The identification and verification of hub genes associated with pulmonary arterial hypertension using weighted gene co-expression network analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, with complex etiology, difficult treatment and poor prognosis. The objective of this study was to investigate the potential biomarkers for PAH based on bioinformatics analysis. METHODS: The GSE117261 datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by screening PAH patients and controls. Then the DEGs were analyzed using a Weighted Gene Co-expression Network Analysis (WGCNA) and the key modules were determined, and to further explore their potential biological functions via Gene Ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes Pathway analysis (KEGG), and Gene Set Enrichment Analysis (GSEA). Moreover, Protein-protein interaction (PPI) networks were constructed to identify hub gene candidates in the key modules. Finally, real-time quantitative polymerase chain reaction was supplied to detect the expressions of hub genes in human pulmonary arterial smooth cells treated with cobalt chloride (COCl2) which was used to mimic hypoxia. RESULTS: There were 2299 DEGs identified. WGCNA indicated that yellow module was the key one correlated with PAH. GO and KEGG analysis demonstrated that genes in the yellow module were mainly enriched in 'Pathways in cancer'. GSEA revealed that 'HALLMARK_MYC_TARGETS_V1' was remarkably enriched in PAH. Based on the PPI network, vascular endothelial growth factor A, proto-oncogene receptor tyrosine kinase (KIT), PNN interacting serine and arginine rich protein (PNISR) and heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) were identified as the hub genes. Additionally, the PCR indicated that the elevated expressions of PNISR and HNRNPH1 were in line with the bioinformatics analysis. ROC analysis determined that PNISR and HNRNPH1 may be potential biomarkers to provide better diagnosis of PAH. CONCLUSION: PNISR and HNRNPH1 were potential biomarkers to diagnosis PAH. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of PAH.

Developing a nomogram for forecasting the 28-day mortality rate of individuals with bleeding esophageal varices using model for end-stage liver disease scores.

BACKGROUND: This study aimed to create a nomogram using the model for end-stage liver disease (MELD) that can better predict the risk of 28-day mortality in patients with bleeding esophageal varices. METHODS: Data on patients with bleeding esophageal varices were retrospectively collected from the Medical Information Mart for Intensive Care database. Variables were selected using the least absolute shrinkage and selection operator logistic regression model and were used to construct a prognostic nomogram. The nomogram was evaluated against the MELD model using various methods, including receiver operating characteristic (ROC) curve analysis, calibration plotting, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). RESULTS: A total of 280 patients were included in the study. The patient's use of vasopressin and norepinephrine, respiratory rate, temperature, mean corpuscular volume, and MELD score were included in the nomogram. The area under the ROC curve, NRI, IDI, and DCA of the nomogram indicated that it performs better than the MELD alone. CONCLUSION: A nomogram was created that outperformed the MELD score in forecasting the risk of 28-day mortality in individuals with bleeding esophageal varices.

Elevated Activated Partial Thromboplastin Time as a Predictor of 28-Day Mortality in Sepsis-Associated Acute Kidney Injury: A Retrospective Cohort Analysis.

Purpose: To address the critical mortality rates among sepsis-associated acute kidney injury (SA-AKI) patients, early prognosis is vital. This study investigates the relationship between coagulation indices and the 28-day mortality rate in patients with SA-AKI. Patients and Methods: This study was a retrospective cohort analysis including patients with SA-AKI admitted to the First Hospital of Fujian Medical University as a training cohort (n = 119) and patients admitted to the Third People's Hospital of Fujian University of Traditional Chinese Medicine as a validation cohort (n = 51). We examined the relationship between coagulation indices and 28-day mortality in SA-AKI, the cumulative mortality at different activated partial thromboplastin time (APTT) levels, and the nonlinear relationship between APTT and 28-day mortality. Receiver operating characteristic curves were plotted, and the area under the curve was calculated to assess the predictive power of APTT. Finally, subgroup analyses were performed to assess the robustness of the association. Results: Overall, 119 participants with a mean±standard deviation age of 70.47±15.20 years were included in the training cohort: 54 died, 65 survived. According to univariate and multivariate COX regression analyses, APACHE II score, CRP level, Lac level, and APTT level were independent risk factors for 28-day adverse prognosis. After controlling for some variables, an elevated baseline APTT (≥ 37.7 s) was associated with an elevated risk of 28-day mortality (HR, 1.017; 95% CI, 1.001-1.032), and Kaplan-Meier analyses further confirmed the increased mortality in the group with a higher APTT. The same results were shown when the validation cohort was analyzed (HR, 1.024; 95% CI, 0.958-1.096). Subgroup analyses showed the stability of the association between APTT and poor prognosis in SA-AKI. Conclusion: In essence, APTT elevation is synonymous with increased 28-day mortality rates, indicating a poor prognosis in SA-AKI scenarios.

TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis.

Sarcopenia has become a leading cause of disability and mortality in the elderly. It has been reported that programmed cell death (PCD) is associated with the development of sarcopenia that is characterized by reduction of muscle fiber size and number. TNF-α is also validated to play a prominent role in sarcopenia through its complex signaling pathways including cell death signaling. However, it is still unclear whether TNF-α contributes to sarcopenia by mediating pyroptosis, one type of PCD. Here, we first established naturally aged mice with sarcopenia model and confirmed an inflammatory state represented by TNF-α in aged mice. Evidence of GSDME-mediated pyroptosis and activation of apoptotic caspase-8/-3 were also found in skeletal muscle cells of aged mice with sarcopenia. We demonstrated that TNF-α triggered GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3 by using caspase-8 and caspase-3 inhibitors. Comparing the activation of caspase-8 and GSDME expression between TNF Complex IIa and TNF Complex IIb, TNF-α was found to be more inclined to assemble TNF Complex IIb in activating caspase-8 and triggering pyroptosis. Moreover, pyroptotic myotubes were validated to result in decreased expression of MHC1 and finally loss of myotubes by knockdown of GSDME. Our work reveals a novel mechanism that TNF-ɑ/caspase-8/caspase-3/GSDME signaling-mediated pyroptosis contributes to the development of sarcopenia. Caspase-3/GSDME signaling-mediated pyroptosis may be a promising therapeutic target for sarcopenia.

Exploring potential therapeutic agents for lipopolysaccharide-induced septic cardiomyopathy based on transcriptomics using bioinformatics.

Septic cardiomyopathy (SCM) is a common and severe complication of sepsis, characterized by left ventricular dilation and reduced ejection fraction leading to heart failure. The pathogenesis of SCM remains unclear. Understanding the SCM pathogenesis is essential in the search for effective therapeutic agents for SCM. This study was to investigate the pathophysiology of SCM and explore new therapeutic drugs by bioinformatics. An SCM rat model was established by injection of 10 mg/kg lipopolysaccharide (LPS) for 24 h, and the myocardial tissues were collected for RNA sequencing. The differentially expressed genes (DEGs) between LPS rats and control (Ctrl) with the thresholds of |log2fold change|≥ 1 and P < 0.05. A protein-protein interaction (PPI) network was constructed based on the DEGs. The hub genes were identified using five algorithms of Cytoscape in the PPI networks and validated in the GSE185754 dataset and by RT-qPCR. The hub genes were analyzed by Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG), as well as Gene set enrichment analyses (GSEA). In addition, the miRNAs of hub genes were predicted through miRWalk, and the candidate therapeutic drugs were identified using the Connectivity Map (CMAP) database. This study revealed the identified hub genes (Itgb1, Il1b, Rac2, Vegfa) and key miRNAs (rno-miR-541-5p, rno-miR-487b-3p, rno-miR-1224, rno-miR-378a-5p, rno-miR-6334, and rno-miR-466b-5p), which were potential biological targets and biomarkers of SCM. Anomalies in cytokine-cytokine receptor interactions, complement and coagulation cascades, chemokine signaling pathways, and MAPK signaling pathways also played vital roles in SCM pathogenesis. Two high-confidence candidate compounds (KU-0063794 and dasatinib) were identified from the CMAP database as new therapeutic drugs for SCM. In summary, these four identified hub genes and enrichment pathways may hold promise for diagnosing and treating SCM.

Bioinformatic Exploration of Hub Genes and Potential Therapeutic Drugs for Endothelial Dysfunction in Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension (HPH) is a fatal chronic pulmonary circulatory disease, characterized by hypoxic pulmonary vascular constriction and remodeling. Studies performed to date have confirmed that endothelial dysfunction plays crucial roles in HPH, while the underlying mechanisms have not been fully revealed. The microarray dataset GSE11341 was downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between hypoxic and normoxic microvascular endothelial cell, followed by Gene Ontology (GO) annotation/Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis, and protein-protein interaction (PPI) network construction. Next, GSE160255 and RT-qPCR were used to validate hub genes. Meanwhile, GO/KEGG and GSEA were performed for each hub gene to uncover the potential mechanism. A nomogram based on hub genes was established. Furthermore, mRNA-miRNA network was predicted by miRNet, and the Connectivity Map (CMAP) database was in use to identify similarly acting therapeutic candidates. A total of 148 DEGs were screened in GSE11341, and three hub genes (VEGFA, CDC25A, and LOX) were determined and validated via GSE160255 and RT-qPCR. Abnormalities in the pathway of vascular smooth muscle contraction, lysosome, and glycolysis might play important roles in HPH pathogenesis. The hub gene-miRNA network showed that hsa-mir-24-3p, hsa-mir-124-3p, hsa-mir-195-5p, hsa-mir-146a-5p, hsa-mir-155-5p, and hsa-mir-23b-3p were associated with HPH. And on the basis of the identified hub genes, a practical nomogram is developed. To repurpose known and therapeutic drugs, three candidate compounds (procaterol, avanafil, and lestaurtinib) with a high level of confidence were obtained from the CMAP database. Taken together, the identification of these three hub genes, enrichment pathways, and potential therapeutic drugs might have important clinical implications for HPH diagnosis and treatment.

