Search

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This study was aimed to identify a lipid metabolism-related signature associated with the HCC microenvironment to improve the prognostic prediction of HCC patients. Clinical information and expression profile data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, including the GEO dataset GSE76427. The gene expression profile of lipid metabolism was downloaded from Molecular Signatures Database (MSigDB) database. The infiltrating immune cells were estimated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), MCP-counter, and TIMER algorithms. Functional analysis, including Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were performed to elucidate the underlying mechanisms. The prognostic risk model was performed by Least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis. Two distinct subgroups of survival were identified. Better prognosis was associated with high immune score, high abundance of immune infiltrating cells, and high immune status. GO and KEGG analysis showed that differentially expressed genes (DEGs) between the two subgroups were mainly enriched in immune related pathways. GSEA analysis suggested that the expression of lipid metabolism related genes (LMRGs) was related to dysregulation of immune in the high-risk group. Risk models and clinical features based on LMRGs predicted HCC prognosis. This study indicated that the lipid metabolism-related signature was important for the prognosis of HCC. The expression of LMRGs was related to the immune microenvironment of HCC patients and could be used to predict the prognosis of HCC.

Abstract The rotary motor plays a pivotal role in various motion execution mechanisms. However, an inherent issue arises during the initial installation of the encoder grating, namely, eccentricity between the centers of the encoder grating and motor shaft. This eccentricity substantially affects the accuracy of motor angle measurements. To address this challenge, we proposed a precision encoder grating mounting system that automates the encoder grating mounting process. The proposed system mainly comprises a near-sensor detector and a push rod. With the use of a near-sensor approach, the detector captures rotating encoder grating images, and the eccentricity is computed in real-time. This approach substantially reduces the time delays in image data transmission, thereby enhancing the speed and accuracy of eccentricity calculation. The major contribution of this article is a method for real-time eccentricity calculation that leverages an edge processor within the detector and an edge-vision baseline detection algorithm. This method enables real-time determination of the eccentricity and eccentricity angle of the encoder grating. Leveraging the obtained eccentricity and eccentricity angle data, the position of the encoder grating can be automatically adjusted by the push rod. In the experimental results, the detector can obtain the eccentricity and eccentricity angle of the encoder grating within 2.8 s. The system efficiently and precisely completes a encoder grating mounting task in average 25.1 s, and the average eccentricity after encoder grating mounting is 3.8 µm.

Abstract We aimed to investigate the preventive effect of vitamin D2 on COVID-19 and the improvement of symptoms after COVID-19 infection. The study recruited 228 health care workers who tested negative PCR or antigen for COVID-19. Subjects were randomly allocated to vitamin D2 or non-intervention at a ratio 1:1. Subjects recorded PCR or antigen tests and the symptoms of COVID-19 twice a week during the follow-up visit. The concentration of serum 25-hydroxyvitamin D (25(OH)D), C-reaction protein (CRP), complement component C1q and inflammatory cytokines were measured. The rates of COVID-19 infection were 50.5% in the vitamin D2 group and 52.4% in the non-intervention group (P = 0.785). There was no difference in the COVID-19 symptoms between the two groups. The mean 25(OH)D level significantly increased from 14.1 to 31.1 ng/mL after administration (P 30 ng/mL) and deficient groups (

Abstract. Background:. Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors. Methods:. The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25–70 years old from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020. Results:. The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy. Conclusions:. We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

Abstract This paper introduces the efficient medical-images-aimed segment anything model (EMedSAM), addressing the high computational demands and limited adaptability of using SAM for medical image segmentation tasks. We present a novel, compact image encoder, DD-TinyViT, designed to enhance segmentation efficiency through an innovative parameter tuning method called med-adapter. The lightweight DD-TinyViT encoder is derived from the well-known ViT-H using a decoupled distillation approach.The segmentation and recognition capabilities of EMedSAM for specific structures are improved by med-adapter, which dynamically adjusts the model parameters specifically for medical imaging. We conducted extensive testing on EMedSAM using the public FLARE 2022 dataset and datasets from the First Hospital of Zhejiang University School of Medicine. The results demonstrate that our model outperforms existing state-of-the-art models in both multi-organ and lung segmentation tasks.

Abstract To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

The calcium-activated chloride channel (CLCA4) in colon adenocarcinoma (COAD) and immunological infiltration have not been extensively studied. This work thoroughly employed several datasets to assess the expression, prognosis, and association between immune infiltration and clinicopathological characteristics of CLCA4 in cancer, as well as look into potential signalling pathways. The human protein atlas (HPA), TIMER, UALCAN, TISIDB, GSCA, SangerBox, GeneMANIA, and LinkedOmics were among the datasets that were used. The findings demonstrated that, in comparison to normal tissues, COAD tissues had lower levels of CLCA4 expression. The prognosis was worse for those whose levels of CLCA4 expression were lower. For validation, immunohistochemistry (HPA) was used. Positive correlations between CLCA4 mRNA expression and its copy number variation (CNV) were observed, and CLCA4 CNV was linked to immunological infiltration. Subsequent investigation demonstrated the association between immune cell markers, immune checkpoint genes, and immunological infiltration with CLCA4. The overall survival and disease-free survival of M0 patients were considerably better than those of M1 patients, and the groups with tumour stages M0 and M1 had notably different levels of CLCA4 expression. Its substantial enrichment in ion channel activity, transmembrane transporter activity, digestion, and other biological processes was revealed by gene ontology analysis. Oxidative phosphorylation, pancreatic secretion, Parkinson’s and Alzheimer’s diseases, renin secretion, and other signalling pathways were the primary associations found for CLCA4. It is evident that the immunological microenvironment and functions like ion transport, metabolism, and intestinal digestion are all impacted by CLCA4 expression.

Abstract Our objective was to examine the impact of elective neck dissection (END) on the prognosis of patients with cT2N0 maxillary sinus squamous cell carcinoma (MS-SCC) and to determine factors that predict the occurrence of occult metastasis in this patient population. A retrospective analysis was conducted using data from the SEER database. Patients with cT2N0 MS-SCC were included in the study and divided into two groups: those who received END and those who did not. The impact of END on disease-specific survival (DSS) and overall survival (OS) was assessed using propensity score matching. Multivariate logistic regression analysis was performed to determine predictors for occult metastasis. A total of 180 patients were included in the study, with 40 cases receiving END. Following propensity score matching, patients treated with END and those without showed similar DSS and OS rates. Occult metastasis was observed in 9 patients, corresponding to a rate of 22.5%. High-grade tumors were independently associated with a higher risk of occult metastasis compared to low-grade tumors (hazard ratio 1.52, 95% confidence interval 1.17–2.00). cT2 MS-SCC carries an occult metastasis rate of 22.5%, with histologic grade being the primary determinant of occult metastasis. END does not confer a significant survival benefit in this patient population.

