BackgroundSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early diagnosis remains challenging due to substantial clinical and biological heterogeneity. CD14 is a central pattern-recognition receptor in innate immune activation, but the downstream network linking CD14 to immunometabolic regulation remains incompletely defined. We aimed to identify CD14-associated blood-based diagnostic biomarkers for sepsis and explore potential regulatory mechanisms.MethodsWhole-blood transcriptomic datasets were retrieved from the Gene Expression Omnibus. GSE236713 was the discovery cohort and GSE65682 the external validation cohort. Candidate genes were identified through overlap of differentially expressed genes between CD14-high and CD14-low samples and sepsis-related WGCNA modules. Hub genes were prioritized by protein-protein interaction analysis, and feature genes were identified by LASSO and random forest. Multiple machine learning algorithms were compared, and an artificial neural network (ANN) classifier was established. Clinical associations, immune cell composition (CIBERSORT), and pathway activity (GSEA) were assessed. Mechanistic validation was performed in LPS-stimulated RAW264.7 macrophages using CD14 knockout/overexpression and SN50-mediated inhibition of NF-κB nuclear translocation.ResultsFive feature genes (MMP9, PPARG, C1QC, MS4A4A, and ARG1) were identified. Among seven algorithms, the ANN achieved the best performance (internal AUC = 0.974, external AUC = 0.953). PPARG showed the strongest single-gene diagnostic ability (AUC = 0.994) and correlated with SOFA score (r = 0.50, P = 1.5 × 10-²9), and was prioritized as a diagnostic biomarker. In a Cox model, PPARG was associated with ICU short-term outcome risk (HR = 1.64, 95% CI 1.34–2.01, P = 1.3 × 10-6). GSEA indicated enrichment of NF-κB-related pathways in samples with low PPARG expression. CIBERSORT suggested the strongest correlation between PPARG and monocyte proportion (r = 0.328, P = 1.06 × 10-6). In vitro, LPS-induced PPARG downregulation was CD14-dependent, and SN50 partially reversed PPARG suppression and reduced TNF-α secretion in CD14-overexpressing cells.ConclusionBy integrating machine learning with experimental validation, this study prioritized PPARG as a diagnostic biomarker for sepsis and provided supportive evidence for its association with CD14/NF-κB signaling. These findings offer a basis for developing host-response-based diagnostic signatures and further investigation of PPARG-related immunometabolic regulation in sepsis.

Objective: This study aimed to develop a prognostic model for patients with sepsis complicated by autoimmune diseases using machine learning methods and validate the model. Methods: Data on patients with sepsis and autoimmune diseases were extracted from the MIMIC-IV database. Participants were randomly divided into training set and validation set according to the ratio of 7:3. The predictors were selected by using LASSO regression analysis and the Boruta algorithm which affect the 28-day prognosis of patients. A nomogram was developed based on independent risk factors identified by logistic regression for 28-day prognosis and was internally and externally validated using calibration curves and DCA. Based on nomogram scores, patients were stratified into high-and low-score groups, with KM analysis demonstrating significant differences in mortality between the cohorts. Results: A total of 1,481 patients from the MIMIC-IV database met inclusion criteria and an external validation set included 57 patients from the Department of Critical Care Medicine of the First Affiliated Hospital of Soochow University. Ten overlapping predictors (Age, Gender, BMI, WBC, BUN, PT, APTT, history of cerebrovascular disease, history of liver disease, and CRRT) were identified by LASSO and Boruta algorithms and were subsequently confirmed as statistically significant independent risk factors through logistic regression. The prediction model built by the ten predictors showed superior predictive performance compared to the SOFA score in training (AUC=0.772), internal validation (AUC=0.771), and external validation cohorts (AUC=0.787). Hosmer-Lemeshow tests and calibration curves indicated strong agreement between predicted outcomes and actual observations across all cohorts, and DCA suggested significant clinical utility. The KM curve shows that the mortality rate of the high-score group is significantly higher than that of the low-score group. Conclusion: A prognostic model for predicting 28-day mortality in sepsis patients with autoimmune diseases demonstrated robust predictive performance and clinical applicability upon internal and external validation.

