Hospital-associated venous thromboembolism (HA-VTE) causes significant morbidity, but risk prediction models are inconsistently validated, especially in non-Western populations. We prospectively validated five HA-VTE risk scores (Caprini, Padua, IMPROVE, Kucher, and Intermountain) in a prospective multicenter cohort of 2,948 adult inpatients from 17 Chinese hospitals. Symptomatic VTE events were recorded through 3-months follow-up. The 90-day HA-VTE incidence was 2.54%. All five models showed moderate discrimination (AUC 0.726–0.759). Caprini, Padua, and Intermountain did not differ significantly (DeLong test, P > 0.05). Caprini had the highest sensitivity (0.83) but classified 42.6% of patients as high-risk. Padua and Intermountain favored specificity (0.75-0.81) with lower sensitivity (0.64-0.67). Clinical model selection should align with specific balances between sensitivity and utility. In surgical inpatients, Caprini performed best (AUC 0.804, sensitivity 0.90, NPV 1.00), though its more than 40 input variables limit practical use. Calibration was generally acceptable. Performance varied across subgroups. The prophylaxis subgroup showed attenuated performance, with reduced discrimination (e.g., Caprini AUC decreased to 0.682) and less stable calibration. Western-derived HA-VTE models have moderate predictive value in East Asian Populations inpatients. Performance differs across subgroups. Local recalibration and development of simpler, population-specific scores are needed.

BACKGROUND:The complex and heterogeneous molecular mechanisms of asthma are currently unclear, and treatment outcomes are dismal in some patients. This study aimed to identify biomarkers with diagnostic and therapeutic potential. METHODS:Gene Expression Omnibus was used to obtain asthma-related gene expression data for identifying differentially expressed genes. They were subjected to functional and pathway enrichment analyses using the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Disease Ontology. Gene Set Enrichment Analysis and Gene Set Variation Analysis were used to explore potential asthma-related mechanisms. Candidate biomarkers were identified using two machine learning algorithms and evaluated via ROC curve analysis. Immune cell fractions were assessed using CIBERSORT, and biomarker expression was validated in external database, in vivo, and in vitro studies. RESULTS:The 168 differentially expressed genes (96 upregulated and 72 downregulated) were enriched for xenobiotic stimuli, glutathione transferase activity, negative regulation of proteolysis, and endopeptidase inhibitor activity; the pathways for glutathione metabolism, xenobiotic metabolism via cytochrome P450, and chemical carcinogenesis involving DNA adducts; and for periodontitis and asthma. WNK4 and FKBP5 were identified as critical genes and were validated using ROC assays. Correlations were found between WNK4 and M2-macrophages, and between FKBP5 expression and mast cells, resting NK cells, and T cells. Our findings demonstrated increased FKBP5 expression and decreased WNK4 expression in the asthmatic cohort, aligning with the results from dataset analyses. This concordance reinforces the reliability and validity of the bioinformatics assessments. CONCLUSIONS:This study identified WNK4 and FKBP5 as candidate biomarkers of asthma warranting further clinical validation, thus contributing to a deeper understanding of asthma pathogenesis and offering a theoretical basis for future treatment strategies.

Venous thromboembolism (VTE) is a common but preventable complication in hospitalized patients, yet standardized risk scoring using unstructured electronic health records (EHRs) remains challenging. We retrospectively analyzed anonymized EHRs from a nationwide multicenter cohort across 30 hospitals. Using stratified random sampling, 50 cases from 10 hospitals were used for development and 200 cases from the remaining 20 hospitals for testing. Expert knowledge-augmented prompts for the Padua and Caprini scores were developed through a Delphi process involving 19 specialists and compared with basic and complex prompts. Performance was evaluated using six open-source large language models (LLMs), with prevalence-adjusted bias-adjusted kappa (PABAK) and F1 score as primary metrics. Expert knowledge-augmented prompts showed the highest performance in both datasets. In the test dataset, mean item-level PABAK and F1 scores were 0.97 and 0.96 for Padua, and 0.97 and 0.93 for Caprini; most items showed PABAK and F1 scores above 0.90. Risk stratification was better for Padua (PABAK 0.92; F1 score 0.96) than for Caprini (PABAK 0.73; F1 score 0.64), with processing times of 6.07 s and 12.82 s per case, respectively. These findings indicated that LLMs with expert knowledge-augmented prompting could efficiently support automated Padua and Caprini scoring and risk stratification in thrombosis prevention workflows.

