Causal relationship between immune cells and pulmonary arterial hypertension: Mendelian randomization analysis.

Immunity and inflammation in pulmonary arterial hypertension (PAH) has gained more attention. This research aimed to investigate the potential causal connections between 731 immunophenotypes and the likelihood of developing PAH. We obtained immunocyte data and PAH from openly accessible database and used Mendelian randomization (MR) analysis to evaluate the causal association between each immunophenotype and PAH. Various statistical methods were employed: the MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode. In the study of 731 different types of immune cells, it was found that 9 showed a potential positive connection (IVW P < .05) with increased risk of PAH, while 19 had a possible negative link to decreased risk. Following false discovery rate (FDR) adjustment, the analysis using the IVW method demonstrated that 5 immune phenotypes were significantly associated with PAH (FDR < 0.05, OR > 1). Conversely, there was a negative correlation between PAH and 4 immune cell types (FDR < 0.05, OR < 1). Sensitivity analyses suggested the robustness of all MR findings. This research, for the first time, has revealed indicative evidence of a causal link between circulating immune cell phenotypes and PAH through genetic mechanisms. These results underscore the importance of immune cells in the pathogenesis of PAH.

Microbial signatures predictive of short-term prognosis in severe pneumonia.

Objective: This retrospective cohort study aimed to investigate the composition and diversity of lung microbiota in patients with severe pneumonia and explore its association with short-term prognosis. Methods: A total of 301 patients diagnosed with severe pneumonia underwent bronchoalveolar lavage fluid metagenomic next-generation sequencing (mNGS) testing from February 2022 to January 2024. After applying exclusion criteria, 236 patients were included in the study. Baseline demographic and clinical characteristics were compared between survival and non-survival groups. Microbial composition and diversity were analyzed using alpha and beta diversity metrics. Additionally, LEfSe analysis and machine learning methods were employed to identify key pathogenic microorganism associated with short-term mortality. Microbial interaction modes were assessed through network co-occurrence analysis. Results: The overall 28-day mortality rate was 37.7% in severe pneumonia. Non-survival patients had a higher prevalence of hypertension and exhibited higher APACHE II and SOFA scores, higher procalcitonin (PCT), and shorter hospitalization duration. Microbial α and ß diversity analysis showed no significant differences between the two groups. However, distinct species diversity patterns were observed, with the non-survival group showing a higher abundance of Acinetobacter baumannii, Klebsiella pneumoniae, and Enterococcus faecium, while the survival group had a higher prevalence of Corynebacterium striatum and Enterobacter. LEfSe analysis identified 29 distinct terms, with 10 potential markers in the non-survival group, including Pseudomonas sp. and Enterococcus durans. Machine learning models selected 16 key pathogenic bacteria, such as Klebsiella pneumoniae, significantly contributing to predicting short-term mortality. Network co-occurrence analysis revealed greater complexity in the non-survival group compared to the survival group, with differences in central genera. Conclusion: Our study highlights the potential significance of lung microbiota composition in predicting short-term prognosis in severe pneumonia patients. Differences in microbial diversity and composition, along with distinct microbial interaction modes, may contribute to variations in short-term outcomes. Further research is warranted to elucidate the clinical implications and underlying mechanisms of these findings.

Development and external validation of a nomogram for predicting short-term prognosis in patients with acute pulmonary embolism.

BACKGROUND: Accurate assessment and timely intervention play a crucial role in ameliorating poor short-term prognosis of acute pulmonary embolism (APE) patients. The currently employed scoring models exhibit a degree of complexity, and some models may not comprehensively incorporate relevant indicators, thereby imposing limitations on the evaluative efficacy. Our study aimed to construct and externally validate a nomogram that predicts 30-day all-cause mortality risk in APE patients. METHODS: Clinical data from APE patients in Intensive Care-IV database was included as a training cohort. Additionally, we utilized our hospital's APE database as an external validation cohort. The nomogram was developed, and its predictive ability was evaluated using receiver operating characteristic (ROC) curves, calibration plots and decision curve analysis. RESULTS: A collective of 1332 patients and 336 patients were respectively enrolled as the training cohort and the validation cohort in this study. Five variables including age, malignancy, oxygen saturation, blood glucose, and the use of vasopressor, were identified based on the results of the multivariate Cox regression model. The ROC value for the nomogram in the training cohort yielded 0.765, whereas in the validation group, it reached 0.907. Notably, these values surpassed the corresponding ROC values for the Pulmonary Embolism Severity Index, which were 0.713 in the training cohort and 0.754 in the validation cohort. CONCLUSIONS: The nomogram including five indicators had a good performance in predicting short-term prognosis in patients with APE, which was easier to apply and provided better recommendations for clinical decision-making.

