Disruption of parasympathetic pulmonary nerves, which release acetylcholine and trigger airway smooth muscle constriction, has been shown to improve lung function and alleviate symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the current targeted lung denervation (TLD) mono-polar radiofrequency (RF) ablation system has the potential for structural improvement to enhance the generalizability and safety of the TLD procedure. To develop a novel TLD multi-polar RF ablation for COPD treatment and evaluate its feasibility, safety, and efficacy. In the preclinical study, we performed TLD in vitro (porcine lung and liver model) to validate its feasibility and in vivo (dogs and sheep) to ensure its safety and preliminary efficacy. Subsequently, we conducted a first-in-man study to evaluate TLD in patients with COPD forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (FEV1/FVC < 0.70; FEV1 20

RATIONALE:High loop gain (HLG) of the respiratory control system during sleep, by enhancing respiratory drive, may reflect a more responsive ventilatory control mechanism and thereby be related to a lower rate of chronic airway disease progression. OBJECTIVE:To determine the effect of computationally determined expressed high loop gain via respiratory self-similarity (SS%) during sleep and the related central respiratory event index (CREI), on new onset of chronic airway disease and lung disease related mortality. METHODS:A secondary analysis of the Sleep Heart Health Study (SHHS) and the Osteoporotic Fractures in Men Study (MrOS). Both SS% and CREI were calculated from the chest and abdominal RIP signal. Logistic regression was applied to assess risk factors for incident chronic airway disease in the SHHS. Cox regression was done to explore the relationship between SS%, CREI and lung disease related mortality in the MrOS study. RESULTS:A SS% >3.80% (OR: 0.566, 95% CI 0.373-0.857, p: 0.007) and CREI >10.20 events/h (OR: 0.604, 95% CI 0.389-0.937, p: 0.025) was related with a lower incidence of chronic airway disease in the SHHS. Individuals with SS% (Q3: HR: 0.539, 95% CI 0.327-0.888, p: 0.015; Q4: HR: 0.480, 95% CI 0.293-0.786, p: 0.004) and CREI (Q3: HR: 0.471, 95% CI 0.286-0.776, p:0.003; Q4: HR: 0.398, 95% CI 0.232-0.682, p:0.001) in the highest two quartiles had lower lung disease related mortality, respectively. CONCLUSION:Expressed high loop gain during sleep was associated with a lower incidence of chronic airway disease and lung disease related mortality.

Background:High altitude polycythaemia (HAPC) has posed a major burden due to its high prevalence and multisystem involvement among highlanders, but clinical data on HAPC is scarce. We aimed to describe the clinical characteristics of patients with HAPC in China. Methods:Adult patients diagnosed with HAPC in five hospitals of China between August 2012 to May 2024 were retrospectively enrolled. We analysed information including demographics, living altitude, haemoglobin concentration (Hb) and comorbidities, and fitted restricted cubic splines models with multivariable adjustments to investigate the relationship between age, altitude and Hb. Results:A total of 1098 HAPC patients were included and 97 individuals of them did not provide information on ethnicity. Of the remaining 1001 participants, 93% were native Tibetans. The median Hb showed a significant difference (P < 0.0001) between male (21.9 g/dL, interquartile range (IQR) = 21.4-22.9 g/dL) and female patients (19.6 g/dL, IQR = 19.2-20.8 g/dL), and was slightly higher in Tibetans than Han migrants, especially in females (19.6 g/dL, IQR = 19.2-20.7 g/dL vs. 19.3 g/dL, IQR = 19.2-19.5 g/dL) (P = 0.198). Restricted cubic splines models revealed Hb exhibited a positive linear correlation with altitude (P-overall = 0.027, P-nonlinear = 0.291), with a rate of 0.3g/dL/1000 m of elevation, whereas no significant relationship with age (P-overall = 0.974, P-nonlinear = 0.860). The commonest comorbidities were hypertension (18.5%) and pneumonia (17.6%). Besides, heart failure (P < 0.001), chronic airway disease (P = 0.018) and pulmonary heart disease (P < 0.001) were more prominent in females while liver disease (P = 0.079) was more frequent in males. Conclusions:This study suggests a much higher proportion of HAPC in native Tibetans, and the Hb in HAPC patients remains significant gender-specific and altitude-dependent variations. Moreover, in addition to hypertension and pneumonia, gender-specific comorbidity surveillance should pay attention to digestive system disease in male HAPC patients and cardiopulmonary system disease in female HAPC patients.