Current pulmonary arterial hypertension (PAH) diagnostic approaches rely on right heart catheterization to measure the mean pulmonary artery pressure (≥ 20 mmHg), but limit early screening. Imaging techniques lack sensitivity for detecting early pulmonary pressure changes and are subject to variability, often resulting in diagnosis at an irreversible stage. The PAH pathogenesis remains incompletely understood, and improved diagnosis and treatment are urgently needed. In the present study, the Gene Expression Omnibus GSE113439 dataset underwent differential expression analysis of mRNA and Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were identified using weighted gene co-expression network and protein–protein interaction network analyses. Immune infiltration and correlation analyses were subsequently performed. We established a PAH rat model, validated the expression of hub genes in human pulmonary arterial smooth muscle cells (hPASMCs) and lung tissues of PAH rats using qRT-PCR, and conducted sequencing on the lung tissues of PAH rat models. PAH involved 547 differentially expressed genes. GO and KEGG enrichment analyses revealed that the focal adhesion, vascular smooth muscle contraction, RNA degradation, ferroptosis, and 2-oxocarboxylic acid metabolism pathways were closely associated with PAH development (P < 0.05). PAH patients had significantly upregulated NOP58, DDX21, ABCE1, CDC5L, and HSP90AA1 expression. Memory B cells, CD8 T cells, follicular helper T cells, activated natural killer cells, monocytes, activated mast cells, and neutrophils were significantly different between PAH patients and controls. Neutrophils, macrophages, and NOP58 expression were closely associated. NOP58, DDX21, ABCE1, CDC5L, and HSP90AA1 may be novel PAH diagnostic biomarkers and therapeutic targets. Their clinical applicability should be validated in larger-sample studies to explore gene-guided personalized therapies.

Despite the increasing prevalence of metabolic syndrome (MetS) worldwide, its environmental determinants in complex occupational settings remain unclear. This study aimed to evaluate the associations between occupational mixed exposure to polycyclic aromatic hydrocarbons (PAHs), benzene, toluene, and xylene (BTX), and metals and MetS risk, and identify key pollutants for occupational health monitoring and risk management. We recruited 1205 coal chemical workers in central China and measured urinary levels of 14 PAH metabolites, 6 BTX metabolites, and 40 metals. Associations between mixed exposures and MetS and its components were analyzed using weighted quantile sum (WQS) regression and restricted cubic spline (RCS) models.Among the participants, 245 individuals (20.33%) were diagnosed with MetS. Exposure to PAH mixtures was significantly associated with an increased risk of MetS (OR = 1.28, 95% CI: 1.08, 1.52). Mixed exposure to BTX and PAHs further increased MetS risk (OR = 1.77, 95% CI: 1.35, 2.31). Notably, mixed exposure to PAHs, BTX, and metals was associated with a substantially increased risk of MetS (OR = 3.49, 95% CI: 2.38, 5.18), exceeding the effects observed for individual chemical groups.The study identified 9-hydroxyfluorene (9-OHFlu) and zinc (Zn) as key pollutants contributing to MetS risk among workers. Similar associations were observed for MetS components (high fasting glucose, triglycerides, low high-density lipoprotein cholesterol (HDL-C), high blood pressure). Mixed exposure to PAHs, BTX, and metals increased MetS risk more than single pollutants. 9-OHFlu and Zn were identified as key contributors, highlighting their importance for future occupational health monitoring and risk management.

