Prophylactic cranial irradiation (PCI) is the standard preventive strategy for limited-stage small-cell lung cancer (LS-SCLC). However, the evidence supporting this strategy is largely based on the pre-MRI era. With the advancement of modern MRI and treatment techniques, the survival benefit of PCI remains unclear, particularly given the potential for neurocognitive toxicity to impair quality of life. This study aims to re-evaluate the value of PCI in contemporary LS-SCLC patients and investigate whether active MRI surveillance is non-inferior to PCI regarding overall survival (OS). This is a prospective, randomized, multicenter, phase III trial, enrolling patients with LS-SCLC who achieve complete response (CR) or partial response (PR) after platinum-based chemoradiotherapy. Participants will be randomly assigned (1:1) to receive either PCI or active MRI surveillance. The primary endpoint is OS. Secondary endpoints include 1- and 3-year OS rates, progression-free survival (PFS), brain metastasis rate, and neurocognitive function. Exploratory analyses will integrate clinical characteristics with the longitudinal kinetics of tumor biomarkers in collected peripheral blood to identify patient subgroups who are more likely to benefit from PCI. This study will re-evaluate the role of PCI in the MRI era for LS-SCLC. If active MRI surveillance proves non-inferior, it may provide evidence supporting a less intensive management approach that could potentially reduce treatment-related neurotoxicity and preserve quality of life. Furthermore, our trial aims to identify patient subgroups that derive a clinical benefit from PCI, and leverage serial biomarker dynamics to guide personalized clinical management for LS-SCLC patients. This trial is registered at ClinicalTrials.gov (NCT04829708).
Currently, there remains a lack of effective prognostic biomarkers specifically for ARDS patients. We conducted a retrospective study profiling plasma metabolomics (ARDS = 55, non-ARDS = 37) via high-throughput NPELDI-MS. Machine learning (LR, SVM, NN) developed age-stratified prognostic models (< 65 vs. ≥65 years). Univariate logistic regression identified key mortality-associated metabolites in elderly ARDS, followed by cross-platform validation. The plasma metabolic fingerprints-based model distinguished ARDS from non-ARDS with an AUC of 0.928, revealing systemic metabolic dysregulation involving amino acid metabolism, one‑carbon metabolism, cofactor biosynthesis, and glutathione‑related pathways. Furthermore, we developed age‑stratified prognostic prediction models: the AUC for distinguishing non‑survivors from survivors was 0.989 in < 65 years patients and 0.937 in ≥ 65 years patients, whereas mixed-age analysis showed limited metabolic separation between survivors and non-survivors. Importantly, age-stratified analyses identified distinct exploratory metabolite panels: phenylalanine and glycine showed nominal positive associations with mortality in patients aged ≥ 65 years, whereas taurine, hypotaurine and niacinamide showed nominal inverse associations in those aged < 65 years. Cross-platform validation confirmed the generalizability of elderly derived panel (AUC = 0.829), and further identified phenylalanine remained significantly elevated in elderly non-survivors. Our study establishes an integrated plasma metabolic fingerprinting framework for ARDS age‑stratified prognosis, and further identifies phenylalanine and glycine as elderly-specific metabolic risk factors for mortality, highlighting age-dependent metabolic vulnerability in ARDS. This trial is registered at ClinicalTrials.gov (identifier: NCT07380997).
