Serum Mrp 8/14 as a Potential Biomarker for Predicting the Occurrence of Acute Respiratory Distress Syndrome Induced by Sepsis: A Retrospective Controlled Study.

Background: To date, there are no studies regarding the Mrp 8/14 in predicting the occurrence of acute respiratory distress syndrome (ARDS) induced by sepsis. Thus, the objective of this study was to investigate the expression of Myeloid-related proteins 8 and 14 (Mrp 8/14) and its role in ARDS induced by sepsis. Methods: A total of 168 septic patients were enrolled in the observational study. The baseline information and clinical outcomes were obtained retrospectively. Serum Mrp 8/14 level was determined by enzyme linked immunosorbent assay (ELISA). The patients were categorized into sepsis and ARDS group based on whether they developed ARDS during the intensive care unit (ICU) hospitalization. Results: There was significant difference in the level of Mrp 8/14 between the sepsis group and ARDS groups (P < 0.05). Mrp 8/14 correlated positively with procalcitonin (PCT), interleukin-6 (IL-6), acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score on day 1, mechanical ventilation time, length of ICU stay and hospitalization expenses in ICU (all P < 0.05). Logistic regression analysis showed Mrp 8/14 was the independent factor for forecasting the occurrence of sepsis- induced ARDS (P < 0.05). The areas under receiver operating characteristic curves for Mrp 8/14 were higher than that of PCT, APACHE II score and SOFA score on day 1 (P < 0.05). Conclusion: The serum Mrp 8/14 level at admission may be a potential marker for predicting the occurrence of ARDS induced by sepsis. Early detection of serum Mrp 8/14 could help clinicians to identify and evaluate the severity of ARDS induced by sepsis.

Diagnostic value of DNA or RNA-based metagenomic next-generation sequencing in lower respiratory tract infections.

Objectives: We aimed to evaluate and compare the diagnostic performance of RNA-mNGS and DNA-mNGS workflow in bacterial pneumonia, fungal pneumonia and tuberculosis. Methods: A total of 134 cases suspected pneumonia undergoing both DNA and RNA based mNGS of bronchoalveolar lavage fluid (BALF) and also traditional etiological examination were evaluated retrospectively.Sensitivity, specificity, PPV, NPV and accuracy rate of DNA and RNA based mNGS were estimated. Results: In the diagnosis performance of bacterial pathogens in LRTIs,the specificity of RNA-mNGS was higher than that of DNA-mNGS(82.3 % vs. 61.9 %, P < 0.01). There was no significant difference of sensitivity between the two process(71.4 % vs. 85.7 %, P = 0.375).In the diagnosis performance of fungal pathogens in LRTIs,the specificity of RNA-mNGS was higher than that of DNA-mNGS (72.3 % vs. 27.3 %,p < 0.001). There was no significant difference of sensitivity between the two process(96.5 % vs. 98.8 %,p = 0.125).In the diagnosis performance of tuberculosis in LRTIs,the sensitivity of DNA-mNGS was higher than that of RNA-mNGS (91.7 % vs. 33.3 %,p = 0.016),the specificity was similar in the two process (100 %). Conclusions: RNA-mNGS may reduced the misdiagnosis rate of bacterial and fungal pathogens in LRTIs.Compared to RNA-mNGS, DNA-mNGS may could improve the diagnostic rate of tuberculosis.

Development and validation of a CT-based deep learning radiomics nomogram to predict muscle invasion in bladder cancer.

Objective: This study aimed to develop a nomogram combining CT-based handcrafted radiomics and deep learning (DL) features to preoperatively predict muscle invasion in bladder cancer (BCa) with multi-center validation. Methods: In this retrospective study, 323 patients underwent radical cystectomy with pathologically confirmed BCa were enrolled and randomly divided into the training cohort (n = 226) and internal validation cohort (n = 97). And fifty-two patients from another independent medical center were enrolled as an independent external validation cohort. Handcrafted radiomics and DL features were constructed from preoperative nephrographic phase CT images. Least absolute shrinkage and selection operator (LASSO) regression was used to identify the most discriminative features in train cohort. Multivariate logistic regression was used to develop the predictive model and a deep learning radiomics nomogram (DLRN) was constructed. The predictive performance of models was evaluated by area under the curves (AUC) in the three cohorts. The calibration and clinical usefulness of DLRN were estimated by calibration curve and decision curve analysis. Results: The nomogram that incorporated radiomics signature and DL signature demonstrated satisfactory predictive performance for differentiating non-muscle invasive bladder cancer (NMIBC) from muscle invasive bladder cancer (MIBC), with an AUC of 0.884 (95 % CI: 0.813-0.953) in internal validation cohort and 0.862 (95 % CI: 0.756-0.968) in external validation cohort, respectively. Decision curve analysis confirmed the clinical usefulness of the nomogram. Conclusions: A CT-based deep learning radiomics nomogram exhibited a promising performance for preoperative prediction of muscle invasion in bladder cancer, and may be helpful in the clinical decision-making process.

