BACKGROUND:COPD frequently coexists with cardiovascular diseases. Cardiovascular death is also a major contributor to mortality in COPD patients. Inhaled corticosteroids (ICS), as the most commonly prescribed inhaled anti-inflammatory medications, have been widely used for management of COPD patients who experience frequent exacerbations. However, whether ICS have a cardiovascular protective effect remains unclear. The purpose of this work was to comprehensively ascertain the risks of cardiovascular deaths related to ICS in COPD patients. METHODS:PubMed, the Cochrane Library and Embase were searched to screen qualifying articles from September to November 2022. An updated search was conducted in October 2025. We identified trials of any ICS for treatment of COPD and reported on cardiovascular deaths. Meta-analyses were conducted to calculate risk ratios with 95% confidence intervals. The primary end-point was cardiovascular mortality. FINDINGS:35 randomised controlled trials enrolling 74 004 subjects were analysed. Inhaled formulations containing ICS significantly reduced the risk of cardiovascular deaths compared with inhaled formulations without ICS (risk ratio 0.84, 95% CI 0.74-0.95). ICS/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) significantly reduced the risk of cardiovascular deaths compared with dual LAMA/LABA therapy (risk ratio 0.56, 95% CI 0.37-0.86). ICS monotherapy also significantly reduced the risk of cardiovascular deaths compared with placebo (risk ratio 0.81, 95% CI 0.66-0.99). However, ICS/LABA did not significantly reduce the risk of cardiovascular deaths compared to LABA monotherapy (risk ratio 0.98, 95% CI 0.80-1.20). CONCLUSIONS:Inhaled formulations containing ICS are associated with a reduced risk of cardiovascular deaths in patients with COPD.

INTRODUCTION:Ventilator-induced diaphragmatic dysfunction (VIDD) is associated with diaphragm atrophy and decreased contractility, leading to difficult weaning. Respiratory muscle training could prevent diaphragmatic dysfunction. IGF-1 is correlated with the enhancement of muscle mass and strength. The aim of this study was to investigate the effect of dual-mode ventilation (DMV) on diaphragm function recovery in VIDD rats, and to explore the role of insulin-like growth factor-1 (IGF-1) as an underlying mechanism. METHODS:Adult male Sprague-Dawley rats were used to establish the VIDD model and randomly divided into seven groups. Diaphragm morphology, myofiber cross-sectional area, diaphragm contractility, reactive oxygen species production, superoxide dismutase activity, IGF-1 expression and protein levels related to muscle differentiation and protein synthesis were examined. Adeno-associated virus transfection was used to downregulate IGF-1 expression. Overexpression of IGF-1 was performed by subcutaneous injection of rhIGF-1 to explore the possible mechanism. RESULTS:DMV increased myofiber cross-sectional area, improved diaphragm contractility, reduced reactive oxygen species production, enhanced superoxide dismutase activity, and upregulated the expression of Myod, Myogenin, MyHC, and a-actinin. DMV also upregulated the protein level of IGF-1 in the diaphragm of VIDD rats. In vivo, IGF-1 knockdown aggravated diaphragmatic dysfunction, increased oxidative stress injury, reduced protein synthesis and muscle differentiation, and decreased p-protein kinase B (Akt)/AKT and p-mammalian target of rapamycin (mTOR)/mTOR expression, while overexpression of IGF-1 reversed these changes. CONCLUSIONS:DMV is beneficial for diaphragm function recovery. And IGF-1 plays an important role in DMV to enhance diaphragm mass and strength of VIDD rats, which may promote protein synthesis and muscle differentiation through activating Akt/mTOR signaling pathway.

Ischemic stroke remains a major cause of long-term neurological disability, and effective strategies that promote brain repair during the subacute phase are limited. Here, using a clinical cohort of patients with acute ischemic stroke, adult male C57BL/6J mouse models, and complementary in vitro fibroblast models, we identify vitamin B12 as a metabolic regulator of post-ischemic reparative remodeling and functional recovery. Vitamin B12 deficiency was associated with greater stroke severity, impaired neurological recovery, and weakened reparative fibrotic remodeling, whereas vitamin B12 supplementation under physiological nutritional conditions improved neurological recovery and enhanced reparative fibrotic remodeling. Mechanistically, vitamin B12 restored metabolic homeostasis in fibroblasts, increased intracellular acetyl-CoA availability, enhanced H3K27 acetylation, upregulated RUNX2 expression, enhanced RUNX2-p300 interaction, and activated RUNX2-dependent fibroblast programs. RUNX2 suppression or pharmacological inhibition of histone acetylation attenuated fibroblast activation and blunted the pro-repair effects of vitamin B12. Moreover, RUNX2 overexpression preferentially targeting fibroblast-associated cells improved defective reparative remodeling in vitamin B12-deficient mice. These findings identify a vitamin B12-dependent metabolic and epigenetic mechanism that activates RUNX2-associated fibroblast responses and supports subacute brain repair after ischemic stroke.