OBJECTIVE:To investigate the prevalence and clinical characteristics of sleep apnea (SA) in patients with hypertrophic cardiomyopathy (HCM). METHODS:Eligible studies were screened and selected from four databases. The pooled prevalence of SA in HCM was calculated and presented as proportion with 95% confidence intervals (CI). Comparison of clinical characteristics between HCM patients with or without SA was then assessed and presented as mean difference (MD) or odds ratio (OR) with 95%CI. Sensitivity analyses, subgroup analyses and meta-regression were then applied for heterogeneity assessment. RESULTS:Eight studies with 3,922 HCM patients was included, revealing an SA prevalence of 53% (95% CI 39%, 67%). HCM patients with SA were associated with older age (MD 8.91, 95% CI 7.28, 10.54), male (OR 1.59, 95%CI 1.30, 1.95). elevated body mass index (MD 2.59, 95%CI 1.36, 3.81), smoking (OR 1.86, 95%CI 1.39, 2.49), hypertension (OR 2.54, 95%CI 2.06, 3.14), diabetes (OR 2.03, 95%CI 1.31, 3.13) and atrial fibrillation (OR 1.96, 95%CI 1.51, 2.54). Echocardiographic findings revealed that HCM with SA was associated with reduced interventricular septum thickness (MD -1.25, 95%CI -2.44, -0.06), increased left atrial diameter (MD 1.48, 95%CI 0.49, 2.47) and left ventricular end-diastolic diameter (MD 2.81, 95%CI 1.99, 3.62). Additionally, HCM patients with SA showed increased application of hypertensive drugs, and application of calcium channel blockers was identified as source of heterogeneity in meta-regression. CONCLUSION:SA is highly prevalent in HCM, and HCM patients with comorbid SA exhibit distinct baseline characteristics, cardiac structure and drug application.

Exposure to hazardous aerosol represent critical driver of chronic and acute pulmonary diseases. Conventional inhalation risk assessments frequently rely on mean deposition indices and simplified mechanical models, failing to reproduce ventilatory heterogeneity, thereby masking regional difference in aerosol deposition. To elucidate the correlation between regional airflow dynamics and tissue vulnerability, we developed an anatomically full-scale digital lung model that incorporates nonlinear compliance and gravity-driven pleural pressure gradients to simulate particle deposition during quiet, up-right breathing in healthy adults. Numerical simulations of aerosol particles (0.1-10 µm) over a complete respiratory cycle revealed a distinct gravity-dependent heterogenous deposition pattern: The highest deposition intensity was observed in the right lower lobe and left lower lobe, while the lowest occurred in the right upper lobe. Three deposition hotspots were identified: two in the right lower lobe (0.53 %/m2) and left lower lobe (0.51 %/m2), spanning generations G21-G23 and enriched with particles of 3 µm in diameter, and one in the right lower lobe (0.48 %/m2), spanning generations G7-G10 and enriched with particles of 10 µm in diameter. Additionally, we use wielding fume as an example to demonstrate how to quantitatively calculate the regional surface deposition density and exposure time required to reach cytotoxicity thresholds, highlighting the model's ability to translate regional deposition patterns into biologically meaningful risk metrics. In conclusion, our full-scale digital lung model replicates human-specific airway branching and ventilation dynamics, offering a non-invasive digital platform for temporospatial evaluation of inhalation risks from hazardous aerosol.