A CT-based deep learning model predicts overall survival in patients with muscle invasive bladder cancer after radical cystectomy: a multicenter retrospective cohort study.

BACKGROUND: Muscle invasive bladder cancer (MIBC) has a poor prognosis even after radical cystectomy (RC). Postoperative survival stratification based on radiomics and deep learning (DL) algorithms may be useful for treatment decision-making and follow-up management. This study was aimed to develop and validate a DL model based on preoperative computed tomography (CT) for predicting postcystectomy overall survival (OS) in patients with MIBC. METHODS: MIBC patients who underwent RC were retrospectively included from four centers, and divided into the training, internal validation, and external validation sets. A DL model incorporated the convolutional block attention module (CBAM) was built for predicting OS using preoperative CT images. The authors assessed the prognostic accuracy of the DL model and compared it with classic handcrafted radiomics model and clinical model. Then, a deep learning radiomics nomogram (DLRN) was developed by combining clinicopathological factors, radiomics score (Rad-score) and deep learning score (DL-score). Model performance was assessed by C-index, KM curve, and time-dependent ROC curve. RESULTS: A total of 405 patients with MIBC were included in this study. The DL-score achieved a much higher C-index than Rad-score and clinical model (0.690 vs. 0.652 vs. 0.618 in the internal validation set, and 0.658 vs. 0.601 vs. 0.610 in the external validation set). After adjusting for clinicopathologic variables, the DL-score was identified as a significantly independent risk factor for OS by the multivariate Cox regression analysis in all sets (all P <0.01). The DLRN further improved the performance, with a C-index of 0.713 (95% CI: 0.627-0.798) in the internal validation set and 0.685 (95% CI: 0.586-0.765) in external validation set, respectively. CONCLUSIONS: A DL model based on preoperative CT can predict survival outcome of patients with MIBC, which may help in risk stratification and guide treatment decision-making and follow-up management.

Association of elastic power in mechanical ventilation with the severity of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Mechanical power (MP) is the total energy released into the entire respiratory system per minute which mainly comprises three components: elastic static power, Elastic dynamic power and resistive power. However, the energy to overcome resistance to the gas flow is not the key factor in causing lung injury, but the elastic power (EP) which generates the baseline stretch of the lung fibers and overcomes respiratory system elastance may be closely related to the ARDS severity. Thus, this study aimed to investigate whether EP is superior to other ventilator variables for predicting the severity of lung injury in ARDS patients. METHODS: We retrieved patient data from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The retrieved data involved adults (≥ 18 years) diagnosed with ARDS and subjected to invasive mechanical ventilation for ≥ 48 h. We employed univariate and multivariate logistic regression analyses to investigate the correlation between EP and development of moderate-severe ARDS. Furthermore, we utilized restricted cubic spline models to assess whether there is a linear association between EP and incidence of moderate-severe ARDS. In addition, we employed a stratified linear regression model and likelihood ratio test in subgroups to identify potential modifications and interactions. RESULTS: Moderate-severe ARDS occurred in 73.4% (296/403) of the patients analyzed. EP and MP were significantly associated with moderate-severe ARDS (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.15-1.28, p < 0.001; and OR 1.15, 95%CI 1.11-1.20, p < 0.001; respectively), but EP showed a higher area-under-curve (95%CI 0.72-0.82, p < 0.001) than plateau pressure, driving pressure, and static lung compliance in predicting ARDS severity. The optimal cutoff value for EP was 14.6 J/min with a sensitivity of 75% and specificity of 66%. Quartile analysis revealed that the relationship between EP and ARDS severity remained robust and reliable in subgroup analysis. CONCLUSION: EP is a good ventilator variable associated with ARDS severity and can be used for grading ARDS severity. Close monitoring of EP is advised in patients undergoing mechanical ventilation. Additional experimental trials are needed to investigate whether adjusting ventilator variables according to EP can yield significant improvements in clinical outcomes.

The association between blood eosinophils and clinical outcome of acute exacerbations of chronic obstructive pulmonary disease: A systematic review and meta-analysis.