Although immune checkpoint inhibitors (ICIs) have led to a fundamental shift in lung cancer treatment, evidence regarding infections remains limited. Pneumocystis jirovecii pneumonia (PJP) is a rare but life-threatening opportunistic infection with high mortality if undiagnosed or untreated, making its risk assessment clinically critical. This study aimed to provide population-based comparative evidence on the risk of PJP between ICI therapy and conventional cytotoxic chemotherapy (CC) in patients with lung cancer. Using the Korean nationwide claims data, we conducted a retrospective cohort study of patients newly diagnosed with lung cancer who initiated CC or ICI therapy between 2017 and 2022. After propensity score matching, incidence rate ratios (IRRs), Cox hazard ratios (HRs), and Fine-Gray subdistribution HRs (sHRs) were estimated. Sensitivity analyses were performed across clinically relevant subgroups, including those defined by advanced stage, surgical resection, radiotherapy, treatment line, ICI monotherapy, and systemic corticosteroid use. Additionally, risk patterns across specific ICI agents, including atezolizumab, pembrolizumab, durvalumab, and nivolumab, were evaluated in an exploratory analysis. After matching, 13,426 patients were included in each group. During follow-up, 27 and 66 PJP events occurred in the CC and ICI groups, respectively, corresponding to IRs of 3.35 and 7.77 per 1,000 person-years. ICI therapy was associated with a significantly higher risk of PJP (adjusted IRR 2.26, 95
Invasive pulmonary aspergillosis (IPA) is associated with elevated mortality among intensive care unit (ICU) patients. Early prognostic risk stratification is of great importance; however, validated clinical tools remain limited. This study aimed to develop and validate an interpretable machine-learning (ML) model to predict ICU mortality in critically ill patients with IPA. This multicenter study included a retrospective derivation cohort (n = 267, 2015–2025) and an independent prospective external validation cohort (n = 129, 2022–2025) of critically ill patients with IPA diagnosed per modified AspICU (BM-AsperICU) algorithm. Using baseline clinical features acquired within 24 h of initial IPA diagnosis, we evaluated 11 individual ML algorithms and 9 ensemble models to predict ICU mortality. Performance was assessed via area under the receiver operating characteristic curve (AUROC) with 95
Postnatal hypoxia in high-altitude regions drives pulmonary developmental impairment in neonates, which may subsequently progress to pulmonary hypertension and right ventricular failure. N6-methyladenosine (m6A) RNA modification regulates mRNA fate and cellular responses to stress; however, its role in neonatal PH remains unknown. In this study, we established a neonatal rat model of PH by chronic hypoxia exposure and investigated the role of the m6A demethylase AlkB homolog 5 (ALKBH5) using pharmacological inhibition, siRNA knockdown, and integrated m6A‑seq/RNA‑seq. Hypoxia reproduced the key features of pulmonary developmental impairment and pulmonary hypertension, including alveolar simplification, reduced vascular density, increased medial wall thickness, elevated right ventricular systolic pressure, and right ventricular hypertrophy. Hypoxia increased ALKBH5 protein in pulmonary vascular smooth muscle, which was inhibited by an ALKBH5 inhibitor 5-Carboxy-8-hydroxyquinoline. In pulmonary artery smooth muscle cells (PASMCs), hypoxia increased ALKBH5 protein levels. ALKBH5 knockdown increased total m6A levels and suppressed proliferation and migration of PASMCs. Integrated MeRIP-seq/RNA-seq identified enolase 2 (ENO2) as a downstream target of ALKBH5 in PASMCs. ALKBH5 knockdown decreased ENO2 mRNA stability; ENO2 overexpression rescued proliferation and migration suppressed by ALKBH5 knockdown in PASMCs. Furthermore, hypoxia increased ALKBH5 promoter activity and expression via hypoxia-inducible factor-1 alpha (HIF-1α), thereby promoting proliferation of PASMCs and pulmonary vascular remodeling. Targeting the HIF-1α/ALKBH5/ENO2 axis may represent a therapeutic strategy for neonatal PH.
Abstract Background Persistent airway epithelial abnormalities contribute to chronic obstructive pulmonary disease (COPD), but it remains unclear whether smoking- and COPD-associated epithelial remodeling is retained in airway basal cells and transmitted during differentiation. We determined whether current smoking and COPD are associated with methylation-linked regulatory programs in airway basal cells that shape epithelial differentiation in patient-derived bronchial organoids. Methods We integrated DNA methylation profiling and bulk transcriptomics in patient-derived airway basal cells and matched three-dimensional bronchial organoids. Methylation-defined gene sets were mapped to organoid epithelial cell states using single-cell RNA-seq and contextualized with publicly available airway epithelial datasets. Results In this exploratory cohort, current smoking was associated with a predominant shift toward promoter hypomethylation in airway basal cells and matched organoids. Hypomethylated promoters were enriched for genes preferentially expressed in secretory epithelial cells, including BPIFB1 , BPIFA2 , MSMB and GALNT6 . These genes showed little smoking-associated expression difference in basal-cell culture but were upregulated after organoid differentiation, indicating a differentiation-dependent epithelial memory of smoking. In COPD-derived basal cells, promoter methylation changes involved reduced xenobiotic metabolism and enhanced immune- and infection-related programs. Consistently, COPD-derived organoids showed reduced expression of detoxification-associated pathways and increased lysosomal, endocytic and host-defense programs. Conclusions Current smoking and COPD are associated with persistent methylation-linked regulatory alterations in airway basal cells that become functionally apparent during epithelial differentiation. These findings support a model in which airway basal-cell memory contributes to secretory, inflammatory and host-defense remodeling in chronic airway disease.