BACKGROUND:Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC). In our previous report of the HARMONi-6 study, we aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. Ivonescimab combined with chemotherapy significantly prolonged progression-free survival compared with tislelizumab plus chemotherapy. Here we report the prespecified interim overall survival analysis. METHODS:HARMONi-6 is a double-blind, randomised, phase 3 trial, which was conducted at 50 hospitals across China. Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Eligible patients were randomly assigned in a 1:1 ratio to receive ivonescimab or tislelizumab, in combination with paclitaxel and carboplatin for four cycles, followed by maintenance ivonescimab or tislelizumab monotherapy. The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Overall survival was a key secondary endpoint; an interim analysis was planned when approximately 225 overall survival events were observed, but it was triggered after 204 overall survival events to meet regulatory deadlines. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrials.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Aug 17, 2023, to Jan 21, 2025, 761 patients were assessed for eligibility, and after 229 exclusions a total of 532 patients were randomly allocated (266 per group). 494 (93%) of patients were male and 38 (7%) of patients were female. The median age was 64 years (IQR 59-69). At data cutoff (Feb 27, 2026), 204 deaths had occurred: 84 (32%) patients in the ivonescimab plus chemotherapy group and 120 (45%) in the tislelizumab plus chemotherapy group. With a median follow-up of 21·4 months (95% CI 20·27-21·91), the median overall survival was 27·9 months (95% CI 27·89-not evaluable [NE]) with ivonescimab versus 23·7 months (20·11-NE) with tislelizumab (hazard ratio for death 0·66 [95% CI 0·50-0·87]; pone-sided=0·0017), meeting the prespecified boundary (p<0·0049). The overall survival benefit with ivonescimab plus chemotherapy was consistent across key subgroups. Treatment-related adverse events of grade 3 or higher occurred in 184 (69%) of 266 patients in the ivonescimab group and 156 (59%) of 265 patients in the tislelizumab group. The incidence of grade 3 or higher haemorrhage was seven (3%) of 266 and two (1%) of 265, respectively. INTERPRETATION:Ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with tislelizumab plus chemotherapy in previously untreated patients with advanced squamous NSCLC. This regimen could provide a novel treatment option as first-line treatment in this patient group. FUNDING:Akeso Biopharma.

Although PD-1/PD-L1 inhibitors have revolutionized advanced non-small cell lung cancer (NSCLC) treatment, systemic administration is limited by suboptimal local drug concentrations in tumors and the occurrence of immune-related adverse events (irAEs). This study aimed to evaluate the efficacy and safety of local administration of PD-1 inhibitors via bronchial artery infusion (BAI) for the treatment of NSCLC. This single-center prospective cohort study enrolled a total of 47 patients with advanced NSCLC (stage IIIB-IV) who were EGFR and ALK wild-type and exhibited poor response following 2 to 4 cycles of standard treatment. Patients were divided into BAI (n = 23) and Venous (n = 24) groups based on the route of PD-1 inhibitor administration. Both groups received PD-1 inhibitors combined with platinum-based chemotherapy. Notably, chemotherapy was administered via BAI in both groups, with the only difference being the route of PD-1 inhibitor delivery. The primary endpoints of the study was progression-free survival (PFS), and the secondary endpoints were objective response rates(ORR), disease control rates (DCR), overall survival (OS) and safety. At 6-month follow-up, higher ORR (47.8% vs. 16.7%, P = 0.026) and DCR were observed in the BAI group compared to the Venous group (73.9% vs. 41.6%, P = 0.014). The BAI cohort was associated with longer median PFS (11.1 vs. 6.6 months; HR = 0.372, 95% CI: 0.150-0.919; P = 0.030), with a trend toward improved OS (17.9 vs. 15.2 months, P = 0.085). Multivariable analysis identified BAI administration (HR = 0.372, P = 0.032) and younger age (HR = 2.838, P = 0.039) as independent predictors of prolonged PFS. No grade 3-4 treatment-related adverse events were observed in either group of patients. Immune-related pneumonitis (grade 1-2) occurred in 4.3% of patients in the BAI group and 4.2% in the venous group. Due to the limited sample size, a statistical comparison between groups was not performed. All adverse events were manageable with appropriate supportive treatment. BAI administration of PD-1 inhibitors was associated with improved therapeutic efficacy in advanced NSCLC, yielding longer PFS and higher ORR and DCR compared to the Venous group, without increasing severe toxicity.