Abstract Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Abstract Background This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT). Methods The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR. Results No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUCαbin = 0.933 and AUCemp = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962. Conclusions The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.

Abstract Glioma, particularly glioblastomas (GBM), is incurable brain tumor. The most targeted receptor tyrosine kinase (RTKs) drugs did not bring benefit to GBM patients. The mechanism of glioma growth continues to be explored to find more effective treatment. Here, we reported that Ser/Thr protein kinase YANK2 (yet another kinase 2) is upregulated in glioma tissues and promotes the growth and proliferation of glioma in vitro and in vivo. Further, we confirmed that oncogene Fyn directly activated YANK2 through phosphorylation its Y110, and Fyn-mediated YANK2 phosphorylation at Y110 site promotes glioma growth by increasing its stability. Finally, YANK2 was proved to be a novel upstream kinase of p70S6K and promotes glioma growth by directly phosphorylating p70S6K at T389. Taken together, we found a new mTOR-independent p70S6K activation pathway, Fyn-YANK2-p70S6K, which promotes glioma growth, and YANK2 is a potential oncogene and serves as a novel therapeutic target for glioma.

Background: Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others. Aims: To investigate the role of TSLP in the pathogenesis of psoriasis. Study Design: In vitro and in vivo study. Methods: To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells. Conclusion: These findings indicated that TSLP exerted its immune-modulating effect in psoriasis through the JAK/SYK pathway.

Abstract Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1β expression in the myocardial tissue of EAM mice. Notably, IL-1β expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1β expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Abstract Background Radiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood. Methods RIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus. Results rTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1β were upregulated. Conclusion Our study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

Abstract In industry, the task of defect classification and defect localization is an important part of defect detection system. However, existing studies only focus on one task and it is difficult to ensure the accuracy of both tasks. This paper proposes a defect detection system based on improved Yolo_v4, which greatly improves the detection ability of minor defects. For K_Means algorithm clustering prianchors question with strong subjectivity, the paper proposes the Density Based Spatial Clustering of Applications with Noise (DBSCAN) algorithm to determine the number of Anchors. To solve the problem of low detection rate of small targets caused by insufficient reuse rate of low-level features in CSPDarknet53 feature extraction network, this paper proposes an ECA-DenseNet-BC-121 feature extraction network to improve it. And the Dual Channel Feature Enhancement (DCFE) module is proposed to improve the local information loss and gradient propagation obstruction caused by quad chain convolution in PANet networks to improve the robustness of the model. The experimental results on the fabric surface defect detection datasets show that the mAP of the improved Yolo_v4 is 98.97%, which is 7.67% higher than SSD, 3.75% higher than Faster_RCNN, 10.82% higher than Yolo_v4 tiny, and 5.35% higher than Yolo_v4, and the detection speed reaches 39.4 fps. It can meet the real-time monitoring needs of industrial sites.

Abstract Background O-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered O-GlcNAcylation was reported to participate in antivirus response. Stimulator of interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune response. Whether STING is able to be modified by O-GlcNAcylation and how O-GlcNAcylation affects STING-mediated anti-DNA virus response remain unknown. Methods Metabolomics analysis was used for detecting metabolic alterations in HSV-1 infection cells. Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, and pull-down assay were employed for determining O-GlcNAcylation. Mutagenesis PCR was applied for the generation of STING mutants. WT and Sting1 −/− C57BL/6 mice (KOCMP-72512-Sting1-B6NVA) were infected with HSV-1 and treated with O-GlcNAcylation inhibitor for validating the role of STING O-GlcNAcylation in antiviral response. Results STING was functionally activated by O-GlcNAcylation in host cells challenged with HSV-1. We demonstrated that this signaling event was initiated by virus infection-enhanced hexosamine biosynthesis pathway (HBP). HSV-1 (or viral DNA mimics) promotes glucose metabolism of host cells with a marked increase in HBP, which provides donor glucosamine for O-GlcNAcylation. STING was O-GlcNAcylated on threonine 229, which led to lysine 63-linked ubiquitination of STING and activation of antiviral immune responses. Mutation of STING T229 to alanine abrogated STING activation and reduced HSV-1 stimulated production of interferon (IFN). Application of 6-diazo-5-oxonorleucine (DON), an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAcylation, markedly attenuated the removal of HSV-1 in wild type C57BL/6 mice, leading to an increased viral retention, elevated infiltration of inflammatory cells, and worsened tissue damages to those displayed in STING gene knockout mice. Together, our data suggest that STING is O-GlcNAcylated in HSV-1, which is crucial for an effective antiviral innate immune response. Conclusion HSV-1 infection activates the generation of UDP-Glc-NAc by upregulating the HBP metabolism. Elevated UDP-Glc-NAc promotes the O-GlcNAcylation of STING, which mediates the anti-viral function of STING. Targeting O-GlcNAcylation of STING could be a useful strategy for antiviral innate immunity.

Objectives: To assess the efficacy and safety of rifampicin-based triple therapy (rifampicin, isoniazid, and ethambutol) for treating NPM. Methods: This single-center, single-arm, prospective clinical trial was conducted at the Second Hospital of Shandong University (Jinan, China). Patients with pathologically diagnosed granulomatous lobular mastitis and periductal mastitis received triple drugs, i.e., rifampicin (450 mg/day), isoniazid (300 mg/day), and ethambutol (15 mg/kg/day), until complete response or the investigator decided to discontinue treatment. The primary endpoint was the complete response rate (CRR) assessed by the investigator. The secondary endpoints included the overall remission rate (ORR), recurrence rate (RR), and safety. Results: A total of 218 patients were enrolled in the study between January 1, 2013 and October 31, 2020. With a median follow-up time of 48 months, the CRR and the ORR were 78.44% and 94.04%, respectively. While 13 patients (5.96%) demonstrated no response and 19 relapsed (8.72%). Adverse events (AEs) were not common. The most common AEs during treatment were liver dysfunction (1.83%), gastrointestinal reactions (1.83%), fatigue (1.83%), erythema (1.38%), and menstrual disorders (0.92%). Conclusion: Rifampicin, isoniazid, and ethambutol demonstrated promising response rates with acceptable safety profiles in patients with NPM. Further confirmatory trial is warranted in the future. Trial registration: The study was approved by the Ethics Committee of the Second Hospital of Shandong University and retrospectively registered at the China Clinical Trial Registration Center (registration number: ChiCTR2100049591).