OBJECTIVES: Studies have shown an association between eosinophilia and clinical outcomes in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, contradictory findings exist. Our study aims to systematically evaluate the association between elevated peripheral blood eosinophils and clinical outcome of patients with AECOPD. METHODS: An electronic search was conducted for relevant studies published from database inception to February 28, 2023, on PubMed, EMBASE, Cochrane Library, and Web of Science. The analysis covered studies on the correlation between EOS AECOPD and mortality, hospital stay duration, readmission and hospitalization rates, and invasive mechanical ventilation. Where applicable, relative risk (RR) and weighted mean difference (WMD) were extracted, pooled, and assessed using meta-analysis. Sensitivity analysis was performed to explore the source of heterogeneity. RESULTS: Fifteen high-quality studies including 14 cohort studies and one case-control study were included in the meta-analysis. Compared with non-eosinophilic AECOPD patients, those with eosinophilic AECOPD had a lower risk of mortality (RR = 0.65, 95 % confidence interval [CI] 0.54, 0.77, P < 0.001), shorter length of hospital stay (WMD = -1.56, 95%CI -2.16, -0.96, P < 0.001), and higher readmission rate (RR = 1.07, 95%CI 1.01,1.13, P = 0.029). No difference was found concerning the rate of hospitalization and invasive mechanical ventilation between the two groups. CONCLUSION: Individuals diagnosed with eosinophilic AECOPD had a reduced mortality rate, a truncated period of hospitalization, and an insubstantial increase in the probability of readmission relative to their non-eosinophilic AECOPD counterparts. The level of eosinophils in blood has been shown to serve as a potential predictive biomarker for AECOPD patients.

GPR146 regulates pulmonary vascular remodeling by promoting pulmonary artery smooth muscle cell proliferation through 5-lipoxygenase.

The pathological feature of hypoxic pulmonary hypertension (PH) is pulmonary vascular remodeling (PVR), primarily attributed to the hyperproliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Existing PH-targeted drugs have difficulties in reversing PVR. Therefore, it is vital to discover a new regulatory mechanism for PVR and develop new targeted drugs. G protein-coupled receptor 146 (GPR146) is believed to participate in this process. This study aimed to investigate the role of GPR146 in PASMCs during PH. We investigated the role of GPR146 in PVR and its underlying mechanism using hypoxic PASMCs and mouse model (Sugen 5416 (20 mg/kg)/hypoxia). In our recent study, we have observed a significant increase in the expression of GPR146 protein in animal models of PH as well as in patients diagnosed with pulmonary arterial hypertension (PAH). Through immunohistochemistry, we found that GPR146 was mainly localized in the smooth muscle and endothelial layers of the pulmonary vasculature. GPR146 deficiency induction exhibited protective effects against hypoxia-induced elevation of right ventricular systolic blood pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling in mice. In particular, the deletion of GPR146 attenuated the hypoxia-triggered proliferation of PASMCs. Furthermore, 5-lipoxygenase (5-LO) was related to PH development. Hypoxia and overexpression of GPR146 increased 5-LO expression, which was reversed through GPR146 knockdown or siRNA intervention. Our study discovered that GPR146 exhibited high expression in the pulmonary vessels of pulmonary hypertension. Subsequent research revealed that GPR146 played a crucial role in the development of hypoxic PH by promoting lipid peroxidation and 5-LO expression. In conclusion, GPR146 may regulate pulmonary vascular remodeling by promoting PASMCs proliferation through 5-LO, which presents a feasible target for PH prevention and treatment.

Paraneoplastic syndrome in malignant lymphoma: A case report.

Hypercalcaemia associated with malignancy is a complication of advanced tumors. Lactic acidosis is also an extremely rare paraneoplastic syndrome of malignancy, and the presence of both usually indicates an extremely poor prognosis for the tumour. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma and is also a common aggressive lymphoma. It is extremely rare for patients with diffuse large B-cell lymphoma to develop both hypercalcaemia and severe lactic acidosis. In this article, we report a case of CD5 positive diffuse large B-cell lymphoma with hypercalcaemic crisis and persistent lactic acidosis, in which calcium was rapidly reduced to normal after rehydration, diuresis, calcitonin and zoledronate, and continuous renal replacement therapy (CRRT). After correction of acidosis with sodium bicarbonate, diuresis, vitamin B1 and CRRT, the patient's lactate remained at a high level. The aim of this article is to analyse the experience of the combination of hypercalcaemia and intractable lactic acidosis, which should be considered as a serious electrolyte disorder possibly associated with abnormal metabolism of malignant tumors, and to identify and treat the primary lesion as early as possible.

[Development and validation of a mechanical power-oriented nomogram model for predicting the risk of weaning failure in mechanically ventilated patients: an analysis using the data from MIMIC-IV].

OBJECTIVE: To develop and validate a mechanical power (MP)-oriented nomogram prediction model of weaning failure in mechanically ventilated patients. METHODS: Patients who underwent invasive mechanical ventilation (IMV) for more than 24 hours and were weaned using a T-tube ventilation strategy were collected from the Medical Information Mart for Intensive Care-IV v1.0 (MIMIC-IV v1.0) database. Demographic information and comorbidities, respiratory mechanics parameters 4 hours before the first spontaneous breathing trial (SBT), laboratory parameters preceding the SBT, vital signs and blood gas analysis during SBT, length of intensive care unit (ICU) stay and IMV duration were collected and all eligible patients were enrolled into the model group. Lasso method was used to screen the risk factors affecting weaning outcomes, which were included in the multivariate Logistic regression analysis. R software was used to construct the nomogram prediction model and build the dynamic web page nomogram. The discrimination and accuracy of the nomogram were assessed by receiver operator characteristic curve (ROC curve) and calibration curves, and the clinical validity was assessed by decision curve analysis (DCA). The data of patients undergoing mechanical ventilation hospitalized in ICU of the First People's Hospital of Lianyungang City and the Second People's Hospital of Lianyungang City from November 2021 to October 2022 were prospectively collected to externally validate the model. RESULTS: A total of 3 695 mechanically ventilated patients were included in the model group, and the weaning failure rate was 38.5% (1 421/3 695). Lasso regression analysis finally screened out six variables, including positive end-expiratory pressure (PEEP), MP, dynamic lung compliance (Cdyn), inspired oxygen concentration (FiO2), length of ICU stay and IMV duration, with coefficients of 0.144, 0.047, -0.032, 0.027, 0.090 and 0.098, respectively. Logistic regression analysis showed that the six variables were all independent risk factors for predicting weaning failure risk [odds ratio (OR) and 95% confidence interval (95%CI) were 1.155 (1.111-1.200), 1.048 (1.031-1.066), 0.968 (0.963-0.974), 1.028 (1.017-1.038), 1.095 (1.076-1.113), and 1.103 (1.070-1.137), all P < 0.01]. The MP-oriented nomogram prediction model of weaning failure in mechanically ventilated patients showed accurate discrimination both in the model group and external validation group, with area under the ROC curve (AUC) and 95%CI of 0.832 (0.819-0.845) and 0.879 (0.833-0.925), respectively. Furthermore, its predictive accuracy was significantly higher than that of individual indicators such as MP, Cdyn, and PEEP. Calibration curves showed good correlation between predicted and observed outcomes. DCA indicated that the nomogram model had high net benefits, and was clinically beneficial. CONCLUSIONS: The MP-oriented nomogram prediction model of weaning failure accurately predicts the risk of weaning failure in mechanical ventilation patients and provides valuable information for clinicians making decisions on weaning.

[Based on the Hippo signaling pathway to explore the mechanism of autophagy in lung injury of acute respiratory distress syndrome induced by sepsis].

The systemic inflammatory response caused by various pathogenic factors is a key stage in the development of acute respiratory distress syndrome (ARDS). At present, suppression of the inflammatory response and symptomatic support are main methods for the treatment of ARDS. Alveolar epithelial autophagy has an important role in the regulation of the inflammatory response in ARDS. Autophagy is a normal immune mechanism in the body, and it is a metabolic process by which phagocytes degrade intracellular components with the help of lysosomes to maintain intracellular homeostasis. Current studies have shown that pathogenic factors both inside and outside the lung can cause alveolar epithelial cells to form an unfavorable internal environment of hypoxia, starvation, infection, and even apoptosis by triggering inflammatory responses, leading to autophagy dysfunction. Excessive autophagy activation can continue to aggravate inflammatory responses. Autophagy related proteins such as Beclin1, microtubule-associated protein 1 light chain 3 (LC3), mammalian target of rapamycin (mTOR), and p62 are common autophagic markers in current research, which play a crucial role in regulating the autophagic process and the development of lung injury. Therefore, the expression of cellular autophagy genes can be used as early markers and important mechanisms of lung injury in septic ARDS. The Hippo signaling pathway is derived from the protein kinase Hippo in Drosophila, and the Hippo and autophagy are two conserved pathways that are essential for the protection of homeostasis in vivo. The mutual regulation of Hippo signaling pathway and autophagy is currently a hot topic in the academic community. This paper reviews the relevant literature to explore whether the Hippo signaling pathway can regulate cellular autophagy to alleviate the inflammatory response in septic ARDS, so as to provide further research directions for the treatment of ARDS.

Elastic power, a novel predictor of the severity and prognosis of ARDS.