Relationship between Children's Independent Activities and the Built Environment of Outdoor Activity Space in Residential Neighborhoods: A Case Study of Nanjing.

Children are a vulnerable population that is frequently overlooked in urban planning. The spatial demands of children are garnering broader consideration in the development of public spaces in cities as efforts to promote child-friendly cities. Children's independent activities (CIAs) during childhood are undeniably beneficial to their physical and mental health. Residential areas are the main places for children's daily activities. Building a suitable outdoor activity space in the community for children's recreation is an essential foundation for improving CIAs and promoting the development of child-friendly neighborhoods. A sample of 15 typical children's outdoor activity spaces in residential neighborhoods of Nanjing, China, was selected for the study to observe and record CIAs. The built environment indicators of residential outdoor spaces were extracted, and correlation analysis was employed to investigate the residential outdoor space elements relevant to CIAs. The results indicated that at the site level, higher percentages of tree coverage and soft paving enhanced CIAs, while high functional mix inhibited them. Additionally, gated communities, top-notch sanitation, secure facilities, neighborhoods with higher residential densities, and a diversity of activity facilities all stimulated children to engage in independent activities. Furthermore, questionnaires for the guardian indicated that they placed a high priority on site safety, and that waterfront areas and activity sites where incidents had occurred decreased parents' willingness to allow participation in CIAs, whereas safety education or the use of positioning devices may promote CIAs. Based on the above results, we proposed appropriate adaptations for places in residential neighborhoods. The study expects to create a higher quality environment in residential neighborhoods for children to play in public spaces and provide beneficial help to improve the child-friendly neighborhood.

[Procedure and teaching verses of supraclavicular subclavian catheterization].

In order to improve the success rate of supraclavicular deep venous catheterization and reduce mechanical complications, we present an auxillary maneuver in regard to supraclavicular subclavian catheterization basing on the relatively fixed anatomy of subclavian vein and its adjacent surroundings, furthermore, we revised the standardized procedure of supraclavicular subclavian catheterization. The maneuver is summarized in the shape of verses (verses: thumb navigation is well designed according to anatomy. Needle penetrated into vein should be parallel to coronal plane. Fine needle in position should be immobilized. Is it difficult for parallel puncture? Pressure determination is required when needle is in place. It is critical to distinguish which vessel has been inserted. Guidewire is advanced smoothly. Check blood return after expansion of skin and catheterization.). For teaching convenience, verses are considered to be more concise and memorable, as well as applicable to clinical practice, in order to provide some help for clinical teaching.

Does high-flow nasal cannula oxygen improve outcome in acute hypoxemic respiratory failure? A systematic review and meta-analysis.

INTRODUCTION: To evaluate the efficacy of high-flow nasal cannula (HFNC) in the rate of intubation and mortality for patients with acute hypoxemic respiratory failure. METHODS: We searched Pubmed, EMBASE, and the Cochrane Library for relevant studies. Two reviewers extracted data and reviewed the quality of the studies independently. The primary outcome was the rate of intubation; secondary outcome was mortality in the hospital. Study-level data were pooled using a random-effects model when I2 was >50% or a fixed-effects model when I2 was <50%. RESULTS: Eight randomized controlled studies with a total of 1,818patients were considered. Pooled analysis showed that no statistically significant difference was found between groups regarding the rate of intubation (odds ratio [OR] = 0.79; 95% confidence interval [CI]: 0.60-1.04; P = 0.09; I2 = 36%) and no statistically significant difference was found between groups regarding hospital mortality (OR = 0.89; 95% CI: 0.62-127; P = 0.51; I2 = 47%). CONCLUSIONS: The use of HFNC showed a trend toward reduction in the intubation rate, which did not meet statistical significance, in patients with acute respiratory failure compared with conventional oxygen therapy (COT) and noninvasive ventilation (NIV). Moreover no difference in mortality. So, Large, well-designed, randomized, multi-center trials are needed to confirm the effects of HFNC in acute hypoxemic respiratory failure patients.