NRF2 is an important transcription factor that regulates redox homeostasis in vivo and exerts its anti-oxidative stress and anti-inflammatory response by binding to the ARE to activate and regulate the transcription of downstream protective protein genes, reducing the release of reactive oxygen species. Ferroptosis is a novel iron-dependent, lipid peroxidation-driven cell death mode, and recent studies have shown that ferroptosis is closely associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). NRF2 is able to regulate ferroptosis through the regulation of the transcription of its target genes to ameliorate ALI/ARDS. Therefore, This article focuses on how NRF2 plays a role in ALI/ARDS by regulating ferroptosis. We further reviewed the literature and deeply analyzed the signaling pathways related to ferroptosis which were regulated by NRF2. Additionally, we sorted out the chemical molecules targeting NRF2 that are effective for ALI/ARDS. This review provides a relevant theoretical basis for further research on this theory and the prevention and treatment of ALI/ARDS. The intended audience is clinicians and researchers in the field of respiratory disease.

Abstract Cleft lip and palate is a congenital craniofacial anomaly that affects the lip and oral cavity. The management and orthodontic treatment of this anomaly is important but challenging. This article reports the successful treatment of a patient with bilateral cleft lip and palate, Class III malocclusion, bilateral crossbite, crowding and microdontic maxillary lateral incisors. One mandible incisor was extracted, and three miniscrew anchorages were utilized to distalize the maxillary left dental arch and retract the mandibular arch. After treatment, ideal occlusion and a better profile were established, and long-term stability was confirmed by a 4-year follow-up. This article represents a successful attempt of orthodontic camouflage treatment of severe dentofacial discrepancy, as an important part of the series treatment of cleft lip and palate, to provide some insight into the clinical field.

Abstract Background Vascular endothelial cells are pivotal in the pathophysiological progression following spinal cord injury (SCI). The UTX (Ubiquitously Transcribed Tetratripeptide Repeat on Chromosome X) serves as a significant regulator of endothelial cell phenotype. The manipulation of endogenous neural stem cells (NSCs) offers a compelling strategy for the amelioration of SCI. Methods Two mouse models were used to investigate SCI: NSCs lineage-traced mice and mice with conditional UTX knockout (UTX KO) in endothelial cells. To study the effects of UTX KO on neural differentiation, we harvested extracellular vesicles (EVs) from both UTX KO spinal cord microvascular endothelial cells (SCMECs) and negative control SCMECs. These EVs were then employed to modulate the differentiation trajectory of endogenous NSCs in the SCI model. Results In our NSCs lineage-traced mice model of SCI, a marked decrease in neurogenesis was observed post-injury. Notably, NSCs in UTX KO SCMECs mice showed enhanced neuronal differentiation compared to controls. RNA sequencing and western blot analyses revealed an upregulation of L1 cell adhesion molecule (L1CAM), a gene associated with neurogenesis, in UTX KO SCMECs and their secreted EVs. This aligns with the observed promotion of neurogenesis in UTX KO conditions. In vivo administration of L1CAM-rich EVs from UTX KO SCMECs (KO EVs) to the mice significantly enhanced neural differentiation. Similarly, in vitro exposure of NSCs to KO EVs resulted in increased activation of the Akt signaling pathway, further promoting neural differentiation. Conversely, inhibiting Akt phosphorylation or knocking down L1CAM negated the beneficial effects of KO EVs on NSC neuronal differentiation. Conclusions In conclusion, our findings substantiate that EVs derived from UTX KO SCMECs can act as facilitators of neural differentiation following SCI. This study not only elucidates a novel mechanism but also opens new horizons for therapeutic interventions in the treatment of SCI. Video Abstract Graphical Abstract

Abstract Background Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. Methods An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5ʹ-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. Results Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. Conclusions IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.

Abstract Background The associations between trajectories of different health conditions and cognitive impairment among older adults were unknown. Our cohort study aimed to investigate the impact of various trajectories, including sleep disturbances, depressive symptoms, functional limitations, and multimorbidity, on the subsequent risk of cognitive impairment. Methods We conducted a prospective cohort study by using eight waves of national data from the Health and Retirement Study (HRS 2002–2018), involving 4319 adults aged 60 years or older in the USA. Sleep disturbances and depressive symptoms were measured using the Jenkins Sleep Scale and the Centers for Epidemiologic Research Depression (CES-D) scale, respectively. Functional limitations were assessed using activities of daily living (ADLs) and instrumental activities of daily living (IADLs), respectively. Multimorbidity status was assessed by self-reporting physician-diagnosed diseases. We identified 8-year trajectories at four examinations from 2002 to 2010 using latent class trajectory modeling. We screened participants for cognitive impairment using the 27-point HRS cognitive scale from 2010 to 2018 across four subsequent waves. We calculated hazard ratios (HR) using Cox proportional hazard models. Results During 25,914 person-years, 1230 participants developed cognitive impairment. In the fully adjusted model 3, the trajectories of sleep disturbances and ADLs limitations were not associated with the risk of cognitive impairment. Compared to the low trajectory, we found that the increasing trajectory of depressive symptoms (HR = 1.39; 95% CI = 1.17–1.65), the increasing trajectory of IADLs limitations (HR = 1.88; 95% CI = 1.43–2.46), and the high trajectory of multimorbidity status (HR = 1.48; 95% CI = 1.16–1.88) all posed an elevated risk of cognitive impairment. The increasing trajectory of IADLs limitations was associated with a higher risk of cognitive impairment among older adults living in urban areas (HR = 2.30; 95% CI = 1.65–3.21) and those who smoked (HR = 2.77; 95% CI = 1.91–4.02) (all P for interaction

Abstract Background Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity. Methods We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments. Results The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients. Conclusions Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1 P409L , ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Abstract Live bacteria-mediated antitumor therapies mark a pivotal point in cancer immunotherapy. However, the difficulty in reconciling the safety and efficacy of bacterial therapies has limited their application. Improving bacterial tumor-targeted delivery while maintaining biosafety is a critical hurdle for the clinical translation of live microbial therapy for cancer. Here, we developed “dead” yet “functional” Salmonella-loaded macrophages using liquid nitrogen cold shock of an attenuated Salmonella typhimurium VNP20009-contained macrophage cell line. The obtained “dead” macrophages achieve an average loading of approximately 257 live bacteria per 100 cells. The engineered cells maintain an intact cellular structure but lose their original pathogenicity, while intracellular bacteria retain their original biological activity and are delay freed, followed by proliferation. This “Trojan horse”-like bacterial camouflage strategy avoids bacterial immunogenicity-induced neutrophil recruitment and activation in peripheral blood, reduces the clearance of bacteria by neutrophils and enhances bacterial tumor enrichment efficiently after systemic administration. Furthermore, this strategy also strongly activated the tumor microenvironment, including increasing antitumor effector cells (including M1-like macrophages and CD8+ Teffs) and decreasing protumor effector cells (including M2-like macrophages and CD4+ Tregs), and ultimately improved antitumor efficacy in a subcutaneous H22 tumor-bearing mouse model. The cryo-shocked macrophage-mediated bacterial delivery strategy holds promise for expanding the therapeutic applications of living bacteria for cancer.