Ultrasound-induced afterglow has emerged as a promising modality for in vivo imaging, yet achieving sufficient afterglow brightness remains a challenge. Here, we report the inaugural realization of ultrasound-induced afterglow from carbon nanodots using engineered carbon nanodots, the elucidation of the resonance amplification mechanism during the ultrasound process, and the facilitation of high-contrast tumor imaging and precise resection. Through ultrasound frequency matching, we achieved up to 51-fold enhancement in sonoluminescence from carbon nanodots as fluorophore matrice, far surpassing the ultrasound-induced conventional organic polymer-based afterglow materials. Experimental and finite element analyses reveal an inverse monotonic relationship between ultrasound frequency and matrix dimensions, where resonant ultrasound enhances reactive oxygen species generation, leading to intermediate oxidation-derived near-infrared afterglow lasting over 240 min following a single 2-min ultrasound pulse. With significant amplification in afterglow brightness via precise frequency decoding, this approach evokes a 2.5 cm tissue penetration enabling high-contrast tumor imaging and precise resection in animal models, outperforming conventional optical-excited afterglow agents and fluorescence imaging. Our work elucidates the mutual size-frequency selection mechanism in ultrasound-induced afterglow and establishes a non-invasive, sensitive platform for advanced bioimaging and therapeutic monitoring. Ultrasound-induced afterglow is promising for deep-tissue imaging but suffers from low brightness. Here, authors uncover a size–frequency resonance rule that amplifies sonoluminescence in carbon nanodot matrices, achieving >50 fold afterglow enhancement, 2.5 cm tissue penetration, and high‑contrast tumor imaging and resection guidance in vivo.

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive, high‑mortality disease driven in part by maladaptive vascular remodeling. Phenotypic conversion of vascular smooth muscle cells (VSMCs) is implicated in this process, but the cellular heterogeneity and regulatory drivers in IPAH remain incompletely defined. We integrated scRNA‑seq datasets from IPAH and control lungs samples with bulk RNA‑seq from IPAH patients, MCT‑induced rat IPAH models, applying diffusion‑map dimensionality reduction, pseudotime inference, CellChat, and machine learning to nominate phenotypic conversion regulatory genes (PCRGs). Candidate genes were validated in independent cohorts and functionally tested in hypoxia‑induced human PASMCs. Single-cell analysis identified three VSMC clusters-contractile, proliferative, and synthetic-and reconstructed a dedifferentiation trajectory. 40 PCRGs correlated with the primary diffusion-map component, of which POSTN and CCDC80 emerged as hub genes up-regulated in rat and human IPAH cohorts. Hypoxia induced their expression in PASMCs, and siRNA knockdown attenuated hypoxia‑driven proliferation and migration. A multivariable VSMC phenotypic conversion signature (VPCS) integrating these biomarkers and clinical variables demonstrated robust diagnostic discrimination in validation datasets. Our from high‑dimensional datasets.integrative VSMC‑centered approach delineates dynamic state transitions in IPAH, nominates CCDC80 and POSTN as candidate regulators and biomarkers, and offers a practical framework for prioritizing targets

Background:The impact of cardiometabolic multimorbidity (CMM), defined as the coexistence of multiple cardiometabolic diseases (CMD), on acute pulmonary embolism (PE) outcomes remains understudied. We investigated the burden of CMM and its association with short-term outcomes, treatment patterns, and potential mediators in PE. Methods:We analyzed 7284 patients with acute PE from a nationwide multicenter prospective registry. CMM was defined as the presence of ≥2 CMDs (hypertension, diabetes, dyslipidemia, pre-existing cardiovascular disease, or stroke). The primary objective was to evaluate the association between CMM and 30-day all-cause death and bleeding events. Cox regression models were used to estimate hazard ratios (HR). Sensitivity and subgroup analyses confirmed the robustness of findings, while causal mediation analysis explored underlying pathways. Results:Overall, 54.2% of patients had ≥1 CMD, and 24.8% had CMM. After multivariable adjustment, CMM was independently associated with increased risks of 30-day all-cause death (HR = 1.28, 95% CI 1.02-1.65) and bleeding (HR = 1.45, 95% CI 1.04-2.01), with mortality rising stepwise with increasing CMD burden. In intermediate-high risk PE, the presence of CMM was linked to lower use of reperfusion therapy. Mediation analysis identified body mass index, blood glucose, and renal function markers as partial drivers of these associations. Conclusion:CMM is prevalent in PE and not only independently increases the risk of 30-day all-cause death and bleeding but also may influence reperfusion treatment choices. Future studies should test adding CMM to risk assessment to improve stratification and decision-making.