INTRODUCTION:Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). However, the learning curve associated with this technique remains unclear. METHODS:This retrospective analysis included the first 100 patients suspected of having ILD for whom TBLC was performed by six physicians (three chief physicians and three attending physicians) across three centers in China. The diagnostic yield, procedural information, and complications were compared between consecutive groups of patients. Logistic regression was employed to analyze the median diagnostic yields across ten subgroups of operative experience, categorized in intervals of 10 patients, to delineate the learning curve. RESULTS:The overall multidisciplinary discussion (MDD)-based diagnostic rate for ILD after TBLC was 75% (450 of 600 procedures). The diagnostic yield increased with time. Learning curves revealed that chief physicians achieved proficiency after approximately 60 procedures and attending physicians after approximately 90. The sample biopsy was larger for chief physicians than for attending physicians (median, 19 mm2 vs. 15.25 mm2, p < 0.001). The complication rates were acceptable, with no significant difference between the chief and attending physicians over their first 100 procedures. CONCLUSION:TBLC is a safe and effective diagnostic approach for ILD, but operators require extensive training to achieve proficiency. Senior physicians reached competency earlier than junior colleagues (after several dozen procedures), underscoring the importance of structured training programs and standardized protocols for facilitating safe implementation.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent oxidative stress and inflammation, for which current antioxidant therapies lack efficiency and targeting. Here, we developed macrophage membrane-biomimetic bimetallic manganese-platinum nanozymes (MM-BiMP NZs) for targeted pulmonary delivery. The synthesized MM-BiMP NZs retained potent scavenging activity against multiple reactive oxygen species (ROS), including hydroxyl radicals, singlet oxygen, and superoxide anions. Using an acute lipopolysaccharide-induced lung injury model, we determined 2.5 mg/kg as a safe and effective dose for intratracheal administration. In a cigarette smoke-induced COPD mouse model, treatment with MM-BiMP NZs significantly attenuated pulmonary oxidative stress, reduced inflammatory cytokine levels, improved lung function, and ameliorated emphysema and airway remodeling. The vitro experiments demonstrated that MM-BiMP NZs were efficiently internalized, mitigated cigarette smoke extract-induced oxidative damage, and suppressed pro-inflammatory cytokine release both in the bronchial epithelial cells and alveolar macrophages. Mechanistically, transcriptomic and biochemical analyses revealed that the therapeutic effects of MM-BiMP NZs were mediated through the inhibition of the ROS-PI3K-AKT signaling pathway. This study presents a novel biomimetic nanoplatform that effectively targets the pulmonary microenvironment, combats oxidative stress, and alleviates experimental COPD, offering a promising strategy for this debilitating disease.

Background: From 2019 July 15 to 2022 February 14, the REZOR study enrolled 369 treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R mutation). Patients were randomly assigned 1:1 to receive either rezivertinib (180 mg/d) plus gefitinib placebo or gefitinib (250 mg/d) plus rezivertinib placebo. Previous results demonstrated significantly improved progression-free survival (PFS) with rezivertinib versus gefitinib and a favorable safety profile. Here, we update the analyses of central nervous system (CNS) outcomes in patients with baseline CNS metastases. Methods: All patients underwent brain magnetic resonance imaging at baseline and each subsequent efficacy evaluation until radiological disease progression or any other treatment discontinuation criteria were met. EGFR mutation status was determined by testing using tissue or plasma samples during screening. Patients with stable, asymptomatic CNS metastasis were eligible for enrollment. The CNS full analysis set (cFAS) comprised patients with baseline CNS metastasis identified on magnetic resonance imaging and evaluated by blinded independent central review according to the Response Assessment in Neuro-Oncology Brain Metastases criteria. Patients with measurable CNS target lesions formed the CNS evaluable-for-response set (cEFR). Results: As of the 2023 November 30 data cutoff, 159 patients had baseline CNS metastasis in the cFAS (rezivertinib: n = 81; gefitinib: n = 78) and 25 in the cEFR (rezivertinib: n = 12; gefitinib: n = 13) per blinded independent central review. In the cFAS, 59 CNS PFS events occurred (rezivertinib: n = 30; gefitinib: n = 29). Median CNS PFS was significantly longer with rezivertinib (24.9 months; 95% confidence interval [CI], 16.5 months-not estimable [NE]) than with gefitinib (15.2 months; 95% CI, 10.5 months-NE), with a hazard ratio of 0.58 (95% CI, 0.34 to 0.99; P = 0.047). In the cEFR, the CNS objective response rate was 83.3% (95% CI, 51.6% to 97.9%) with rezivertinib and 76.9% (95% CI, 46.2% to 95.0%) with gefitinib (odds ratio = 1.50; 95% CI, 0.20 to 11.0; P = 0.690). No new safety findings were observed. Conclusions: Rezivertinib demonstrated a statistically significant superior CNS efficacy over gefitinib as first-line treatment in advanced EGFR-mutated non-small cell lung cancer patients with baseline CNS metastases. The safety profile was consistent with previous analyses. Trial registration: NCT03866499 (ClinicalTrials.gov).