HIF­1 and macrophage activation signalling pathways are potential biomarkers of invasive aspergillosis.

Invasive aspergillosis (IA) is a severe disease, the pathogenesis of which remains unclear. The present study aimed to determine the molecular mechanism of IA and to identify potential biomarkers using bioinformatics analysis. The GSE78000 dataset, which includes data from patients with IA and healthy individuals, was downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) between the IA and control groups were identified with the 'affy' package in R software. The Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases were then used to analyse the function and pathway enrichment of DEGs. The protein-protein interaction network was analysed with the Search Tool for the Retrieval of Interacting Genes (STRING) website. In addition, DEGs were confirmed using reverse transcription-quantitative PCR and western blotting in samples with IA (n=6) and control samples (n=6) collected from the Department of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Henan University of Science and Technology (Luoyang, China). The present study identified 735 DEGs, including 312 upregulated and 423 downregulated genes. Through GO and KEGG analyses of the DEGs, macrophage activation and hypoxia-inducible factor 1 (HIF-1) signalling pathways were revealed to be significantly upregulated and downregulated, respectively, in patients with IA compared with that of the healthy individuals. Subsequently, correlation analysis of macrophage activation and HIF-1 signalling pathways was revealed using correlation as a distance metric for hierarchical clustering correlation analysis. However, there was no protein-protein interaction between the macrophage activity regulation and HIF-1 signalling pathways based on STRING analysis. In summary, the present study identified candidate genes and associated molecules that may be associated to IA and revealed potential biomarkers and therapeutic targets for IA.

Serum Albumin for Short-Term Poor Prognosis in Patients With Acute Pulmonary Embolism: A Clinical Study Based on a Database.

The relationship between serum albumin (ALB) and short-term prognosis in patients with acute pulmonary embolism (APE) remains unclear. We investigated the predictive value of ALB for short-term prognosis in APE patients using our hospital pulmonary embolism (PE) database (384 patients consecutively collected). Logistic regression analysis and nomograms were applied to construct the predictive model, and validation was assessed. A total of 340 APE patients were included, with a 30-day all-cause mortality rate of 8.5%. The incidence of hypoalbuminemia was 15.9%. The odds ratio (OR) for short-term mortality in patients with high ALB was 0.89 (0.886, 95% CI: 0.812-0.967). Additionally, we created a nomogram for individualized mortality risk prediction. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic area under the curve (AUC) of ALB was 0.758 (95% CI 0.683-0.833), and the best cut-off value was 33.85 g/L. Optimal simplified Pulmonary Embolism Severity Index (sPESI) (ALB combined sPESI) AUC was 0.835 (95% CI 0.775-0.896). Baseline hypoalbuminemia may be an independent prognostic indicator of short-term mortality in patients with APE.

Association of red blood cell distribution width to albumin ratio with the prognosis of acute severe pulmonary embolism: A cohort study.

Red blood cell distribution width (RDW) to human serum albumin (ALB) ratio (RDW/ALB Ratio, RAR) is a prognostic factor for adverse outcomes in different disease populations. However, the relationship between RAR and pulmonary embolism outcomes remains unclear. Therefore, this study set out to investigate the association between RAR and the risk of all-cause death in acute pulmonary embolism (APE) patients admitted to the intensive care unit (ICU). This is a retrospective study based on the MIMIC-IV database. The primary outcome was all-cause mortality among patients with APE (in-hospital and 1-year mortality). The relationship between RAR and all-cause mortality was assessed using Cox regression analysis. The survival curve was drawn to evaluate the predictive value of RAR for patient mortality. Correlations and threshold effects between RAR and all-cause mortality were analyzed using the generalized additive model (GAM). The study included 773 patients, and fully adjusted Cox regression models showed that RAR was associated with higher all-cause mortality in the hospital and one year later (all P < .05). In the GAM, the relationship between RAR and all-cause mortality was shown to be nonlinear, with a positive association between RAR and all-cause mortality in APE patients when RAR values were at low to moderate levels. This study revealed a significant association between RAR and the risk of all-cause day death in patients with pulmonary embolism. Higher RAR value was associated with increased in-hospital mortality and 1-year mortality.

