Signal Transduction and Targeted Therapy

BackgroundMore than 6.2 million people have died already from COVID-19. Drug resistance and relapse cases from first generation therapeutics calls for development of new drugs in alternative medicine. Complementary and Alternative Medicines (CAM) that include herbal remedies and phytochemicals are usually not fully integrated into mainstream healthcare systems. The study proposes a CAM remedy, a new polyherbal formulation NAOQ19 against the SARS-CoV-2. MethodsThe present study consists of invitro and invivo evaluation of NAOQ19 against SARS-CoV-2 infection. First, invitro testing of NAOQ19 anti-viral activity was carried out on three relevant cell lines: Vero E6, A549ACE2 and Huh 7.5.1 ACE2TMPRSS2. Next, animal model testing of NAOQ19 was performed in Syrian golden hamsters along with positive control Remdesivir and infection control for 3 days to determine the efficacy and safety of the formulation. Finally, a double blind randomized clinical trial with mild to moderate COVID-19 infected patients were evaluated to test the efficacy of NAOQ19 in human settings. ResultsThis study demonstrated a strong anti-viral (low EC50) activity in cell culture with live virus and exhibits reduced plaque forming units (high antiviral activity) in the Syrian golden hamster model. Moreover, in the clinical trials, NAOQ19 shows high efficacy demonstrating early recovery and reduced levels of inflammatory biomarkers among COVID-19 infected patients. ConclusionThis novel polyherbal formulation NAOQ19, demonstrates strong anti-viral activity in preclinical and clinical study; thereby proving its candidacy as a low-cost alternative medicine with minimal adverse effects.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapies and poorly defined cross-tissue immune mechanisms. We performed single-cell RNA sequencing and TCR profiling of paired lung, lymph node, and peripheral blood samples from patients with IPF, combined with functional coculture assays and mouse model. We identified GZMK-high CD8 T cells enriched in fibrotic lungs, displaying inflammatory but low-cytotoxic features. TCR and trajectory analyses indicated that these cells originate from lymph-node CD8_HSPA1A cells and migrate to the lung. Higher GZMKCD8 T-cell levels correlated with impaired lung function and worse outcomes. Mechanistically, GZMK-overexpressing CD8 T cells promoted fibroblast-to-myofibroblast differentiation and proliferation through TGF-{beta}1 signalling, while GZMK inhibition reduced fibroblast activation and collagen deposition. Pharmacological blockade of TGF{beta}R1/ALK4 with TEW suppressed fibroblast activation in vitro and significantly attenuated pulmonary fibrosis in vivo. Together, these findings identify a lymph node-to-lung migration axis of GZMKCD8 T cells that drives fibroblast activation through TGF{beta}R1/ALK4 signalling, highlighting GZMK as a potential biomarker and therapeutic target in IPF.

IntroductionThe Japanese Ministry of Health, Labour, and Welfare proposed increased copayments for over-the-counter (OTC)-like drugs, with possible special consideration for certain chronic diseases, although the specific diseases to be included were not clarified as of January 2026. The costs attributable to OTC-like drugs indicated for chronic diseases in adults remain unclear. MethodsUsing the DeSC database (individual-level claims data) in fiscal year 2023, we estimated the average per-person annual costs of the study OTC-like drugs indicated for adults with representative chronic diseases. The estimates were stratified by sex and age. We also computed the national estimates of the numbers of adults with representative chronic diseases who would need OTC-like drugs and the costs attributable to these drugs by applying stratum-specific estimates from the DeSC database to national population counts and aggregated claims data from the National Database of Health Insurance Claims Open Data. The study OTC-like drugs included oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), topical anti-inflammatory patches, oral second-generation antihistamines, and heparinoid-containing topical preparations. ResultsThe average per-person annual costs were several hundred yen for acetaminophen and several thousand yen for the other drug categories, with marked variation by drug category, chronic disease, age, and sex. In the national estimates, the proportion of OTC-like drug users with representative chronic diseases was <10% in every disease-age-sex stratum; nevertheless, the maximum stratum-specific shares of total OTC-like drug costs attributable to these groups were high (up to 50-60% for osteoarthritis for acetaminophen/NSAIDs/patches and up to [~]60% for atopic dermatitis/asteatosis for heparinoids). ConclusionsThe average per-person annual costs for OTC-like drugs varied substantially across drug categories and patient subgroups. Indicated chronic diseases in adults may account for substantial OTC-like drug costs within some strata, despite representing a small fraction of users.