Fast risk stratification is essential for patients with sepsis, a life-threatening condition associated with high mortality, as it guides clinical decision-making and management. In this study, we aimed to evaluate the predictive performance of a novel model—termed SOLAR—which integrates the lactate dehydrogenase-to-albumin ratio (LAR) with the Sequential Organ Failure Assessment (SOFA) score and lactate for 28-day mortality in sepsis. Data for the derivation cohort were collected from the Medical Information Mart for Intensive Care IV database. The validation cohort was from the Department of Critical Care Medicine at the First Affiliated Hospital of Soochow University. Patients admitted to ICU for sepsis were enrolled. Model performance was analyzed by using multivariable logistic regression and Harrell’s c-index. Reclassification ability of the model was evaluated by using net reclassification index (NRI) and Integrated discrimination improvement (IDI). Benefits in clinical decision making was estimated by using decision curve analysis. Super learner analysis was used to identify the optimal machine learning algorithm for model construction. Nomograms and an online calculator were used to deploy the model for point-of-care utilization. The derivation cohort comprised 4936 patients with sepsis and sufficient SOFA, LAR, and lactate data were obtained from MIMIC database. The validation cohort contained 371 patients with sepsis admitted to the First Affiliated Hospital of Soochow University. In both cohorts, an increasing trend of 28-day mortality was observed with elevating SOFA scores, lactate levels, and LAR quartiles. Compared to the SOFA-lactate score, the SOLAR score demonstrated improved 28-day mortality discrimination, reflected by an increase in c-index (Derivation cohort: 0.695 [0.680–0.711] vs. 0.660 [0.644–0.676], P < 0.001), Validation cohort: 0.706 [0.651–0.761] vs. 0.638 [0.581–0.695], P < 0.001). The SOLAR score also displayed a superior reclassification ability over the SOFA-lactate score (NRI: Derivation cohort: 0.393 [0.335–0.451], P < 0.001), Validation cohort: 0.506 [0.302–0.709], P < 0.001, IDI: Derivation cohort: 0.034 [0.029–0.039], P < 0.001), Validation cohort: 0.044 [0.026–0.062], P < 0.001). Super learner analysis showed that the logistic regression model achieved the highest c-index (0.749 [0.694–0.803]) based on the SOLAR score. A simplified online calculator of the SOLAR score was deployed for point-of-care risk stratification. The SOLAR score combining LAR, SOFA score and lactate provides improved accuracy and sensitivity over the SOFA-lactate score for 28-day mortality prediction in sepsis.

Viperin is considered as an antiviral protein known to directly target a variety of viruses. However, whether and how Viperin affects virus infection by targeting intracellular immune signaling remain unexplored. Here, we reveal that Viperin inhibits type-I interferon (IFN-I) antiviral immune signaling by degrading STAT1. We found that IFN-I upregulates the ubiquitin E3 ligase ITCH to degrade UBR5, while Viperin subsequently recruits another ubiquitin E3 ligase UBE4A to promote STAT1 ubiquitination and degradation to attenuate IFN-I signaling. Moreover, the multifunctional interfering peptide VS-IP1 can block Viperin-mediated STAT1 degradation, thus enhancing IFN-I antiviral immune function. This study reveals that Viperin is a suppressor of IFN-I immune signaling, which could renew understanding of the biological function of Viperin, and provide a strategy for enhancing clinical IFN-I therapeutic efficacy.