Patients with sarcoidosis have an increased risk for calcium metabolism disturbances, such as hypercalcemia and hypercalciuria. Previous studies suggest that nephrolithiasis (stone formation in the renal and ureter, often caused by dysregulated calcium balance) may occur long before sarcoidosis diagnosis and may be an early sign of not-yet-diagnosed sarcoidosis. We hypothesized that a history of nephrolithiasis is associated with future risk of sarcoidosis. In this population-based matched case-control study, we included individuals with sarcoidosis and matched general population controls and identified those with a history of nephrolithiasis in Swedish nationwide registers. Patients with sarcoidosis who received treatment within three months of their sarcoidosis diagnosis were classified as severe. Nephrolithiasis severity was defined based on the need for intervention, multiple stones and early onset. Conditional logistic regression models estimated adjusted odds ratios with 95
PESI and ESC risk classification are widely used for early risk stratification of acute pulmonary embolism (PE). The Composite PE Shock (CPES) score has been proposed to better identify normotensive shock. We compared the prognostic performance of PESI, ESC risk class, and CPES. We performed a retrospective chart review of consecutive adults with acute PE managed by PERT (PE Response Team) at three teaching hospitals within the Mount Sinai Health System from January 2020 through June 2024. Multivariable logistic regression was used to predict 30-day mortality. Discrimination was assessed using area under the receiver operating characteristic (AUROC) curves. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were calculated to assess incremental utility of CPES over PESI and ESC risk class. A total of 404 patients were included (median age: 65 years; 223 [55.2
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterized by high clinical heterogeneity. The conventional binary classification based on antineutrophil cytoplasmic antibody (ANCA) status inadequately captures this heterogeneity and provides limited guidance for individualised treatment decisions. This study aimed to identify and validate clinical-biological endophenotypes in EGPA using unsupervised machine learning methods based on multidimensional real-world clinical data, to inform precision medicine approaches. In this retrospective single-centre observational study, we included 205 patients diagnosed with EGPA between January 2015 and December 2023 at China-Japan Friendship Hospital. Comprehensive data on demographics, clinical manifestations, laboratory tests, imaging features, and treatment information were systematically collected. Consensus clustering combined with K-means algorithm was applied to identify patient subgroups based on 14 core features, including peripheral blood eosinophil count, fractional exhaled nitric oxide (FeNO), serum total IgE, C-reactive protein (CRP), ANCA status, and multi-system involvement. Principal component analysis was used for dimensionality reduction and visualisation. Differences in clinical characteristics, laboratory parameters, imaging patterns, and treatment responses were compared among the subgroups. An online prediction tool was developed and validated based on the clustering results. Consensus clustering analysis identified three stable endophenotypes (optimal cluster number k = 3). Subgroup 1 (n = 78, 38.0
Pediatric acute respiratory distress syndrome (ARDS) is a severe complication of community-acquired pneumonia (CAP) with high mortality, but the microbial and metabolic mechanisms driving its onset remain unclear. This study aimed to characterize these disturbances and identify potential biomarkers of progression using an integrated multi-omics approach. We conducted a multi-omics analysis of bronchoalveolar lavage fluid from 81 children with CAP, including those who progressed to ARDS, using 16 S rRNA gene sequencing and untargeted LC-MS/MS metabolomics. Microbial diversity, community composition, metabolic profiles, and functional predictions were compared between groups, and machine learning was applied to identify predictive metabolic signatures. Paired fecal multi-omics data from a subset of patients were analyzed to explore potential gut–lung interactions. The CAP-ARDS group exhibited significantly reduced microbial α-diversity, as indicated by lower Shannon (p = 0.012), Simpson (p = 0.015), and Sobs (p = 0.046) indices, alongside distinct compositional shifts characterized by Pseudomonas enrichment and Streptococcus depletion. Metabolomic profiling identified 83 differential metabolites, with pathway topology analysis highlighting perturbations in pantothenate and CoA biosynthesis, indole alkaloid biosynthesis, and steroid degradation. Terpenoid metabolism emerged as a convergent signal across omics layers: PICRUSt2-based prediction revealed increased terpenoid and polyketide metabolism (adj. p = 0.0642), and 7 terpenoid compounds were among the differential metabolites. Machine learning–selected metabolites demonstrated predictive potential for CAP progression in receiver operating characteristic (ROC) analysis. Correlation analyses based on paired fecal datasets tentatively imply that ectopic gut microbiota translocation may constitute a plausible factor linked to disease progression. This multi-omics study reveals marked microbial and metabolic alterations in pediatric CAP patients progressing to ARDS, with convergent terpenoid metabolism and possible gut–lung microbial translocation implicated in pathogenesis. This study was registered in the Chinese Clinical Trial Registry (ChiCTR) under the registration number ChiCTR2400089037 on 30 August 2024.