Acute respiratory failure causes millions of deaths worldwide each year, highlighting the need for a better understanding of its pathophysiology and approaches to identify treatment-responsive subphenotypes of patients. Although subphenotypes of acute respiratory failure have been described using peripheral blood biomarkers, it remains unclear whether lung-specific molecular profiles can define biologically and clinically meaningful subphenotypes. In this study, we identified four distinct subphenotypes based on the measurement of twenty-five soluble proteins in alveolar fluid collected from 466 patients with acute respiratory failure. Forty-eight of these participants also underwent immunophenotyping by spectral flow cytometry to characterize immune cell populations. Twenty-eight-day mortality was significantly different across the four subphenotypes. The subphenotype with lowest mortality (12.7%) showed elevated levels of soluble PD-L1, enrichment of T cell-related chemokines, and the highest proportion of memory CD8+ T cells. A subphenotype characterized by globally low soluble protein levels and higher proportions of exhausted T cell subsets had a mortality rate of 22.1% despite relatively moderate illness severity. The subphenotype with the highest mortality (29.4%) exhibited increased pyrogenic and neutrophil-associated alveolar mediators. Severity of respiratory failure varied markedly between subphenotypes, while non-pulmonary organ failures were similar across groups. We developed a parsimonious classifier to predict subphenotypes in two additional cohorts totaling 122 patients. The clinical differences between the subphenotypes were similar across cohorts, although associations with mortality were not detected in the smaller validation cohorts. These findings identify novel subphenotypes of acute respiratory failure and support integrating lung-specific molecular measures into future studies to advance precision-medicine approaches. One Sentence SummaryThis study identifies novel subphenotypes of acute respiratory failure that exhibit highly distinct immune signatures and associations with clinical outcomes.

Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza and SARS-COV-2 driven pneumonia. Our analysis revealed highly pneumonia type specific proteomic signatures, including COVID-19 specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V-domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry driven autoantibody profiling in two independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.

There is an unmet need to identify biomarkers of active thyroid eye disease (TED). scRNAseq revealed that orbital fibroblasts from orbital decompressions in people with TED express high levels of thyroid hormone receptors, growth factor receptors, including insulin-like growth factor 1 receptor (IGF1R), and extracellular matrix proteins including SPARC (osteonectin), whereas orbital fat endothelial cells expressed thyroid peroxidase (TPO). SPARC was significantly raised in the serum of people with thyroid disease compared to healthy controls. Furthermore, those with moderate, severe and sight threatening TED had higher SPARC levels than those with thyroid disease but free of TED or mild TED. Free-triiodothyronine (FT3) levels were positively correlated with SPARC in moderate-sight threatening TED. SPARC and IGF1 were positively correlated across people with thyroid disease alone, as well as TED. Thyroid stimulating hormone (TSH) levels were negatively correlated with SPARC in moderate-sight threatening TED. When participants were followed longitudinally, SPARC decreased after the active phase of TED. At the protein level, immunohistochemistry indicated that SPARC was heterogeneously expressed by fibroblasts in both control and TED orbital fat. SPARC is a key mediator of fibrosis and deposition of extracellular matrix and the correlation of SPARC serum levels to TED status and FT3 make it a promising biomarker of active TED.

ObjectivePost-thrombotic syndrome (PTS), a common complication of deep vein thrombosis, lacks objective diagnostic biomarkers and its molecular mechanisms remain poorly understood. This study aimed to identify plasma biomarkers and clarify pathways using integrated multi-omics and machine learning. MethodsProteomic and metabolomic profiling of 75 PTS patients and 75 controls was performed. Differential expression analysis, pathway enrichment, and protein-metabolite network analysis were conducted. A multi-algorithm machine learning with 8 feature selection methods prioritized biomarkers. Validations and 14 models were assessed. Results1,104 proteins and 1,891 metabolites were differentially expressed. Citrate cycle and unsaturated fatty acid biosynthesis were enriched. Three proteins, namely DIP2B, KNG1, and SUCLG2, were consistently selected as core biomarkers. All of these proteins were significantly downregulated in PTS and externally validated. A random forest model utilizing these proteins achieved an accuracy of 97.7% in independent testing, with SUCLG2 being the most influential predictor. ConclusionThis study identifies a novel three - protein biomarker panel for the diagnosis of PTS and reveals an immunometabolic axis in the pathogenesis of PTS, which links inflammatory regulation with mitochondrial energy metabolism. These findings provide valuable insights into the development of diagnostic tools and targeted therapeutic approaches.

