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Abstract Background: Acute pulmonary embolism (APE) is a fatal cardiovascular disease, yet missed diagnosis and misdiagnosis often occur due to non-specific symptoms and signs. A simple, objective technique will help clinicians make a quick and precise diagnosis. In population studies, machine learning (ML) plays a critical role in characterizing cardiovascular risks, predicting outcomes, and identifying biomarkers. This work sought to develop an ML model for helping APE diagnosis and compare it against current clinical probability assessment models. Methods: This is a single-center retrospective study. Patients with suspected APE were continuously enrolled and randomly divided into two groups including training and testing sets. A total of 8 ML models, including random forest (RF), Naïve Bayes, decision tree, K-nearest neighbors, logistic regression, multi-layer perceptron, support vector machine, and gradient boosting decision tree were developed based on the training set to diagnose APE. Thereafter, the model with the best diagnostic performance was selected and evaluated against the current clinical assessment strategies, including the Wells score, revised Geneva score, and Years algorithm. Eventually, the ML model was internally validated to assess the diagnostic performance using receiver operating characteristic (ROC) analysis. Results: The ML models were constructed using eight clinical features, including D-dimer, cardiac troponin T (cTNT), arterial oxygen saturation, heart rate, chest pain, lower limb pain, hemoptysis, and chronic heart failure. Among eight ML models, the RF model achieved the best performance with the highest area under the curve (AUC) (AUC = 0.774). Compared to the current clinical assessment strategies, the RF model outperformed the Wells score (P = 0.030) and was not inferior to any other clinical probability assessment strategy. The AUC of the RF model for diagnosing APE onset in internal validation set was 0.726. Conclusions: Based on RF algorithm, a novel prediction model was finally constructed for APE diagnosis. When compared to the current clinical assessment strategies, the RF model achieved better diagnostic efficacy and accuracy. Therefore, the ML algorithm can be a useful tool in assisting with the diagnosis of APE.

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.

The object of the study was to evaluate comprehensively the value of chest non-contrasted CT (NC-CT) in detecting acute pulmonary thromboembolism (APE). All patients were categorized into two groups: i) With APE; and ii) without APE based on clinical diagnosis. Using the clot distribution on computed tomography pulmonary angiography (CTPA), APE was divided into central and peripheral APE. Imaging features including hyperdense lumen sign and peripheral wedge-shaped opacity on chest NC-CT were evaluated. The attenuation value of peripheral wedge-shaped opacity on NC-CT was compared between patients with and without APE. Among the 273 patients, there were 110 patients with APE, 49 patients with central APE and 61 patients with peripheral APE and 163 patients without APE. The hyperdense lumen sign had a sensitivity of 30.0% and a specificity of 97.6% in detecting APE. The sensitivity and specificity of hyperdense lumen sign in detecting central APE were 57.1 and 97.6%, respectively, while the relevant percentages in detecting peripheral APE were 8.2 and 97.6%, respectively. The mean attenuation value of peripheral wedge-shaped opacity in patients with APE was significantly lower than that in patients without APE (P<0.001). Regarding the age-adjusted D-dimer, there was a decrease of eight D-dimer positive cases for patients >50 years old without APE, confirmed by CTPA. In conclusion, chest NC-CT cannot be used as an alternative modality for CTPA in diagnosing APE, however, the hyperdense lumen sign had high specificity in the diagnosis of central APE. Patients with this symptom and increased D-dimer may not require further CTPA. The lower attenuation value of peripheral wedge-shaped opacity on NC-CT suggested APE, and CTPA confirmation was required. The age-adjusted D-dimer had higher specificity in excluding APE.