Lung adenocarcinoma (LUAD) escapes immune surveillance by building an immunosuppressive tumor microenvironment. Within that microenvironment, impaired natural killer (NK) cell function is considered an important mechanism promoting tumor progression and immune escape. However, the molecular networks that control NK cell function in LUAD remain incompletely defined. We therefore examined the role of the SOX2-OT/E2F1/HES6 axis in LUAD immunosuppression and defined its regulatory mechanism. We used the TIMER3.0 database to analyze the correlation between HES6 and NK cell infiltration. Clinical LUAD samples were then used to validate this correlation. The effect of HES6 on NK cell function was assessed by RT-qPCR, Western blotting, flow cytometry, LDH release assay, and ELISA. ChIP, dual-luciferase reporter assays, RNA pull-down, and immunofluorescence were used to define the regulatory relationships among SOX2-OT, E2F1, and HES6. Finally, we used a tumor-bearing mouse model to test how the SOX2-OT/E2F1/HES6 axis affects tumor growth and NK cell infiltration. HES6 expression was prominently downregulated in LUAD and positively correlated with NK cell infiltration levels. Functional assays unveiled that HES6 overexpression potentiated NK cell cytotoxicity directly, elevated the proportion of activated NK cells, and promoted the secretion of effector cytokines IFN-γ and TNF-α. Mechanistic investigations elucidated that the transcription factor E2F1 directly integrated with the HES6 promoter and repressed its transcriptional activity. The lncRNA SOX2-OT served as a molecular scaffold to potentiate the transcriptional repression of E2F1 targeting HES6. In vivo experiments confirmed that SOX2-OT overexpression prominently facilitated tumor growth and attenuated NK cell infiltration, while co-overexpression of HES6 abrogated this effect. SOX2-OT potentiates the E2F1-HES6 interaction via its molecular scaffold function, thereby suppressing NK cell function and driving immunosuppression in LUAD.
Alarmins, including Thymic Stromal Lymphopoietin (TSLP) and Interleukins 33 and 25 (IL-33 and IL-25), contribute to the pathophysiology of allergic and nonallergic asthma by evoking exacerbations in response to allergens, viruses, and environmental irritants (as reviewed in [1]). Current evidence shows that inhibiting alarmins reduces symptoms and exacerbations in obstructive lung diseases, including asthma [1]. Preclinical work has largely focused on alarmins’ role in modulating airway inflammation, but far less is known about how alarmins regulate airway tone (contraction and relaxation). We posit that IL-33, TSLP, and IL-25 exert distinct effects on airway contraction and relaxation in airways from non-diseased subjects and those with asthma.