AimsNonsteroidal anti inflammatory drugs (NSAIDs) are a leading cause of drug hypersensitivity reactions (HRs), yet genetic determinants of individual susceptibility remain unclear. Growing evidence implicates oxidative stress in these reactions. This study aimed to identify genetic variants in redox and immune related pathways associated with cross reactive NSAID hypersensitivity (CR NSAIDs) and single NSAID induced urticaria/angioedema/anaphylaxis (SNIUAA), and to characterize their functional relevance. ResultsGenetic association analyses identified significant associations between NSAID HRs and single nucleotide variants (SNVs) in genes involved in redox homeostasis. In CR NSAIDs patients, SNV GSTM5 rs11101989 and GSTZ1 haplotype (rs1046428, rs7975, rs7972) were associated with increased risk of developing HRs, suggesting impaired glutathione dependent detoxification as the underlying factor. Functional analyses demonstrated that carriers of the GSTM5 rs11101989 CC genotype had significantly reduced serum GST activity. In SNIUAA patients, SOD1 variants (rs2070424 and rs2833483) were consistently associated with increased susceptibility and reduced serum superoxide dismutase activity. Additionally, AKR1C3 rs34186955 is also associated with increased susceptibility whereas the variants AKR1C3 rs12529 and IL4R rs1805016 are associated with decreased susceptibility, highlighting the interplay between prostaglandin metabolism, redox regulation, and immune signalling. InnovationIntegration of genetic and functional enzymatic validation provides mechanistic evidence that oxidative stress pathways modulate distinct NSAID hypersensitivity phenotypes. Identification of GSTM5 and SOD1 variants with measurable functional impact establishes promising biomarkers to guide personalized risk assessment. ConclusionGenetic variability in oxidativestress and immune regulatory pathways influences susceptibility to cross reactive and selective NSAID hypersensitivity, supporting biomarker based strategies for safer NSAID prescribing.

ObjectivesTo evaluate the efficacy and safety of sitafloxacin-containing regimens versus non-sitafloxacin therapy in patients with nontuberculous mycobacterial (NTM) pulmonary disease, focusing on sputum/BALF conversion rate, time of sputum/BALF culture conversion and radiographic improvement. MethodsThis retrospective cohort study analyzed 149 adults (76 control group vs. 73 sitafloxacin group) with NTM pulmonary disease treated between 2021 to 2024. Inclusion criteria: (1) Sitafloxacin group: [&ge;] 3 months of sitafloxacin-based therapy; (2) Both groups: Confirmed diagnosis of NTM pulmonary disease and age [&ge;] 18 years old. Exclusion criteria: extrapulmonary/disseminated NTM, HIV, active tuberculosis, or incomplete clinical data. Primary endpoint: culture conversion rate and time to culture conversion. Secondary endpoints: radiographic improvement and adverse events (AEs). ResultsThe sitafloxacin group demonstrated significantly higher conversion rate (53.8% vs. 22.1%, P 0.001) and faster culture conversion than the control group without sitafloxacin (median 195 vs. 292 days, P 0.001). Radiographic improvement was more frequent with the sitafloxacin group (54.5% vs. 36.1%, P = 0.046). Compared to the control group, the sitafloxacin group exhibited no significant adverse events. ConclusionsSitafloxacin-based regimens accelerate microbiological clearance and promote radiographic healing in NTM pulmonary disease with good safety, positioning it as a viable drug for improved treatment of NTM infections.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pathway-specific markers. We demonstrate that BMPR-II in flow cytometrically characterised white blood cell subsets is reduced in a proportion of patients, however proteomic analysis demonstrates pleiotropic alterations of TGF{beta}/BMP modulators. Downstream BMPR-II canonical and non-canonical signalling is impacted and measurable in whole blood. We present discovery and international replication cohorts for a transcriptomic BMPR-II signalling signature. The composite biomarker panel is repeatable, reproducible, longitudinally stable and expressed in correlated gene modules in PAH which associate with clinical outcomes. The assay performance characteristics of the biomarker panel make it feasible for early phase, target engagement clinical trials and an adaptive three arm study of two pre- clinically validated modulators of BMPR-II is underway. One Sentence SummaryThe first demonstration of clinically-relevant BMP biomarker panels validated in international populations of patients with PAH.

