Effects of beta-blockers use on mortality of patients with acute respiratory distress syndrome: a retrospective cohort study.

Introduction: Acute respiratory distress syndrome (ARDS) remains a challenging disease with limited prevention and treatment options. The usage of beta-blockers may have potential benefits in different critical illnesses. This study aimed to investigate the correlation between beta-blocker therapy and mortality in patients with ARDS. Materials and methods: This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care (MIMIC) IV database and focused on patients diagnosed with ARDS. The primary outcome of the study was 30-day mortality. To account for confounding factors, a multivariable analysis was performed. Propensity score matching (PSM) was carried out on a 1:1 ratio. Robust assessments were conducted using inverse probability weighting (IPTW), standardized mortality ratio weighting (SMRW), pairwise algorithms (PA), and overlap weights (OW). Results: A total of 1,104 patients with ARDS were included in the study. Univariate and multivariate Cox regression analyses found that the 30-day mortality for 489 patients (23.7%) who received beta-blockers was significantly lower than the mortality rate of 615 patients (35.9%) who did not receive beta-blockers. After adjusting for potential confounders through PSM and propensity score, as well as utilizing IPTW, SMRW, PA, and OW, the results remained robust, with the hazard ratios (HR) ranging from 0.42 to 0.58 and all p-values < 0.001. Evaluation of the E-values indicated the robustness of the results even in the presence of unmeasured confounding. Conclusion: The findings suggest a potential association between beta-blocker usage and reduced mortality in critically ill patients with ARDS. However, further validation of this observation is needed through randomized controlled trials.

[Time-related association between fluid balance and prognosis in sepsis patients: a cohort study based on MIMIC-IV database].

OBJECTIVE: To investigate time-related association between fluid balance and prognosis in sepsis patients. METHODS: A retrospective cohort study was conducted based on the data of sepsis patients in the Medical Information Database for Intensive Care-IV 2.0 (MIMIC-IV 2.0) from 2008 to 2019. Sepsis patients aged ≥ 18 years who were admitted to intensive care unit (ICU) for at least 2 days were included. The daily fluid balance and cumulative fluid balance (CFB) were calculated from days 1 to 7 after ICU admission. According to CFB,the patients were divided into negative fluid balance group (CFB% < 0%), fluid balance group (0% ≤ CFB% ≤ 10%), and fluid overload group (CFB% > 10%). In-hospital mortality was the primary outcome. Multifactorial Logistic regression was used to analyze time-related association between different CFB and the risk of in-hospital mortality in patients with sepsis during 7 days after ICU admission. In addition, subgroup analysis was performed on patients with septic shock and patients with sepsis who stayed in the ICU for 7 days or longer. RESULTS: A total of 11 437 patients with sepsis were included, of which 6 595 were male and 4 842 were female. The mean age was (64.4±16.4) years. A total of 10 253 patients (89.6%) survived and 1 184 patients (10.4%) died during hospitalization. Compared with the survival group, patients in the death group were older, lighter, had higher sequential organ failure assessment (SOFA), simplified acute physiology score II (SAPS II), longer ICU stay, higher incidence of septic shock, and higher proportion of invasive mechanical ventilation, renal replacement therapy (RRT) and vasoactive drugs. In terms of comorbidities, congestive heart failure, renal disease, liver disease, and malignancy were more common in the death group. The death group had a higher daily fluid balance than the survival group during 7 days after ICU admission, the CFB in the two groups gradually increased with length of ICU stay. After adjusting variables such as age, gender, race, SOFA score, SAPS II score, comorbidities, and the use of invasive mechanical ventilation, RRT and vasoactive drugs, multivariate Logistic regression analysis showed that fluid overload on day 1 after ICU admission was a protective factor for the reduced risk of in-hospital mortality in sepsis patients [odds ratio (OR) = 0.74, 95% confidence interval (95%CI) was 0.64-0.86, P = 0.001]. However, fluid overload on day 3 was a risk factor for in-hospital mortality in sepsis patients (OR = 1.70, 95%CI was 1.47-1.97, P < 0.001) and the risk of in-hospital mortality was significantly increased from day 4 to day 7. Furthermore, the same results were obtained in patients with septic shock and sepsis patients who stayed in the ICU for 7 days or longer. CONCLUSIONS: Fluid overload on day 1 was associated with reduced in-hospital mortality. However, from the third day, fluid overload increases the risk of in-hospital mortality. Thus, managing fluid balance at different times may improve prognosis.