Zinc transporters regulate intracellular zinc homeostasis, but their role in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remains underexplored. Here, we show that the zinc transporter SLC39A1 is highly upregulated in alveolar type II (AT2) cells from male murine ALI models and patients with ARDS. AT2-specific Slc39a1 deletion or zinc chelation exacerbates lung injury, whereas overexpression or zinc supplementation attenuates it. Notably, zinc supplementation fails to rescue Slc39a1-deficient mice, indicating SLC39A1 governs zinc uptake to control ALI. Zinc likely directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis in AT2 cells. Lc3b- or Tfe3-deficient mice show heightened lung injury, which remain unmitigated by zinc supplementation. Importantly, administration of AAV-shLc3b to AT2 Slc39a1-deficient mice did not further aggravate lung injury beyond that caused by either intervention alone. This epistatic relationship places SLC39A1 upstream of autophagy activation within a linear pathway. Collectively, we define an essential role for epithelial SLC39A1 in host defense against ALI/ARDS, which is mediated by a protective zinc-autophagy axis.

BACKGROUND:Lower respiratory tract infections (LRTIs) are complicated by diverse pathogens, posing challenges to traditional diagnostics. However, robust evidence on LRTI pathogen spectra and metagenomic next-generation sequencing (mNGS) clinical utility remains limited. METHODS:A retrospective analysis was conducted among 815 patients with suspected LRTIs who underwent mNGS and conventional microbiological testing(CMT) of bronchoalveolar lavage fluid. We evaluated the pathogen spectrum, the diagnostic value of mNGS across different infection categories, and its utility in guiding antibiotic therapy. RESULT:Following exclusions, 754 patients demonstrated 84.5% mNGS positivity. mNGS detected DNA viruses (33.85%, EBV predominating), bacteria (30.83%), fungi (23.30%), mycobacteria (9.43%), and special pathogens (2.59%). Confirmed pathogens included Mycobacterium tuberculosis (n = 124), Candida albicans (n = 118), Pseudomonas aeruginosa (n = 87), Pneumocystis jirovecii (n = 65), Haemophilus influenzae (n = 50) and Aspergillus fumigatus (n = 48). mNGS showed higher positivity than CMT (84.5% vs 53.6%, P < 0.05), with sensitivities of 90.6% (LRTIs), 73.3% (bacterial), 74.7% (fungal), and 81.9% (tuberculosis); specificities were 22.6%, 56.5%, 73.5%, and 96.4%. Its high sensitivity but modest specificity necessitates cautious interpretation. mNGS guided treatment adjustments in 48.4% of patients, with higher rates in critically ill patients (60.1% vs 45.7%, P < 0.05), though clinical improvement was lower in this group (54.7% vs 79.2%, P < 0.05). CONCLUSIONS:mNGS comprehensively detects pathogens in LRTIs, including bacteria, fungi, mycobacteria, DNA viruses, and special pathogens. While its broad diagnostic value and treatment guidance utility are significant, integration with clinical context is essential to distinguish true pathogens from colonization.