PURPOSE: To explore the predictive value of the new comprehensive respiratory mechanics parameters elastic power (EP) and elastic power normalized to the compliance (Cst-EP) in the evaluation of the severity and 28-day prognosis of ARDS patients. METHODS: The MIMIC-III database was used to identify ARDS patients under invasive mechanical ventilation for at least 48 h. Their baseline data and ventilatory variables were collected. EP, elastic energy, driving pressure and mechanical power were calculated according to the corresponding formulas. Their value in assessing the severity of ARDS was evaluated. The correlation between Cst-EP and 28-day prognosis of ARDS patients was analyzed. RESULTS: EP was independently associated with the severity of the ARDS and the odds ratio (OR) was 1.301 [95% CI (1.190-1.423), p < 0.001]. It has higher accuracy for the severity of ARDS, with an optimal cut-off value of 14.6 J/min. The Cst-EP was significantly associated with increased risk of death and the hazard ratio (HR) per 100 J/min × cmH2O/ml × 10-3 was 1.169 [95% CI (1.093-1.250), p < 0.001]. In addition, the 28-day cumulative survival rate of the high Cst-EP group was significantly lower than that of the low Cst-EP group. CONCLUSION: EP can be used to predict the severity of ARDS, and Cst-EP is associated with mortality during controlled mechanical ventilation in ARDS.

SnRNA-Seq analysis reveals ten hub genes associated with alveolar epithelial cell injury during pulmonary acute respiratory distress syndrome.

Background: Alveolar epithelial cell injury is a key factor in the occurrence and development of pulmonary acute respiratory distress syndrome (ARDSp). Yet the gene expression profile of alveolar epithelial cells of patients with ARDSp remains unclear. Methods: We analyzed single nuclear RNA sequencing (snRNA-Seq) data from autopsy lung tissues of both ARDSp patients and healthy donors. Sequence data for type 2 alveolar epithelizal cells (AT2) were extracted by the Seurat package. Differentially expressed genes (DEGs) in AT2 were identified by the criteria |log2FC| ≥ 0.25 and P < 0.05 with DESeq2. A protein interaction network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software to identify hub genes. We then constructed an ARDSp rat model through induction by lipopolysaccharide (LPS) airway instillation. Left lung RNA was extracted and sequenced via Illumina Hiseq platforms. Analysis of the rat RNA sequencing data was then used to verify hub genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the identified hub genes. Results: In AT2, a total of 289 genes were identified as differentially expressed between those from ARDSp patients and healthy donors, and these included 190 upregulated and 99 downregulated genes. Ten hub genes were further identified (RPS27A, ACTG1, CAV1, HSP90AA1, HSPA5, CCND1, ITGA3, B2M, NEDD4L, and SEMA5A). There was a similar expression trend of HSPA5 between rat RNA and snRNA sequencing data. Discussion: ARDSp altered the gene expression profile of AT2. The identified hub genes were enriched in biological processes mainly involved in cell growth and transformation. Relatedly, ferroptosis and autophagy are possibly involved in AT2 injury during ARDSp. These novel insights into ARDSp may aid the discovery of potential targets for the diagnosis and treatment of ARDSp.

Effects of early standardized enteral nutrition on preventing acute muscle loss in the acute exacerbation of chronic obstructive pulmonary disease patients with mechanical ventilation.

BACKGROUND: To investigate the effects of early standardized enteral nutrition (EN) on the cross-sectional area of erector spine muscle (ESMcsa), plasma growth differentiation factor-15 (GDF-15), and 28-day mortality of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with invasive mechanical ventilation (MV). METHODS: A total of 97 AECOPD patients with invasive MV were screened in the ICUs of the First People's Hospital of Lianyungang. The conventional EN group (stage I) and early standardized EN group (stage II) included 46 and 51 patients, respectively. ESMcsa loss and GDF-15 levels on days 1 and 7 of ICU admission and 28-day survival rates were analyzed. RESULTS: On day 7, the ESMcsa of the early standardized EN group was significantly higher than that of the conventional EN group, while the plasma GDF-15 levels were significantly lower than those in the conventional EN group (ESMcsa: 28.426±6.130 cm2 vs. 25.205±6.127 cm2; GDF-15: 1661.608±558.820 pg/mL vs. 2541.000±634.845 pg/mL; all P<0.001]. The 28-day survival rates of the patients in the early standardized EN group and conventional EN group were 80.40% and 73.90%, respectively (P=0.406). CONCLUSION: ESMcsa loss in AECOPD patients with MV was correlated with GDF-15 levels, both of which indicated acute muscular atrophy and skeletal muscle dysfunction. Early standardized EN may prevent acute muscle loss and intensive care unit-acquired weakness (ICU-AW) in AECOPD patients.