Elarekibep (AZD1402/PRS-060) is an Anticalin, a new class of inhaled therapeutic proteins, which has been engineered to inhibit interleukin-4 receptor α-subunit (IL-4Rα) signalling, a key target in asthma. Two phase 1 randomized, first-in-human, dose-escalating, single-blind studies (NCT03384290; NCT03574805) investigated single ascending doses (SADs) or multiple ascending doses (MADs) of elarekibep compared with placebo. In the SAD study, healthy participants received a single inhaled dose of elarekibep 0.1–160 mg, intravenous doses of 1 mg or 2 mg, or matched placebo. In the MAD study, participants with mild asthma and elevated fractional exhaled nitric oxide (FeNO) received inhaled doses of elarekibep 0.2–60 mg or placebo twice daily for 10 or 17 days (single dose on day 10 in all but one cohort), continuously or intermittently. In total, 148 participants were enrolled across both studies. No safety concerns were reported. Treatment-emergent adverse events were experienced by 34.7
According to the French 2022 National guideline, antifibrotic therapy should be initiated as soon as a diagnosis of idiopathic pulmonary fibrosis (IPF) is made, taking into account the individual assessment of the expected benefit and risks of treatment. However, in practice, treatment may be deferred for various reasons. We aimed to assess the association between deferred antifibrotic initiation and survival, disease worsening, and healthcare resource utilization in incident IPF patients. We conducted a retrospective analysis of the French National Health Data System (SNDS) linked to the Colibri-ILD registry between 2016 and 2023. Clinical outcomes were compared between patients who initiated antifibrotic therapy promptly (up to 181 days after IPF diagnosis) and those initiating treatment between 182 and 365 days after IPF diagnosis (‘deferred initiation’). Stabilized Inverse Probability of Treatment Weighting (SIPTW) was used to minimize between-groups differences in demographic and clinical characteristics at diagnosis. The primary outcome was overall survival. Secondary outcomes included healthcare resource utilization and several time‑to‑event outcomes: initiation of supplemental oxygen therapy, respiratory‑related hospitalization, and disease worsening, defined as a composite of death, respiratory‑related hospitalization (including IPF exacerbation), or lung transplantation. A total of 207 patients (mean age 72.7 years; 23.2
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder driven by immune dysregulation and ferroptosis, with limited therapies addressing its underlying pathogenesis. Maxing Loushi Decoction (MXLS), a modified traditional Chinese medicine (TCM) formula, has shown clinical efficacy in COPD, but its molecular mechanisms remain unclear. This study aimed to explore the therapeutic mechanisms of MXLS in COPD. A COPD mouse model was established via cigarette smoke (CS) exposure combined with lipopolysaccharide (LPS) administration. MXLS was intragastrically administered, with dexamethasone (DX) as a positive control. Lung function, histopathological changes, CD4+ T cell subsets, PD-1/PD-L1 expression, and ferroptosis-related indicators were evaluated. In vitro experiments included Th17 polarization induction, CD4+ T cell-MLE-12 cell co-culture, and intervention with anti-PD-1 antibody. MXLS significantly improved lung function, alleviated airway inflammation and alveolar destruction in cigarette smoke- and LPS-induced COPD mice, with efficacy comparable to DX. MXLS downregulated PD-1/PD-L1 expression in lung tissue and CD4+ T cells, restored Th17/Treg balance by reducing Th17 cell frequency and increasing Treg cell proportion, and inhibited ferroptosis by reducing Fe2+ accumulation, restoring GSH/SOD levels, and upregulating ferroptosis-related protective proteins (GPX4, SLC7A11, FTH1). In vitro, MXLS-modulated CD4+ T cells alleviated epithelial cell inflammation and ferroptosis, and combining MXLS with anti-PD-1 antibody enhanced these effects. MXLS may exerts therapeutic effects in a cigarette smoke- and LPS-induced COPD model, at least in part through modulation of the PD-1/PD-L1 pathway, concurrently restoring Th17/Treg immune homeostasis and inhibiting ferroptosis. This study provides a scientific basis for MXLS as a potential COPD therapy. MXLS alleviates cigarette smoke- and LPS-induced COPD by targeting the PD-1/PD-L1 pathway, regulating immune dysregulation and ferroptosis. MXLS can both restore Th17/Treg immune balance and inhibit lung epithelial ferroptosis, thereby alleviating COPD-induced lung injury. MXLS exhibits efficacy comparable to dexamethasone with potential advantages in safety, offering a promising alternative for glucocorticoid-intolerant COPD patients.