ABSTRACT Right ventricular dysfunction (RVD) due to pulmonary embolism (PE) is associated with poor prognosis and serves as a potential contributor to the occurrence and development of post‐PE syndrome (PPES). However, the longitudinal evolution of right ventricular function remains poorly understood due to the limited feasibility of repeated assessments. We aim to characterize the dynamic progression of RVD after acute PE using longitudinal electrocardiogram (ECG) signals analyzed with artificial intelligence (AI), together with selected biomarkers. China pUlmonary thromboembolism REgistry Study‐CARioElectro (CURES‐CARE) study, a prospective multicenter cohort study, will enroll 500 patients with intermediate‐ or high‐risk acute PE from seven tertiary hospitals in China. All enrolled patients will be followed up for 12 months. During hospitalization, patients will undergo continuous ECG monitoring for 72 h, followed by daily ECG recording by a portable device throughout the follow‐up period. Blood samples will be collected at admission, discharge, and at 3, 6, and 12 months. AI‐based approaches will be applied to identify dynamic patterns in ECG signals and biomarker trajectories, integrated with biomarkers and imaging, to identify phenotypes of RVD progression and prognosis. CURES‐CARE study will determine the incidence and risk factors of persistent RVD after acute PE, explore ECG‐derived features associated with RV function, and evaluate the predictive value of multimodal data integration for long‐term outcomes of PE. The study is expected to provide new insights into evolution of RVD, enable earlier risk stratification, and inform personalized management strategies to improve long‐term outcomes in PE survivors. Trial Registration: ClinicalTrials.gov Identifier: NCT06541353

BACKGROUND:Older patients with pulmonary embolism (PE) are at increased risk of bleeding, which is associated with adverse outcomes, making early risk assessment particularly important. This study evaluated the short-term performance of commonly used bleeding risk scores in patients aged ≥65 years. METHODS:An analysis was conducted in a multicenter, prospective study of patients aged ≥65 years with PE receiving anticoagulation (NCT02943343, 2016). The performance of the PE-SARD, Kuijer, RIETE, BACS, and ATRIA scores was evaluated using the time-dependent area under the curve (AUC) analysis. Calibration was assessed with calibration plots. Sensitivity, specificity, and positive predictive values were calculated. The primary outcomes were major bleeding (MB) at 7 and 14 days. RESULTS:Among 3661 anticoagulated patients aged ≥65 years with acute PE, MB occurred in 18 (0.5%) and 36 (1.0%) patients at 7 and 14 days, respectively, and clinically relevant non-major bleeding (CRNMB) in 69 (1.9%) and 105 (2.9%) patients. Patients with bleeding events had higher mortality than those without bleeding. Discrimination for short-term MB was low to moderate across scores, with RIETE (AUC 0.76, 95% CI 0.65-0.87) and PE-SARD (AUC 0.74, 95% CI 0.63-0.85) showing the most consistent performance at 7 days. Overall discrimination declined at 14 days. All scores demonstrated limited ability to predict CRNMB, and no model showed a consistent net clinical benefit. CONCLUSIONS:In older patients with PE, bleeding risk scores showed low-to-moderate discrimination for short-term bleeding, with moderate early performance observed only in selected scores. None of the scores reliably identified CRNMB, highlighting the limitations of baseline risk assessment in acute care settings.