CONTEXT:The etiological confirmation of pulmonary tuberculosis typically relies on sputum or bronchoalveolar lavage fluid (BALF). Oral sampling offers a non-invasive and non-sputum alternative, but evidence varies widely due to inconsistent methods. This study employed the Cepheid Gene Xpert® MTB/RIF Ultra (Xpert-Ultra) to compare the diagnostic performance of tongue swabs, pharyngeal swabs, and posterior oropharyngeal saliva (POS) collected from the same patient to identify the optimal option. METHODS:The diagnosis was based on a composite microbiological reference standard. Tongue swabs, pharyngeal swabs, and POS were sequentially collected from each participant. Sputum and BALF underwent acid-fast bacilli smear microscopy, Cepheid Gene Xpert® MTB/RIF (Xpert), and culture, while oral samples were tested with Xpert-Ultra. RESULTS:All three oral sample types demonstrated 100 % specificity. Compared to tongue swabs and pharyngeal swabs, POS showed the highest sensitivity, both overall and in subgroup analyses, along with the highest bacterial load and the lowest cycle threshold values. CONCLUSION:Compared with tongue swabs and pharyngeal swabs, POS exhibits the best diagnostic efficacy, and is more suitable for no-sputum or paucibacillary tuberculosis patients, and shows potential as an alternative to BALF.

BACKGROUND:Squamous non-small-cell lung cancer (NSCLC) is associated with worse clinical outcomes than non-squamous NSCLC, but treatment options are scarce. We aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. METHODS:We conducted a randomised, double-blind, phase 3 trial at 50 sites across China (HARMONi-6). Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive intravenous ivonescimab (20 mg/kg) or tislelizumab (200 mg), plus intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve 5 mg/mL per min) once every 3 weeks for four cycles, followed by ivonescimab (20 mg/kg) or tislelizumab (200 mg) monotherapy as maintenance treatment for up to 24 months. Randomisation was stratified by disease stage (IIIB or IIIC vs IV) and PD-L1 tumour proportion score (≥1% vs <1%). The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrial.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Aug 17, 2023, to Jan 21, 2025, 761 patients were screened for eligibility, among whom 532 (70%) patients were enrolled and randomly assigned to receive ivonescimab plus chemotherapy (266 [50%] patients) or tislelizumab plus chemotherapy (266 [50%] patients). As of Feb 28, 2025, median follow-up time was 10·3 months (95% CI 9·5-11·0). Median progression-free survival was 11·1 months (95% CI 9·9-not evaluable) in the ivonescimab group and 6·9 months (5·8-8·6) in the tislelizumab group (hazard ratio 0·60 [95% CI 0·46-0·78]; one-sided p<0·0001). The progression-free survival benefit with ivonescimab plus chemotherapy was consistent regardless of PD-L1 status. 170 (64%) patients in the ivonescimab group and 144 (54%) patients in the tislelizumab group had grade 3 or higher treatment-related adverse events, with grade 3 or higher immune-related adverse events occurring in 24 (9%) patients in the ivonescimab group and in 27 (10%) patients in the tislelizumab group. Grade 3 or higher treatment-related haemorrhage occurred in five (2%) patients in the ivonescimab group and in two (1%) patients in the tislelizumab group. INTERPRETATION:In patients with untreated advanced squamous NSCLC, ivonescimab plus chemotherapy showed significantly improved progression-free survival compared with tislelizumab plus chemotherapy, regardless of PD-L1 status, as well as a manageable safety profile. This regimen could be used as a novel first-line treatment in this patient group. FUNDING:Akeso Biopharma.

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality, particularly among critically ill patients. Despite the well-established role of inflammation in COPD pathogenesis, the prognostic significance of the systemic immune-inflammatory index (SII) in these patients remains unclear. This study aimed to investigate the relationship between SII and mortality risk in critically ill patients with COPD.MethodsThis retrospective observational cohort study utilized data from 3,291 COPD patients extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV 2.2) database. The participants were divided into quartiles based on their SII values. The primary endpoint was in-hospital mortality. The primary endpoint was compared across the four quartiles using Kaplan–Meier analysis. The relationship between the SII and mortality was analyzed using Cox proportional hazards models. Subgroup analyses and interaction tests were conducted to assess the robustness of the findings.ResultsA total of 3,291 patients with COPD were included in the study. The in-hospital, 90-day, and 1-year mortality rates were 15.1, 27.9, and 39.4%, respectively. The results of the multivariate Cox regression analysis revealed that an elevated SII was significantly associated with in-hospital mortality (HR: 1.17; 95% CI: 1.07–1.27; p < 0.001), mortality at 90 days (HR: 1.26; 95% CI: 1.17–1.34; p < 0.001), and mortality at 1 year (HR: 1.19; 95% CI: 1.13–1.26; p < 0.001). Furthermore, patients in the higher quartiles of SII demonstrated an increased risk of in-hospital mortality, as well as mortality at 90 days and 1 year. The trend test across quartiles showed a statistically significant positive association between higher SII levels and increased mortality risk in all models. Stratified analysis and interaction tests demonstrated that the association between SII and in-hospital mortality remained stable.ConclusionOur study demonstrates that a high SII is independently associated with an increased risk of mortality in critically ill COPD patients. SII may serve as a risk stratification and prognostication tool in patients with COPD. Larger prospective studies are needed to validate these findings.

Multi-Cancer Early Detection (MCED) represents a promising approach with the potential for high sensitivity in detecting rare tumor-derived signals in the blood. However, contamination from adjacent samples or from environmental sources poses significant challenges that can compromise the accuracy of these results. Current contamination detection methods primarily designed for tissue samples, leaving a notable gap in methodologies for assessing low-level contamination in cfDNA targeted methylation sequencing data in blood. The challenges include the absent of matched control samples, low sequencing depth, and probe capture bias. To address these limitations, we have developed a machine learning-based method aimed at improving contamination detection accuracy in MCED datasets. We first identified single nucleotide polymorphisms (SNPs) with high prevalence in the East-Asian population. We calculated the allele frequencies of SNPs using in-silico synthetic contaminated samples and fitted the distributions of allele frequencies at varying contamination levels to identify informative SNPs. To enhance signal-to-noise value, we constructed features based on reads containing alternative bases of these informative SNPs at each tier, which was categorized according to its coverage and assumed contamination levels. This comprehensive feature matrix was used to train an XGBoost algorithm on 185 normal samples and their corresponding in-silico synthetic contaminated samples. The performance of our approach was validated using two distinct datasets: the first set comprised in-silico simulated contamination samples with contamination levels ranging from 0.05% to 10%, while the second was built by titrating three healthy cfDNA samples into three other healthy cfDNA backgrounds, with titration levels ranging from 0.05% to 2%. This method effectively identifies contamination, particularly in scenarios where coverage at SNPs is relatively low, ranging from 50X to 300X. It demonstrated the ability to detect contamination levels as low as 0.2% in the titrated samples, with an in-silico limit of detection (LoD) established at 0.1%. We have developed SCANs, a tool designed to address the challenges posed by low sequencing depth and capture bias-induced abnormal allele signals in methylation data. SCANs enables the detection of low-level contamination, thereby facilitating the precise analysis of cfDNA methylation data in MCED. Shaohua Ma, Chaoyang Liang, Shuliang Guo, Luyan Shen, XiaoSheng He, Zhihui Xu, Jing Zhao, Yonghui Li, Shiqing Chen, Baoliang Zhu, Xiaohui Wu. SCANs: SNP-based contamination assessment with nuanced signal in targeted methylation sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2493.

Background: The relationship between albumin-corrected anion gap (ACAG) and in-hospital mortality in critically ill patients with COPD remains unclear. Objective: This study investigated the association between ACAG levels and the risk of in-hospital mortality in critically ill patients with COPD. Design: A retrospective cohort study. Methods: This study uses data from the Medical Information Mart for Intensive Care (MIMIC-IV) database. The receiver operating characteristic (ROC) curve was used to determine the optimal threshold for ACAG, and participants were divided into two categories based on this threshold. The primary outcome was in-hospital mortality. We employed univariable and multivariable logistic regression analyses and Kaplan–Meier (KM) survival curves to assess the relationship between ACAG and the risk of in-hospital mortality. Moreover, subgroup analyses were conducted. Results: A total of 2121 patients (54.7% male) were enrolled in the study. The in-hospital mortality rate was 18.9%. In patients with elevated ACAG levels, the in-hospital mortality rate was significantly higher than in those with lower ACAG levels (27.7% vs 11.3%, p < 0.001). Multivariate logistic regression analysis indicated that even after mitigating for potential confounders, patients in the high ACAG group had significantly greater odds of in-hospital mortality across all models (Model I: OR = 3.000, 95% CI: 2.383–3.777, p < 0.001; Model II: OR = 3.021, 95% CI: 2.397–3.808, p < 0.001; Model III: OR = 1.916, 95% CI: 1.458–2.519, p < 0.001). Patients with elevated ACAG levels have more than twice the risk of in-hospital mortality compared to those with lower levels (hazard ratio (HR): 2.1277, 95% CI: 1.7490–2.5884). Conclusion: This study demonstrates that elevated ACAG levels are strongly associated with an increased risk of in-hospital mortality in critically ill COPD patients, suggesting that ACAG could serve as a potential predictor of adverse outcomes in this patient population.