PU.1-CD23 signaling mediates pulmonary innate immunity against Aspergillus fumigatus infection by driving inflammatory response.

BACKGROUND: Aspergillosis is a common cause of morbidity and mortality in immunocompromised populations. PU.1 is critical for innate immunity against Aspergillus fumigatus (AF) in macrophages. However, the molecular mechanism underlying PU.1 mediating immunity against AF infection in human alveolar macrophages (AMs) is still unclear. METHODS: In this study, we detected the expressions of PU.1, CD23, p-ERK, CCL20 and IL-8 and key inflammatory markers IL-1ß, IL-6, TNF-α and IL-12 in human THP-1-derived macrophages (HTMs) or PU.1/CD23-overexpressed immunodeficient mice with AF infection. Moreover, we examined these expressions in PU.1-overexpressed/interfered HTMs. Additionally, we detected the phagocytosis of macrophages against AF infection with altered PU.1 expression. Dual luciferase, ChIP and EMSAs were performed to detect the interaction of PU.1 and CD23. And we invested the histological changes in mouse lung tissues transfected with PU.1/CD23-expressing adenoviruses in AF infection. RESULTS: The results showed that the expressions of PU.1, CD23, p-ERK, CCL20, IL-8, IL-1ß, IL-6, TNF-α and IL-12 increased significantly with AF infection, and PU.1 regulated the later 8 gene expressions in HTMs. Moreover, CD23 was directly activated by PU.1, and overexpression of CD23 in PU.1-interfered HTMs upregulated IL-1ß, IL-6, TNF-α and IL-12 levels which were downregulated by PU.1 interference. PU.1 overexpression strengthened the phagocytosis of the HTMs against AF. And injection of PU.1/CD23-expressing adenoviruses attenuated pathological defects in immunodeficient mouse lung tissues with AF infection. Adenovirus (Ad)-PU.1 increased the CD23, p-ERK, CCL20, IL-8 levels. CONCLUSIONS: Our study concluded that PU.1-CD23 signaling mediates innate immunity against AF in lungs through regulating inflammatory response. Therefore, PU.1-CD23 may be a new anti-aspergillosis therapeutic for the treatment of invasive aspergillosis with the deepening of gene therapy and its wide application in the clinic.

Plasma Angiopoietin-2 as a Promising Biomarker for the Prognosis of Acute Pulmonary Embolism.

BACKGROUND: Endothelial damage is one of the pathogenic conditions of acute pulmonary embolism (APE). The essential role of angiogenin, ribonuclease A family, member 2 (Ang-2) in APE remains unclear. This study aimed to investigate the predictive value of Ang-2 in the clinical outcomes of patients with APE. METHODS: Plasma Ang-2 levels were measured by an enzyme-linked immunosorbent assay kit using a DuoSet methodology in 118 APE patients and 53 healthy controls. Baseline data relevant to mortality over time were obtained from hospital databases or by patient's follow-up (median follow-up time: 25.0 ± 13.2 months). The main outcome was all-cause mortality. RESULTS: Plasma Ang-2 level was significantly higher in APE patients than in healthy controls (p < 0.001). Patients dying during the first 30 days presented higher baseline levels of Ang-2 than the survivors (p < 0.001). Patients dying during the follow-up also showed higher baseline levels of Ang-2 than the survivors (p < 0.001). The multi-variable logistic regression analysis showed that the N-terminal propeptide of B-type natriuretic peptide (NT-proBNP) [odds ratio (OR): 19.8; 95% CI: 1.5 - 255.8; p = 0.022] and Ang-2 (OR: 9.9; 95% CI: 1.4 - 70.5; p = 0.022) emerged as independent predictors of the 30-day mortality. Furthermore, the multivariable Cox's regression identified plasma Ang-2 [hazards ratio (HR): 1.35; 95% CI: 1.10 - 1.66; p = 0.004] as an independent predictor of long-term mortality in patients with APE. CONCLUSIONS: A high circulating level of Ang-2 can be considered as an independent predictor for the poor outcome of APE and may serve as a biomarker for the risk stratification in patients with APE.

A modified Khorana score as a risk assessment tool for predicting venous thromboembolism in newly diagnosed advanced lung cancer.