In asthma, chronic inflammation and injurious microenvironment drive bronchial epithelial cells to undergo epithelial-mesenchymal transition (EMT)‑like phenotypic changes. This process disrupts the epithelial barrier, and facilitates extracellular matrix deposition, thereby constituting a pivotal mechanism underlying irreversible airway remodeling. Ring Finger Protein 6 (RNF6), an E3 ubiquitin ligase, was highly expressed in lung tissues of asthma mice. The combined Label-free and Co-Immunoprecipitation (Co-IP)/Mass Spectrometry proteomic profile revealed that OTU Deubiquitinase With Linear Linkage Specificity (OTULIN) was the downstream protein of RNF6. Here, we investigated whether RNF6 modulated OTULIN to participate in partial EMT progression of bronchial epithelial cells. Ovalbumin-induced asthma mouse model was established and BEAS-2B cells were treated with Transforming Growth Factor-Beta 1 (TGF-β1, 10 ng/mL) to construct in vitro model. Histologic analyses revealed that RNF6 knockdown ameliorated airway wall thickening, goblet cell metaplasia and inflammatory cell infiltration of lung tissues of asthma mice. Moreover, silencing RNF6 suppressed EMT‑like phenotypic changes of TGF-β1-stimulated BEAS-2B cells. Thereafter, the interaction between RNF6 and OTULIN was verified by Co-IP and immunofluorescence assays. The addition of cycloheximide and MG132 was used to identify that RNF6 downregulation inhibited the ubiquitination and degradation of OTULIN. Furthermore, overexpressed OTULIN was able to impede TGF-β1-triggered EMT‑like phenotypic changes. Interestingly, downregulated OTULIN reversed the weakened partial EMT progression caused by knocked down RNF6. In summary, RNF6 promoted the ubiquitination and degradation of OTULIN, thereby inducing partial EMT and ultimately exacerbating asthma. Thus, silencing RNF6 might be developed as a potential therapeutical strategy for asthma.

The potential association between birthweight and adult lung function has been postulated, yet the precise nature of this association in later life remains inconclusive. The analysis included 201,615 individuals from the UK Biobank dataset. To identify birthweight subgroups differences in lung function, propensity score matching and a pairwise t-test were conducted. The association between birthweight and lung function was assessed using a linear regression, gradually adjusting for variables. Subgroup analyses were conducted to investigate whether the relationship between birthweight and lung function was modified by variations in age-related lung function changes. The low birthweight group demonstrated significantly lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in comparison to those in the adequate birthweight group (P < 0.001). Conversely, no statistically significant distinction was observed in macrosomia. A positive linear correlation between birthweight and lung function was observed within each interval. In the adequate birthweight group, every 1 Kg increase in birthweight was found to be significantly associated with a mean increase in FEV1 of 70.9 mL in males and 56.0 mL in females. Additionally, there was a significant increase in FVC of 86.7 mL in males and 62.2 mL in females. Macrosomia group demonstrated a more pronounced decrease in lung function, in contrast to the adequate birthweight group which exhibited a similar decline pattern to the low birthweight group. Our study suggests an association between optimal birthweight and later-life respiratory health, as observed through stringent statistical analysis.