Background:Although the link between smoking and various sleep disorders has been well-established, it is still unknown whether smoking increases the risk of restless legs syndrome (RLS). We investigated this association using a meta-analysis and explored the causality through Mendelian randomisation (MR). Methods:We searched six databases for studies reporting associations between smoking and RLS in overall adults, and the results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). We performed sensitivity, subgroup and meta-regression analyses to identify potential sources of heterogeneity. We obtained data used in MR analyses from the UK Biobank and the Genome-wide Association Studies Catalogue. We applied the inverse-variance weighted method, MR Egger, weighted median, simple mode and weighted mode for data analyses, and further conducted pleiotropy and heterogeneity tests, as well as leave-one-out analyses. Results:Based on 30 studies, we found that smoking was associated with increased risk of RLS (OR = 1.40; 95% CI = 1.17, 1.67, P < 0.001), with the risk significantly increased (P = 0.04) in pregnant women (OR = 2.41; 95% CI = 1.39, 4.16, P = 0.002) than in the non-pregnant adults (OR = 1.30, 95% CI = 1.09, 1.55, P = 0.004), and in current smokers compared with former smokers (OR = 1.09; 95% CI = 1.02, 1.16, P = 0.01). We identified multi-centre studies, diagnostic criteria for RLS and participants' age as potential sources of heterogeneity; however, MR results did not show any causal association between smoking and RLS (OR = 0.50; 95% CI = 0.16, 1.56, P = 0.23). Conclusions:Although the meta-analysis suggested that smoking increases the risk of RLS, MR analyses did not provide evidence for a causal relationship. Future studies are needed to elucidate the biological mechanisms underlying this association. Registration:PROSPERO: CRD420251048406.

Immunosenescence, the age-related decline in immune function, plays a crucial role in the pathogenesis and progression of lung diseases, including chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, asthma, and respiratory tract infections. This comprehensive review examines the hallmarks of immunosenescence, and illustrates the association between immunosenescence and the pathogenesis of lung diseases. In addition, we discuss current and emerging therapeutic strategies that have been evaluated in human clinical trials for targeting immunosenescence in lung diseases. Specifically, this review provides in-depth insights into the therapeutic strategies, including senolytics and senomorphics, immunotherapy, stem cell therapy, thymic rejuvenation, probiotics, and lifestyle. We also highlight the potential of personalized approaches integrating multi-omics data and artificial intelligence to guide biomarker-driven interventions, enabling truly personalized therapeutic strategies. Finally, this review underscores the imperative for rigorously designed clinical trials to develop and validate interventions that specifically target immunosenescence, with the ultimate goal of improving clinical outcomes for the aged population with lung diseases.

The impact of high altitude on patients with interstitial lung disease (ILD) remains unclear. This study aimed to describe the clinical characteristics of ILD patients in high-altitude regions. This retrospective observational study included patients diagnosed with Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease-associated ILD (CTD-ILD) hospitalized at two hospitals in Qinghai and Tibet between April 2018 and September 2021. Patients were categorized into high-altitude (≥ 2500 m) and low-altitude (< 2500 m) groups. Demographic, clinical, hematological, and pulmonary function data were collected and analysed. A total of 119 patients were enrolled, with 56 in the high-altitude group and 63 in the low-altitude group. Compared with the low-altitude group, the high-altitude group had a significantly greater proportion of CTD-ILD patients (42.2

Introduction This study investigated if high loop gain (HLG), a specific sleep apnea endotype characterized by unstable respiratory control, is independently associated with adverse cardiac remodeling. Methods Using the Multi-Ethnic Study of Atherosclerosis (MESA) data, a HLG surrogate was quantified using a polysomnographic algorithm measuring respiratory self-similarity (Central Respiratory Event Index [CREI] and respiratory Self-Similarity [SS%]). Cardiac structure was assessed via MRI. Multivariable linear regression analyzed probable HLG associations with the left ventricular mass-to-volume ratio (LVMVR). Propensity score matching compared SS and CREI between participants with and without reduced left ventricular ejection fraction (LVEF). Results Severe expressed HLG was defined as the top 2.5 % of CREI values, a criterion that categorized 35 of the 1440 participants, and showed higher LVMVR (1.23 ± 0.31 vs 1.03 ± 0.22, p < 0.001). After central sleep apnea (CSA) adjustment, severe expressed HLG remained an independent predictor for LVMVR (β = 0.110 ± 0.068, p = 0.002) with a significant sex interaction (p for interaction = 0.041), observed in males (β = 0.15 ± 0.09, p < 0.001) but not females. Reduced LVEF participants exhibited elevated SS% (11.41 ± 8.07 vs 8.13 ± 6.26, p = 0.037) and CREI (29.25 ± 19.50 vs 21.49 ± 19.86, p = 0.032). Post-PSM, differences persisted (SS%: 11.53 ± 8.26 vs 7.26 ± 7.07, p = 0 0.032; CREI: 28.96 ± 19.60 vs 18.15 ± 18.46, p = 0.041). Conclusion Expressed HLG may be an important biomarker for left ventricular modeling/HF progression and allow risk stratification for targeted management.