Diagnosis of Mycoplasma hominis Meningitis with Metagenomic Next-Generation Sequencing: A Case Report.

Background: Mycoplasma hominis meningitis is a rare postoperative complication of neurosurgery. Accurate and early diagnosis of M. hominis remains challenging because of the limitations of traditional detection methods. Metagenomic next-generation sequencing (mNGS) is an advanced technique with high sensitivity and specificity for identifying infectious pathogens; however, its application in diagnosing M. hominis meningitis has not been widely studied. Case Presentation: We report the case of a 61-year-old man who presented with fever and headache after neurosurgical treatment for a cerebral hemorrhage. Empiric antibiotic therapy was ineffective. Traditional culture of pathogens and serological testing yielded negative results, but M. hominis was detected in the cerebrospinal fluid by mNGS. After further verification by polymerase chain reaction (PCR), the patient's clinical treatment was adjusted accordingly. With targeted antibiotic intervention, the patient's symptoms were effectively alleviated, and clinical indicators returned to normal levels. Furthermore, the abundance of M. hominis decreased significantly compared to the initial mNGS reading after targeted treatment, indicating that the infection caused by M. hominis was effectively controlled. Conclusion: Using mNGS, we found that M. hominis may be a candidate causative agent of meningitis. The technique also has the advantage of timeliness and accuracy that traditional cultures cannot achieve. A combination of mNGS with PCR is recommended to identify pathogens in the early stages of infectious diseases to administer targeted clinical medication.

MicroRNA-128b mediates lipopolysaccharide-induced apoptosis via reactive oxygen species in human pulmonary microvascular endothelial cells.

OBJECTIVES: This study aimed to explore the effects of miR-128b in the regulation of Lipopolysaccharide (LPS) induced apoptosis. METHODS: Human Pulmonary Microvascular Endothelial Cells (HPMECs) were transfected with an miR-128b inhibitor and stimulated with LPS for 24 h. FCM was performed to detect apoptosis and Reactive Oxygen Species (ROS) production. In addition, miRNA and caspase-3 expression levels were determined using real-time quantitative polymerase chain reaction and western blotting. RESULTS: LPS significantly induced apoptosis and ROS production and upregulated miR-128b and caspase-3 expressions in HPMECs. However, LPS-induced effects were suppressed when an miR-128b inhibitor was used. Preincubation with NAC decreased the LPS-induced apoptosis of HPMECs. CONCLUSIONS: These effects were mediated by miR-128b via the caspase-3 pathway.

MicroRNA-128b mediates lipopolysaccharide-induced apoptosis via reactive oxygen species in human pulmonary microvascular endothelial cells

ABSTRACT Objectives: This study aimed to explore the effects of miR-128b in the regulation of Lipopolysaccharide (LPS) induced apoptosis. Methods: Human Pulmonary Microvascular Endothelial Cells (HPMECs) were transfected with an miR-128b inhibitor and stimulated with LPS for 24 h. FCM was performed to detect apoptosis and Reactive Oxygen Species (ROS) production. In addition, miRNA and caspase-3 expression levels were determined using real-time quantitative polymerase chain reaction and western blotting. Results: LPS significantly induced apoptosis and ROS production and upregulated miR-128b and caspase-3 expressions in HPMECs. However, LPS-induced effects were suppressed when an miR-128b inhibitor was used. Preincu-bation with NAC decreased the LPS-induced apoptosis of HPMECs. Conclusions: These effects were mediated by miR-128b via the caspase-3 pathway.

LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3.

LINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen-glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

LncRNA HOTAIR Promotes Neuronal Damage Through Facilitating NLRP3 Mediated-Pyroptosis Activation in Parkinson's Disease via Regulation of miR-326/ELAVL1 Axis.