Background Pulmonary embolism (PE) as a preventable and potentially fatal noncommunicable disease was believed to have a lower incidence in Asian populations compared to Western populations. However, the incidence and mortality rates of PE in China and the impact of venous thromboembolism (VTE) prevention system constructions on PE still lack nationwide evidence. Methods For this nationwide hospital-based observational study, we used data from the National Hospital Quality Monitoring System (HQMS) and public database in China. We estimated the incidence and in-hospital mortality rates of PE by age group, sex, and regions of geographical and socioeconomic level. VTE prevention and management system constructions were quantified by geographical density. We then calculated the incidence and mortality rates in different conditions of VTE prevention and management system construction. Findings During the 12 months period between January and December 2021, a total number of 200,112 PE patients and 14,123 deaths were recorded from 5101 hospitals in the HQMS database. The incidence of PE was 14.19 (200,112, 95% CI 14.13-14.26) per 100,000 population and the mortality rate was 1.00 (95% CI 0.99-1.02) per 100,000 population. The incidence of PE was higher in male patients (14.43 per 100,000 population) than in female patients (13.95 per 100,000 population). Disparities of incidence and mortality rates were shown within age groups and geographical regions. The incidence and mortality rates of PE showed decreasing trend with increasing geographical density of VTE-related facilities and VTE prevention system developments. Interpretation China had a substantially large number of PE patients. The incidence and mortality rates of PE showed disparities in terms of sex, age, and geography. The incidence and mortality rates of PE decrease across regions with increasing levels of socioeconomic development, potentially influenced by the existing VTE prevention and management systems. Optimizing the health policies and healthcare investment in VTE prevention may help reduce the disease burden of PE. Funding CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-A-014); National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-01-0108); National Key Research and Development Program of China (2023YFC2507200); Discipline-Innovation and Talent-Introduction Program for Colleges and Universities (111 Plan, B23038). Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background:Most bleeding risk scores for pulmonary embolism (PE) were developed in patients receiving traditional anticoagulants. Evidence in East Asian populations and its applicability to direct oral anticoagulants (DOACs) remain limited. Methods:This post-hoc analysis was based on a multicentre, prospective study (NCT02943343) conducted from 2016 to 2021. The predictive performance of bleeding risk scores was assessed using a time-dependent area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and decision curve analysis (DCA). Propensity score matching (PSM) was adjusted for baseline characteristics. We analyzed the impact of initial DOAC versus low-molecular-weight heparin (LMWH) on outcomes. The endpoint was major bleeding (MB) within 90 days and composite outcomes (all-cause mortality, recurrent VTE, and MB). Results:Of 7,619 patients with PE, 1.4% (107 patients) experienced MB within 90 days. The RIETE score showed a modest predictive ability (AUC: 0.70; 95% CI, 0.65-0.75) for predicting 90-day MB and demonstrated a predictive advantage in the DCA results. NRI also revealed significantly better reclassification capability than the other scores, except for HAS-BLED. Among low-risk patients classified by the RIETE score, initial DOAC treatment significantly reduced 14-day composite outcomes compared with LMWH (HR = 0.13; 95% CI, 0.02-0.93). Furthermore, DOACs at discharge did not increase the risk of MB or composite outcomes. Conclusion:RIETE score shows modest performance in predicting MB and identifying low bleeding risk in PE patients, which could potentially guide early DOAC use. Further studies are needed to test its clinical utility, especially in East Asian populations.

Current pulmonary arterial hypertension (PAH) diagnostic approaches rely on right heart catheterization to measure the mean pulmonary artery pressure (≥ 20 mmHg), but limit early screening. Imaging techniques lack sensitivity for detecting early pulmonary pressure changes and are subject to variability, often resulting in diagnosis at an irreversible stage. The PAH pathogenesis remains incompletely understood, and improved diagnosis and treatment are urgently needed. In the present study, the Gene Expression Omnibus GSE113439 dataset underwent differential expression analysis of mRNA and Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were identified using weighted gene co-expression network and protein–protein interaction network analyses. A hub gene-based PAH disease risk prediction model was constructed, followed by immune cell infiltration and correlation analyses. The hub gene expression was validated using qRT-PCR. PAH involved 547 differentially expressed genes. GO and KEGG enrichment analyses revealed that the focal adhesion, vascular smooth muscle contraction, RNA degradation, ferroptosis, and 2-oxocarboxylic acid metabolism pathways were closely associated with PAH development ( P < 0.05). PAH patients had significantly upregulated NOP58 , DDX21 , ABCE1 , CDC5L , and HSP90AA1 expression. Memory B cells, CD8 T cells, follicular helper T cells, activated natural killer cells, monocytes, activated mast cells, and neutrophils were significantly different between PAH patients and controls. Neutrophils, macrophages, and NOP58 expression were closely associated. NOP58 , DDX21 , ABCE1 , CDC5L , and HSP90AA1 may be novel PAH diagnostic and therapeutic targets. Their clinical applicability should be validated in larger-sample studies to explore gene-guided personalized therapies.

INTRODUCTION:Interleukin 18 receptor 1 (IL18R1) is involved in the pathogenesis of asthma and atopic phenotypes. However, IL18R1 expression level in induced sputum supernatant of asthma remains unclear. METHODS:IL18R1, IL-4, IL-5, IL-13, IFN-r, and MUC5AC level in induced sputum supernatant was detected by ELISA in patients with asthma, and the correlation of IL18R1 expression with clinical parameters (FeNO, peripheral blood eosinophil count, serum IgE, and lung function), Th1 cytokine (IFN-r), T helper cell 2 (Th2) cytokine (IL-4, IL-5, and IL-13), and mucus (MUC5AC) were analyzed. Asthma subjects were categorized as IL18R1low and IL18R1high (below or above the upper quartile of the control group, respectively). Clinical features were compared between the IL18R1low and IL18R1high asthma subgroups. Subjects with asthma underwent a 4-week treatment with inhaled budesonide. RESULTS:We found that IL18R1 level in induced sputum increased and was correlated with FeNO, peripheral blood eosinophil count, serum IgE, FEV1 (%predicted), FEV1/FVC%, and Th2 cytokine (IL-4, IL-5, and IL-13) in patients with asthma. IL18R1 expression was not correlated with Th1 cytokine IFN-r and MUC5AC in induced sputum. IL18R1high asthma had higher FeNO levels, higher peripheral blood eosinophil counts, lower FEV1/FVC%, and higher Th2 cytokine (IL-4, IL-5, and IL-13) expression than IL18R1low subgroup or controls. IL18R1high asthma had a significant decrease in FeNO and more improvement in FEV1 during inhaled corticosteroid (ICS) treatment compared with patients having the IL18R1low subgroup. CONCLUSIONS:IL18R1 level in induced sputum was increased. IL18R1low and IL18R1high asthma subgroups had different clinical features and responses to ICS treatment. IL18R1 level in induced sputum may be a novel marker of Th2-high asthma and has potential application in predicting treatment response.

Uric acid metabolism is implicated in the pathogenesis of pulmonary arterial hypertension, wherein the key metabolite hypoxanthine exhibits elevated levels, thereby promoting pulmonary vascular remodeling through facilitation of cell proliferation and migration as well as regulation of adenosine triphosphate binding cassette transport signaling pathway. Consequently, therapeutic interventions targeting hypoxanthine synthesis may hold promise for the management of pulmonary arterial hypertension.

This study aims to explore how microRNA-145 (miR-145) affects airway remodeling and cytokine expression by targeting epidermal growth factor receptor (EGFR) to regulate mucin 5AC (MUC5AC).Mice alveolar epithelial cells (AECs) were divided into a control, blank, miR-145 mimics, mimic control, miR-145 inhibitors, inhibitor control, si-EGFR and miR-145 inhibitors + si-EGFR group. Asthma mice models with airway remodeling were induced with an Ovalbumin (OVA) solution and randomly divided into a normal, asthma, asthma + miR-145 mimics, asthma + miR-145 mimic control, asthma + si-EGFR or asthma + si-EGFR NC group. Airway remodeling degree and histomorphology was measured using hematoxylin-eosin (HE), Masson and periodic acid-Schiff (PAS) staining. Flow cytometry was used to detect Th2 and Th17 cells in peripheral blood, ELISA was used to measure inflammatory factors. qRT-PCR and western blotting was adapted to detect the expressions of EGFR and the relevant cytokines that are regulated by miR-145.The control, miR-145 mimics and si-EGFR groups showed a higher expression of miR-145 and a lower expression of EGFR and cytokines than the blank, mimic control, inhibitor control and miR-145 inhibitor + si-EGFR groups. Mice in the asthma + miR-145 mimics and asthma + si-EGFR groups showed lower WAt/Pbm, WAi/Pbm and WAm/Pbm, less inflammatory cells, less airway modeling and alleviated goblet cell hyperplasia and mucus obstruction than the asthma group. Furthermore, the expressions of EGFR and cytokines of transfected cells and lung tissues were negatively related to those of miR-145. MiR-145 can down-regulate MUC5AC by negatively targeting EGFR and thereby relieving airway remodeling.