Abstract. Recent decades have seen the remarkable development of China in medical accessibility and quality index, and the application of a number of new advanced cardiovascular technologies benefits more patients. However, according to the Annual Report on Cardiovascular Health and Diseases in China published in this article, which was organized and summarized by National Center for Cardiovascular Diseases, there is still a huge population living with risk factors of cardiovascular diseases (CVD), and the morbidity and mortality of CVD are increasing. It is estimated that there are around 330 million patients suffering from CVD currently, including 245 million of hypertension, 13 million of stroke, 45.3 million of peripheral artery disease, 11.39 million of coronary heart disease (CHD), 8.9 million of heart failure, 5 million of pulmonary heart disease, 4.87 million of atrial fibrillation, 2.5 million of rheumatic heart disease, and 2 million of congenital heart disease. Tobacco use, diet and nutrition factors, physical activity, overweight and obesity, and psychological factors are what affect cardiovascular health, while hypertension, dyslipidemia, diabetes, chronic kidney disease, metabolic syndrome, and air pollution are the risk factors for CVD. In this article, in addition to risk factors for CVD, we also report the epidemiological trends of CVD, including CHD, cerebrovascular disease, arrhythmias, valvular heart disease, congenital heart disease, cardiomyopathy, heart failure, pulmonary vascular disease and venous thromboembolism, and aortic and peripheral artery diseases, as well as the basic research and medical device development in CVD. In a word, China has entered a new stage of transforming from high-speed development focusing on scale growth to high-quality development emphasizing on strategic and key technological development to curb the trend of increasing incidence and mortality of CVD.

Ultrasmall silica nanoparticles, as one type of nanocarriers featured by excellent biocompatibility and efficient renal clearance, are of rapidly growing interest for biomedical applications, particularly in oncology. Undesirably, the intrinsic issues of low site-targeting capability, short circulation time, and limited functionalities of ultrasmall silica nanoparticles severely impede their widespread application in the biomedical domain. Recent researches on surface modification for improved physical properties, enhanced site-specific abilities and multimodality imaging have been continuously emerging, which provide the prerequisite for possible application in the integration of diagnosis and treatment. On this basis, this review summarizes the most widely used synthesis approaches for well-ordered ultrasmall silica nanoparticles with uniform diameter and tunable pore size, and simultaneously highlights the diverse surface functionalization for versatile purposes and biomedical applications, including site-targeted delivery of drugs, stimuli-responsive cargo release, real-time bioimaging as well as cancer theranostics. Finally, the challenges of ultrasmall silica nanoparticles in oncology are further discussed with the aim of promoting their future clinical application.

Abstract The increasing number of approved nucleic acid therapeutics demonstrates the potential for the prevention and treatment of a broad spectrum of diseases. This trend underscores the significant impact and promise of nucleic acid-based treatments in the field of medicine. Nevertheless, employing nucleic acids as therapeutics is challenging due to their susceptibility to degradation by nucleases and their unfavorable physicochemical characteristics that hinder delivery into cells. Appropriate vectors play a pivotal role in improving nucleic acid stability and delivering nucleic acids into specific cells. The maturation of delivery systems has led to breakthroughs in the development of therapeutics based on nucleic acids such as DNA, siRNA, and mRNA. Non-viral vectors have gained prominence among the myriad of nanomaterials due to low immunogenicity, ease of manufacturing, and simplicity of cost-effective, large-scale production. Here, we provide an overview of the recent advancements in nanomaterials for nucleic acid delivery. Specifically, we give a detailed introduction to the characteristics of polymers, lipids, and polymer-lipid hybrids, and provide comprehensive descriptions of their applications in nucleic acid delivery. Also, biological barriers, administration routes, and strategies for organ-selective delivery of nucleic acids are discussed. In summary, this review offers insights into the rational design of next-generation delivery vectors for nucleic acid delivery.

Abstract Background In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. Methods A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children’s Hospital of Fudan University, Shanghai, China. Results Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). We filtered out 3 genes (ITGB4, TXNRD2, RRM2B) as potential causative genes for SGA and 1 gene (ADIPOQ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84–0.96] vs. AUC=0.74 [0.64–0.84]; P=0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6–0.93] vs. AUC=0.53[0.29–0.76]; P=0.0117). Conclusion SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction.

A total of 265 Salmonella Enteritidis isolates collected from retail markets and children’s hospitals in Shanghai were used to investigate the prevalence and molecular epidemiology of plasmid-mediated fosfomycin resistance genes. Nine of the isolates—7 from the 146 (4.79%) retail chicken-related samples and 2 from the 119 (1.68%) samples from clinical children—were fosfomycin-resistant (FosR). The fosA3 gene was detected in all of the nine FosR isolates, which were located on Inc F-type (8/9, 88.9%) and unknown-type (1/9, 11.1%) transferable plasmids. In total, five plasmid types, namely Inc HI2 (1/9, 11.1%), Inc I1 (3/9, 33.3%), Inc X (8/9, 88.9%), Inc FIIs (9/9, 100%), and Inc FIB (9/9, 100%), were detected in these FosR isolates, which possessed five S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) profiles. The extended-spectrum β-lactamase determinant blaCTX-M-14 subtype was identified in one FosR S. Enteritidis isolate, which was located in a transferable unknown-type plasmid co-carrying fosA3 and tetR genes. Sequence homology analysis showed that this plasmid possessed high sequence similarity to previously reported blaCTX-M-14- and fosA3-positive plasmids from E. coli strains, implying that plasmids carrying the fosA3 gene might be disseminated among Enterobacterales. These findings highlight further challenges in the prevention and treatment of Enterobacteriaceae infections caused by plasmids containing fosA3.

