Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

OBJECTIVE: To explore the clinical significance of circulating tumor DNA (ctDNA) in response evaluation and relapse monitoring for patients with primary mediastinal large B-cell lymphoma (PMBCL). METHODS: The clinical characteristics, efficacy and survival of 38 PMBCL patients in our hospital from January 2010 to April 2020 were retrospectively analyzed. The ctDNA monitoring was conducted by targeted next-generation sequencing (NGS). RESULTS: Among the 38 patients, 26 cases were female, and 32 cases were diagnosed with Ann Arbor stage I-II. The 5-year overall survival (OS) rate and progression-free survival (PFS) rate were 74.7% and 61.7%, respectively. Males and those with high aaIPI scores (3 points) had a relatively poor prognosis. The NGS results of 23 patients showed that STAT6 (65.2%), SOCS1 (56.5%), and TNFAIP3 (56.5%) were the most common mutated genes. Patients with stable disease (SD)/progressive disease (PD) exhibited enrichment in cell cycle, FoxO, and TNF signaling pathways. A total of 29 patients underwent end-of-treatment PET/CT (EOT PET/CT), and 16 of them received ctDNA monitoring with 12 negative. Among 6 patients with EOT PET/CT positive (Deauville 4), 4 underwent ctDNA monitoring, and 3 of them were negative, being still in continuous remission without any subsequent anti-tumor therapy. CONCLUSION CtDNA may be combined with PET/CT to assess efficacy, monitor relapse, and guide treatment of PMBCL.
Humans ; Circulating Tumor DNA/blood* ; Female ; Mediastinal Neoplasms ; Male ; Retrospective Studies ; High-Throughput Nucleotide Sequencing ; Prognosis ; Lymphoma, Large B-Cell, Diffuse/genetics* ; Middle Aged ; Adult ; Aged ; Neoplasm Recurrence, Local ; Mutation

OBJECTIVE: Observational studies have found associations between inflammatory bowel disease (IBD) and the risk of dementia, including Alzheimer's dementia (AD) and vascular dementia (VD); however, these findings are inconsistent. It remains unclear whether these associations are causal. METHODS: We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia. Mendelian randomization (MR) analysis based on summary genome-wide association studies (GWASs) was performed. Genetic correlation and Bayesian co-localization analyses were used to provide robust genetic evidence. RESULTS: Ten observational studies involving 80,565,688 participants were included in this meta-analysis. IBD was significantly associated with dementia (risk ratio [ RR] =1.36, 95% CI = 1.04-1.78; I ² = 84.8%) and VD ( RR = 2.60, 95% CI = 1.18-5.70; only one study), but not with AD ( RR = 2.00, 95% CI = 0.96-4.13; I ² = 99.8%). MR analyses did not supported significant causal associations of IBD with dementia (dementia: odds ratio [ OR] = 1.01, 95% CI = 0.98-1.03; AD: OR = 0.98, 95% CI = 0.95-1.01; VD: OR = 1.02, 95% CI = 0.97-1.07). In addition, genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia. CONCLUSION Our study did not provide genetic evidence for a causal association between IBD and dementia risk. The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.
Humans ; Mendelian Randomization Analysis ; Inflammatory Bowel Diseases/complications* ; Dementia/etiology* ; Observational Studies as Topic ; Genome-Wide Association Study