Sepsis remains a life-threatening syndrome, and septic liver injury is a frequent and critical complication for which no specific pharmacological therapy exists. Current biomarkers lack sufficient specificity for early diagnosis and severity assessment, highlighting an urgent need for novel diagnostic and therapeutic strategies. To identify key metabolites involved in sepsis pathogenesis and to evaluate the diagnostic and therapeutic potential of cholesterol sulfate (CS) in sepsis-induced liver injury, as well as to elucidate the underlying molecular mechanisms. We performed transcriptomic (GSE65682) and metabolomic (SepsisLiMetDB) screens sequentially and independently to identify sepsis-associated metabolites. The functional role of CS was evaluated in cecal ligation and puncture (CLP) mouse model using both exogenous CS supplementation and Sult2b1 genetic knockout approaches, as well as in vitro using primary hepatocytes and AML12 cells. The underlying molecular mechanisms were explored via molecular docking, molecular dynamics simulation, cellular thermal shift assay, co-immunoprecipitation, MDC staining, GFP-LC3/LysoTracker Red co-localization, ROS detection, and pyroptosis marker analysis in AML12 cells with or without Beclin1 knockdown. Therapeutic efficacy was compared with clinically used agents (reduning and ulinastatin) in a mouse endotoxemia model. Diagnostic potential was assessed in independent bacterial sepsis (n = 114) and COVID-19 (n = 43) cohorts. Through unbiased multi-omics screening, we identified CS as one of the most markedly depleted metabolites in sepsis. Sult2b1-deficient mice lacking endogenous CS showed exacerbated systemic inflammation, aggravated liver injury, and mortality—all of which were significantly reversed by exogenous CS supplementation. Mechanistically, CS directly bound Beclin1, suppressed its ubiquitin-proteasome degradation, enhanced autophagic flux, and attenuated oxidative stress and GSDMD-mediated pyroptosis. Notably, CS exhibited superior efficacy to Reduning and comparable therapeutic effects to Ulinastatin. Clinically, reduced circulating CS levels correlated with both bacterial and viral sepsis and with disease severity, supporting its potential diagnostic value. Our study establishes, for the first time, CS as a functionally protective metabolite in sepsis, with therapeutic efficacy superior to existing clinical agents, and identify circulating CS as a potential diagnostic biomarker for sepsis and disease severity.

Sensitive circulating tumor DNA (ctDNA) analysis is increasingly important for mutation monitoring and molecular stratification in cancer management, yet most current approaches depend on complex signal transducers, fluorescent labels and sophisticated instrumentation. Here, we present an amplification byproduct-induced nanozyme suppression (ABINS) strategy that uses amplification byproducts as functional signals for colorimetric ctDNA detection. By coupling exponential amplification reaction (EXPAR) with Cu3(PO4)2 microflower nanozymes (Cu3(PO4)2 MFs), pyrophosphate (PPi) generated during amplification selectively inhibits the peroxidase-like activity of the nanozymes, resulting in a straightforward signal-off visual readout. This assay enables highly sensitive detection of KRAS G12D ctDNA at the femtomolar level and effectively discriminates target mutants from wild-type sequences. Furthermore, as a proof-of-concept, the sensing paradigm reliably discriminated KRAS-mutant patients from healthy donors in clinical plasma samples, showing good agreement with PCR-based analysis. The ABINS strategy provides a simple amplification-coupled and label-free colorimetric approach for mutation-associated ctDNA analysis, while broader validation in larger clinical cohorts and more representative ctDNA models will still be needed to further define its practical performance.