BackgroundInsomnia (IS) and circadian rhythm sleep-wake disorders (CRSWD) are complex disorders with limited and unsatisfactory treatment options that can even cause some side effects. By analyzing blood metabolites to reveal underlying biological processes, studies of sleep and the complex interactions between its influencing factors can be elucidated. Therefore, we hope to bring new hope for the treatment of these diseases through blood metabolites.AimsInvestigating the causal link between blood metabolites and IS and CRSWD.MethodsA genome-wide association study (GWAS) for 486 metabolites was used as the exposure, whereas two different GWAS datasets for sleep disorders were the outcome, and all datasets were obtained from publicly available databases. We employed the standard inverse variance weighting (IVW) method for causal analysis, supported by the MR-Egger method, weighted median (WM) method, and MR-PRESSO method for sensitivity analysis to mitigate the impact of pleiotropy. Genetic correlation between IS, CRSWD, and blood metabolites was explored through linkage disequilibrium analysis (LDSC), while Multivariable MR analysis (MVMR) elucidated whether these metabolites exhibit a direct association with IS and CRSWD. Further, we conducted metabolic pathway analysis to identify the specific metabolites driving these relationships.ResultsEmploying meticulous MVMR analysis, we have identified specific metabolites that independently influence IS, including 2-hydroxypalmitate (OR 2.95, 95%CI 1.05–8.31 P = 0.040), X-11786-Methylcysteine (OR = 0.25, 95%CI 0.08–0.76 P = 0.014), and salicylate (OR 0.89, 95%CI 0.83–0.95 P = 9 × 10–4). In the context of CRSWD, our findings reveal direct associations with metabolites such as carnitine (OR 0.02, 95%CI: 0.00–0.20, P = 0.002), levulinate (OR 0.06, 95%CI: 0.01–0.64, P = 0.020), p-cresol sulfate (OR 0.25, 95% CI: 0.09–0.67, P = 0.006), and X-14208-Phenylalanylserine (OR 0.36, 95% CI: 0.16–0.81, P = 0.014). These discoveries contribute to a nuanced understanding of the distinct metabolic signatures underlying IS and CRSWD.

Objectives Clinical practice guideline (CPG) developers conduct systematic summaries of research evidence, providing them great capacity and ability to identify research priorities. We systematically analysed the reporting form and content of research priorities in CPGs related to knee osteoarthritis (KOA) to provide a valuable reference for guideline developers and clinicians.Design A methodological literature analysis was done and the characteristics of the reporting form and the content of the research priorities identified in KOA CPGs were summarised.Data sources Six databases (PubMed, Embase, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Wanfang and Chinese Biomedical Literature Database) were searched for CPGs published from 1 January 2017 to 4 December 2022. The official websites of 40 authoritative orthopaedic societies, rheumatology societies and guideline development organisations were additionally searched.Eligibility criteria We included all KOA CPGs published in English or Chinese from 1 January 2017 that included at least one recommendation for KOA. We excluded duplicate publications, older versions of CPGs as well as guidance documents for guideline development.Data extraction and synthesis Reviewers worked in pairs and independently screened and extracted the data. Descriptive statistics were used, and absolute frequencies and proportions of related items were calculated.Results 187 research priorities reported in 41 KOA CPGs were identified. 24 CPGs reported research priorities, of which 17 (41.5%) presented overall research priorities for the entire guideline rather than for specific recommendations. 110 (58.8%) research priorities were put forward due to lack of evidence. Meanwhile, more than 70% of the research priorities reflected the P (population) and I (intervention) structural elements, with 135 (72.2%) and 146 (78.1%), respectively. More than half of the research priorities (118, 63.8%) revolved around evaluating the efficacy of interventions. Research priorities primarily focused on physical activity (32, 17.3%), physical therapy (30, 16.2%), surgical therapy (27, 14.6%) and pharmacological treatment (26, 14.1%).Conclusions Research priorities reported in KOA CPGs mainly focused on evaluating non-pharmacological interventions. There exists considerable room for improvement for a comprehensive and standardised generation and reporting of research priorities in KOA CPGs.

Objectives Social isolation may affect diabetes self-management. This study aimed to explore the relations between social isolation and glycaemic control in patients with diabetes and to explore lifestyle differences among individuals with different levels of social isolation.Methods The relevant data of 665 people previously diagnosed with diabetes included in the China Health and Retirement Longitudinal Study from 2011 to 2015 were extracted and analysed. The study included patient general information, blood glucose, lipids, glycosylated haemoglobin, social isolation index, health-related lifestyle factors and diabetes-related factors. Differences in metabolic abnormalities and modifiable lifestyles were compared among patients with varying levels of social isolation.Results Multiple linear regression analysis demonstrated that among men aged 45–64 years, the high social isolation group had significantly higher glycosylated haemoglobin levels compared with the low isolation group (7.29±1.81 vs 6.59±1.63, p=0.026). A positive correlation was observed between social isolation and blood glucose (β=14.16; 95% CI 2.75 to 25.57; p=0.015) and glycosylated haemoglobin (β=0.35; 95% CI 0.10 to 0.60; p=0.006), indicating that higher social isolation was associated with higher fasting blood glucose and glycosylated haemoglobin levels. However, no significant associations were observed in other age groups. Notably, men aged 45–65 years with high social isolation had higher depression rates (44.10% vs 24.60%, p=0.024), lower engagement in moderate exercise (5.70% vs 23.50%, p=0.019) and shorter 10-minute walks (17.10% vs 36.80%, p=0.027). Differences in other health-related and diabetes-related factors were not statistically significant.Conclusion Middle-aged men with diabetes with higher social isolation tend to have higher blood glucose and glycosylated haemoglobin levels. This subset of patients requires targeted attention to provide social support from family and friends for improved glycaemic control. If necessary, education on diabetes should be made available to family members and friends.

Introduction The PRaG regimen, which consists of hypofractionated radiotherapy combined with a programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor and granulocyte-macrophage colony stimulating factor (GM-CSF), has been demonstrated to have a survival benefit in patients with advanced solid tumours who have failed at least two lines of treatment. Nonetheless, lymphopenia poses an impediment to the enduring efficacy of PD-1/PD-L1 inhibitor therapy. Adequate lymphocyte reserves are essential for the efficacy of immunotherapy. Coupling the PRaG regimen with immunomodulatory agents that augment the number and functionality of lymphocytes may yield further survival benefits in this cohort of patients.Objective The aim of this study is to investigate the effectiveness and safety of a meticulously thymalfasin-controlled PRaG regimen in patients with advanced and chemotherapy-resistant solid tumours.Methods and analysis The study has a prospective, single-arm, open-label, multicentre design and aims to recruit up to 60 patients with histologically confirmed advanced solid tumours that have relapsed or metastasised. All eligible patients will receive a minimum of two cycles of the PRaG regimen comprising thymalfasin followed by maintenance treatment with a PD-1/PD-L1 inhibitor and thymalfasin for 1 year or until disease progression. Patients will be monitored according to the predetermined protocol for a year or until disease progression after initiation of radiotherapy.Ethics and dissemination The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University, on 25 November 2022 (JD-LK-2022-151-01) and all other participating hospitals. Findings will be disseminated through national and international conferences. We also plan to publish our findings in high-impact peer-reviewed journal.Trial registration number NCT05790447.