Neoadjuvant chemoimmunotherapy has reshaped the treatment landscape for non-small cell lung cancer (NSCLC), yet critical gaps remain in real-time monitoring and personalized adaptation. In this observational study, patients were evaluated via imaging and multidisciplinary review for subsequent surgery or radiotherapy after neoadjuvant chemoimmunotherapy. Serial plasma samples for circulating tumor DNA (ctDNA) dynamics and mutational analyses were collected. The endpoint was event-free survival (EFS). A pognostic mutational signature was developed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression. Among the 138 patients, 46.4
Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy worldwide. Its pronounced heterogeneity and limited therapeutic options present substantial clinical challenges. Mitochondria and programmed cell death (PCD) markedly regulate tumor development, but their precise roles in LUAD pathogenesis remain unclear. This study aims to identify key genes associated with mitochondrial function and PCD, construct a prognostic model for LUAD, and investigate the prognostic significance and potential protumorigenic mechanisms of VDAC1 in this context. We integrated single‑cell RNA‑seq (GSE131907) with bulk transcriptomic data from TCGA‑LUAD and GEO. A LASSO‑Cox regression‑based prognostic signature was built and validated. Single‑cell subclustering, pseudotime trajectory, and cell–cell communication analyses were performed to dissect VDAC1’s cell‑type‑specific roles. In vitro functional assays (CCK‑8, colony formation, Transwell, flow cytometry, Western blot) and rescue experiments with the ROS scavenger NAC were conducted in A549 and H1975 cells. Co‑immunoprecipitation was used to examine the VDAC1–AKT interaction. A five‑gene prognostic signature (ACSL1, VDAC1, CYCS, GLS2, MPV17L) was established and validated, effectively stratifying patients into high‑ and low‑risk groups with distinct survival outcomes. Single‑cell resolution revealed that VDAC1 is highly enriched in malignant epithelial cells, inflammatory cancer‑associated fibroblasts, and immunosuppressive M2 macrophages, where it drives proliferation, extracellular matrix (ECM) remodeling, and lipid metabolic reprogramming, respectively. VDAC1 was markedly overexpressed in LUAD tissues and cell lines; high VDAC1 expression independently correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. VDAC1 knockdown suppressed proliferation, migration, invasion, and EMT, induced G0/G1 arrest and apoptosis, decreased ATP production and oxygen consumption rates, and increased ROS levels. Mechanistically, VDAC1 activated the PI3K/AKT/mTOR pathway and directly interacted with AKT (co‑immunoprecipitation). NAC‑mediated ROS scavenging only partially rescued the si‑VDAC1‑induced suppression of signaling, EMT, and proliferation, indicating a ROS‑dependent mechanism complemented by a ROS‑independent direct interaction. Additionally, VDAC1 expression was negatively correlated with most antitumor immune cells and positively associated with immune checkpoint molecules (e.g., PD‑L1), suggesting an immunosuppressive microenvironment. We present a novel mitochondria‑ and PCD‑related five‑gene prognostic model for LUAD. VDAC1 is identified as a key oncogenic driver that promotes LUAD progression through dual mechanisms: ROS‑mediated activation of PI3K/AKT/mTOR signaling and direct physical interaction with AKT, leading to EMT, metabolic reprogramming, and immunosuppressive microenvironment remodeling. These findings establish that VDAC1 is a promising prognostic biomarker and a potential therapeutic target in LUAD.
Abstract Background Respiratory syncytial virus (RSV) is a major cause of acute respiratory infection (ARI) in adults aged ≥ 60 years, but data on its outpatient epidemiology and societal costs remain limited. Methods BUCOSS was a prospective observational study conducted over 3 seasons (2022/23–2024/25) in adults aged ≥ 60 years presenting with ARI to 29 outpatient practices in Germany. Multiplex PCR testing was performed at baseline. RSV-positive patients were prospectively followed for up to 28 days. Clinical and socioeconomic burden, including direct medical, indirect, and patient-borne out-of-pocket costs, was assessed using structured questionnaires on days 0, 14, and 28. Approximate national burden was estimated using incidence-based and ARE–prevalence-based extrapolation, including an additional scenario analysis excluding indirect costs. Results Among 3,261 patients with ARI, 192 (5.9%) had PCR-confirmed RSV infection. RSV prevalence was 5.49%, and estimated RSV incidence was 1,030.6 cases per 100,000 population. After exclusion of 4 patients hospitalized at baseline, 188 patients were included in the outpatient cost analysis. Mean age was 71.6 (SD 8.52) years, 57.4% were female, and 60.1% met the study high-risk criteria. Mean societal cost per episode was €510.0 (SD €742.58); costs were highest in patients aged 60–64 years. Total costs comprised direct medical costs of €161.3 (SD €59.57), indirect costs of €331.8 (SD €746.75), and out-of-pocket costs of €16.9 (SD €22.25), corresponding to 31.6%, 65.1%, and 3.3% of total societal costs, respectively. Indirect costs were driven almost entirely by productivity losses. Approximately 40% of cases occurred in adults without study-defined high-risk status. The two extrapolation approaches yielded approximate estimates of 258,000–374,000 medically attended outpatient RSV cases per season among adults aged ≥ 60 years in Germany, corresponding to €131.7–190.9 million in societal costs. In a scenario analysis excluding indirect costs, the estimated burden decreased to €46.0–66.7 million per season. Conclusions RSV is an economically important cause of outpatient ARI in older adults. These findings highlight a substantial outpatient burden beyond inpatient care and support RSV prevention strategies in aging populations.