BackgroundCYFRA 21-1, a cytokeratin-19 fragment, is a validated serum biomarker for non-small cell lung cancer (NSCLC). However, most studies rely on single time-point measurements, limiting its specificity in differentiating malignancy from benign pulmonary conditions. Inspired by the clinical utility of serial PSA measurements in prostate cancer, we investigated whether longitudinal trends in CYFRA 21-1 could enhance diagnostic and monitoring capabilities in patients with pulmonary nodules Methods and FindingsWe analyzed 132 patients with pulmonary nodules, including 41 with lung cancer and 91 with benign diagnoses. CYFRA 21-1 levels were measured serially using electrochemiluminescence assays. Longitudinal trends were assessed using linear mixed-effects models to estimate biomarker trajectories. Subgroup analyses examined differences between benign, untreated cancer, and post-treatment cancer groups, as well as within-patient changes in a subset of 16 cancer patients with both pre- and post-surgical measurements. Log-transformed data were used for the analysis. At baseline, CYFRA 21-1 levels were significantly higher in malignant versus benign nodules. Over time, CYFRA trajectories diverged: benign cases showed slight increases, whereas cancer patients exhibited greater biomarker volatility. In treated cancer patients, trend of CYFRA levels on the natural log scale decline from -0.00137 pre-surgery to - 0.00263 to post-surgery, and both cancer groups showed significantly higher absolute slopes than the benign group (p < 0.05). While pre- vs post-treatment slope differences did not reach significance (p = 0.211), the general pattern indicated that CYFRA 21-1 is a dynamic marker responsive to tumor presence and removal. ConclusionsCYFRA 21-1 exhibits substantial within-patient variability over time, with trajectories that reflect disease state and treatment. These findings suggest that longitudinal monitoring of CYFRA 21-1--analogous to PSA velocity in prostate cancer-- may offer improved diagnostic and prognostic insight in the evaluation of pulmonary nodules. Further studies in larger cohorts are warranted to validate these findings and explore clinical implementation of CYFRA trajectory analysis.

Inflammatory pain is a major clinical challenge, yet appropriate human models mimicking local infection are lacking. We established a novel human pain model based on intradermal administration of lipopolysaccharide (LPS), a component of Gram-negative bacteria, and investigated the time course and underlying molecular mechanisms of inflammatory pain hypersensitivity. In a placebo-controlled pilot study with 12 healthy subjects, the intradermal LPS injection induced hyperaemia peaking at 4.5 h and mechanical hypersensitivity peaking at 6 h. Hypersensitivity to increasingly acidic injections and mechanical pinch lasted longer than hyperaemia. The double-blind, randomized, placebo-controlled full crossover main study was completed by 40 subjects and investigated the role of the Receptor for Advanced Glycation End-products (RAGE). Co-injection of the RAGE antagonist azeliragon largely reduced LPS-induced hyperaemia (-87%) and significantly attenuated hypersensitivity to mechanical (-55%) and increasingly acidic stimuli (-40%). In contrast, the Toll-like receptor 4 antagonist resatorvid had no effect on any readout. In both naive and inflamed skin, TRPV1 antagonist BCTC inhibited the majority of acid-induced pain. LPS-induced inflammation caused a substantial shift in the pH sensitivity of pain, suggesting that even mild tissue acidification contributes to inflammatory pain. The human LPS skin inflammation model is largely RAGE-dependent, highlighting its potential as a target in inflammation.