Stanniocalcin-1 secreted by human umbilical mesenchymal stem cells regulates interleukin-10 expression via the PI3K/AKT/mTOR pathway in alveolar macrophages.

Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure caused by infection, trauma, shock, aspiration or drug reaction. The pathogenesis of ARDS is characterized as an unregulated inflammatory storm, which causes endothelial and epithelial layer damage, leading to alveolar fluid accumulation and pulmonary edema. Previous studies have shown the potential role of mesenchymal stem cells (MSC) in combating the inflammatory cascade by increasing the anti-inflammatory mediator interleukin-10 (IL-10). However, the involved mechanisms are unclear. Here we investigated whether a key immunomodulatory regulator, stanniocalcin-1 (STC-1), was secreted by MSC to activate phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)/ mammalian target of rapamycin (mTOR) signaling pathway to increase IL-10 expression in alveolar macrophages. Lipopolysaccharide (LPS)-stimulated alveolar macrophages co-cultured with human umbilical mesenchymal stem cells (HUMSC) secreted high levels of IL-10. HUMSC co-cultured with alveolar macrophages expressed high STC-1 levels and increased PI3K, AKT and mTOR phosphorylation after LPS activation in alveolar macrophages. STC-1 knockdown in HUMSC decreased the phosphorylation of PI3K, AKT and mTOR and suppressed IL-10 expression in alveolar macrophages. Rapamycin (an mTOR inhibitor) reduced IL-10 secretion in alveolar macrophages. These results, together with our previous study and others, indicate that the PI3K/AKT/mTOR pathway is involved in the regulation of IL-10 production by STC-1 secreted by HUMSC in alveolar macrophages.

A two-sample mendelian randomization analysis excludes causal relationships between non-alcoholic fatty liver disease and kidney stones.

Objectives: Non-alcoholic fatty liver disease (NAFLD) has been linked to an increased risk of kidney stones in prior observational studies, However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between NAFLD and kidney stones using two-sample Mendelian randomization (MR). Methods: Genetic instruments were used as proxies for NAFLD. Summary-level data for the associations of exposure-associated SNPs with kidney stones were obtained from the UK Biobank study (6536 cases and 388,508 controls) and the FinnGen consortium (9713 cases and 366,693 non-cases). MR methods were conducted, including inverse variance weighted method (IVW), MR-Egger, weighted median, and MR-PRESSO. MR-Egger Regression Intercept and Cochran's Q test were used to assess the directional pleiotropy and heterogeneity. Results: cALT-associated NAFLD did not exhibit an association with kidney stones in the Inverse variance weighted (IVW) methods, in both the FinnGen consortium (OR: 1.02, 95%CI: 0.94-1.11, p = 0.632) and the UKBB study (OR: 1.000, 95%CI: 0.998-1.002, p = 0.852). The results were consistent in European ancestry (FinnGen OR: 1.05, 95%CI: 0.98-1.14, p = 0.144, UKBB OR: 1.000, 95%CI: 0.998-1.002, p = 0.859). IVW MR analysis also did not reveal a significant causal relationship between NAFLD and the risk of kidney stone for the other three NAFLD-related traits, including imaging-based, biopsy-confirmed NAFLD, and more stringent biopsy-confirmed NAFLD. The results remained consistent and robust in the sensitivity analysis. Conclusions: The MR study did not provide sufficient evidence to support the causal associations of NAFLD with kidney stones.

Development and validation of a mechanical power-oriented prediction model of weaning failure in mechanically ventilated patients: a retrospective cohort study.

OBJECTIVE: To develop and validate a mechanical power (MP)-oriented prediction model of weaning failure in mechanically ventilated patients. DESIGN: A retrospective cohort study. SETTING: Data were collected from the large US Medical Information Mart for Intensive Care-IV (MIMIC-IV) V.1.0, which integrates comprehensive clinical data from 76 540 intensive care unit (ICU) admissions from 2008 to 2019. PARTICIPANTS: A total of 3695 patients with invasive mechanical ventilation for more than 24 hours and weaned with T-tube ventilation strategies were enrolled from the MIMIC-IV database. PRIMARY AND SECONDARY OUTCOME: Weaning failure. RESULTS: All eligible patients were randomised into development cohorts (n=2586, 70%) and validation cohorts (n=1109, 30%). Multivariate logistic regression analysis of the development cohort showed that positive end-expiratory pressure, dynamic lung compliance, MP, inspired oxygen concentration, length of ICU stay and invasive mechanical ventilation duration were independent predictors of weaning failure. Calibration curves showed good correlation between predicted and observed outcomes. The prediction model showed accurate discrimination in the development and validation cohorts, with area under the receiver operating characteristic curve values of 0.828 (95% CI: 0.812 to 0.844) and 0.833 (95% CI: 0.809 to 0.857), respectively. Decision curve analysis indicated that the predictive model was clinically beneficial. CONCLUSION: The MP-oriented model of weaning failure accurately predicts the risk of weaning failure in mechanical ventilation patients and provides valuable information for clinicians making decisions on weaning.