Diagnostic value of brain natriuretic peptide and ß-endorphin plasma concentration changes in patients with acute left heart failure and atrial fibrillation.

RATIONALE: This study aims to evaluate the diagnostic value of beta-endorphin (ß-EP) and brain natriuretic peptid (BNP) plasma concentrations for the early diagnosis of acute left heart failure and atrial fibrillation. PATIENT CONCERNS: A total of 45 patients were included. These patients comprised 23 male and 22 female patients,and 20 healthy subjects who underwent physical examinations in the Outpatient Department during the same periodwere included and assigned to the control group. DIAGNOSES: The diagnos stand was that of the Chinese guidelines for the diagnosis and treatment of heart failure. INTERVENTIONS: Enzyme-linked immunosorbent assay was performed to detect the plasma concentration of ß-EP and BNP in the treatment and control groups, and electrocardiogram targeting was performed to determine the left ventricular ejection fraction (LVEF). OUTCOMES: BNP, ß-EP, and LVEF levels were higher in the treatment group (688.01 ±â€Š305.78 ng/L, 394.06 ±â€Š180.97 ng/L, and 70.48 ±â€Š16.62%) compared with the control group (33.90 ±â€Š8.50 ng/L, 76.87 ±â€Š57.21 ng/L, and 32.11 ±â€Š5.25%). The P-values were .015, .019, and .026, respectively, which were <.05. The difference was statistically significant. The BNP and ß-EP's 4 correlations (r = 0.895, P <.001), BNP, ß-EP, and the combination of BNP and ß-EP for acute left heart failure diagnosis in maximizing Youden index sensitivity, specific degree, area under the ROC curve (AUC), and 95% confidence interval (CI) were respectively 93.5%, 81.3%, 0.921, 0.841, 0.921; 80.5%, 78.6%, 0.697, 0.505, 0.697; 94.1%, 83.5%, 0.604 to 0.979, and 0.604. Acute left heart failure in patients with LVEF acuity plasma BNP and ß-EP 50% group was obviously lower than that in the LVEF <50% group (P <.01). BNP, ß-EP, and LVEF were negatively correlated (r = -0.741, -0.635, P = .013, .018). LESSONS: ß-EP and BNP have high specificity and sensitivity for detecting early acute left heart failure and atrial fibrillation in patients, which is convenient, easy to perform, and suitable for clinical applications.

Artificial biological ligament: its making, testing, and experimental study on animals.

By applying a novel biochemical technique using porcine tendon as the raw material with its antigen minimized, we developed an artificial biological ligament (ABL). We examined and tested its structure, mechanical properties, and biocompatibility and explored the feasibility of reconstructing the anterior cruciate ligament (ACL) with ABL. By means of treating porcine tendon with epoxy crosslinking fixation, diversified antigen minimization process, mechanic enhancement modification, and surface activating process, we fabricated the ABL samples. We then analyzed its in vivo and in vitro performances, respectively, with animal (goat) implantation, histological examination, scanning electron microscope, cells culture, and mechanical tests before and after animal implants. The appearance of ABL was similar to that of normal human ligament. Histological examination showed that the ABL was composed of collagen fibers with no cells. Electron microscope examination revealed that the ABL was composed of hair-appearing and fiber-like objects running uniformly in a certain direction and closely parallel-arranged. Three weeks after xenogenic marrow matrix cells were cultured on the surface of the ABL, it was noted that cells adhered and the matrix secreted by the cells precipitated around the cells. There were no cells found inside the ABL. The average diameter of ABL was 5 mm and the mechanical test at a speed of 100 mm/min showed that its average tensile limit was 927.19 N; the tension-resistant strength was 47.22 N/mm. Those measurements were close to the corresponding parameters of the normal goat ACL. Twelve weeks after ABL replacement of the goat ACL, synovial membrane covering with the ingrowths of small blood vessels was seen on the surface of the implant. Fifty weeks after the replacement, the ABL material was partially replaced by regenerated host ligament-like tissue. Around the ABL material fibers in the bone tunnel close to the joint surface the direct connection mode, ligament-fibro cartilage-calcified cartilage-bone, was seen. As we used the unique biochemical technique and minimized the xenogenic protein immunogenicity of the porcine tendon, ABL showed acceptable biomechanical properties and superior biocompatibility. As a substitute for ligament in the reconstruction of the ACL, ABL has a promising prospect in clinical applications.