The aim of this study was to evaluate the Khorana score and modified Khorana score as risk assessment tools for predicting the development of VTE in newly diagnosed advanced lung cancer. Information on the clinical data and laboratory indicators of the study group between 2014 and 2018 and the validation group between January 2019 to June 2020 of newly diagnosed advanced lung cancer patients at The First Affiliated Hospital of Henan University of Science and Technology was collected. We conducted an analysis of the risk factors affecting VTE development and the predictive risk value of the Khorana score and the modified Khorana score for VTE in newly diagnosed advanced lung cancer patients. A total of 124 patients were included in the study group. D-dimer is an independent risk factor for VTE in newly diagnosed advanced lung cancer patients (OR 1.620, 95% CI 1.220, 2.152, p = 0.001). The best cutoff value of D -dimer for the prediction of VTE development risk was 1.14 mg/L. The AUC of the Khorana score to predict the occurrence risk of VTE in newly diagnosed advanced lung cancer patients was 0.706; when the best cutoff value was 2, the sensitivity was 70.83%, and the specificity was 65%. The AUC of the modified Khorana score was 0.870; when the cutoff value was 2, the sensitivity was 100%, and the specificity was 50%. A total of 237 patients were included in the validation group, the AUC of the modified Khorana score for predicting the occurrence risk of VTE was 0.875; when the cutoff value was 2, the sensitivity was 100%, and the specificity was 52.1%. The modified Khorana score after incorporating D-dimer has a higher predictive value for the occurrence risk of VTE in newly diagnosed lung cancer patients; when the score ≥ 2, its sensitivity is higher, and it can more fully identify high-risk groups of VTE.

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly.

Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA. Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA. Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient's family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members. Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively. Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.

Efficacy and safety of Sildenafil treatment in pulmonary hypertension caused by chronic obstructive pulmonary disease: A meta-analysis.

AIMS: Pulmonary hypertension (PH) is a severe and prevalent complication of chronic obstructive pulmonary disease (COPD), with low quality of life and poor prognosis. This study was designed to evaluate the efficacy and safety of Sildenafil in the treatment of PH caused by COPD (COPD-PH) and provide reference for clinical treatment. MATERIALS AND METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, Clinical Trials.gov databases, Wanfang Data and CNKI for comprehensive literature reporting Sildenafil for randomized controlled trials (RCT) of COPD-PH. Quality assessment, data analysis used the modified Jadad scale and RevMan5.3 software. KEY FINDINGS: A total of 9 RCTs involving 579 patients were included in our study. The primary outcome measure was Six minutes walking distance (6MWD). Secondary observations were Pulmonary artery systolic pressure (PASP), Borg dyspnea index, and Survey scale (SF-36). Our data demonstrate that Sildenafil can improve 6WMD [29.64, 95% CI (13.78, 45.50), P < 0.00001] and PASP [-7.86, 95% CI (-11.26, -4.46) P < 0.00001] of COPD-PH, compared with the control group. However, SF-36 [2.64, 95% CI (-6.85, 12.14) P = 0.59] and Borg dyspnea index [-0.28, 95% CI (-1.08, 0.52) P = 0.49] have no significant difference between those two groups. Adverse reactions in the Sildenafil treatment group were tolerated headaches and digestive symptoms, which were relatively safe. SIGNIFICANCE: Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD. However, large-sample, high-quality multicenter RCTs are still needed to provide stronger evidence-based medical evidence.

Catheter-directed therapy as a treatment for submassive pulmonary embolism: A meta-analysis.

AIMS: Catheter-directed therapy (CDT) is included in the guidelines for diagnosing and treating massive pulmonary embolism. However, few studies have evaluated the efficacy of CDT as a treatment for submassive pulmonary embolism (SPE). Therefore, we used evidence-based medicine to evaluate the effectiveness and safety of CDT in treating SPE. METHODS: Search terms describing CDT in SPE and patients with intermediate pulmonary embolism were entered into the PubMed, Embase and Cochrane Library databases to identify relevant articles without language restrictions published between January 1990 and December 2016. A quality assessment and data extraction were performed by two investigators. The clinical efficacy of and major complications associated with treatment were analysed using a fixed effects model. KEY FINDINGS: A total of 552 patients in 16 studies were included in this meta-analysis. The clinical success rate in CDT was approximately 100% (95% confidence interval (CI): 99%, 100%), the primary bleeding rate was 0.02% (95% CI: 0%, 0.05%), and mortality during hospitalization was approximately 0% (95% CI: 0%, 0.01%). The mean decrease in pulmonary artery systolic pressure after treatment was -14.9% (95% CI: -19.25%, -10.55%), and the mean post-treatment change in the ratio of the right to the left ventricle (RV/LV) was -0.35% (95% CI: -0.48%, -0.22%). SIGNIFICANCE: CDT is effective and safe as a treatment for SPE and could be a first-line treatment for SPE under specific conditions.