BACKGROUND:Interstitial lung disease (ILD) comprises a heterogeneous group of disorders with diverse clinical behaviors, for which early diagnosis, accurate risk stratification, and timely intervention remain challenging. High-resolution computed tomography (HRCT) plays a pivotal role in ILD evaluation; however, conventional visual interpretation is limited by subjectivity and inter-observer variability. Recent advances in artificial intelligence (AI), particularly deep learning, have created new opportunities to improve imaging-based assessment throughout the ILD care pathway. SUMMARY:This review summarizes current applications of AI in ILD, with a focus on early detection, diagnostic classification, prognostic assessment, and longitudinal monitoring. AI-driven imaging analysis can enhance the identification of subtle interstitial abnormalities, improve classification of radiologic patterns, and generate quantitative biomarkers associated with disease severity and progression. Emerging multimodal models integrating imaging, clinical, and functional data may further refine risk stratification and support individualized management. Despite these advances, important barriers to widespread clinical implementation remain, including limited external validation, poor interpretability, data heterogeneity, and uncertain impact on patient-centered outcomes. KEY MESSAGES:AI is reshaping the role of thoracic imaging in ILD from descriptive interpretation toward quantitative and decision-supportive analysis. It also has the potential to optimize multidisciplinary discussion and improve efficiency in routine clinical workflows. To facilitate translation into clinical practice, future efforts should prioritize prospective validation, multimodal integration, and clinically meaningful implementation.

With rising global high-altitude travel, occupational exposure, and permanent habitation, the health burden of high-altitude-specific diseases and high-altitude-related diseases has become increasingly prominent, highlighting an urgent need for in-depth research and clinical solutions in high-altitude medicine. To bridge this gap, this prospective review first proposes the Hypoxia Stress-induced Multi-organ Injury (HSMI) Spectrum as a novel, unifying research paradigm—one that seeks to overcome the limitations of fragmented traditional research by integrating insights into hypoxia-driven multi-organ pathophysiology. Despite growing foundational advances, critical barriers remain: incomplete understanding of individual hypoxia susceptibility mechanisms, overreliance on subjective and non-mechanism-based diagnostic tools, and a profound translational chasm between basic research and clinical therapeutics, especially for vulnerable groups like neonates, the elderly, and females. Building on the HSMI framework, we outline a comprehensive advancement strategy that includes establishing an integrated systems-based research model leveraging multi-omics and machine learning, deciphering core hypoxia-driven molecular pathways, developing objective real-time diagnostic systems with biomarkers and portable imaging, and innovating mechanism-based precision therapeutics. Implementing this HSMI-centered model will strengthen the scientific foundation of high-altitude medicine, optimize the prevention, diagnosis, and treatment of high-altitude illnesses, and offer a scalable framework for addressing health challenges in extreme hypoxic environments worldwide.