Background Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process. Methods We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR). Results We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure. Conclusion The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

BackgroundPulmonary vessel-related structural (PVRS) abnormalities have been implicated in usual interstitial pneumonia; however, their significance in idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) remains unclear. In this two-centre study, we evaluated the associations between PVRS parameters on high-resolution computed tomography (HRCT) and rapid progression and prognosis in patients with IIM-ILD.MethodsA total of 578 IIM-ILD patients (412 females; median age, 53 years) were included from retrospective ILD cohorts of two centres. Artificial intelligence (AI)-based quantification was performed on baseline HRCT to assess PVRS and interstitial lesions. The value of PVRS for rapid progression and prognosis was first evaluated in the cohort from the first centre using logistic regression, Kaplan-Meier analysis and Cox models. An independent cohort of 64 patients (43 female; median age, 54 years) from the second centre then served to validate the generalisability of the PVRS-based model of IIM-ILD progression.ResultsIn the first-centre cohort, 249 patients with rapidly progressive ILD (RP-ILD) showed significantly elevated mean pulmonary vascular diameter (mPVD) (p<0.05), shorter vascular-pleural distances, greater PVRS volume and higher standard deviation of pulmonary vascular diameter (sdPVD) (p<0.001) compared with non-RP-ILD patients. Multivariate analysis identified age (HR 1.03, 95% CI 1.01 to 1.06), ground glass opacity percentage (HR 1.04, 95% CI 1.02 to 1.06) and sdPVD at 6 mm and 18 mm from the pleura as independent risk factors for poor prognosis in antisynthetase syndrome (ASS) patients (concordance index (C-index)=0.819). In contrast, for patients with antimelanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5+DM), the independent risk factors were age (HR 1.06, 95% CI 1.02 to 1.11), mPVD at 6 mm from the pleura and lactic dehydrogenase levels (C-index=0.835). When applied to the external validation cohort, the respective multivariate Cox models yielded C-indices of 0.841 for ASS and 0.814 for MDA5+DM, confirming their generalisability.ConclusionsOur study demonstrates that baseline PVRS parameters on HRCT are robust imaging biomarkers associated with rapid progression and poor prognosis in IIM-ILD. These findings underscore the clinical relevance of PVRS assessment in risk stratification and management.

Background The gut microbiota of venous thromboembolism (VTE) patients exhibited significant alterations. However, the causal relationship between gut microbiota and VTE has not been fully understood. This study aimed to assess the causal relationship between gut microbiota and the risk of VTE using a two-sample Mendelian Randomization (MR) study. Methods The gut microbiota and VTE genetic data were collected from the MiBioGen consortium and the UK biobank, respectively. The potential causal relationship between gut microbiota and VTE was investigated using a two-sample MR analysis, including inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Cochran’s Q-test, MR-PRESSO, and MR-Egger regression intercept analysis were utilized to perform sensitivity analysis. Results At the genus level, the results of MR analysis found that Coprococcus1 (OR: 1.0029, 95% CI: 1.0005–1.0054, p =  0.0202) was suggestively linked with an increased risk of VTE, while Slackia (odds ratio (OR): 0.9977, 95% confidence interval (CI): 0.9957–0.9998, p =  0.0298), Butyricicoccus (OR: 0.9971, 95% CI: 0.9945–0.9997, p =  0.0309), Eubacterium coprostanoligenes group (OR: 0.9972, 95% CI: 0.9946–0.9999, p =  0.0445), and Bacteroides (OR: 0.9964, 95% CI: 0.9932–0.9995, p =  0.0234) were suggestively associated with a reduced risk of VTE. No heterogeneity and horizontal pleiotropy was detected. Conclusion This study found that there were potential causal relationships between five gut microbiota and VTE. Our findings may provide new insights into the mechanisms of VTE.

