslinking degree of the hydrogel was enhanced. When ratio of fixed CMCS to SA was 1∶1 and the GDL content was 0.15 g·mL−1, the formability of CMCS-SA hydrogel was good. In addition, when BBH was transferred in hydrogel with different concentrations of GDL, the transfer efficiency increased with the increase of GDL content. When BBH was delivered in different thickness hydrogel, the delivery efficiency of CMCS-SA hydrogel increased with the decrease of thickness. CONCLUSION The CMCS-SA hydrogel system, as a potential drug carrier for traditional Chinese medicine extracts such as BBH, is expected to serve as a gel carrier for transdermal drug delivery.

Objective To analyze the expression level,clinical significance and prognostic value of adenylate cyclase 1(ADCY1)in clear cell renal cell carcinoma(ccRCC).Methods ADCY1 expression level and correlation with pathological features were analyzed with UALCAN database.The prognostic value of ADCY1 in ccRCC was analyzed with GEPIA2 database.The protein expression level and three-dimensional structure of ADCY1 were analyzed with HPA database.The subcellular localization of ADCY1 was analyzed with Genecard database.ADCY1 interacting proteins were obtained using the STRING database and enriched with R software.Mutations of ADCY1 gene were analyzed with cBioPortal database.Immune cell infiltration of ADCY1 in ccRCC was analyzed with R language.ADCY1 expression level in ccRCC tissues was verified with quantitative real-time polymerase chain reaction(qRT-PCR)and immunohistochemical staining.Results ADCY1 was down-regulated in ccRCC and significantly correlated with pathological staging and grading.Patients with low ADCY1 expression had poorer overall and disease-free survival.ADCY1 was mainly expressed in the plasma membrane,extracellular,and nucleus of the cells.ADCY1 was closely related to morphine addiction,regulation of circadian rhythm,dopaminergic synapses,and cAMP signaling pathway.The main mutation type of ADCY1 in ccRCC was missense mutation.ADCY1 was positively correlated with CD4 T cell and macrophage infiltration in ccRCC.The gene and protein expressions of ADCY1 were decreased in ccRCC tissues.Conclusion ADCY1 is a new prognostic marker and potential clinical therapeutic target for ccRCC.

Objective:To analyze the characteristics of postoperative thoracic deformation in patients who underwent multi-rib autologous rib cartilage transplantation auricle reconstruction based on 3dMD imaging system.Methods:A retrospective study was conducted using 3dMD data of the thorax from patients who underwent auricle reconstruction surgery using multiple autologous costal cartilages at the First Department of Ear Reconstruction of the Plastic Surgery Hospital, Chinese Academy of Medical Sciences, from July to September 2019. The normal-side chest wall image was superimposed on the rib-harvested side chest wall for automatic registration and alignment, with distance numerical data presented in a Cartesian heat map through color mapping technology. By observing the areas where the rib-harvested side thorax had obvious deformation, the distance difference of the concave and convex peaks on the sagittal diameter was measured to judge the degree of thoracic deformation in children (≤10 mm as none; >10-20 mm as mild; >20-30 mm as moderate; >30 mm as severe).Results:A total of 42 children were included, with 27 males and 15 females, aged from 7 to 12 years old. The Cartesian heat map of thoracic deformation showed that the obvious concave area of the chest wall was located at the junction of the middle and inner one-third of the clavicle and the 7th rib, and the obvious convex area was located in the area from the nipple to the 5th rib. The measurement range of the protrusion peak in the upper chest nipple area was from -7.638 9 to -14.288 4 mm; the measurement range of the depression peak in the rib arch area was from 7.238 7 to 14.653 2 mm. The range of the distance difference between the concave and convex peaks was from 14.877 6 to 28.941 6 mm.The degree and incidence of thoracic deformation in children: mild in 5 cases; moderate in 37 cases.Conclusion:Based on the analysis with 3dMD photogrammetry, the overall characteristics of chest wall deformation in patients who underwent ear reconstruction with autologous rib cartilage grafts were the coexistence of protrusion in the upper chest nipple area and depression in the area where the rib cartilage was harvested, with changes occurring on the sagittal diameter.