Abstract This study aimed to examine the association of hemoglobin concentration with a 90-day mortality of young adult patients with ICH in a large retrospective cohort. A retrospective observational study was conducted between December 2013 and June 2019 in two tertiary academic medical centers in China. We defined patients with hemoglobin concentration 160 g/L as high hemoglobin. Associations of hemoglobin and outcomes were evaluated in multivariable regression analyses. The primary outcome was mortality at 90 days. We identified 4098 patients with ICH who met the inclusion criteria. After adjusting primary confounding variables, the 90-day mortality rate was significantly higher in young patients with severe anemia (OR, 39.65; 95% CI 15.42–101.97), moderate anemia (OR, 2.49; 95% CI 1.24–5.00), mild anemia (OR, 1.89; 95% CI 1.20–2.98), and high hemoglobin (OR, 2.03; 95% CI 1.26–3.26) group than in young patients of the normal group. The younger age was associated with a higher risk of death from anemia in patients with ICH (P for interaction = 0.01). In young adult patients with ICH, hemoglobin concentration was associated with 90-day mortality, and even mild to moderate anemia correlated with higher mortality. We also found that in ICH patients with anemia, younger age was associated with higher risk.

Abstract Thyroid eye disease (TED), an autoimmune inflammatory disorder affecting the orbit, exhibits a range of clinical manifestations. While the disease presentation can vary, cases that adhere to a prototypical pattern typically commence with mild symptoms that subsequently escalate in severity before entering a phase of stabilization. Notably, the metabolic activity of cells implicated in the disease substantially deviates from that of healthy cells, with purine metabolism representing a critical facet of cellular material metabolism by supplying components essential for DNA and RNA synthesis. Nevertheless, the precise involvement of Purine Metabolism Genes (PMGs) in the defensive mechanism against TED remains largely unexplored. The present study employed a bioinformatics approach to identify and validate potential PMGs associated with TED. A curated set of 65 candidate PMGs was utilized to uncover novel PMGs through a combination of differential expression analysis and a PMG dataset. Furthermore, GSEA and GSVA were employed to explore the biological functions and pathways associated with the newly identified PMGs. Subsequently, the Lasso regression and SVM-RFE algorithms were applied to identify hub genes and assess the diagnostic efficacy of the top 10 PMGs in distinguishing TED. Additionally, the relationship between hub PMGs and clinical characteristics was investigated. Finally, the expression levels of the identified ten PMGs were validated using the GSE58331 and GSE105149 datasets. This study revealed ten PMGs related with TED. PRPS2, PFAS, ATIC, NT5C1A, POLR2E, POLR2F, POLR3B, PDE3A, ADSS, and NTPCR are among the PMGs. The biological function investigation revealed their participation in processes such as RNA splicing, purine-containing chemical metabolism, and purine nucleotide metabolism. Furthermore, the diagnostic performance of the 10 PMGs in differentiating TED was encouraging. This study was effective in identifying ten PMGs linked to TED. These findings provide light on potential new biomarkers for TED and open up possibilities for tracking disease development.

Abstract Underground mining activities can easily trigger surface subsidence and cause damage to surface soil. However, there is still a lack of studies on damaged soil, restricting ecological remediation in mining-induced subsidence regions to a certain degree. Focusing on the particular example of No. 4 Mine in Yili, Xinjiang, China, this study comprehensively combined field sampling, laboratory experiments, and data analysis to investigate the variation rules of basic physical properties and shear characteristics of soil samples. The latter had different subsidence degrees (0, 0–20, 20–40, and above 40 cm) and various depths (0– 10, 10–20, 20– 40, 40–60, and 60–80 cm). The experimental results show that: First, the natural density and dry unit weight of shallow soil in the serious-subsidence region were more significantly affected by mining-induced subsidence than the conditions in the deep layer, which also dropped with the increase in subsidence degree (with a mean drop rate of 7%). Second, serious subsidence could greatly counteract the positive effect of slight and moderate subsidence on the soil shear strength, with a drop rate of up to 30.7%. Third, compared with soil physical indices, mining-induced subsidence more easily affected shear strength indices. In particular, the soil samples taken from 0 to 10 cm depth in the slight subsidence area and 60–80 cm depth in the moderate subsidence area were most significantly affected by mining-induced subsidence, with PCA comprehensive scores of over 1.5. The present study can con-tribute to gaining in-depth knowledge of the damage characteristics of surface soil under mining-induced subsidence and provide a theoretical foundation for formulating reasonable coal mining strategies and ecological protection measures.

Safflower yellow is an extract of the famous Chinese medicine Carthamus tinctorious L, and safflower yellow injection (SYI) is widely used clinically to treat angina pectoris. However, there are few studies on the anti-myocardial ischemia/reperfusion (I/R) injury effect of SYI, and its mechanisms are unclear. In the present study, we aimed to investigate the protective effect of SYI on myocardial I/R injury and explore its underlying mechanisms. Male Sprague Dawley rats were randomly divided into a control group, sham group, model group, and SYI group (20 mg/kg, femoral vein injection 1 h before modeling). The left anterior descending coronary artery was ligated to establish a myocardial I/R model. H9c2 cells were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) after incubation with 80 μg/mL SYI for 24 h. In vivo, TsTC, HE, and TUNEL staining were performed to evaluate myocardial injury and apoptosis. A kit was used to detect superoxide dismutase (SOD) and malondialdehyde (MDA) to assess oxidative stress. In vitro, flow cytometry was used to detect the reactive oxygen species (ROS) content and apoptosis rate. Protein levels were determined via Western blotting. Pretreatment with SYI significantly reduced infarct size and pathological damage in rat hearts and suppressed cardiomyocyte apoptosis in vivo and in vitro. In addition, SYI inhibited oxidative stress by increasing SOD activity and decreasing MDA content and ROS production. Myocardial I/R and OGD/R activate endoplasmic reticulum (ER) stress, as evidenced by increased expression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), cysteinyl aspartate-specific proteinase caspase-12, and C/EBP-homologous protein (CHOP), which were all inhibited by SYI. SYI ameliorated myocardial I/R injury by attenuating apoptosis, oxidative damage, and ER stress, which revealed new mechanistic insights into its application.

Acute ischemic stroke (AIS) is a cerebrovascular disease that seriously affects the physical and mental health and quality of life of patients. However, there is a lack of reliable prognostic prediction methods. The main objective of this study was to investigate the prognostic value of long non-coding RNA (lncRNA) H19 in lymphocytes of patients with AIS, and to construct a prognostic prediction model for AIS including lncRNA H19 in lymphocytes, which would provide new ideas for the prognostic evaluation of AIS. Poor prognosis was defined when the patient’s modified Rankin scale (mRS) score at 3 months after AIS onset was greater than 2. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the level of lncRNA H19 in lymphocytes. Spearman correlation analysis revealed a positive correlation between lncRNA H19 and mRS score at 3 months after AIS onset (r = 0.1977, p = 0.0032), while lncRNA H19 was negatively correlated with white blood cells counts, lymphocytes counts, and neutrophils counts. Logistic regression analysis identified lncRNA H19 as an independent predictor of poor prognosis (OR = 3.062 [1.69–5.548], p < 0.001). Moreover, a nomogram prediction model incorporating lncRNA H19 in lymphocytes demonstrated effective discrimination, calibration, and clinical applicability in predicting AIS outcomes. The findings suggest that lncRNA H19 in lymphocytes could be a valuable prognostic indicator and a potential pharmacological target for AIS patients, and might be a novel pathway for enhanced prognostic evaluation and targeted therapeutic strategies.