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patients and 9 healthy controls. Differential expression, weighted gene co-expression network analysis (WGCNA), and protein-glycosylation correlation analyses were used to characterize molecular features. Clinical relevance was assessed via correlation and survival analyses. ResultsExtensive N-glycosylation reprogramming was observed in sepsis plasma,with marked enrichment in complement and coagulation pathways(KEGG p=7.76x10- {superscript 2}{superscript 1}).Pro-coagulant proteins(eg,vWF,fibrinogen)showed increased abundance together with enhanced site-specific glycosylation,potentially amplifying their activity.In contrast,key anticoagulant proteins(eg,SERPINC1)displayed unchanged glycosylation at critical sites despite abundance changes,which may impair function.Survival analysis revealed distinct prognostic values of glycoproteins and specific glycosylation sites.For instance,high vWF protein levels predicted mortality(HR=2.83),whereas elevated glycosylation at vWF N211 was associated with improved survival(HR=0.135),suggesting a negative regulatory role.These glycosylation markers correlated closely with disease severity and prognosis,representing potential early-warning biomarkers independent of current clinical coagulation indicators. ConclusionOur study demonstrates widespread reprogramming of the plasma proteome and N-glycome in sepsis.We propose that decoupling of protein function from abundance through N-glycosylation in the complement-coagulation network contributes to immunothrombotic imbalance.Specific N-glycosylation sites may serve as novel prognostic biomarkers,offering new perspectives for early risk stratification and glycosylation-targeted therapies in sepsis. Key PointsO_LISepsis plasma exhibits specific N-glycosylation reprogramming overwhelmingly focused on the complement and coagulation cascade. C_LIO_LIA dominant "glycosylation-dominated co-upregulation" mode in procoagulant factors, coupled with a "silent" glycosylation state in key anticoagulants, drives prothrombotic imbalance. C_LIO_LISite-specific N-glycosylation levels provide prognostic information distinct from, and often superior to, their carrier protein abundance, offering novel early-risk biomarkers. C_LI

ObjectiveMyositis-associated interstitial lung disease (myositis-ILD) consists of two predominant radiologic patterns of lung injury--nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)--that oftentimes coexist. However, it remains unclear whether either is associated with clinical outcomes. We aimed to assess the therapeutic response in patients with NSIP-compared to those with OP-predominant myositis-ILD. MethodsThis retrospective, single-center cohort study recruited participants from the Northwestern University ILD Registry with a circulating myositis-associated antibody, ILD, and at least 6 months of follow-up while on immunomodulatory therapy during a 24-month observation period after diagnosis. Two thoracic radiologists determined the predominant radiologic pattern (NSIP or OP). The primary outcome was the absolute change in forced vital capacity (FVC) at 24 months post-diagnosis. Secondary outcomes included changes in the diffusing capacity of the lung for carbon monoxide (DLCO) and radiologic qualitative and quantitative measures of lung injury. ResultsForty-one participants were included in analyses. 71% had an OP-predominant while 29% had an NSIP-predominant radiologic pattern of lung injury. Both exposure cohorts had improvement in mean absolute FVC (OP cohort = +0.18L [p=0.005], NSIP cohort = +0.24L [p=0.07]) over the 24-month observation period. The OP (p<0.05) but not the NSIP cohort (p=0.20) had an increase in DLCO. The OP cohort demonstrated improvement in the qualitative assessment of follow-up imaging (p<0.05), driven by quantitative improvement in groundglass/consolidative opacities (p=0.006). A subset of participants demonstrated features of NSIP/OP overlap and had greater baseline radiologic severity of lung injury. ConclusionPatients with circulating myositis-associated antibodies and an OP-predominant pattern of lung injury may have a more favorable response to therapy than those with NSIP. Further studies are needed to validate our findings and delineate other features cognate with these associations. Significance and InnovationsO_LIRadiologic phenotyping may predict therapeutic response in myositis-ILD. This study demonstrates that an OP-predominant computed tomography (CT) pattern of lung injury is associated with greater improvement in lung function and radiologic signs of inflammation over 24 months on at least 6 months of immunomodulatory therapy compared with an NSIP-predominant pattern, suggesting that CT pattern may provide clinically meaningful prognostic information. C_LIO_LIFirst study to integrate blinded qualitative radiologic adjudication with quantitative CT scoring in myositis-ILD. By combining dual-radiologist review with Kazerooni quantitative scoring and longitudinal pulmonary function testing, this study offers a rigorous and multidimensional assessment of treatment response. C_LIO_LIExpands risk stratification beyond antibody-based toward imaging-based phenotyping strategies. In a heterogeneous population defined by diverse myositis-associated antibodies, this work introduces radiologic pattern as a practical and accessible framework for anticipating treatment responsiveness. C_LIO_LIProvides hypothesis-generating data for precision management in myositis-ILD. The findings support the concept that imaging-defined subgroups may exhibit differential therapeutic trajectories, laying groundwork for future multicenter studies integrating CT phenotype, antibody profile, and treatment strategy. C_LI