Objective:To compare the efficacy and impact on the quality of life of elderly patients of minimally invasive percutaneous nephrolithotomy(MPCNL)and retrograde intrarenal surgery(RIRS)in the treatment of unilateral upper ureteral calculi larger than 1.0 cm in diameter.Methods:A total of 104 patients were prospectively collected from January 2021 to December 2022 in the First Hospital of Shanxi Medical University.Based on the inclusion and exclusion criteria, 88 patients were finally included, 32 patients in the MPCNL group and 56 patients in the RIRS group, and the independent samples t-test, χ2 test, or Fisher's exact probability method were used to compare the differences in the general information, stone characteristics, and intraoperative and postoperative indexes between the two groups, and the quality-of-life scores were applied with the SF-36 Health Survey form. Results:There were no significant differences in age[(67.52±7.41)years and(67.38±7.25)years], gender[male/female: 19/13 cases and 36/20 cases], body mass index[(23.74±2.93)kg/m 2 and(23.70±2.57)], stone location(left/right: 20/12 cases and 38/18 cases), degree of hydronephrosis(mild/moderate/severe: 9/20/3 cases and 16/38/2 cases), stone maximum diameter[(14.12±3.69)mm and(13.34±2.99)mm], stone CT values[(1 035.7±275.7)HU and(973.3±253.8)HU]and postoperative complications[15.6%(5/32)and 14.3%(8/56)]between the two groups of patients( P>0.05).However, there were significant difference in stone clearance rate[96.9%(31/32) vs.80.4%(45/56)], and the operation time[(44.44±9.91)min vs.(54.69±11.94)min]between the two groups.The hospital stay in the RIRS group was shorter than that in the MPCNL group[(5.27±2.27)d vs.(8.00±2.19)d, P<0.05].There was no significant difference in the scores of eight dimensions between the two groups before surgery( P<0.05).At the day of discharge, patients in the MPCNL group had significantly lower mean scores than the RIRS group on six different subscales of the SF-36 questionnaire, namely, physical functioning, role-physical, bodily pain, social functioning, role-emotional and mental health.No differences in the mean scores for general health and vitality between the two groups were noted.In terms of SF-36 scores at one month after operation, the MPCNL group had lower scores in physical pain and social function than the RIRS group and the difference was statistically significant( P<0.05).No differences in the mean scores for other domains at one month after operation between patients undergoing MPCNL and those undergoing RIRS were noted. Conclusions:For patients with unilateral upper ureteral calculi larger than 1.0 cm in diameter, MPCNL has higher stone-free rate and shorter operation time than RIRS, but longer hospitalization time, and MPCNL has a greater impact on the quality of life of patients with ureteral calculi than RIRS in many aspects.

Background and Aims:In the era of minimally invasive surgery,the role of pancreatic tumor enucleation(PTE)in treating benign or low-grade malignant tumors is gaining attention.The Da Vinci robot offers advantages such as enhanced visualization and flexible instrument manipulation,which can ensure the safe implementation of PTE.However,whether robotic pancreatic tumor excision(RPTE)is superior to laparoscopic pancreatic tumor enucleation(LPTE)remains undetermined.Therefore,this study was performed to explore this aspect. Methods:The clinical data of 38 patients who underwent surgical treatment for benign or low-grade malignant tumors in the Third Xiangya Hospital of Central South University from April 2020 to May 2024 were collected.Among them,18 cases underwent RPTE(RPTE group),and 20 cases underwent LPTE(LPTE group).Relevant clinical variables were compared between the two groups,and subgroup comparisons were further conducted for patients with tumors in the head and neck/body/tail of the pancreas. Results:The average operative time for the entire group was 125 min,with an average intraoperative blood loss of 67.89 mL,and no C-grade pancreatic fistula occurred.The incidence rates of B-grade pancreatic fistula,postoperative bleeding,and readmission were 39.5％,21.1％,and 18.4％,respectively,with an average postoperative hospital stay of 11.44 d.Overall,the RPTE group had shorter operative time and less intraoperative blood loss than the LPTE group(both P＜0.05).There were no statistically significant differences between the two groups regarding the incidence of B-grade pancreatic fistula,intraoperative bleeding,readmission rate,and postoperative hospital stay(all P＞0.05).Subgroup analysis showed that for patients with head tumors,the RPTE group had shorter operative time,less intraoperative blood loss,and a lower incidence of postoperative bleeding than the LPTE group(all P＜0.05).However,the differences in the incidence of B-grade pancreatic fistula,readmission rate,and postoperative hospital stay were not statistically significant(all P＞0.05).In patients with neck/body/tail tumors,the RPTE group also had shorter operative time and less intraoperative blood loss(both P＜0.05),but the differences in incidence of B-grade pancreatic fistula,incidence of postoperative bleeding,readmission rate,and postoperative hospital stay were not statistically significant(all P＞0.05). Conclusion:Minimally invasive PTE for the treatment of benign or low-grade malignant pancreatic tumors is safe.Compared to LPTE,RPTE can significantly reduce operative time and intraoperative blood loss and shows certain advantages in reducing postoperative complications,particularly for patients with head tumors.However,the conclusion of this study needs to be confirmed by larger prospective studies.

Objective:To construct a virtual-real interactive system HE-01 for the treatment of microtia based on HoloLens and verify the feasibility of applying HE-01 in ear reconstruction.Methods:Six volunteers (3 males and 3 females, average age: 20.5 years old) and six patients with microtia(3 males and 3 females, average age: 7.6 years old) were recruited from Plastic Surgery Hospital of Chinese Academy of Medical Sciences from August to September 2021. The Mimics Research 21.0 software and 3-matic research software were used to construct a virtual three-dimensional auricle model. Based on HoloLens and occlusal splint navigation marker device, the virtual-real interactive system HE-01 for the treatment of microtia was constructed. The registration accuracy, tracking delay and display effect of different colors (red, green, blue and skin color) of HE-01 were evaluated through repeated experiments of volunteers. The operation process was defined through repeated experiments of patients and the feasibility of applying HE-01 in auricular reconstruction was verified.Results:HE-01 was built successfully and the operation flow was clear. The experiment of six volunteers (12 ears) showed a high registration accuracy (average error rate 2.3%-2.4%, less than 2.7% of the bilateral auricle size difference of normal people), low tracking delay (six volunteers were all less than 0.1 s), and best green and red display effect of virtual auricle guide under different angles (-60°, -30°, 0°, 30°, 60°). Experiments of patients with microtia showed that HE-01 could be applied to auricular reconstruction, and there were no obvious complications in wearing the navigation marker device, which had repeatability and stability.Conclusion:This study has completed the conceptual design of augmented-reality assisted auricular reconstruction based on navigation device, CT data and HoloLens. HE-01 has good registration accuracy, tracking speed and display effect, laying a good foundation for further software development and clinical transformation.

Objective:To construct a virtual-real interactive system HE-01 for the treatment of microtia based on HoloLens and verify the feasibility of applying HE-01 in ear reconstruction.Methods:Six volunteers (3 males and 3 females, average age: 20.5 years old) and six patients with microtia(3 males and 3 females, average age: 7.6 years old) were recruited from Plastic Surgery Hospital of Chinese Academy of Medical Sciences from August to September 2021. The Mimics Research 21.0 software and 3-matic research software were used to construct a virtual three-dimensional auricle model. Based on HoloLens and occlusal splint navigation marker device, the virtual-real interactive system HE-01 for the treatment of microtia was constructed. The registration accuracy, tracking delay and display effect of different colors (red, green, blue and skin color) of HE-01 were evaluated through repeated experiments of volunteers. The operation process was defined through repeated experiments of patients and the feasibility of applying HE-01 in auricular reconstruction was verified.Results:HE-01 was built successfully and the operation flow was clear. The experiment of six volunteers (12 ears) showed a high registration accuracy (average error rate 2.3%-2.4%, less than 2.7% of the bilateral auricle size difference of normal people), low tracking delay (six volunteers were all less than 0.1 s), and best green and red display effect of virtual auricle guide under different angles (-60°, -30°, 0°, 30°, 60°). Experiments of patients with microtia showed that HE-01 could be applied to auricular reconstruction, and there were no obvious complications in wearing the navigation marker device, which had repeatability and stability.Conclusion:This study has completed the conceptual design of augmented-reality assisted auricular reconstruction based on navigation device, CT data and HoloLens. HE-01 has good registration accuracy, tracking speed and display effect, laying a good foundation for further software development and clinical transformation.