[Transcriptomics analysis of key genes and signaling pathways in sepsis-related exogenous acute respiratory distress syndrome].

OBJECTIVE: To analyze the differentially expressed gene (DEG) in rats with sepsis-induced exogenous acute respiratory distress syndrome (ARDS) and explore the early diagnosis and protective mechanism of sepsis-induced ARDS at the transcriptome level. METHODS: Twelve 6 to 8 weeks old male Sprague-Dawley (SD) rats were randomly divided into lipopolysaccharide (LPS) induced sepsis-induced ARDS model group (model group, intraperitoneal injection of LPS 15 mg/kg) and control group (intraperitoneal injection of the same volume of normal saline), with 6 rats in each group. RNA was extracted from the left lung tissue of the two groups, and the paired-end sequencing mode of the illumina Hiseq sequencing platform was used for high-throughput sequencing. The DESeq2 software was used to screen DEG with |log2 (fold change, FC)| ≥ 3 and P < 0.001. Gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on DEG. STRING and CytoScape software were used to construct a protein-protein interaction (PPI) network and screen key genes. The peripheral blood mononuclear cell (PBMC) of 20 septic patients admitted to the emergency and critical care medical department of Lianyungang First People's Hospital from March to November 2021 and 20 age-matched healthy people in the same period were isolated and extracted, and the key genes were verified by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). RESULTS: A total of 286 DEG were screened, including 202 up-regulated genes and 84 down-regulated genes. GO enrichment analysis showed that DEG was mainly involved in biological processes such as neutrophil chemotaxis migration, antibacterial humoral response, host immune response, and humoral immune response. KEGG analysis showed that DEG mainly played a biological role through interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and chemokine signaling pathway. In PPI analysis, a total of 262 node proteins were screened, and the interaction relationship was 852 edges. The first 15 key genes were IL-6, TNF, IL-10, IL-1ß, chemokine ligand 1 (CXCL1), CXCL10, chemokine receptor 3 (CXCR3), CXCR2, CXCL9, chemokine ligand 7 (CCL7), CXCL11, CCL1, CXCL13, CCL12, and CCL22. Five representative key genes were performed on PBMC of blood samples from septic ARDS patients and healthy controls by RT-qPCR. The results showed that their expression was significantly higher than that in the healthy controls [IL-6 mRNA (2-ΔΔCt): 2.803±1.081 vs. 0.951±0.359, TNF mRNA (2-ΔΔCt): 2.376±0.799 vs. 1.150±0.504, CXCL10 mRNA (2-ΔΔCt): 2.500±0.815 vs. 1.107±0.515, CXCR3 mRNA (2-ΔΔCt): 1.655±0.628 vs. 0.720±0.388, CCL22 mRNA (2-ΔΔCt): 1.804±0.878 vs. 1.010±0.850, all P < 0.05], and the trends were consistent with the RNA-Seq results. CONCLUSIONS: Biological processes such as chemotactic migration and degranulation of inflammatory cells, cytokine immune response, and signal pathways such as CXCL10/CXCR3 and IL-17 play important roles in the occurrence and development of sepsis-related exogenous ARDS, which would provide new ideas and targets for further study of lung injury mechanisms and clinical prevention and treatment.

Mechanical power is associated with weaning outcome in critically ill mechanically ventilated patients.

Several single-center studies have evaluated the predictive performance of mechanical power (MP) on weaning outcomes in prolonged invasive mechanical ventilation (IMV) patients. The relationship between MP and weaning outcomes in all IMV patients has rarely been studied. A retrospective study was conducted on MIMIC-IV patients with IMV for more than 24 h to investigate the correlation between MP and weaning outcome using logistic regression model and subgroup analysis. The discriminative ability of MP, MP normalized to dynamic lung compliance (Cdyn-MP) and MP normalized to predicted body weight (PBW-MP) on weaning outcome were evaluated by analyzing the area under the receiver-operating characteristic (AUROC). Following adjustment for confounding factors, compared with the reference group, the Odds Ratio of weaning failure in the maximum MP, Cdyn-MP, and PBW-MP groups increased to 3.33 [95%CI (2.04-4.53), P < 0.001], 3.58 [95%CI (2.27-5.56), P < 0.001] and 5.15 [95%CI (3.58-7.41), P < 0.001], respectively. The discriminative abilities of Cdyn-MP (AUROC 0.760 [95%CI 0.745-0.776]) and PBW-MP (AUROC 0.761 [95%CI 0.744-0.779]) were higher than MP (AUROC 0.745 [95%CI 0.730-0.761]) (P < 0.05). MP is associated with weaning outcomes in IMV patients and is an independent predictor of the risk of weaning failure. Cdyn-MP and PBW-MP showed higher ability in weaning failure prediction than MP.