BackgroundPeanut allergies continuously present urging public health challenges. Oral immunotherapy (OIT) is an important treatment option for peanut allergies, but its effectiveness varies, in terms of inducing desensitization (DS) or achieving long-term sustained unresponsiveness (SU). Identifying biomarkers to predict OIT outcomes is thus of great translational interests. MethodsWe thoroughly analyzed data from the POISED trial and our in-house OPIA trial, with a particular focus on the peanut-reactive T cells, in an attempt to identify potential biomarkers at baseline before OIT to distinguish DS and SU outcomes. ResultsIn both the POISED trial and OPIA trial, we found that functional profiles of peanut-reactive T cells at baseline before OIT, such as their type II T helper (Th2) cell cytokine productions, including IL-4, were associated with the DS versus SU outcomes after OIT cessation. ConclusionsBaseline peanut-reactive T cell functional profiles might provide new possibilities for biomarker discovery to predict peanut allergy OIT outcomes.

BackgroundInterstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD), share similar features that complicate diagnosis. Tumor markers are often elevated in ILD, yet their diagnostic utility remains unclear. MethodsThis retrospective study included ILD patients hospitalized between 2018 and 2025. Serum levels of alpha-fetoprotein, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 199, CA125, CA153, neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA 21-1) were analyzed. Arterial blood gases and erythrocyte sedimentation rates (ESRs) were also collected. Statistical analyses involved the Kruskal-Wallis test, Dunns post hoc test, Spearmans correlation, logistic regression, and receiver operating characteristic (ROC) curve analysis. ResultsCEA, CA199, and CA125 levels varied significantly among ILD subtypes (all p < 0.05). NSE differed among CTD-ILD subgroups (p = 0.0409). In IPF, CEA and NSE correlated inversely with PaO2 (r = -0.1556, p = 0.0380; r = -0.2205, p = 0.0031). In CTD-ILD, NSE correlated negatively with PaCO2 (r = -0.1811, p = 0.016), and CYFRA 21-1 with PaO2 (r = -0.1999, p = 0.0078). A diagnostic model incorporating CEA, CA199, sex, age, smoking, PaO2, and ESR differentiated IPF from CTD-ILD with an AUC of 0.833 (95% CI: 0.790-0.876), showing 73.6% sensitivity and 82.4% specificity at a cutoff of 0.569, outperforming single markers. ConclusionCEA, CA199, and CA125 aid in distinguishing ILD subtypes, while CEA, NSE, and CYFRA 21-1 correlate with impaired gas exchange. The combined clinical and biomarker model demonstrated superior performance in discriminating IPF from CTD-ILD, highlighting its clinical potential.

Withdrawal StatementThe authors have withdrawn this manuscript because We request withdrawal as the current version is incomplete and requires additional experimental data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

