ObjectiveTo investigate the changes and effects of fatty acid metabolism in folic acid （FA）-induced kidney injury and diabetic nephropathy （DN） mouse models. MethodsThe FA-induced kidney injury model was established via intraperitoneal injection of FA. Nine adult C57BL/6J mice were randomly allocated to two groups： saline control group （Saline， n=5） and FA intervention group （n=4）. Mice in the FA group received a single intraperitoneal injection of FA （250 mg/kg）， whereas those in the Saline group were administered an equivalent volume of normal saline. The DN model was constructed using a high-fat diet combined with streptozotocin （STZ） injection. Eleven adult C57BL/6J mice were randomly divided into two groups： normal diet control group （ND， n=6） and DN model group （DN， n=5）. The ND group was fed a normal diet throughout the experiment； the DN group was maintained on a high-fat diet for 8 weeks， followed by a single intraperitoneal injection of STZ （100 mg/kg）， and then continued on the high-fat diet until week 16. （1） Hematoxylin and eosin （HE） and sirius red staining were used to observe pathological changes in the kidneys of the four groups of mice. （2） RNA-Seq was performed on mouse kidney tissues to screen for differentially expressed genes （DEGs）， followed by Gene Ontology （GO）， Kyoto Encyclopedia of Genes and Genomes （KEGG）， and Gene Set Enrichment Analysis （GSEA）. RT-qPCR was used to detect the mRNA levels of fatty acid synthesis and fibrosis-related genes. Lipid droplet accumulation was assessed by Oil Red O staining on frozen kidney sections. （3） Human renal cortical proximal tubular epithelial cells （HK-2） and proximal tubular epithelial cells （PTECs） were treated with 10 ng/mL recombinant human TGF-β1 or high glucose. RT-qPCR was used to measure the mRNA levels of fatty acid synthesis and fibrosis-related genes in HK-2 cells. Lipid droplet accumulation in HK-2 cells and PTECs was detected using Bodipy 493/503 staining. （4） HK-2 cells were treated with 100 µmol/L palmitic acid （PA）. Bodipy 493/503 staining was used to evaluate lipid droplet accumulation. （5） SA-β-gal staining was used to assess senescence in kidney tissues from all four mouse groups. Cellular senescence and the expression of senescence-associated secretory phenotype （SASP） factors in PA-treated HK-2 cells were assessed using SA-β-gal staining， Western blot， and RT-qPCR. The effect of PA-treated PTECs on renal fibroblast activation was assessed by immunofluorescence. Results（1） Both FA and DN groups showed pathological changes in kidney tissue， including renal tubular structural damage and collagen fiber deposition. （2） DEGs in both FA and DN groups were significantly enriched in metabolism-related pathways， especially lipid metabolism pathways. Compared to the Saline control， the expression of fatty acid synthesis genes Srebp1 and Fasn was significantly upregulated in the FA group （Srebp1： t=2.445， P=0.044 4； Fasn： t=2.571， P=0.037 0）. Compared to the ND group， Srebp1， Acc1， and Fasn gene expression was upregulated in the DN group （Srebp1： t=3.354， P=0.010 0； Acc1： t=2.602， P=0.031 5； Fasn： t=2.358， P=0.046 1）. The fibrosis-related gene Col1a1 was also upregulated in both FA and DN groups （FA： t=2.628， P=0.034 0； DN： t=3.602， P=0.007 0）， accompanied by pathological signs of lipid accumulation. （3） In HK-2 cells treated with TGF-β1 or high glucose， the mRNA expression levels of SREBP1 （F=15.41， P=0.004 3； TGFβ： P=0.002 9； HG： P=0.045 2）， ACC1 （F=30.30， P=0.000 7； HG： P=0.001 4）， and FASN （F=18.76， P=0.002 6； TGFβ： P=0.001 7； HG： P=0.031 0） were significantly upregulated. Both treatments also induced lipid accumulation in HK-2 cells and PTECs. （4） There was an increase in senescent cells in the kidneys of both the FA and DN groups. PA treatment induced lipid accumulation， accelerated senescence， and activated fibroblasts in renal tubular epithelial cells. ConclusionsTranscriptional abnormalities of lipid metabolism-related genes were observed in the kidneys of both FA-induced kidney injury and diabetic nephropathy models. Excessive fatty acid synthesis leads to lipid accumulation， which induces senescence in PTECs and ultimately promotes the development and progression of fibrosis.