Integrated metabolomic and lipidomic profiling,utilizing liquid chromatography coupled with high-resolution mass spectrometry(LC-HRMS),has emerged as a pivotal strategy for biomarker discovery.However,the inherent polarity disparity between metabolites and lipids complicates simultaneous analysis.To address this,a dual-stationary phase polarity-extended liquid chromatography(PELC)system was developed,which surpassed conventional one-dimensional LC(1D-LC)by enabling comprehensive coverage of both polar and non-polar compounds within a single injection.This system enhanced chromatographic resolution,peak capacity,and throughput while minimizing analytical variability.Extracellular vesicles(EVs),lipid bilayer-enclosed nanoparticles ubiquitously present in biofluids,had gained prominence as reservoirs of cancer biomarkers due to their cargo stability and pathophysiological relevance.Herein,the application of PELC-HRMS for concurrent metabolome-lipidome profiling in EVs was pioneered.A total of 193 metabolites were identified using this technique coupled with MS-DIAL software and Human Metabolome Database.Subsequently,this technique was employed to explore potential biomarkers for prostate cancer(PCa).Multivariate analysis identified 17 differentially abundant metabolites in PCa,implicating dysregulated pathways including purine metabolism,starch and sucrose metabolism,galactose metabolism,cysteine and methionine metabolism,and biosynthesis of unsaturated fatty acids.Notably,creatine(AUC=0.92)and DG 42:5(AUC=0.80)demonstrated robust diagnostic efficacy,attributable to their broad polarity ranges and EV-specific enrichment.This study established PELC as a high-fidelity platform for multi-omics integration in complex biospecimens,advancing mechanistic insights into metabolic rewiring and disease pathophysiology.

Objective To investigate the pathological and molecular characteristics of subcutaneous implanted thyroid lesions after endoscopic thyroid surgery.Methods A retrospective analysis was conducted on three postoperative implantation cases diagnosed in the Department of Pathology of our hospital from 2017 to 2024.Morphological evaluation,immunohistochemical staining,and next generation sequencing(NGS)targeting 66 cancer-related genes and 177 fusion loci were performed to compare features between primary and implanted lesions.Results All three implanted lesions exhibited morphological similarity to their primary counterparts,but displayed enriched mutational profiles.Case 1:a 13-year-old female.The primary lesion was an atypical follicular adenoma progressing to follicular carcinoma,while the implanted lesion was follicular carcinoma.Both lesions harbored MEN1 mutations,with an additional PTPRT mutation detected in the implanted lesion.Case 2:a 45-year-old male.The primary lesion was bilateral nodular goiter,and the implanted lesion showed follicular epithelial hyperplasia with a 0.3 cm papillary carcinoma focus.No mutations were identified in the primary lesion,whereas the implanted lesion exhibited MEN1,GLIS3,EZH1,and KMT2C mutations.Case 3:a 42-year-old female.The primary lesion included a left thyroid adenoma with cystic degeneration and right nodular goiter.A nodular goiter-like implanted lesion was detected in the right breast 5 years postoperatively.The primary lesion harbored TERT,GLIS3,and SPOP mutations,while the implanted lesion showed TERT,GLIS3,EIF1AX,and KMT2C mutations.Conclusions Endoscopic thyroid surgery is widely applied in clinical practice,however,implantation dissemination of thyroid lesions along surgical pathways may occur,encompassing both benign and malignant entities.Implanted lesions exhibit pathological similarities to their primary counterparts,but demonstrate mutational enrichment.

