TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury.

Vascular endothelial cell barrier disruption is a hallmark of sepsis-induced acute lung injury (ALI). Mesenchymal stem cells (MSCs)-based therapy has been regarded as a promising treatment for repairing injured lungs, and mitochondrial transfer was shown to be important for the therapeutic effects of MSCs. Here we investigated the ability of MSCs to modulate endothelial barrier integrity through mitochondrial transfer in sepsis-induced ALI. We found that mitochondrial transfer from MSCs to LPS-induced PMVECs through forming tunneling nanotubes (TNTs). Due to the inhibition of TNTs (using LAT-A), MSCs-mediated reparation on PMVECs functions, including cell apoptosis, MMP, ATP generation, TEER level and monolayer permeability of FITC-dextran were greatly inhibited. In addition, silencing of mitochondrial transcription factor A (TFAM) in MSCs could also partly inhibit the TNTs formation and aggravate the LPS-induced mitochondrial dysfunction and permeability barrier in PMVECs. Furthermore, the LPS-induced pulmonary edema and higher pulmonary vascular permeability were alleviated by MSCs while that of lung tissue bounced back after MSCs were pre-incubated by LAT-A and or down-regulation of TFAM. Therefore, we firstly revealed that regulation of TFAM expression in MSCs played a critical role to improve the permeability barrier of PMVECs by TNTs mediating mitochondrial transfer in sepsis-associated ALI. This study provided a new therapeutic strategy for the treatment of sepsis-induced ALI.

Thiamine May Be Beneficial for Patients With Ventilator-Associated Pneumonia in the Intensive Care Unit: A Retrospective Study Based on the MIMIC-IV Database.

Background: Ventilator-associated pneumonia (VAP) is a common infection complication in intensive care units (ICU). It not only prolongs mechanical ventilation and ICU and hospital stays, but also increases medical costs and increases the mortality risk of patients. Although many studies have found that thiamine supplementation in critically ill patients may improve prognoses, there is still no research or evidence that thiamine supplementation is beneficial for patients with VAP. The purpose of this study was to determine the association between thiamine and the prognoses of patients with VAP. Methods: This study retrospectively collected all patients with VAP in the ICU from the Medical Information Mart for Intensive Care-IV database. The outcomes were ICU and in-hospital mortality. Patients were divided into the no-thiamine and thiamine groups depending upon whether or not they had received supplementation. Associations between thiamine and the outcomes were tested using Kaplan-Meier (KM) survival curves and Cox proportional-hazards regression models. The statistical methods of propensity-score matching (PSM) and inverse probability weighting (IPW) based on the XGBoost model were also applied to ensure the robustness of our findings. Results: The study finally included 1,654 patients with VAP, comprising 1,151 and 503 in the no-thiamine and thiamine groups, respectively. The KM survival curves indicated that the survival probability differed significantly between the two groups. After multivariate COX regression adjusted for confounding factors, the hazard ratio (95% confidence interval) values for ICU and in-hospital mortality in the thiamine group were 0.57 (0.37, 0.88) and 0.64 (0.45, 0.92), respectively. Moreover, the results of the PSM and IPW analyses were consistent with the original population. Conclusion: Thiamine supplementation may reduce ICU and in-hospital mortality in patients with VAP in the ICU. Thiamine is an inexpensive and safe drug, and so further clinical trials should be conducted to provide more-solid evidence on whether it improves the prognosis of patients with VAP.

Risk factor analysis and nomogram for predicting in-hospital mortality in ICU patients with sepsis and lung infection.