Adult eosinophilic asthma (EA) is a predominant phenotype of severe asthma. Induced sputum cytology, the diagnostic gold standard, is limited by complex procedures and poor feasibility. Non-invasive type 2 markers perform unsatisfactorily, and existing machine learning models lack interpretability and clinical accessibility. This study aimed to construct a machine learning (ML)-based prediction model for EA to enable accurate phenotyping and personalized precision treatment of asthma. A single-center retrospective study was performed at a tertiary hospital in China. A total of 734 asthmatic patients who underwent induced sputum cytology were screened, and 503 were ultimately included. Data preprocessing, missing value imputation, and feature normalization were conducted within the training set to avoid data leakage. Ten ML algorithms were developed with hyperparameter tuning and internal cross-validation for model optimization. Model performance was assessed using AUC, calibration curves, DCA, accuracy, sensitivity, specificity, precision, F1-score, and confusion matrix. The SHapley Additive exPlanations (SHAP) method was used to improve model interpretability. Our results showed that the K-Nearest Neighbors (KNN) model outperformed the other 9 ML algorithms. After feature selection, an interpretable final KNN model incorporating 6 features was developed, achieving the following performance metrics: AUC = 0.814, accuracy = 0.780, sensitivity = 0.845, specificity = 0.697, precision = 0.780, and F1-score = 0.811. Fractional exhaled nitric oxide (FeNO50) was the most important predictor, followed by blood eosinophil count (bEOS). A web-based prediction tool with a probability threshold of 0.391 was developed for clinical use. The developed ML model holds promise as a non-invasive alternative to induced sputum cytology for EA diagnosis. The corresponding web-based prediction tool is accessible at https://mm-zhou-2026.shinyapps.io/adult-eosinophilic-asthma-prediction/ and may help clinicians achieve rapid phenotyping and personalized precision treatment for adult asthma.
In patients requiring mechanical ventilation, normal aerosol dynamics are disrupted by the artificial airway, circuit configuration and humidification systems. These factors can result in substantial drug losses within the ventilator circuit and markedly lower lung deposition than during spontaneous breathing, thereby potentially limiting therapeutic efficacy. A mechanistic proof-of-concept study using an in silico model has been conducted to evaluate aerosol deposition in the lung under differing delivery flow profiles. Digital Twinhale® technology was used to generate a subject-specific whole-lung model from CT-derived airway and lung geometry data from a healthy adult, using a 16-generation airway tree and calibrated physiological parameters. Aerosol transport was simulated with three-dimensional Lagrangian particle dynamics using in vitro droplet properties. Phase 1 of the study evaluated Aerogen vibrating mesh nebuliser (A-VMN), jet nebuliser (JN) and pressurised metered dose inhaler (pMDI) use under identical delivery flow profiles to assess the impact of the device on delivery efficiency and deposition patterns. In the second phase, deposition via VMN was assessed under two representative simulation scenarios: B1, a sinusoidal (volume controlled ventilation-like) waveform, and B2, a rectangular pressure (pressure controlled ventilation-like) waveform, using matched respiratory settings, including respiratory rate, inhalation-to-exhalation ratio and nominal tidal volume. Digital modelling allowed observation of differences in device performance, with the A-VMN yielding the highest deposited mass fraction across all lobes and lung regions, as well as the greatest level of functional deposition within the alveolar airways. Modelling ventilator mode-like inspiratory flow profiles allowed the observation that the highest deposited mass fraction was obtained with the B1 flow profile, whereas use of B2 resulted in a greater proportion of the emitted dose being lost to exhalation. Overall, differing flow profile had little effect on central-to-peripheral ratios, indicating that deposition patterns were mainly influenced by aerosol characteristics rather than differences in delivered dose or ventilation parameters. These findings support the feasibility of using a patient-specific in silico whole-lung model to compare predicted aerosol deposition under controlled conditions. However, further validation in multi-subject models and clinical studies will be required to determine whether these predicted deposition differences translate into meaningful clinical benefit.