Objective:To analyze the characteristics of postoperative thoracic deformation in patients who underwent multi-rib autologous rib cartilage transplantation auricle reconstruction based on 3dMD imaging system.Methods:A retrospective study was conducted using 3dMD data of the thorax from patients who underwent auricle reconstruction surgery using multiple autologous costal cartilages at the First Department of Ear Reconstruction of the Plastic Surgery Hospital, Chinese Academy of Medical Sciences, from July to September 2019. The normal-side chest wall image was superimposed on the rib-harvested side chest wall for automatic registration and alignment, with distance numerical data presented in a Cartesian heat map through color mapping technology. By observing the areas where the rib-harvested side thorax had obvious deformation, the distance difference of the concave and convex peaks on the sagittal diameter was measured to judge the degree of thoracic deformation in children (≤10 mm as none; >10-20 mm as mild; >20-30 mm as moderate; >30 mm as severe).Results:A total of 42 children were included, with 27 males and 15 females, aged from 7 to 12 years old. The Cartesian heat map of thoracic deformation showed that the obvious concave area of the chest wall was located at the junction of the middle and inner one-third of the clavicle and the 7th rib, and the obvious convex area was located in the area from the nipple to the 5th rib. The measurement range of the protrusion peak in the upper chest nipple area was from -7.638 9 to -14.288 4 mm; the measurement range of the depression peak in the rib arch area was from 7.238 7 to 14.653 2 mm. The range of the distance difference between the concave and convex peaks was from 14.877 6 to 28.941 6 mm.The degree and incidence of thoracic deformation in children: mild in 5 cases; moderate in 37 cases.Conclusion:Based on the analysis with 3dMD photogrammetry, the overall characteristics of chest wall deformation in patients who underwent ear reconstruction with autologous rib cartilage grafts were the coexistence of protrusion in the upper chest nipple area and depression in the area where the rib cartilage was harvested, with changes occurring on the sagittal diameter.

Objective:To screen key genes of renal clear cell carcinoma based on bioinformatics methods, identify possible microRNA (miRNA)-mRNA action axis, and explore the expression of related genes in clear cell renal cell carcinoma tissues and cells.Methods:Gene expression profiles of GSE40435 and GSE71302 datasets were obtained from the Gene Expression Omnibus (GEO) database. TCGA-KIRC datasets were obtained from The Cancer Genome Atlas (TCGA) database. R software was used to identify the differentially expressed mRNA and miRNA, and the functional enrichment analysis was performed. STRING database and Cytoscape software were used to perform the protein interaction analysis. The prognosis-related differentially expressed miRNA was evaluated by the Oncomir database. The potential targeted genes regulated by miRNA were determined by using TargetScan and miRDB targeted gene prediction tools. The tissue samples and clinicopathological features of 34 patients with clear cell renal cell carcinoma in the First Hospital of Shanxi Medical University from June to December 2021 were collected, and normal renal cell line 293T and clear cell renal cell carcinoma cell line 786O were selected. The real-time fluorescence quantitative polymerase chain reaction (qRT-PCR), was used to detect the relative expression of genes; Western blotting and immunohistochemical staining were used to detect the expression levels of the targeted proteins. The dual luciferase reporter gene assay was carried out to verify the targeting relationship between genes.Results:A total of 1 351 differentially expressed mRNA and 50 differentially expressed miRNA were screened and identified. The result of functional enrichment analysis suggested that the fatty acid metabolism pathway and xenobiotic metabolism pathway were suppressed in clear cell renal cell carcinoma, while the apoptosis and immune response pathways were activated. Protein interaction analysis suggested that the signal transduction and protein ubiquitination pathways might play a key role in clear cell renal cell carcinoma. The screening results showed that miRNA-224-5p (miR-224-5p) was most closely associated with clear cell renal cell carcinoma progression and was highly expressed in tumor tissues, and its prognosis-related target gene was NEDD4L. The relative expression of NEDD4L mRNA in clear cell renal cell carcinoma tissues and paraneoplastic tissues were 0.138±0.103 and 1.000±0.026 ( t = 46.23, P < 0.05), and the relative expression of miR-224-5p was 1.000±0.043 and 0.129±0.108 ( t = 45.28, P < 0.05). The differences of NEDD4L mRNA and miR-224-5p expressions in different grades and stages of clear cell renal cell carcinoma tissues were statistically significant (all P < 0.05). The expression of NEDD4L protein was decreased in clear cell renal cell carcinoma. The relative expression of NEDD4L gene in 293T and 786O cells were 1.000±0.125 and 0.210±0.044 ( t = 17.52, P < 0.05); the relative expressions of miR-224-5p gene were 0.209±0.049 and 1.000±0.234 ( t = 10.61, P < 0.05). The relative expressions of NEDD4L mRNA in miRNA mimic group and negative control group were 0.236±0.062 and 1.000±0.024, and the difference was statistically significant ( t = 43.56, P < 0.05). NEDD4L protein expression was reduced in the miRNA mimic group. Dual luciferase reporter gene assay suggested that NEDD4L was a direct target gene of miR-224-5p. Conclusions:In clear cell renal cell carcinoma, miR-224-5p targets and regulates NEDD4L expression, and this mechanism may be related to carcinogenesis and progression of clear cell renal cell carcinoma.