BackgroundBronchiectasis is a debilitating respiratory condition characterized by chronic cough with expectoration of thick sputum. It accounts for significant morbidity and mortality, especially when associated with exacerbations. Assessing the health-related quality of life (HR-QoL) of patients with bronchiectasis is important to ascertain the impact of the disease on day-to-day life, as well as to gauge the effect of targeted interventions. Conventionally used methods for assessing HR-QoL such as the St. Georges Respiratory Questionnaire (SGRQ) are time-consuming and have limitations in day-to-day application. The Bronchiectasis Health Questionnaire (BHQ) is a novel, compact tool used for assessing the HR-QoL, and has been validated for use in Korean and Turkish populations. MethodsWe attempted to develop and validate the Hindi version of the Bronchiectasis Health Questionnaire (BHQ) in Indian adults with bronchiectasis. We assessed the correlation between the Hindi BHQ (H-BHQ) scores and other measures of lung health including the Hindi version of the COPD Assessment Tool (H-CAT), pulmonary function tests and the bronchiectasis severity index (BSI). In addition, we assessed the correlation between the H-BHQ scores and the number of exacerbations and hospital admissions in the previous year. ResultsA total of 145 subjects with bronchiectasis were included. The mean ({+/-} SD) H-BHQ total score was 49.10 {+/-} 10.3. The H-BHQ score correlated well with the H-CAT score (Correlation coefficient -0.6534, p value < 0.0001) and the mMRC scale (Correlation coefficient of -0.4459,p value < 0.0001). The H-BHQ score also had a moderate correlation with the number of exacerbations and low correlation with hospital admissions in the previous year, with correlation coefficients of -0.4193 (p < 0.0001) and -0.3030 (p < 0.0001), respectively. The correlation between the H-BHQ and the Bronchiectasis Severity Index (BSI) score was weak (Correlation coefficient of -0.3012, p value < 0.01). ConclusionThe H-BHQ offers a simple and convenient method to assess the HR-QoL in patients with bronchiectasis, and correlates well with other measures of respiratory health, including the H-CAT, the mMRC score and the number of exacerbations and hospital admissions in the previous year.

Respiratory monitoring in daily-life settings is important for health assessment, yet extracting physiologically interpretable information from breathing signals under natural conditions remains challenging, as breathing is inherently dynamic and strongly modulated by behavior. Here, a portable breathing monitoring device based on a flexible lead zirconate titanate sensor is developed to address this challenge. By exploiting polarity-opposed piezoelectric and pyroelectric responses through sensor orientation, the recorded breathing waveform exhibits a characteristic dual-component structure, consisting of a narrow transient spike followed by a broad quasi-steady peak within each breathing phase. This intrinsic waveform structure enables phase-resolved quantification of how breathing effort is distributed between transient and quasi-steady components during inhalation and exhalation. Pilot measurements in healthy subjects and patients with chronic obstructive pulmonary disease or asthma reveal systematic shifts toward transient-enhanced breathing in patients, providing clearer differentiation than conventional descriptors based on breathing duration or amplitude. By transforming complex breathing dynamics into stable and physiologically meaningful signal components under daily-life conditions, this dual-response sensing approach enables more robust access to function-related changes in natural breathing.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are phenotypically divergent disorders arising from similar exposures (including cigarette smoke). Differences in DNA methylation may drive the exposed lung towards COPD vs. IPF. To characterize differential methylation in COPD and IPF lung tissue relative to controls, we conducted epigenome-wide association studies of COPD and IPF in lung tissue from the Lung Tissue Research Consortium (N=1029), adjusting for age, sex, smoke exposure, ancestry, estimated cell type composition, and plate. "Switch probes" were defined as CpGs differentially methylated in COPD vs. control and IPF vs. control in opposite directions. Gaussian graphical models were used to mine network properties of switch probes. Differential methylation of genes related to COPD/IPF in the literature was assessed. Switch probe methylation was compared with previously reported gene expression to identify multi-omic switches. We found 13,313 CpGs were associated with COPD and 43,359 with IPF (3,163 overlapping). We identified 1,091 switch CpGs enriched for endocytosis, glycosphingolipid biosynthesis, and pathways in cancer. 24 genes exhibited multi-omic switch behavior, many related to lipid metabolism (ACSL1; FASN; LPCAT1; MED27; NCOR2). LPCAT1 is of particular interest due to its role in maintaining phosphatidylcholine, the majority component of surfactant. Further related to surfactant, we observed strong divergent methylation and expression of ATP11A, which facilitates endocytosis of surfactant lipids. CONCLUSIONS Our findings suggest multi-omic switch-like regulation may underlie differential COPD/IPF etiology. Future investigation of LPCAT1 and ATP11A could provide new mechanistic understanding and therapeutic avenues.