Whole Transcriptomic Analysis of Key Genes and Signaling Pathways in Endogenous ARDS.

Objective: To analyze the differentially expressed genes (DEGs) in rats with endogenous acute respiratory distress syndrome (ARDS) lung injury and explore the pathogenesis and early diagnostic molecular markers using whole transcriptomic data. Methods: Twelve 8-week-old male Sprague Dawley rats were selected and randomly and equally divided into ARDS lung injury group and normal control group. RNA was extracted from the left lung tissues of both the groups and sequenced using the paired-end sequencing mode of the Illumina Hiseq sequencing platform. The DEGs of miRNA, cirRNA, lncRNA, and mRNA were screened using DESeq2 software, and the ceRNA regulatory network was constructed using Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the mRNA DEGs. STRING and Cytoscape software were used to construct the protein interaction network and identify the 15 key genes, which were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Results: Based on different screening conditions, and compared with the control group, the ARDS lung injury group showed 836 mRNA DEGs (386 upregulated and 450 downregulated), 110 lncRNA DEGs (53 upregulated and 57 downregulated), 19 circRNA DEGs (3 upregulated and 16 downregulated), and 6 miRNA DEGs (5 upregulated and 1 downregulated gene). GO showed that the DEGs of mRNA were mainly involved in biological processes, such as defense response to lipopolysaccharide and other organisms, leukocyte chemotaxis, neutrophil chemotaxis, and cytokine-mediated signaling. KEGG enrichment analysis showed that the DEGs played their biological roles mainly by participating in IL-17, TNF, and chemokine signaling pathways. The PPI analysis showed a total of 281 node proteins and 634 interaction edges. The top 15 key genes, which were screened, included Cxcl10, Mx1, Irf7, Isg15, Ifit3, Ifit2, Rsad2, Ifi47, Oasl, Dhx58, Usp18, Cmpk2, Herc6, Ifit1, and Gbp4. The ceRNA network analysis showed 69 nodes and 73 correlation pairs, where the key gene nodes were miR-21-3p, Camk2g, and Stx2. Conclusions: The chemotaxis, migration, and degranulation of inflammatory cells, cytokine immune response, autophagy, and apoptosis have significant biological functions in the occurrence and development of endogenous acute lung injury during ARDS. Thus, the camk2g/miR-21-3p/lncRNA/circRNA network, CXCL10/CXCR3, and IL-17 signaling pathways might provide novel insights and targets for further studying the lung injury mechanism and clinical treatment.

Identification and validation of autophagy-related genes in exogenous sepsis-induced acute respiratory distress syndrome.

OBJECTIVE: To analyze the differential expression of autophagy-related genes of sepsis-induced acute respiratory distress syndrome (ARDS) as potential markers for early diagnosis. METHODS: Male Sprague-Dawley rats (aged 8 weeks) were selected and randomly divided into sepsis-induced ARDS group (n = 6) and a normal control group (n = 6). Lung tissue samples were collected for high-throughput sequencing using Illumina HiSeq sequencing platform in the paired-end sequencing mode. Differentially expressed genes (DEGs) were screened by DESeq. 2 software [|log2FC | ≥1 and p < .05] and autophagy-related genes were identified using Mouse Genome Informatics. Co-expressed autophagy-related DEGs from these two datasets were filtered by construction of a Venn diagram. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these autophagy-related DEGs and a protein interaction network was constructed using STRING and Cytoscape software to identify hub genes, which were verified by real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: A total of 42 autophagy-related DEGs (26 upregulated genes and 16 downregulated genes) were identified. The GO and KEGG pathway analyses showed enrichment in 969 biological processes (BPs), three cellular components (CCs), eight molecular functions (MFs) and 27 signaling pathways. The protein interaction (PPI) network revealed 42 node proteins and 75 interacting edges, with an average node degree of 3.52, and an average local clustering coefficient of 0.509. Among the top 10 hub genes with the RNA-Seq, six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) were validated by qRT-PCR (all p < .05). CONCLUSION: 42 potential autophagy-related genes associated with sepsis-induced ARDS lung injury were identified and six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) may affect the development of ARDS by regulating autophagy. These results expanded our understanding of ARDS and might be useful in treatment of exogenous sepsis-induced ARDS.