Background Undissolved thrombus blocks the pulmonary arteries in chronic thromboembolic pulmonary hypertension (CTEPH), a potentially fatal illness that raises pulmonary resistance, causes right heart failure, and even results in death. Although platelets are linked to vascular dysfunction and thrombus formation, it is yet unknown what precise proteome alterations and mechanistic roles they play in CTEPH. Methods We extracted platelet-rich plasma from peripheral blood and separated the plasma to obtain enriched platelet pellet (EPP). Quantitative proteomics was used to examine EPP from CTEPH patients and healthy controls using mass spectrometry. The relationship between protein levels and clinical markers of right heart function was examined. Platelet activity, morphology, and interactions with other blood components were evaluated using transmission electron microscopy, immunofluorescence, and flow cytometry. Results The proteomic investigation found that 179 proteins were differentially expressed in CTEPH patients. The analysis revealed that these proteins were involved in crucial processes such as complement and coagulation cascades, phagosome, and neutrophil extracellular trap (NET) formation. Elevated proteins, specifically NOX2, PAD4, ITGB2, and HMGB1, have been associated to platelet-neutrophil aggregates and NET formation. In addition, enhanced P-selectin expression in platelets and plasma confirmed greater platelet activation in CTEPH patients. Notably, PAD4 and NOX2 levels showed a substantial correlation with hemodynamic parameters and right heart dysfunction. MPO-DNA, a NET marker associated with P-selectin and ITGB2 expression, was discovered in higher concentrations in CTEPH patients' plasmas. Conclusion Platelet aggregation and activation in CTEPH encourage the formation of NETs, which advances the disease and prolongs thrombus. Right heart insufficiency and hemodynamic markers had a strong correlation with PAD4 and NOX2 levels, indicating that these biomarkers may be employed to assess the severity and prognosis of CTEPH disease and offer a fresh approach to targeted treatment. The results highlight the need for additional study to elucidate platelet-mediated pathways and create therapies for CTEPH that target platelets. Graphical abstract

Background This study aimed to investigate longitudinal change of idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) on high-resolution computed tomography (HRCT). Methods This prospective cohort study was undertaken involving 514 IIM-ILD patients (367 females; median age 54 years) from 2016 to 2022. Deep learning algorithms were employed to quantify interstitial lesions on HRCT, while clinical parameters including pulmonary function tests, serum biomarkers, and arterial blood gas analysis were also considered. Results The study identified anti-MDA5 antibody positivity (OR: 10.46, 95% CI: 3.40–32.22), reduced FVC (OR: 0.91, 95% CI: 0.84–0.98), and extensive ground-glass opacity (GGO) (OR: 1.07, 95% CI: 1.01–1.13)/ reticulation (OR: 1.23, 95% CI: 1.07–1.41) involvement as independent risk factors for rapidly progressive interstitial lung disease (RP-ILD) within IIM. During the rapid progressive period of RP-ILD, anti-MDA5-positive dermatomyositis (MDA5 + DM) showed greater progression in fibrotic, inflammatory, and emphysema lesions compared to anti-synthetase syndrome (ASS). In the slow progressive period, MDA5 + DM tended towards chronic fibrosis, while ASS exhibited overall improvement. The extent of lesion increase in non-RP-ILD patients is significantly smaller than in those who have experienced RP. Reticular and consolidation changes were strongly correlated with variations in VC%, FVC%, and FEV 1 %, and moderately associated with changes in TLC and DL CO . The prognostic impact of GGO proportion on adverse outcomes intensified with longer follow-up durations, with each 1-unit increase in whole-lung GGO proportion linked to a 0.56% higher risk of adverse outcomes (HR: 1.0056, 95% CI: 1.001–1.010). Conclusions IIM-ILD cases with prior rapid progression will develop chronic fibrotic trajectories with persistent inflammation compared to non-progressive cases. ASS is characterized by sustained inflammatory activity in imaging manifestations, whereas MDA5 + DM shows post-acute fibrotic remodeling following initial injury. Longitudinal GGO emerges as a critical prognostic indicator, demonstrating time-dependent cumulative risk effects.

Background Studies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization. Materials and methods In this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed. Results Among 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097–8.321, P  < 0.001), respiratory failure (OR 2.382, 95% CI 1.533–3.702, P  < 0.001) and varicose veins (OR 3.718, 95% CI 1.066–12.964, P  = 0.039) were independent risk factors of VTE. The incidence of VTE in patients with ILD increased with the length of time in hospital from 2.2% (< 7 days) to 6.4% (> 21 days). Conclusion The incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.