Objective:To explore the feasibility and effectiveness of full free-breathing cardiac magnetic resonance (CMR) in clinical practice.Methods:The study prospectively included patients who underwent full free-breathing CMR and traditional breath-holding cine imaging between June 1 and June 30, 2024. An analysis and comparison were conducted on the image acquisition time, image quality, and left ventricular function parameters under two scanning methods, including left ventricular ejection fraction (LVEF), left ventricular cardiac output (LVCO),left ventricular end diastolic volume (LVEDV), left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume (LVESV), left ventricular end systolic volume index (LVESVI), left ventricular stroke volume (LVSV), and left ventricular mass (LVM). In addition, the study conducted both quantitative and qualitative analyses of other sequences in full free-breathing CMR, including T 1 mapping, T 2 mapping, flow imaging, and late gadolinium enhancement (LGE). Group comparisons were performed using the Wilcoxon signed-rank test or paired t-test. Consistency assessments included Bland-Altman analysis, intraclass correlation coefficient ( ICC), and linear regression analysis. Results:Totally, 150 patients were recruited into the study. The average acquisition time of full free-breathing CMR was (22.1±3.1) min, with an average short axis cine sequence examination time of (2.7±0.4) min; The average acquisition time of short axis images in a breath-holding state was (4.9±1.4) min, which was significantly longer than the cine scan in the free-breathing state ( P0.001). The cine and LGE images quality scores obtained from full free-breathing CMR were 4 (4, 4) points and 5 (4, 5) points, respectively, while the cine image quality score obtained in a breath-holding state was 5 (4, 5) points. Compared with traditional breath-hold CMR, free-breathing CMR measurements showed slightly higher LVESV, and LVESVI, while LVEDV, LVEDVI, LVSV, LVCO, LVEF, and LVM were slightly lower, except for LVSV and LVCO, which showed no statistically significant difference, the differences in other cardiac function parameters were statistically significant ( P0.05). However, the two methods demonstrated good consistency( ICC0.947) and correlation (0.808 r0.993, P0.001). The Bland-Altman analysis showed that the bias for all cardiac function parameters was within 8.0%. The Native T 1 and T 2 values for free-breathing CMR were (1 277.5±57.0) ms and 40.1 (38.5, 41.4) ms, respectively, and the results of flow imaging and echocardiography were basically consistent. Conclusions:Free-breathing CMR is feasible and effective in clinical practice, showing a high level of consistency with left ventricular functional parameters obtained from traditional breath-hold scanning. It significantly shortens examination time and holds great clinical value for the promotion and widespread use of CMR.

Objective To identify core targets of hepatocellular carcinoma (HCC) by using bioinformatics and specific algorithms, explore their relationships with immune cells, and investigate the causal relationships between immune cells and HCC through Mendelian randomization. Methods Relevant genes associated with the development of HCC were screened using the GEO and TCGA databases. Immune infiltration analysis was conducted using GSVA and CIBERSORT algorithms. A bidirectional Mendelian randomization analysis was then performed to explore the causal relationships between immune cells and HCC. Results A total of 284 HCC-related genes were identified, with 120 genes recognized within the protein interaction network. Immune infiltration analysis revealed significant correlations between key genes and immune cells. Mendelian randomization results indicated that HLA DR on CD33⁺ HLA DR⁺ CD14dim (OR=1.097, 95%CI: 1.002–1.201, P=0.045, P_Bonferroni=0.091) and CD8 on CD28⁺ CD45RA⁺ CD8⁺ T cell (OR=1.123, 95%CI: 1.027–1.228, P=0.011, P_Bonferroni=0.022) were the risk factors for HCC. Conversely, HLA DR⁺⁺ monocyte absolute count was identified as a protective factor for HCC (OR=0.812, 95%CI: 0.702–0.938, P=0.005, P_Bonferroni=0.139). Conclusion The occurrence and development of liver cancer may be related to CDK1, CCNB1, and CDC20, showing a high degree of correlation with Th2 cells, T helper cells, Th17 cells, and DCs. Mendelian randomization shows that HLA DR on CD33⁺HLA DR⁺ CD14dim and CD8 on CD28⁺CD45RA⁺CD8⁺T cells are associated with an increased risk of HCC. The risk of hepatocellular carcinoma is associated with a decrease in the level of HLA DR⁺⁺monocyte absolute count.