Background: Adverse drug reactions (ADRs) refer to an unintended harmful reaction that occurs after the administration of a medication for therapeutic purposes, which is unrelated to the intended pharmacological action of the drug. In the United States, ADRs account for 6% of all hospital admissions annually. The cost of ADR-related illnesses in 2016 was estimated at USD 528.4 billion. Increasing the awareness of ADRs is an effective measure to prevent them. Assessing suspected drugs in adverse events helps to enhance the awareness of ADRs. Methods: In this study, a suspect drug assisted judgment model (SDAJM) is designed to identify suspected drugs in adverse events. This framework utilizes the graph isomorphism network (GIN) and an attention mechanism to extract features based on patients’ demographic information, drug information, and ADR information. Results: By comparing it with other models, the results of various tests show that this model performs well in predicting the suspected drugs in adverse reaction events. ADR signal detection was conducted on a group of cardiovascular system drugs, and case analyses were performed on two classic drugs, Mexiletine and Captopril, as well as on two classic antithyroid drugs. The results indicate that the model can accomplish the task of predicting drug ADRs. Validation using benchmark datasets from ten drug discovery domains shows that the model is applicable to classification tasks on the Tox21 and SIDER datasets. Conclusions: This study applies deep learning methods to construct the SDAJM model for three purposes: (1) identifying drugs suspected to cause adverse drug events (ADEs), (2) predicting the ADRs of drugs, and (3) other drug discovery tasks. The results indicate that this method can offer new directions for research in the field of ADRs.

Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal herb with various pharmacological activities, such as anti-inflammatory and analgesic properties. However, the underlying mechanisms of these effects are not fully understood. In the present study, we aimed to investigate DAP’s anti-inflammatory and analgesic effects and explore the underlying mechanisms of action. The NP model was established as chronic constrictive injury (CCI) of the sciatic nerve, and pain sensitivity was evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). The activation of microglia in the spinal dorsal horn was measured via immunofluorescence staining. Protein levels were measured using a western blot assay. Using a mass-spectrometry proteomics platform and an LC-MS/MS-based metabolomics platform, proteins and metabolites in spinal cord tissues were extracted and analyzed. DAP treatment ameliorated the MWT and TWT in CCI rats. The expression of IL-1β, IL-6, and TNF-α was inhibited by DAP treatment in the spinal cords of CCI rats. Moreover, the activation of microglia was suppressed after DAP treatment. The elevation in the levels of P2X4, IRF8, IRF5, BDNF, and p-P38/P38 in the spinal cord caused by CCI was inhibited by DAP. Proteomics and metabolomics results indicated that DAP ameliorated the imbalance of glycerophospholipid metabolism in the spinal cords of CCI rats. DAP can potentially ameliorate NP by regulating microglial responses and glycerophospholipid metabolism in the CCI model. This study provides a pharmacological justification for using DAP in the management of NP.

Abstract Macrophages play an important role in the development of life-threatening sepsis, which is characterized by multiorgan dysfunction, through their ability to produce inflammatory cytokines. Carvacrol is a phenolic compound that has been confirmed to possess strong anti‑inflammatory activity. In this study, we mainly investigated the effect of carvacrol on lipopolysaccharide (LPS)-induced macrophage proinflammatory responses and endotoxic shock. The results showed that carvacrol significantly reduced mouse body weight loss and ameliorated pathological damage to the liver, lung, and heart under LPS-induced sepsis. Carvacrol attenuated inflammatory responses by inhibiting the LPS-induced production of inflammatory cytokine interleukin-6 (IL-6) in vivo and in vitro. Mechanistically, carvacrol inhibited IL-6 production mainly through the ERK1/2 signalling pathway in macrophages. Furthermore, carvacrol improved the survival of septic mice. This study sheds light on the role of carvacrol in the pathogenesis of LPS-induced sepsis, and thus, its potential in treating sepsis patients may be considered.

Abstract Marine microplastics are emerging as a growing environmental concern due to their potential harm to marine biota. The substantial variations in their physical and chemical properties pose a significant challenge when it comes to sampling and characterizing small-sized microplastics. In this study, we introduce a novel microfluidic approach that simplifies the trapping and identification process of microplastics in surface seawater, eliminating the need for labeling. We examine various models, including support vector machine, random forest, convolutional neural network (CNN), and residual neural network (ResNet34), to assess their performance in identifying 11 common plastics. Our findings reveal that the CNN method outperforms the other models, achieving an impressive accuracy of 93% and a mean area under the curve of 98 ± 0.02%. Furthermore, we demonstrate that miniaturized devices can effectively trap and identify microplastics smaller than 50 µm. Overall, this proposed approach facilitates efficient sampling and identification of small-sized microplastics, potentially contributing to crucial long-term monitoring and treatment efforts.

Purpose: No consensus exists about the causal relationship between vitamin D (VD) and male factor infertility due to heterogeneity and confounding factors even in randomized controlled trials (RCTs). This study aimed to investigate the causal association between 25 hydroxyvitamin D (25OHD) levels and male factor infertility through Mendelian randomization (MR) and provide complementary information for optimization of future RCTs. Materials and Methods: Two-sample MR analyses with four steps were performed. Single-nucleotide polymorphisms (SNPs) for VD were extracted from 417,580 Europeans in the UK Biobank, and the summary-level data of male factor infertility (825 cases and 85,722 controls) were extracted from the FinnGen. Results: Totally 99 SNPs robustly associated with the 25OHD were included, and a 1-unit increase in genetically predicted natural-log transformed 25OHD levels was associated with decreased risk of male factor infertility (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.44–0.89; p=0.010), which was consistent in all three sensitivity analyses (MR-Egger, weighted median, and weighted mode methods). The conclusion still stands after removing SNPs which explained more variation in the male factor infertility than the 25OHD (OR, 0.61; 95% CI, 0.42–0.88; p=0.009; n=62), and which were associated with confounders (body mass index, type 2 diabetes, smoking, and coronary artery diseases) of male factor infertility (OR, 0.58; 95% CI, 0.39–0.85; p=0.005; n=55). Conclusions: VD supplement to increase serum 25OHD levels may be clinically beneficial for male factor infertility in the general population. The well-designed RCTs should be performed in priority to address this question.