Efficacy and safety of levosimendan in patients with acute right heart failure: A meta-analysis.

AIMS: Right heart failure (RHF), which is caused by a variety of heart and lung diseases, has a high morbidity and mortality rate. Levosimendan is a cardiac inotropic drug and vasodilator. The effect of levosimendan on RHF remains unclear. We sought to evaluate the efficacy and safety of levosimendan in patients with acute RHF. MATERIALS AND METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov to identify studies reporting the efficacy and safety of levosimendan for the treatment of RHF. KEY FINDINGS: Ten trials, including 359 participants from 6 RCTs and 4 self-controlled trials, were evaluated. In the 6 RCTs, we found that patients treated with levosimendan for 24h showed a significant increase in tricuspid annular plane systolic excursion [1.53; 95% CI (0.54, 2.53); P=0.002] and ejection fraction [3.59; 95% CI (1.21, 5.98); P=0.003] as well as a significant reduction in systolic pulmonary artery pressure [-6.15; 95% CI (-9.29, -3.02); P=0.0001] and pulmonary vascular resistance [-39.48; 95% CI (-65.59, -13.38); P=0.003], whereas changes in mean pulmonary pressure were nonsignificant. Adverse events did not significantly differ between the two groups. SIGNIFICANCE: Our study shows that levosimendan exhibits short-term efficacy for treating RHF in patients with a variety of heart and lung diseases. Additional strict multicentre RCTs with long follow-up times and large sample sizes are required to further validate the efficacy and safety of this treatment.

MiR-557 works as a tumor suppressor in human lung cancers by negatively regulating LEF1 expression.

MicroRNAs play an important role in regulating post-transcriptional gene expression in the progression of various human cancers. In this study, we investigated the role of microRNA-557 in human lung cancer cells. The molecular mechanism of microRNA-557 was also clarified in the proliferation and invasion of human lung cancer cells. Our results showed microRNA-557 levels were obviously decreased in clinical lung cancer specimens and lung cancer cell lines. Cell viability of A549 and NCI-H460 cells transfected with microRNA-557 mimics was significantly decreased than those transfected with negative control mimics. MicroRNA-557 promoted cell death of A549 and NCI-H460 but did not affect the cell apoptosis of lung cancer cells. Overexpression of microRNA-557 inhibited cell invasion of A549 and NCI-H460 cells. TargetScan analysis showed that microRNA-557 might target 3' untranslated region of lymphocyte enhancement factor 1, and the western blotting results showed that transfection of microRNA-557 mimics significantly decreased the levels of lymphocyte enhancement factor 1 in A549 and H460 cells. MicroRNA-557 might work as a tumor suppressor by negatively regulating the expression of lymphocyte enhancement factor 1 in lung cancer cells.

The values of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in predicting 30 day mortality in patients with acute pulmonary embolism.

BACKGROUND: vAcute pulmonary embolism (PE) is a life threatening disease. The treatment options depend on the severity of the disease and the mortality varies widely depending on the severity of the condition. It is important to identify patients who are at high risk of mortality. The aim of the present study was to explore the prognostic alues of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) for 30-day mortality in patients with acute PE. METHODS: The study included 321 patients admitted to our university hospital between January 2013 and May 2015 with the diagnosis of acute PE. Multivariable risk models were developed to assess the predictive values of the NLR and PLR for 30-day mortality. Discrimination was evaluated using receiver operating characteristic (ROC) curves. RESULTS: Two hundred forty-eight patients met our selection criteria. Twenty of them died within 30 days of hospital admission. NLR was found to be an independent predicator after other confounding factors were adjusted in the model. For 1 unit of increase of NLR, the risk of 30-day mortality rose about 13  % (OR = 1.13,95 % CI: 1.04-1.23). The area under ROC for NLR is 0.79 (95 %CI: 0.703-0.880). PLR was associated with 30-day mortality in univariate analysis but the predicative ability diminished with inclusion of other predicators in multivariable model. CONCLUSIONS: NLR is readily available predicator for short-term mortality. It could be a useful indicator for identifying high risk population and guiding clinical management of acute PE.