This study aimed to explore the pharmacological mechanism of Yourenji Capsules(YRJ) in improving osteoporosis by combining network pharmacology and proteomics technologies. The SD rats were randomly divided into a blank control group and a 700 mg·kg~(-1) YRJ group. The rats were subjected to gavage administration with the corresponding drugs, and the blank serum, drug-containing serum, and YRJ samples were compared using ultra performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS) to analyze the main components absorbed into blood. Network pharmacology analysis was conducted based on the YRJ components absorbed into blood to obtain related targets of the components and target genes involved in osteoporosis, and Venn diagrams were used to identify the intersection of drug action targets and disease targets. The STRING database was used for protein-protein interaction(PPI) network analysis of potential target proteins to construct a PPI network. Gene Ontology(GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were performed using Enrichr to investigate the potential mechanism of action of YRJ. Ovariectomy(OVX) was performed to establish a rat model of osteoporosis, and the rats were divided into a sham group, a model group, and a 700 mg·kg~(-1) YRJ group. The rats were given the corresponding drugs by gavage. The femurs of the rats were subjected to label-free proteomics analysis to detect differentially expressed proteins, and GO functional enrichment and KEGG pathway enrichment analyses were performed on the differentially expressed proteins. With the help of network pharmacology and proteomics results, the mechanism by which YRJ improves osteoporosis was predicted. The analysis of the YRJ components absorbed into blood revealed 23 bioactive components of YRJ, and network pharmacology results indicated that key targets involved include tumor necrosis factor(TNF), tumor protein p53(TP53), protein kinase(AKT1), and matrix metalloproteinase 9(MMP9). These targets are mainly involved in osteoclast differentiation, estrogen signaling pathways, and nuclear factor-kappa B(NF-κB) signaling pathways. Additionally, the proteomics analysis highlighted important pathways such as peroxisome proliferator-activated receptor(PPAR) signaling pathways, mitogen-activated protein kinase(MAPK) signaling pathways, and β-alanine metabolism. The combined approaches of network pharmacology and proteomics have revealed that the mechanism by which YRJ improves osteoporosis may be closely related to the regulation of inflammation, osteoblast, and osteoclast metabolic pathways. The main pathways involved include the NF-κB signaling pathways, MAPK signaling pathways, and PPAR signaling pathways, among others.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Osteoporosis/metabolism* ; Proteomics ; Rats ; Rats, Sprague-Dawley ; Network Pharmacology ; Female ; Protein Interaction Maps/drug effects* ; Capsules ; Humans ; Signal Transduction/drug effects*

Objective To explore the application value of combining the ultrasound breast imaging reporting and data system(BI-RADS)classification with serum fibroblast growth factor receptor 1(FGFR1)and growth differentiation factor 3(GDF3)in the differential diagnosis of benign and malignant breast masses.Methods A total of 159 patients with breast masses were selected and divided into the benign mass group(n=83)and the malignant mass group(n=76)based on postoperative pathological diagnosis.All patients underwent ultrasound examination,and enzyme-linked immunosorbent assay(ELISA)was applied to detect serum levels of FGFR1 and GDF3.Receiver operating characteristic(ROC)curve was applied to analyze the diagnostic value of ultrasound BI-RADS classification and serum FGFR1 and GDF3 levels for benign and malignant breast masses.Kappa test was applied to analyze the consistency between various diagnostic methods and pathological diagnosis.Results The serum levels of FGFR1 and GDF3,the proportions of irregular morphology,unclear boundaries,spiculation,microcalcifications,blood flow grade Ⅱ-Ⅲ and posterior echo attenuation,RI and PI were higher in the malignant tumor group than those in the benign tumor group(P＜0.05).The area under the curve(AUC)of FGFR1,GDF3 and ultrasound BI-RADS classification in the differential diagnosis of benign and malignant breast masses separately and in combination was 0.802(95%CI:0.732-0.871),0.817(95%CI:0.751-0.884),0.848(95%CI:0.784-0.912)and 0.956(95%CI:0.918-0.993),respectively.The combined diagnosis was more effective than that of the individual diagnosis of each indicator.The consistency between the individual and combined diagnosis of benign and malignant breast masses and pathological diagnosis showed that the Kappa values were 0.517,0.514,0.688 and 0.912,respectively,with the highest consistency observed in the combined diagnosis(P＜0.05).Conclusion Ultrasound BI-RADS classification combined with serum FGFR1 and GDF3 has high application value in the differential diagnosis of benign and malignant breast masses.