Parkinson's disease (PD) seriously threatens human's health. Researches have shown a close correlation between long non-coding RNAs (lncRNAs) and PD. However, the biological function of lncRNA homeobox transcript antisense RNA (HOTAIR) in PD remains largely unknown. In this study, we established PD models in vivo and in vitro by using 1-methyl-4-phenyl-2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to assess the role of HOTAIR in pyroptotic cell death and neuronal damage. RNA immunoprecipitation (RIP) and dual luciferase reporter assay were used to verify the interaction between miR-326 and HOTAIR or ELAV like RNA binding protein 1 (ELAVL1). LncRNA HOTAIR was upregulated in PD mice and MPP+ induced SH-SY5Y cells. Additionally, knockdown of HOTAIR notably attenuated the symptom of PD in vivo. Downregulation of HOTAIR could obviously promoted cell viability and suppressed NLR family pyrin domain containing 3 (NLRP3) mediated pyroptotic cell death of SH-SY5Y cells in the presence of MPP+. Further, lncRNA HOTAIR positively regulated ELAVL1 expression by targeting miR-326, and downregulation of HOTAIR or ELAVL1 notably suppressed promotive effects of miR-326 inhibitor on MPP+ induced pyroptosis via activation of NLRP3 inflammasome. Collectively, HOTAIR silencing significantly inhibits neuronal damage through repressing NLRP3 mediated pyroptosis activation via regulation of miR-326/ELAVL1 axis in PD, which may contribute to a better understanding of PD pathogenesis and provide new treatment strategies for this disease.

Role of the Nrdp1 in Brain Injury Induced by Chronic Intermittent Hypoxia in Rats via Regulating the Protein Levels of ErbB3.

Obstructive sleep apnea syndrome (OSAS) is known as a repeated obstruction of the upper airway during sleep, leading to generalized hypoxia episodes and associated with cardiovascular and cerebrovascular diseases. We mainly explored the role of neuregulin receptor degradation protein-1 (Nrdp1, also known as FLRF) in brain injury induced by chronic intermittent hypoxia (CIH) in rats. Wistar rats were randomly divided into 4 groups (n = 12 per group), including the sham + adeno-associated virus-NC (AAV-NC) group, the sham + AAV-siNrdp1 group, the IH-4w (intermittent hypoxia for 4 weeks) + AAV-NC group, and the IH-4w + AAV-siNrdp1 group. Morphologic changes in brain tissue were observed by hematoxylin and eosin (HE) staining. Apoptosis in the hippocampus was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Spatial learning and memory were assessed by the Morris water maze test. The expression of Nrdp1 mRNA and protein in the hippocampus was detected by qualitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The concentration of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum was detected via enzyme-linked immunosorbent assay (ELISA) kits. Nrdp1 expression was increased after intermittent hypoxia exposure over time. Western blotting and H&E results showed that pathological changes of hippocampus neurons in chronic intermittent hypoxia rat were diminished by shNrdp1. Western blotting and TUNEL staining showed that apoptotic cells in the hippocampus of CIH rats were decreased by shNrdp1. The Morris water maze results proved that shNrdp1 improved spatial learning performance of chronic intermittent hypoxia rats. ELISA kits results showed that CIH-induced inflammatory response was decreased by shNrdp1. Western blotting and qRT-PCR results showed protein expression of ErbB3 in the hippocampus of CIH rats. Nrdp1 could regulate ErbB3 protein levels in brain-injured rats with CIH, which demonstrates that Nrdp1 is a potential therapeutic target in the cognition deficits associated with OSAS.

[Prognostic value of the dynamic changes in extra vascular lung water index and angiopoietin-2 in severe multiple trauma patients with acute respiratory distress syndrome].