BackgroundAsthma exacerbation significantly contribute to disease mortality and result in heightened health care expenditures. This study was aimed at gaining important new insights into the heterogeneity of epithelial and immune cells and elucidating key regulatory genes involved in the pathogenesis of asthma exacerbation.MethodsFunctional enrichment, pseudotime, metabolism and cell-cell communication analyses of epithelial cells and immune cells in single-cell RNA sequencing (scRNA-seq) dataset were applied. Immune infiltration analysis was performed in bulk RNA sequencing (bulk RNA-seq) dataset. Key regulatory genes were obtained by taking the intersection of the differentially expressed genes (DEGs) between control and asthma group in epithelial cells, immune cells and bulk RNA-seq data. Asthma animal and in vitro cell line models were established to verify the key regulatory genes expression by employing quantitative reverse transcription polymerase chain reaction (qRT-PCR).ResultsScRNA-seq analysis identified 7 epithelial subpopulations and 14 distinct immune cell types based on gene expression profiles. Further analysis demonstrated that these cells manifested high heterogeneity at the levels of functional variations, dynamics, communication patterns and metabolic changes. Notably, TMPRSS11A, TUBA1A, SCEL, ICAM4, TMPRSS11B, IGFBP2, CLC, NFAM1 and F13A1 were identified as key regulatory genes of asthma. The results of the qRT-PCR demonstrated that the 9 key regulatory genes were involved in asthma.ConclusionsWe systematically explored epithelial and immune characteristics in asthma exacerbation and identified 9 key regulatory genes underlying asthma occurrence and progression, which may be valuable for providing new insights into the cellular and molecular mechanisms driving asthma exacerbations.

Background Pulmonary arterial hypertension (PAH) is a clinical illness primarily defined by exertional dyspnea and exhaustion, leading to significant pathophysiological alterations in pulmonary arteries. Several causative factors have been reported, among which dysfunction of fatty acid (FA) metabolism in cardiac and pulmonary vessels has been identified as the cause of structural and functional abnormalities of pulmonary vessels. However, the precise pathophysiological mechanism of FA metabolism dysfunction in PAH remains incompletely studied. Methods This study analyzed the differentially expressed genes (DEGs) in the PAH dataset (GSE117261) acquired from the Gene Expression Omnibus (GEO) database using the limma package in R. Furthermore, these DEGs were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. The DEGs that overlapped with FA metabolism genes were identified. Moreover, hub FA metabolism-related genes were determined via the following machine learning algorithms: support vector machine with recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression. The acquired hub genes were validated in PAH patients’ blood samples and the human pulmonary artery smooth muscle cells (HPASMCs). In addition, the association of key gene levels with mean pulmonary artery pressure (mPAP) of PAH patients was identified via Pearson correlation analysis. Results In total, 419 (221 upregulated and 198 downregulated) DEGs were determined. GO assessment showed that the DEGs were primarily linked with the positive modulation of cytokine synthesis, immune receptor activity, and collagen-containing extracellular matrix. KEGG analyses indicated substantial enrichment of coagulation and complement cascades and pathways related to malaria and leishmaniasis. Machine learning results showed that AKR1C3, CA2, FADS1, GPD1, PTGDS, and TBXAS1 were the key FA metabolism-related genes in PAH: expression of CA2, GPD1, and PTGDS was markedly upregulated, while that of AKR1C3, FADS1, and TBXAS1 was substantially downregulated in hypoxic HPASMCs, with similar results obtained in patients’ blood samples. Additionally, the levels of hub FA metabolism-linked genes in PAH patients’ peripheral blood correlated strongly with mPAP. Conclusions We have identified six key FA metabolism-related genes potentially involved in the pathogenesis of PAH that could prove to be important diagnostic and therapeutic markers.