Hematology patients are highly susceptible to severe bacterial infections, particularly those caused by multidrug-resistant (MDR) gram-negative pathogens, which are associated with significant morbidity and mortality. Eravacycline, a novel fluorocycline antibiotic, demonstrates broad-spectrum activity against MDR bacteria. This real-world study aimed to evaluate the effectiveness and safety of eravacycline in Chinese hematology patients. In this multicenter, retrospective study, hematology patients receiving ≥3 days of eravacycline between September 2023 and September 2024 were included. The outcomes included clinical response rate, microbiological response rate, and safety. Of 796 patients included, most had hematological diseases (94.6%) and recent chemotherapy or radiotherapy (80.2%). The most common infection was pneumonia (57.4%), and sputum (47.2%) was the most frequent specimen type for pathogen isolation. Among 481 patients with microbiological examination results, Klebsiella pneumoniae (30.5%) and Acinetobacter baumannii (17.4%) were predominant. The mean time to defervescence was 3.2 ± 2.1 days. The overall clinical response rate was 88.8%, with response rates of 84.0% in bloodstream infections and 87.5% in pulmonary infections. Microbiological response rate at the end of treatment was 90.7%. Eravacycline exhibited high susceptibility rates across A. baumannii (95.8%), K. pneumoniae (94.3%), and Staphylococcus aureus (100.0%). Only 2.5% of patients reported adverse events. Subgroup analysis showed that pulmonary diseases (P = 0.006), sepsis (P = 0.003), and duration ≤7 days (P < 0.001) of eravacycline 1 mg/kg/12 h were significantly associated with poorer clinical response rate at the end of treatment. Eravacycline demonstrated promising effectiveness and safety in treating infections of patients from the hematology department.

IntroductionAcute graft-versus-host disease (aGVHD) is a major cause of mortality following hematopoietic stem cell transplantation (HSCT). Its pathogenesis is primarily driven by alloimmune T cells, which recognize host tissues as foreign. A deeper characterization of the T cell receptor (TCR) repertoires in patients with aGVHD could provide critical insights into the disease's mechanisms and identify potential predictive biomarkers.MethodsWe employed next-generation sequencing to comprehensively profile the T cell receptor alpha (TRA) and beta (TRB) chains in HSCT recipients, comparing those with and without aGVHD. Our analysis focused on defining the functional kinetics of TCR clones, monitoring changes in overall T-cell diversity through the identification of complementarity-determining region 3 (CDR3) sequences, and quantifying the extent of clonal expansion within the T-cell population.ResultsOur analysis revealed that TCR repertoires exhibited significantly increased diversity in patients with active aGVHD compared to those without. Notably, this elevated diversity was dynamic and decreased as the symptoms of aGVHD improved clinically. Furthermore, TCR clustering analysis identified the presence of common TCR repertoire signatures among different patients who developed aGVHD, suggesting shared antigen-driven T cell responses.DiscussionThe dynamic changes and shared signatures within the TCR repertoire are closely associated with the development and resolution of aGVHD. These findings indicate that monitoring the TCR repertoire could serve as a valuable tool for predicting the onset of aGVHD. This approach holds promise for facilitating more personalized diagnostic and treatment strategies for aGVHD, and potentially for other T-cell-mediated pathologies.

Acquired pure red cell aplasia (aPRCA) is rare and challenging to treat. We investigated the efficacy and safety of sirolimus plus roxadustat in patients with aPRCA (Chinese Clinical Trial Register number, ChiCTR2200065107). We enrolled 82 patients with aPRCA in this prospective single-arm, open-label, multicenter trial between October 2022 and January 2024. Treatment response and safety files were evaluated. The median age was 63 years. Seven patients withdrew during the trial period. Sirolimus plus roxadustat produced an overall response (OR) in 65 patients (90.3%) 3 months after initiation, which included a complete response (CR) in 39 (54.2%) and a partial response in 26 (36.1%). The 3-month CR rate was significantly higher in the newly diagnosed group (65.9% vs. 38.7%; P = 0.022). The 6-month OR rate in the entire cohort was 93.0% (CR, 77.5%; PR, 15.5%). The mean hemoglobin concentration increased from 5.5 ± 1.6 g/dL at baseline to 11.6 ± 2.5 g/dL after 6 months of treatment. The proportions of patients who achieved transfusion independence within 1, 2, and 3 months of treatment were 57.4%, 76.6%, and 89.5%, respectively. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale score and SF-36 survey score significantly improved after treatment. Treatment-related adverse events occurred in 24 patients (29.2%), and four events (4.9%) were grade ≥3. Sirolimus plus roxadustat is a promising treatment for aPRCA and has an acceptable safety profile, which warrants further investigation in a randomized setting.

Cardiac involvement of the disease is a leading cause of death and disability in Fabry disease characterized by pathological accumulation of globotriaosylceramide (Gb3) and lyso-globotriaosylceramide (lyso-Gb3) in multiple organs. In this study, we sought to investigate the electrocardiographic (ECG) changes in different clinical stages and evaluate the value of these parameters in assessing cardiac involvement. 62 patients with Fabry disease and 45 healthy controls were recruited in this study. ECG assessment, echocardiographic assessment and cardiac magnetic resonance (CMR) were recorded at rest in the same day. We divided Fabry disease patients into 4 groups according to echocardiographic assessment and CMR: Pre-detectable group, Non-hypertrophic group, Hypertrophic and pre-fibrotic group as well as Hypertrophic and fibrotic group. Our results showed that Tp-e/QT was significantly decreased and Sokolow-Lyon index was markedly increased following the development of disease. QRS width and Tp-e/QT was associated with the severity of cardiac involvement in Fabry disease. Our results demonstrated that QRS width and Tp-e/QT were associated with the severity of cardiac involvement in patients with Fabry disease and contributed to define the optimal intervention timepoint and assess the severity of cardiac involvement and response to disease-specific therapies.

OBJECTIVE:Exogenous lipoid pneumonia (ELP) is a rare respiratory disorder. We are describing its clinical manifestations, diagnosis, and treatment. METHODS:Patients with ELP were identified by reviewing the hospital medical records between January 2020 and December 2024. Clinical characteristics, disease progression, examination results, treatments, and outcomes were presented. RESULTS:Three male patients and one female patient were identified (59-78 years old), all with a history of oil exposure. They presented with fever, cough, and expectoration. Laboratory tests revealed elevated neutrophil counts, C-reactive protein, and interleukin-6, as well as decreased lymphocyte counts and normal procalcitonin levels. All patients underwent bronchoscopy. Pathological examination revealed neutrophil infiltration, fat droplets, and lipid-laden macrophages. One patient had a positive chylous test in bronchoalveolar lavage fluid. In the chest images, four patients had large areas of consolidation; two patients had exudation and heterogeneous density within the consolidation areas, which were identified as fat attenuation zones on the mediastinal window. Bronchoscopic alveolar lavage and glucocorticoids were the key treatments. Three patients developed respiratory distress. Two of these patients required mechanical ventilation and circulatory support. One patient with esophageal cancer died, while the other patients successfully recovered after veno-venous extracorporeal membrane oxygenation treatment. CONCLUSIONS:ELP is rare. Affected patients can rapidly progress into respiratory failure. Pulmonary imaging with heterogeneous fat attenuation areas in the mediastinal window can suggest its diagnosis. Identification of lipid droplets and lipid-laden macrophages or having a positive chylous test in bronchoalveolar lavage fluid can facilitate its early and rapid diagnosis. ELP treatment requires a comprehensive approach, including bronchoscopic lavage, glucocorticoids, and respiratory and circulatory support.

Purpose: To establish a quadruplex real-time fluorescent quantitative RT-PCR method for the simultaneous detection of respiratory syncytial virus (RSV) and its Subtypes A and B (RSV-A and RSV-B) and to conduct a preliminary analysis of the genetic variation characteristics of RSV strains isolated from our hospital. Methods: Highly specific primers and fluorescently labeled probes were designed using Primer Express 3.0 software. Following optimization of the reaction system, standard curves were constructed, and the sensitivity, reproducibility, and specificity of the quadruplex fluorescent quantitative RT-PCR method were evaluated. The established assay was applied to test 407 sputum specimens collected from pediatric patients with suspected infections. Positive results were confirmed by sequencing, followed by sequence identity comparison and phylogenetic tree construction. Results: The selected primers and probes specifically detected RSV and effectively distinguished between RSV-A and RSV-B subtypes. The method demonstrated a detection limit of 103 copies/mL, with an intra-assay coefficient of variation (CV) of < 2.00%. No cross-reactivity was observed with nucleic acids from other common respiratory viruses. Among the 407 clinical specimens, 47 tested positive for RSV, including 39 RSV-A (positivity rate: 9.6%) and 8 RSV-B (positivity rate: 2.0%). These positive findings were consistent with sequencing results. The four tested RSV-A Subtype G genes showed the highest nucleotide sequence identity (98.9%-99.3%) with the 2013 Beijing strain (NA1/AB470478). Among the four tested RSV-B Subtype G genes, one exhibited the highest nucleotide sequence identity (98.8%) with the 2013 Beijing strain (BA8/HM459873), while the other three showed the highest nucleotide sequence identity (97.7%-99.4%) with the 2013 Hangzhou strain (BA10/KP336526). Conclusion: A quadruplex real-time fluorescent quantitative RT-PCR method was successfully developed for the simultaneous detection of RSV and its A and B subtypes in a single tube. The assay exhibits high specificity, sensitivity, and reproducibility, providing a novel and efficient detection tool for clinical diagnostics and epidemiological studies. RSV infections in our hospital involved cocirculation of Subtypes A and B, with Subtype A being predominant. Furthermore, the G gene of Subtype B may exhibit greater variability than that of Subtype A.

Activating FLT3 mutations confer a poor prognosis in acute myeloid leukemia (AML). FLT3 inhibitors significantly improved the clinical outcomes of FLT3-mutated AML. However, all clinically approved inhibitors target the ATP-binding pocket of FLT3. The acquired FLT3 mutations in the ATP-binding pocket, including mutations at D835 and F691, are common mechanisms of leukemia relapse. Using druggable site prediction (DSP) and high-throughput virtual screening, we revealed that the predicted site 1 region was promising for allosteric inhibitor development, and F-17 was identified as the first potential allosteric FLT3 inhibitor. F-17 exhibited high affinity for site 1 in an ATP non-competitive manner. KINOMEscan analysis showed that F-17 was significantly selective toward FLT3 over other homologous kinases of the RTK family. Moreover, F-17 showed potent selectivity and inhibition activity for FLT3-mutated cells both in vitro and in vivo. Collectively, the work provided a new insight for FLT3 inhibitor development.

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine and participates in multiple cellular processes, such as cell development, proliferation, epithelial mesenchymal transition (EMT), and immune responses through SMAD-dependent or SMAD-independent signaling pathways. Notably, TGF-β signaling plays a dual role in tumors, acting as a potent tumor suppressor during early tumorigenesis by inducing apoptosis or cell-cycle arrest while promoting tumor transformation, progression and metastasis in advanced stage through multidimensional mechanisms. Moreover, it is abundant and functions as a master immune checkpoint in the tumor microenvironment (TME), fostering the development of numerous targeted therapies to rectify its aberrant activity in tumors in the past decades. Thus, a comprehensive overview of the pathologic roles, molecular mechanisms and therapeutic potentials of TGF-β signaling in tumors will benefit both the basic and clinical cancer research. Here, we review the complex biology and context-dependent functions of the TGF-β superfamily in regard to tumor, highlighting how it regulates the latter’s development, growth, and dissemination by mainly targeting tumor cells, tumor-associated fibroblasts and various immune cells. We also summarize recent advances in the preclinical and clinical development of different types of TGF‑β‑targeting agents, and discuss their therapeutic potentials and challenges as well as approaches to improve the safety and efficacy of TGF-β pathway-targeted therapy in cancers. Through the summary of known knowledge and the latest updates, this review may provide a general picture on the biological functions of TGF-β in tumors, and facilitate the clinical implications of TGF-β-targeted therapy in tumor patients.