BACKGROUND: Lung infection is a common cause of sepsis, and patients with sepsis and lung infection are more ill and have a higher mortality rate than sepsis patients without lung infection. We constructed a nomogram prediction model to accurately evaluate the prognosis of and provide treatment advice for patients with sepsis and lung infection. METHODS: Data were retrospectively extracted from the Medical Information Mart for Intensive Care (MIMIC-III) open-source clinical database. The definition of Sepsis 3.0 [10] was used, which includes patients with life-threatening organ dysfunction caused by an uncontrolled host response to infection, and SOFA score ≥ 2. The nomogram prediction model was constructed from the training set using logistic regression analysis, and was then internally validated and underwent sensitivity analysis. RESULTS: The risk factors of age, lactate, temperature, oxygenation index, BUN, lactate, Glasgow Coma Score (GCS), liver disease, cancer, organ transplantation, Troponin T(TnT), neutrophil-to-lymphocyte ratio (NLR), and CRRT, MV, and vasopressor use were included in the nomogram. We compared our nomogram with the Sequential Organ Failure Assessment (SOFA) score and Simplified Acute Physiology Score II (SAPSII), the nomogram had better discrimination ability, with areas under the receiver operating characteristic curve (AUROC) of 0.743 (95% C.I.: 0.713-0.773) and 0.746 (95% C.I.: 0.699-0.790) in the training and validation sets, respectively. The calibration plot indicated that the nomogram was adequate for predicting the in-hospital mortality risk in both sets. The decision-curve analysis (DCA) of the nomogram revealed that it provided net benefits for clinical use over using the SOFA score and SAPSII in both sets. CONCLUSION: Our new nomogram is a convenient tool for accurate predictions of in-hospital mortality among ICU patients with sepsis and lung infection. Treatment strategies that improve the factors considered relevant in the model could increase in-hospital survival for these ICU patients.

The Role of Glucocorticoids in the Treatment of ARDS: A Multicenter Retrospective Study Based on the eICU Collaborative Research Database.

Background: Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in patients in intensive care unit (ICU). The therapeutic value of glucocorticoids (GCs) in the prognosis of ARDS remains controversial. The aim of this research is studying the impacts of GCs treatment on ARDS patients in ICU. Methods: We retrospectively studied 2,167 ARDS patients whose data were collected from the public eICU Collaborative Research Database, among which 254 patients who received glucocorticoid (GCs) treatment were 1:1 matched by propensity matching analysis (PSM). The primary outcome was ICU mortality. Every oxygenation index (PaO2/FiO2) measurement before death or ICU discharge was recorded. A joint model (JM) which combined longitudinal sub-model (mixed-effect model) and time-to-event sub-model (Cox regression model) by trajectory functions of PaO2/FiO2 was conducted to determine the effects of GCs treatment on both ICU mortality and PaO2/FiO2 level and further PaO2/FiO2's effect on event status. The marginal structural cox model (MSCM) adjusted the overall PaO2/FiO2 of patients to further validate the results. Results: The result of the survival sub-model showed that GCs treatment was significantly associated with reduced ICU mortality in ARDS patients [HR (95% CI) = 0.642 (0.453, 0.912)], demonstrating that GCs treatment was a protective factor of ICU mortality. In the longitudinal sub-model, GCs treatment was not correlated to the PaO2/FiO2. After adjusted by the JM, the HR of GCs treatment was 0.602 while GCs was still not significantly related to PaO2/FiO2 level. The JM-induced association showed that higher PaO2/FiO2 was a significant protective factor of mortality in ARDS patients and the HR was 0.991 which demonstrated that one level increase of PaO2/FiO2 level decreased 0.9% risk of ICU mortality. MSCM results also show that GCs can improve the prognosis of patients. Conclusion: Rational use of GCs can reduce the ICU mortality of ARDS patients in ICU. In addition to the use of GCs treatment, clinicians should also focus on the shifting trend of PaO2/FiO2 level to provide better conditions for patients' survival.

Construction and Evaluation of a Sepsis Risk Prediction Model for Urinary Tract Infection.