Objective:To investigate the contents of natural radionuclides in agricultural soils in some of Gansu Hexi area to accumulate the relevant basic data.Methods:A stratified sampling method was used to collect 146 soil samples in the area. ORTEC P-type HPGE gamma spectrometry system was used to measure radionuclides. The measurement data were collated and analyzed.Results:The activity concentrations measured were 232Th 18.94-108.39 Bq/kg, 226Ra 14.37-79.20 Bq/kg and 40K 440.03-1 358.18 Bq/kg, in turn with the mean values of (68.22±16.32), (47.90±11.12) and (763.90±133.93) Bq/kg, respectively. The difference in activity concentrations of 232Th, 226Ra and 40K in agricultural soils in different areas was statistically significant( H=50.87, 45.14, 40.28, P<0.05). Conclusions:The study on the activity concentrations of natural radionuclides in agricultural soils provides basic information for the transfer of radionuclides to crops, which needs further investigation, monitoring and analysis.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

Objective:To evaluate the effect of ciprofol on intraoperative hypotension in patients undergoing bronchoscopy procedures.Methods:In this randomized controlled study, 112 adult patients of either sex, aged 18-64 yr, with a body mass index of 19.8-28.3 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, with estimated operation time of ≥1 h, undergoing elective bronchoscopy procedures, were assigned to one of two groups ( n=56 each) using a random number table method: ciprofol group (C group) and propofol group (P group). All the patients received total intravenous anesthesia. The induction dose of ciprofol was 0.1-0.3 mg/kg, and the maintenance dose was 0.4-1.2 mg·kg -1·h -1 in group C. The induction dose of propofol was 1-3 mg/kg, and the maintenance dose was 4-12 mg·kg -1·h -1 in group P. The primary outcome was the incidence of intraoperative hypotension, and the secondary outcomes were the time of emergence from anesthesia, sleep quality, patients′ and surgeons′ satisfaction with anesthesia, and the incidence of complications within 30 days after surgery. Results:Compared with group P, the incidence of intraoperative hypotension was significantly decreased, and the time of emergence from anesthesia was shortened in group C ( P<0.05). There was no statistically significant difference in secondary outcomes between the two groups ( P>0.05). Conclusions:Ciprofol is superior to propofol in reducing the risk of intraoperative hypotension and facilitates a more rapid emergence from anesthesia in patients undergoing bronchoscopy procedures.

Bone repair remains an important target in tissue engineering, making the development of bioactive scaffolds for effective bone defect repair a critical objective. In this study, β-tricalcium phosphate (β-TCP) scaffolds incorporated with processed pyritum decoction (PPD) were fabricated using three-dimensional (3D) printing-assisted freeze-casting. The produced composite scaffolds were evaluated for their mechanical strength, physicochemical properties, biocompatibility, in vitro pro-angiogenic activity, and in vivo efficacy in repairing rabbit femoral defects. They not only demonstrated excellent physicochemical properties, enhanced mechanical strength, and good biosafety but also significantly promoted the proliferation, migration, and aggregation of pro-angiogenic human umbilical vein endothelial cells (HUVECs). In vivo studies revealed that all scaffold groups facilitated osteogenesis at the bone defect site, with the β-TCP scaffolds loaded with PPD markedly enhancing the expression of neurogenic locus Notch homolog protein 1 (Notch1), vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), and osteopontin (OPN). Overall, the scaffolds developed in this study exhibited strong angiogenic and osteogenic capabilities both in vitro and in vivo. The incorporation of PPD notably promoted the angiogenic-osteogenic coupling, thereby accelerating bone repair, which suggests that PPD is a promising material for bone repair and that the PPD/β-TCP scaffolds hold great potential as a bone graft alternative.
Calcium Phosphates/chemistry* ; Animals ; Bone Regeneration ; Rabbits ; Tissue Scaffolds ; Printing, Three-Dimensional ; Humans ; Human Umbilical Vein Endothelial Cells ; Neovascularization, Physiologic ; Osteogenesis ; Tissue Engineering/methods* ; Biomimetic Materials ; Cell Proliferation ; Angiogenesis

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

Venous system diseases mainly include varicose veins and venous malformations of lower limbs and the genital system. Most of them are chronic diseases that cause serious clinical symptoms to patients and affect their health and quality of life. Sclerotherapy has become the first-line therapy for venous system diseases. However, there are problems such as incomplete fibrosis and vascular recanalization after sclerotherapy, and improper operation will cause serious adverse consequences. Therefore, exploring a safe and effective sclerotherapy strategy is essential for developing clinically successful sclerotherapy. To solve the above problems, we proposed a new sclerotherapy strategy with a dual mechanism of "vascular damage and plasmin (PLA) system inhibition." We intended to construct a novel cationic surfactant (AEO_x-TA) by reacting tranexamic acid (TA), a parent structure, with fatty alcohol polyoxyethylene ether (AEO_x) by ester bonds. AEO_x-TA could damage vascular endothelium and initiate a coagulation cascade effect to induce thrombus. Furthermore, AEO_x-TA could be degraded by esterase and release the parent drug, TA, which could inhibit the PLA system to inhibit the degradation of thrombus and extracellular matrix and promote the process of vascular fibrosis. In addition, such surfactant-based sclerosants have foam-forming properties, and they can be blended with polyvinyl alcohol (PVA) to prepare a highly stable foam formulation (AEO_x-TA/P), which can achieve a precise drug delivery and prolonged drug retention time, thereby improving drug efficacy and reducing the risk of ectopic embolism. Overall, the novel cationic surfactant AEO_x-TA provides a new avenue to resolve the bottleneck: surfactant sclerosants' efficiency is relatively low in the current sclerotherapy.

Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones