BACKGROUND:Endovascular thrombectomy for acute ischemic stroke due to medium-vessel occlusion has had varying results across trials. Whether thrombectomy improves functional outcomes in patients with medium-vessel occlusion and moderate-to-severe deficits is unclear. METHODS:We conducted an open-label, randomized trial with blinded outcome assessment at 48 centers in China. Eligible patients were adults who presented within 24 hours after the onset of a moderate-to-severe stroke (National Institutes of Health Stroke Scale [NIHSS] score, ≥6; scale, 0 to 42, with higher scores indicating greater neurologic deficits) due to occlusion of a medium vessel. Patients were assigned in a 1:1 ratio to thrombectomy plus medical management (thrombectomy group) or medical management alone (control group). The primary outcome was functional disability as measured by the shift in the modified Rankin scale score (scale, 0 [no disability] to 6 [death]) at 90 days. Violation of the proportional-odds assumption precluded the use of shift in the modified Rankin scale score, so as prespecified, functional independence (modified Rankin scale score of 0, 1, or 2) at 90 days was used as the primary outcome. Safety outcomes were symptomatic intracranial hemorrhage and 90-day mortality. RESULTS:Among 280 patients in the thrombectomy group and 283 in the control group, the median age was 71 years, the median NIHSS score was 10 (range, 3 to 36), and 42.8% were women; 36.6% received intravenous thrombolysis. Functional independence at 90 days was seen in 58.6% of the patients in the thrombectomy group and in 46.6% of those in the control group (adjusted rate ratio, 1.24; 95% confidence interval, 1.07 to 1.44; P = 0.004). The incidence of symptomatic intracranial hemorrhage was 4.7% in the thrombectomy group and 2.2% in the control group; 90-day mortality was 11.1% and 10.2%, respectively. CONCLUSIONS:Among patients with acute ischemic stroke due to medium-vessel occlusion and moderate-to-severe deficits, thrombectomy led to a greater likelihood of functional independence than medical management alone but also to a higher risk of symptomatic intracranial hemorrhage. (Funded by the National Natural Science Foundation of China and the Noncommunicable Chronic Diseases-National Science and Technology Major Project; ORIENTAL-MeVO ClinicalTrials.gov number, NCT06146790.).
SALL4 is aberrantly reactivated in multiple malignancies, including breast cancer (BC), where it promotes tumor progression and therapy resistance. However, its therapeutic targeting remains underexplored. This study investigates the antitumor efficacy of a novel SALL4-inhibitory peptide, PEN-FFW, and its regulatory impact on the PI3K/AKT/PD-L1 axis and CD8⁺ T cell-mediated cytotoxicity in BC. SALL4 expression in BC was assessed using public databases and validated in cell lines by RT-qPCR and western blot. The interaction between SALL4 and the NuRD complex was evaluated by co-immunoprecipitation assay. Functional assays were conducted to assess the effects of PEN-FFW in vitro. Co-culture systems were used to evaluate CD8⁺ T cell-mediated cytotoxicity. Mechanistic studies investigated the involvement of the PTEN/PI3K/AKT/mTOR signaling axis. In vivo efficacy was tested in allograft mouse models, including combination therapy with anti-PD-L1 antibody. SALL4 was significantly upregulated in BC and associated with poor prognosis. PEN-FFW disrupted the SALL4-NuRD interaction, restored PTEN expression, and suppressed PI3K/AKT/mTOR signaling. This led to a reduction in PD-L1 expression and increased apoptosis, while inhibiting the proliferation and migration of BC cells. PEN-FFW also enhanced CD8⁺ T cell cytotoxicity by reducing PD-L1-mediated immune evasion. Furthermore, combination treatment with PEN-FFW and anti-PD-L1 antibody showed superior tumor suppression and increased CD8⁺ T cell infiltration compared to either treatment alone. PEN-FFW is a potent SALL4-inhibitory peptide that suppresses BC progression by downregulating PD-L1 through PI3K/AKT pathway inactivation and promoting CD8⁺ T cell-mediated tumor killing. These findings highlight a promising strategy for enhancing immunotherapy in SALL4-positive BC.
Keratoconus (KC) is a progressive corneal disease increasingly linked to immune dysregulation. Epidemiological studies have suggested comorbidity between KC and allergic diseases such as atopic dermatitis (AD), allergic conjunctivitis (AC), allergic rhinitis (AR), and allergic asthma (AA), yet their shared genetic mechanisms remain unclear. To investigate the shared genetic architecture between KC and four common allergic conditions, we integrated genome-wide association study (GWAS) summary statistics using a multi-omics framework. We applied linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) to assess genome-wide genetic correlations. Pleiotropic variants were identified using the PLACO method and functionally annotated with FUMA. Bayesian colocalization and local genetic correlation analyses were conducted to pinpoint shared causal loci. Gene-level associations and pathway enrichment were explored using MAGMA and SMR, and potential regulatory effects were assessed through eQTL mapping and functional databases. All four allergic diseases showed significant positive genetic correlations with KC. PLACO identified 451 pleiotropic SNPs, including 44 independent risk loci. Eight loci showed strong colocalization (PPH4 > 0.8), notably 8q21.13 and 10p14. Functional annotation revealed several variants with regulatory or deleterious potential, such as rs73220641 (KLF5) and rs17686636 (GATA3). MAGMA and SMR prioritized SMAD3, IL18R1, and PCNXL3 as pleiotropic genes, enriched in immune tissues and inflammatory pathways. This multi-omics study uncovers shared genetic loci and immune-related pathways between KC and allergic diseases. The results highlight epithelial barrier dysfunction and immune regulation as converging mechanisms and propose pleiotropic genes as potential therapeutic targets.
To establish and validate age-specific reference intervals for the peripheral blood systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in healthy children. A total of 2106 healthy children undergoing physical examination at The First People’s Hospital of Zigong from April 2023 to February 2025 were enrolled. Blood cell parameters were measured using the XN-1000 hematology analyzer, and SII, NLR, PLR, and LMR were calculated. The non-parametric method was employed to establish the 95
IntroductionTo address the delayed identification of carbapenem-resistant Pseudomonas aeruginosa (CRPA), we developed an interpretable machine-learning (ML) model for early risk stratification. Utilizing routine complete blood count (CBC) and demographic data, this tool targets the critical 48–72 hour interval before final antimicrobial susceptibility results.MethodsData from 1,666 patients with P. aeruginosa infection (223 CRPA) at a primary center were retrospectively analyzed, alongside an independent external validation cohort (n=471). Following the least absolute shrinkage and selection operator (LASSO) regression on 32 variables, eight ML algorithms were trained. Model interpretability and clinical utility were evaluated using Shapley Additive Explanations (SHAP) and decision curve analysis (DCA). Eight ML algorithms were trained using 5-fold cross-validation and Bayesian hyperparameter optimization. To ensure reproducibility and handle class imbalance, fixed random seeds were set, and a sensitivity analysis using the Synthetic Minority Over-sampling Technique (SMOTE) was conducted. Model calibration was assessed using the Brier score.ResultsLASSO identified seven predictors: sex, age, mean corpuscular volume (MCV), hemoglobin (HGB), platelet-to-lymphocyte ratio (PLR), systemic inflammatory response index (SIRI), and intensive care unit (ICU) admission status. Among the evaluated algorithms, the random forest (RF) model achieved the best discrimination. The training area under the receiver operating characteristic curve (AUC) was 0.993; it achieved an average 5-fold cross-validation AUC of 0.929 ± 0.005. In the internal test set, it achieved an AUC of 0.837 (95% CI: 0.779–0.893), specificity of 0.972, and sensitivity of 0.507, with excellent calibration (Brier score = 0.084). The model retained strong performance externally (AUC: 0.898, specificity: 0.985, sensitivity: 0.600, Brier score: 0.073). SHAP analysis indicated that HGB was the most influential feature, inversely associated with CRPA risk. Decision curve analysis supported the clinical utility across threshold probabilities ranging from 15% to 65%.DiscussionThis clinlabomics-based RF model provides a rapid, low-cost adjunct for early CRPA stratification. Given its exceptionally high specificity (>0.97) and modest sensitivity, it functions exclusively as a reliable clinical “rule-in” tool. Positive predictions can confidently guide early targeted therapy and strict infection control. However, negative predictions cannot safely rule out CRPA, emphasizing its role alongside standard empirical practices rather than as a standalone screening instrument.