IntroductionHealth conditions associated with rapid ascent to high altitudes remain prevalent and pose an ongoing challenge. While acute mountain sickness (AMS) typically occurs within the first few days after ascent, the physiological and molecular acclimatization processes during prolonged high-altitude exposure beyond the initial acute phase remain incompletely understood.MethodsThis cross-sectional study investigated physiological and transcriptomic dynamics during prolonged high-altitude exposure over a 23 day period at 4,104 m in 113 Chinese Han individuals. Linear regression analysis, time series analysis, enrichment analysis, and protein-protein interaction analysis were applied to reveal the physiological and molecular dynamic changes.ResultsFour physiological parameters (saturation of peripheral oxygen [SpO2], hemoglobin, hematocrit, and standard deviation of red blood cell distribution width [RDW-SD]) exhibit a significant positive linear trend with the duration of acclimatization at high altitude (DAHA). Notably, two distinct gene expression patterns (GEPs) following DAHA were characterized for the first time: a decreasing expression pattern (Pattern 1) and a “mountain-shaped” expression pattern—upregulated in the first week and then downregulated (Pattern 2). In comparing individuals who experienced or were experiencing acute mountain sickness (eAMS+, n = 56) with those who did not (eAMS-, n = 57), RNA-seq performed in a subset of 48 participants (eAMS+, n = 35; eAMS-, n = 13) identified 583 upregulated and 104 downregulated genes in the eAMS+ group. Among these, 398 upregulated genes and 10 enriched pathways were found to overlap with Pattern 2. By integrating baseline data from the GSE75665 database, five hub differentially expressed genes (DEGs)—BCL2L1, DCAF12, CDC34, PINK1, and UBB—were identified. These genes not only predict AMS susceptibility but also associated with molecular responses to prolonged high-altitude exposure. In particular, CDC34 and UBB are novel genes not previously mentioned.ConclusionThis study provides critical insights into key physiological trends and molecular expression dynamics associated with prolonged exposure to high-altitude environments.

BACKGROUND:The triglyceride-glucose (TyG) index is a new alternative marker for insulin resistance and metabolic dysfunction, which has recently been linked to lung health. However, the link among the TyG index, type 2 (T2) inflammation, and asthma is largely unexplored. OBJECTIVES:To explore clinical, inflammatory characteristics and exacerbations in patients with asthma grouped by the TyG index with or without T2 inflammation. METHODS:This was a prospective cohort study with 12-month follow-up based on the Australasian Severe Asthma Network. Patients with stable asthma were divided into the TyGlow and TyGhigh groups by the 75th percentile values of the TyG index. Subgroups were analyzed based on T2 status. All participants with stable asthma (n = 626) underwent multidimensional assessment and sputum induction. Univariate and multivariable negative binomial regression analyses were used to examine the relationship between asthma exacerbations and TyG index with or without T2 inflammation. RESULTS:Patients with asthma in the TyGhigh group (n = 156) had higher body mass index, worse metabolic function and airway obstruction, more comorbidities including diabetes and metabolic syndrome, and increased risk of exacerbations independent of T2 inflammation, compared with the TyGlow group (n = 470). Furthermore, the TyGhigh T2low group was at significantly increased risk of moderate-to-severe exacerbations (adjusted incidence rate ratio [IRR] = 2.54, 95% confidence interval [CI] = [1.56, 4.15], P < .001), emergency visits (adjusted IRR = 7.88, 95% CI = [2.71, 22.92], P < .001), and unscheduled visits (adjusted IRR = 2.87, 95% CI = [1.65, 4.98], P < .001). CONCLUSIONS:The TyG index is a promising biomarker of asthma exacerbations, highlighting the clinical relevance of assessing the TyG index in asthma management.

Pulmonary injuries resulting from surgical procedures or accidental trauma pose significant clinical challenges, frequently leading to complications such as air leakage, inflammation and abnormal tissue regeneration. Current therapeutic approaches remain inadequate to simultaneously prevent air leakage and facilitate effective pulmonary tissue regeneration. To address this, we developed a photocrosslinkable hydrogel, Lung-ma gel, derived from decellularized porcine lung extracellular matrix. Both in vitro and in vivo results showed that Lung-ma gel exhibits superior adhesive properties, enabling stable attachment to lung wound surfaces throughout respiratory cycles for effective sealing and prevention of air leakage. Moreover, Lung-ma gel preserves the inherent regenerative properties of the lung extracellular matrix, significantly enhancing epithelial cell proliferation, promoting angiogenesis, attenuating inflammatory responses and inhibiting fibrosis in injury sites, outperforming clinically used sealants, AA gel and fibrin gel. Transcriptomic analysis further revealed that Lung-ma gel specifically activates Wnt and Notch signaling pathways, orchestrating coordinated cascades for pulmonary angiogenesis and tissue regeneration. Collectively, Lung-ma gel is a novel dual-functional therapy that promote comprehensive pulmonary repair by combining effective mechanical sealing with functional tissue regeneration.