OBJECTIVE: To observe the dynamic changes in extra vascular lung water index (EVLWI) and angiopoietin-2 (Ang-2) in severe multiple trauma patients with acute respiratory distress syndrome (ARDS), analyze the risk factor for short-term mortality, and to evaluate their prognostic values for prognosis. METHODS: A total of 54 severe multiple trauma patients with ARDS admitted to emergency intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from June 2014 to December 2018 were enrolled. The acute physiology and chronic health evaluation II (APACHE II), injury severity score (ISS) and oxygenation index (PaO2/FiO2), EVLWI [pulse-induced contour cardiac output (PiCCO) monitor] and plasma Ang-2 level [enzyme-linked immunosorbent assay (ELISA)] at 0 (immediately), 24, 48 and 72 hours after ICU admission, and the differences in PaO2/FiO2, EVLWI and Ang-2 between 0 hour and 72 hours (ΔPaO2/FiO2, ΔEVLWI, ΔAng-2) were calculated. The 28-day survival of patients was recorded, and the patients were divided into survival group and non-survival group. The differences in above mentioned parameters between the two groups were compared. Multivariate Logistic regression was used to analyze the independent risk factors associated with the prognosis. Receiver operating characteristic (ROC) curve was drawn to evaluate the prognostic values of ΔEVLWI and ΔAng-2 on the prognosis, and the Kaplan-Meier survival curve was plotted. RESULTS: 115 patients were enrolled in the final analysis, 72 survived in 28 days, 43 died, and the mortality rate was 37.4%. The APACHE II and ISS scores of the non-survival group were significantly higher than those of the survival group [APACHE II score: 25.7±2.7 vs. 20.6±2.2, ISS score: 22.1±3.1 vs. 18.1±2.1, both P < 0.05]. EVLWI and Ang-2 showed a gradual downwards tendency with the prolongation of the length of ICU stay in the survival group, but no significant change was found in the non-survival group. Parallel contour test showed that both P < 0.05, indicating that the curves between the two groups had different tendencies and were not parallel. The levels of EVLWI, Ang-2 and PaO2/FiO2 showed no statistical differences from 0 hour to 24 hours between the two groups, but EVLWI and Ang-2 in the non-survival group were significantly higher than those in the survival group from 48 hours on [EVLWI (mL/kg): 15.5±4.2 vs. 10.8±3.2, Ang-2 (ng/L): 352.7±51.2 vs. 237.9±42.8, both P < 0.05], and PaO2/FiO2 was significantly decreased [mmHg (1 mmHg = 0.133 kPa): 126.1±43.7 vs. 211.2±33.8, P < 0.05]. The ΔEVLWI and ΔAng-2 in the non-survival group were significantly lower than those in the survival group [ΔEVLWI (mL/kg): -0.9±6.1 vs. 3.1±6.4, ΔAng-2 (ng/L): -45.3±32.1 vs. 79.8±58.2, both P < 0.05], but ΔPaO2/FiO2 showed no significant difference as compared with the survival group (mmHg: 23.2±24.2 vs. -22.1±22.8, P > 0.05). Multivariate Logistic regression analysis demonstrated that ΔEVLWI [odds ratio (OR) = 2.811, 95% confidence interval (95%CI) = 1.232-3.161, P = 0.001], ΔAng-2 (OR = 2.204, 95%CI = 1.012-3.179, P = 0.001) and APACHE II (OR = 1.206, 95%CI = 1.102-1.683, P = 0.002) were independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS. ROC curve analysis showed that the area under ROC curve (AUC) of ΔEVLWI for predicting 28-day prognosis of severe multiple trauma patients with ARDS was 0.832, which was higher than ΔAng-2 (AUC = 0.790) and APACHE II (AUC = 0.735). When the cut-off value of ΔEVLWI was 2.3 mL/kg, the sensitivity was 79.1%, and the specificity was 81.9%. Kaplan-Meier survival curve showed that the patients with ΔEVLWI > 2.3 mL/kg had a significantly higher 28-day cumulative survival rate as compared with the patients with ΔEVLWI ≤ 2.3 mL/kg (log-rank test: χ2 = 23.385, P = 0.000). CONCLUSIONS: ΔEVLWI and ΔAng-2 can be used as independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS, and the predictive value of ΔEVLWI was better than Ang-2 and APACHE II. Dynamic observation of EVLWI could improve the accuracy of death forecasting for severe multiple trauma patients with ARDS.