BACKGROUND:To determine the incidence, risk factors, and outcomes of invasive pulmonary aspergillosis (IPA) in critically ill patients with Influenza A pneumonia in post-COVID-19 China. METHODS:We conducted a multicenter retrospective cohort study across 21 ICUs (November 2024-February 2025) including adults with acute respiratory failure due to confirmed severe Influenza A pneumonia. IPA was defined by 2024 FUNDICU criteria. The primary outcome was 60-day all-cause mortality. RESULTS:Among 542 patients, 179 (33.0%) had IPA. Independent risk factors: renal replacement therapy (aOR 1.63), diabetes (aOR 1.79), bacterial co-infection (aOR 1.64), pre-ICU systemic glucocorticoids (aOR 2.13), and ICU steroids (aOR 1.53). Median time from influenza to IPA diagnosis was 2 days. Sixty-day mortality was higher with IPA (47.5% vs 32.0%, P<0.001), persisting after matching. Among IPA patients, hematologic disorders (aHR 5.31) and higher CRP predicted death. CONCLUSIONS:In the post-COVID-19 era, IPA is highly prevalent and lethal in severe influenza, with rapid onset. Protocolized screening and timely diagnostic strategies are urgently needed.

Postoperative deviation (PD) is a complicated and troublesome complication after polydactyly reconstruction. We aim to investigate the clinical efficacy of a novel revision surgery, reconstruction of the balance of bone and soft tissue, treating PD after radial polydactyly reconstruction in comparison with a previous surgical plan. We reconstructed the balance of bone and soft tissue to correct PD and the asymmetrical appearance of the thumb. At the follow-up, we used the digital circumferential ratio (reconstructive/healthy side), Vancouver Scar Scale (VSS) score, Japanese Society for Surgery of the Hand (JSSH), aesthetic scoring system (ASS) modified Tada score and range of motion (ROM) to evaluate the appearance and function outcomes. Seventeen PD patients received our new surgical plan (NG), and 31 patients received the traditional surgical plan (CG). There was no significant difference in gender, age, site of hand and follow-up period, as well as preoperative digital circumference ratio, deviation angle of metacarpophalangeal joints (MP) and interphalangeal joint (IP). At the final follow-up, we found that digital circumference ratio, JSSH and ASS were obviously higher in NG than in CG, implying that our novel surgical plan can provide good aesthetics and excellent postoperative function. The reconstructive balance of bone and soft tissue can effectively improve the appearance and function of PD after polydactyly reconstruction. Mastering the indications for surgery and good microsurgical techniques are the keys to ensuring therapeutic effects.

Background:This study aimed to compare the efficacy and safety of colistimethate sodium (CMS) and polymyxin B (PMB) in treating carbapenem-resistant Gram-negative bacteria (CR-GNB)-induced bloodstream infection (BSI) based on real-world data. While international studies on CMS and PMB have yielded conflicting results, there is a lack of direct comparative data from Chinese cohorts, where the pathogen distribution may influence outcomes. Methods:A retrospective analysis was conducted on 373 Chinese patients with CR-GNB-induced BSI who received CMS-containing therapy (n=132) or PMB-containing therapy (n=241) between Dec 2021 and Dec 2023. Propensity score matching was used to balance the two groups at a ratio of 1:2. The primary outcome was clinical success. The secondary outcomes included inpatient days, in-hospital mortality, 28-day all-cause mortality, and incidence of adverse events. Statistical analysis was performed with Wilcoxon rank sum test, Student's t-test, chi-square test, and Fisher's exact test as appropriate. Results:In this cohort, Acinetobacter baumannii was the predominant pathogen (53.4%). No significant differences were observed in efficacy outcomes between the two groups (p>0.05). For safety, the difference in hyperpigmentation incidences between the two groups was statistically significant (CMS vs PMB: 0.0% vs 6.36%, p=0.04). Incidences of hypersensitivity, neurotoxicity, and nephrotoxicity were similar between groups (p>0.05). A longer treatment course (>12 days), while associated with a higher incidence of hyperpigmentation, was linked to significantly improved clinical outcomes, including higher success rate, reduced in-hospital mortality, and lower 28-day all-cause mortality (p<0.05). Conclusion:This study provides the first large, real-world comparative evidence from a Chinese cohort with CR-GNB BSIs. In this setting, CMS and PMB demonstrated comparable efficacy. The critical difference lay in the safety profile, with CMS associated with a markedly lower incidence of hyperpigmentation. This finding provides a tangible basis for antibiotic stewardship, positioning CMS as a valuable first-line polymyxin option.