Abstract Background Endometriosis (EMs), the ectopic planting of functional endometrium outside of the uterus, is a leading cause of infertility and pelvic pain. As a fundamental mRNA modification, N6-methyladenosine (m6A) participates in various pathological processes. However, the role of m6A RNA modification in endometriosis remains unclear. The present study explores METTL3-mediated m6A modification and the mechanisms involved in endometriosis. Methods The dominant m6A regulators in EMs were analysed using RT‒PCR. Candidate targets and possible mechanisms of METTL3 were assessed by m6A-mRNA epitranscriptomic microarray and RNA sequencing. A primary ESCs model was employed to verify the effect of METTL3 on m6A modification of SIRT1 mRNA, and the mechanism was elucidated by RT‒PCR, Western blotting, MeRIP, and RIP assays. CCK-8 viability assays, Transwell invasion assays, EdU proliferation assays, wound healing migration assays, and senescence-associated β-galactosidase staining were performed to illuminate the potential biological mechanism of METTL3 and SIRT1 in ESCs in vitro. An in vivo PgrCre/ + METTL3 −/− female homozygous mouse model and a nude mouse xenograft model were employed to further investigate the physiologic consequences of METTL3-mediated m6A alteration on EMs. Results Our data show that decreased METTL3 expression significantly downregulates m6A RNA methylation levels in ESCs. Silencing m6A modifications mediated by METTL3 accelerates ESCs viability, proliferation, migration, and invasion in vitro. The m6A reader protein YTHDF2 binds to m6A modifications to induce the degradation of SIRT1 mRNA. SIRT1/FOXO3a signalling pathway activation is subsequently inhibited, promoting the cellular senescence of ESCs and inhibiting the ectopic implantation of ESCs in vitro and in vivo. Conclusions Our findings demonstrate that METTL3-mediated m6A methylation epigenetically regulates the ectopic implantation of ESCs, resulting in the progression of endometriosis. Our study establishes METTL3-YTHDF2-SIRT1/FOXO3a as a critical axis and potential mechanism in endometriosis.

Abstract The objective of this multicenter, single‐arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy‐THPy) in the treatment of patients with stage II–III HER2‐positive breast cancer. The present study enrolled patients with stage II–III HER2‐positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21‐day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention‐to‐treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7–75.8%), while the objective response rate was 89.1%. In the post‐hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy‐THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II–III HER2‐positive breast cancer.

AbstractBackground Breast abscess is a common and intractable clinical condition and the use of needle aspiration (NA) or incision and drainage (ID) in treatment is controversial. This meta-analysis aimed to systematically compare the clinical effectiveness of NA and ID in treating breast abscesses.Methods The Web of Science, ScienceDirect, PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, and Wanfang Data were searched for randomized controlled trials (RCTs) published from inception to January 7, 2022. The ROB-2 tool assessed risk of bias; the GRADE methodology rated certainty in outcomes; and Stata 16.0 performed data analyses.Results Nine RCTs were included, including 703 patients. The results showed there was no significant difference in cure rate between the two groups (relative risk [RR] = 0.96, 95% confidence interval [CI] [0.86, 1.07]; p = .469), and after subgroup analysis, we found that it was not related to the use of ultrasound guidance or not. There was no significant difference in the recurrence rate (RR = 0.68, 95% CI [0.35, 1.30]; p = .241). Furthermore, the NA group was associated with shorter healing time (weighted mean differences = −11.02, 95% CI [−15.14, −6.90]; p

AbstractObjective To compare the postoperative binocular visual quality in six treatment protocols for bilateral age-related cataract surgery with presbyopia correction for clinical decisions.Materials and methods In this prospective two-center single-blinded cohort study, participants from North or South China who underwent bilateral phacoemulsification and intraocular lens implantation were divided into six protocols: monovision, diffractive bifocal, mixed, refractive bifocal, trifocal, and micro-monovision extended range of vision (EROV). Binocular visual quality was evaluated at 3 months postoperatively, including binocular uncorrected full-range visual acuity, binocular defocus curves (depth of focus [DoF] and area under the curve [AUC]), binocular visual function (fusion function and stereopsis), binocular subjective spectacle independence rates, visual analog scale (VAS) of overall satisfaction, 25-item visual function questionnaire (VFQ-25), and binocular dysphotopsia symptoms.Results Of the 300 enrolled patients, 272 (90.7%; 544 eyes) were analyzed. The trifocal protocol showed excellent binocular full-range visual acuity and the best performance for most DoFs and AUCs. The monovision protocol presented the worst binocular visual quality in most perspectives, especially in convergence, distance, and near stereopsis (p 0.05). The EROV protocol achieved the highest VAS and VFQ-25 scores. The incidence of postoperative binocular dysphotopsia symptoms was comparable in all protocols.Conclusions The trifocal protocol showed the best performance, and the monovision protocol presented the worst performance in most perspectives of binocular visual quality for presbyopia correction. The refractive bifocal, mixed, or EROV protocols can provide an approximate performance as a trifocal protocol. Ophthalmologists can customize therapies using different protocols.

Abstract Background Timely and accurate feedback is a crucial component for effective undergraduate learning. However, with the expansion of university enrolment in China, student numbers have increased rapidly and, in traditional university classrooms, it is often difficult for the teacher – as the only evaluator – to accommodate students’ diverse needs and learning styles, and provide timely learning feedback. In our teaching practice research, we combined mutual peer evaluation with cooperative learning, and proposed a peer learning and assessment model (PLAM) that encouraged students to cooperate and compete, leading to greater efficiency in giving feedback. The ultimate goal was to improve students’ learning ability. This study aimed to investigate the effect and influencing factors of PLAM in an undergraduate course entitled ‘Medicinal Chemistry of Natural Products’. Methods We surveyed the entire pharmacy student body (95 students). Each student was required to provide feedback to the other members within the same study group and students in other groups. We evaluated the effectiveness of PLAM in five aspects: basic information, learning attitude, participation, interpersonal relationship, and organizational approach. The questionnaire was administered online using the Star survey platform. Data were exported to Excel and meta-analysis was performed using SPSS. Results PLAM effectively increased feedback efficiency, enhancing students’ learning interest and ability. An ordered logistic regression analysis model was used to analyze the factors influencing the PLAM learning effect. Three factors – learning attitude, participation, and interpersonal relationship – explained up to 71.3% of the model. Conclusions The PLAM adopted in this research is an effective learning and evaluation model that can promote collaborative learning and increase learning enthusiasm. It is more suitable for knowledge expansion learning and comprehensive practical learning where teachers cannot be present for the entire process. Students should be encouraged to establish appropriate learning attitudes and a positive group atmosphere. PLAM can positively impact college curriculum learning and could be extended to other teaching domains.