Background: Urinary tract infection (UTI) is one of the common causes of sepsis. However, nomograms predicting the sepsis risk in UTI patients have not been comprehensively researched. The goal of this study was to establish and validate a nomogram to predict the probability of sepsis in UTI patients. Methods: Patients diagnosed with UTI were extracted from the Medical Information Mart for Intensive Care III database. These patients were randomly divided into training and validation cohorts. Independent prognostic factors for UTI patients were determined using forward stepwise logistic regression. A nomogram containing these factors was established to predict the sepsis incidence in UTI patients. The validity of our nomogram model was determined using multiple indicators, including the area under the receiver operating characteristic curve (AUC), correction curve, Hosmer-Lemeshow test, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision-curve analysis (DCA). Results: This study included 6,551 UTI patients. Stepwise regression analysis revealed that the independent risk factors for sepsis in UTI patients were congestive heart failure, diabetes, liver disease, fluid electrolyte disorders, APSIII, neutrophils, lymphocytes, red blood cell distribution width, urinary protein, urinary blood, and microorganisms. The nomogram was then constructed and validated. The AUC, NRI, IDI and DCA of the nomogram all showed better performance than traditional APSIII score. The calibration curve and Hosmer-Lemeshow test results indicate that the nomogram was well-calibrated. Improved NRI and IDI values indicate that our nomogram scoring system is superior to other commonly used ICU scoring systems. The DCA curve indicates that the DCA map of the nomogram has good clinical application ability. Conclusion: This study identified the independent risk factors of sepsis in UTI patients and used them to construct a prediction model. The present findings may provide clinical reference information for preventing sepsis in UTI patients.

Diagnostic utility of PAX2 and PAX5 in distinguishing non-small cell lung cancer from small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in both men and women and consists of different histological types. Histopathological examination and accurate subtype diagnosis has become increasingly important in guiding patient management and, as such, is the most important currently available lung cancer "biomarker". In this study, we examined the expression of PAX2 and PAX5 by immunohistochemistry in 47 cases of lung cancer and 13 cases of pneumonia. The results demonstrated that PAX2 were detected in 82.8% (24/29) of NSCLC, 0% (0/18) of SCLC and 7.7% (1/13) of pneumonia, respectively; However, PAX5 were detected in 15/18 cases (83.3%) of SCLC, 6.8% (2/29) of NSCLC and 7.7% (1/13) of pneumonia. Further, the samples with lymphatic metastasis had remarkable higher positive PAX2 or PAX5 than that without metastases. Overall, our data indicated that PAX2 and PAX5 differentially expressed in NSCLC and SCLC. Thus, PAX2 and PAX5 are useful biomarker in the differential diagnosis of lung cancer.

Bone marrow mesenchymal stem cell transplantation for treatment of emphysemic rats.

OBJECTIVE: To study the efficacy of bone marrow mesenchymal stem cell (MSC) transplantation to treat pulmonary emphysema in rats. METHODS: Sixty rats were randomly divided into control, model and transplantation groups. Each group contained 20 rats. Rat models of emphysema were established via intratracheal instillation of lipopolysaccharide and exposure of model and transplantation groups to smoke. Then, cultured bone marrow MSCs were injected into rats in the transplantation group via the tail vein. Pathological changes of the lung in rats were observed. RESULTS: Emphysemic pathological changes were found in model and transplantation groups, but changes were significantly attenuated after transplantation, compared with that of the model group. The mean alveoli number (MAN) and pulmonary alveolar area (PAA) showed statistically significant differences among the three groups (P < 0.001). The MAN in the transplantation group was higher than that in the model group, but still lower than that in the control group. The PAA in the transplantation group was lower than that in the model group, but higher than that in the control group (P < 0.05). After transplantation, Brdu-positive cells were observed and CK was expressed in a small number of Brdu-positive cells. Brdu- and CK-positive cells were not found in control and model groups. CONCLUSION: Transplantation of bone marrow MSCs can significantly attenuate lung inflammation and pathological changes in emphysemic rats, which may be associated with MSC differentiation into alveolar epithelial cells in recipient lung tissues.