Objective:To evaluate the prognosis significance of a newly simplified immune-dysregulation index, interleukin-6-to-lymphocyte ratio (IL-6/LY), in individuals diagnosed with sepsis. Methods:This was a retrospective cohort study enrolling consecutive patients diagnosed with sepsis who qualified the inclusion criteria and were admitted to the intensive care unit of the First Affiliated Hospital of Soochow University between March 2017 and January 2023. Multivariate COX and logistic regression models were used to estimate the association between IL-6/LY and 28-day in-hospital mortality or multiple organ dysfunction syndrome (MODS). Restricted cubic splines and survival analysis were used to show a nonlinear correlation between IL-6/LY and mortality. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the prognostic value of IL-6/LY. was performed using the Kaplan‒Meier method. Results:The study encompassed 301 participants, categorized into two groups-those with low IL-6/LY and high IL-6/LY-determined by the cutoff value of 326.04. On multivariate analyses, a high IL-6/LY was independently associated with 28-day in-hospital mortality (hazard ratio [HR]: 8.01, 95% confidence interval [CI] 4.67-13.74, P < 0.001) and MODS (odds ratio [OR] 3.44, 95% CI 1.85‒6.38, P < 0.001). The area under the curve of IL-6/LY for predicting death and MODS were 0.893 (95% CI, 0.855-0.931) and 0.743 (95% CI, 0.688-0.798), respectively. The Kaplan‒Meier analysis showed a significantly higher risk of mortality in the high IL-6/LY group (≥ 326.04) (log-rank P < 0.001). Conclusion:The IL-6/LY is significantly associated with the risk of 28-day in-hospital mortality and MODS in patients with sepsis, making it a potential prognostic marker for risk stratification, which enables early identification of high-risk patients, timely interventions, and personalized treatment strategies to optimize patient outcomes.

Thoracic aortic dissection (TAD) is a life-threatening condition with high mortality rates. Recent research suggests a potential link between early-stage TAD and endothelial barrier dysfunction, although the underlying mechanisms remain unclear. Single-cell RNA sequencing data from patients reveal that dysregulated Calpain-2 expression modulates endothelial focal adhesion proteins, serving as an early pathological hallmark and driver of TAD. Elevated plasma calpain activity is strongly associated with an increased risk of TAD and organ dysfunction. Both endogenous and exogenous calpain inhibitors effectively prevent TAD onset and progression in murine models induced by β-aminopropionitrile (BAPN). In early TAD, endothelial junction integrity in the ascending aorta and aortic arch is compromised. Endothelial-specific deletion of Capns1 mitigates early and sustained endothelial focal adhesion damage by reducing aberrant expression of Integrin alpha-V(Itgav), vinculin, and talin-1, thereby decreasing TAD incidence. In contrast, macrophage-specific Capns1 knockout does not impact TAD development but accelerates aortic dissection rupture in later stages. Mechanistically, angiotensin II upregulates Calpain-2, leading to endothelial focal adhesion activation through talin1 cleavage and Itgav assembly, thereby compromising endothelial integrity and permeability. These findings identify potential therapeutic targets for TAD prevention and treatment.

Aging changes the protein activity status to affect the body’s functions. However, how aging regulates protein posttranslational modifications (PTMs) to modulate the antiviral defense ability of the body remains unclear. Here, we found that aging promotes STAT1 β-hydroxybutyrylation (Kbhb) at Lys592, which inhibits the interaction between STAT1 and type-I interferon (IFN-I) receptor 2 (IFNAR2), thereby attenuating IFN-I-mediated antiviral defense activity. Additionally, we discovered that a small molecule from a plant source, hydroxy camptothecine, can effectively reduce the level of STAT1 Kbhb, thus increasing antiviral defense ability in vivo. Further studies revealed that STAT1 O-GlcNAc modifications at Thr699 block CBP-induced STAT1 Kbhb. Importantly, fructose can improve IFN-I antiviral defense activity by orchestrating STAT1 O-GlcNAc and Kbhb modifications. This study reveals the significance of the switch between STAT1 Kbhb and O-GlcNAc modifications in regulating IFN-I antiviral immunity during aging and provides potential strategies to improve the body’s antiviral defense ability in elderly individuals.