Pyroptosis, an inflammatory form of programmed cell death, is the initiating event of sepsis and results in immune imbalance by releasing IL‐1β and IL‐18 in the early stages. Studies show that enhancing autophagy via genetic manipulation can inhibit pyroptosis and prolong the survival of a sepsis animal model, indicating a possible therapeutic strategy against sepsis. However, almost no study so far has achieved pyroptosis inhibition via pharmacological autophagy induction in a sepsis disease model. To this end, we established an in vitro sepsis model by stimulating primary human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and analyzed the effect of the autophagy agonist rapamycin (RAPA) on pyroptosis. Phorbol 12‐myristate 13‐acetate‐ (PMA‐) activated human THP‐1 cells were used as the positive control. LPS significantly increased the levels of the pyroptotic protein Gasdermin D (GSDMD), cysteinyl aspartate‐specific proteinase 1 (caspase‐1), secreted LDH, IL‐1β, and IL‐18. RAPA treatment downregulated the above factors and enhanced autophagy in the LPS‐stimulated HUVECs and THP‐1 cells. This study shows that RAPA abrogates LPS‐mediated increase in IL‐1β and IL‐18 by inhibiting pyroptosis and enhancing autophagy.

Enhanced antiproliferative activity of antibody-functionalized polymeric nanoparticles for targeted delivery of anti-miR-21 to HER2 positive gastric cancer Enhanced antiproliferative activity of antibody-functionalized polymeric nanoparticles for targeted delivery of anti-miR-21 to HER2 positive gastric cancer

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 (C_dyn-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, C_dyn-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 C_dyn-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. C_dyn-MP and PBW-MP showed higher ability in weaning failure prediction than MP.

Objective. To identify the clinical correlations between plasma growth differentiation factor‐15 (GDF‐15), skeletal muscle function, and acute muscle wasting in ICU patients with mechanical ventilation. In addition, to investigate its diagnostic value for ICU‐acquired weakness (ICU‐AW) and its predictive value for 90‐day survival in mechanically ventilated patients. Methods. 95 patients with acute respiratory failure, who required mechanical ventilation therapy, were randomly selected among hospitalized patients from June 2017 to January 2019. The plasma GDF‐15 level was detected by ELISA, the rectus femoris cross‐sectional area (RFcsa) was measured by ultrasound, and the patient’s muscle strength was assessed using the British Medical Research Council (MRC) muscle strength score on day 1, day 4, and day 7. Patients were divided into an ICU‐AW group and a non‐ICU‐AW group according to their MRC‐score on the 7th day. The differences in plasma GDF‐15 level, MRC‐score, and RFcsa between the two groups were compared on the 1st, 4th, and 7th day after being admitted to the ICU. Then, the correlations between plasma GDF‐15 level, RFcsa loss, and MRC‐score on day 7 were investigated. The receiver operating characteristic curve (ROC) was used to analyze the plasma GDF‐15 level, RFcsa loss, and % decrease in RFcsa on the 7th day to the diagnosis of ICU‐AW in mechanically ventilated patients. Moreover, the predictive value of GDF‐15 on the 90‐day survival status of patients was assessed using patient survival curves. Results. Based on whether the 7th day MRC‐score was <48, 50 cases were included in the ICU‐AW group and 45 cases in the non‐ICU‐AW group. The length of mechanical ventilation, ICU length of stay, and hospital length of stay were significantly longer in the ICU‐AW group than in the non‐ICU‐AW group (all P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF‐15 level was significantly increased, the ICU‐AW group demonstrated a significant decreasing trend in the MRC‐score and RFcsa, while no significant changes were found in the non‐ICU‐AW group. In the ICU‐AW group, the plasma GDF‐15 level was significantly higher than that in the non‐ICU‐AW group, while the RFcsa and the MRC‐score were significantly lower than those in the non‐ICU‐AW group (GDF‐15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm²): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC‐score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all P < 0.001). The plasma GDF‐15 level was significantly negatively correlated with the MRC‐score (r = −0.60), while it was significantly positively correlated with the RFcsa loss (r = 0.18) and the % decrease in RFcsa (r = 0.16). Moreover, the RFcsa loss was significantly negatively correlated with the MRC‐score (r = −0.27) (all P < 0.001). The ROC curve analysis showed that plasma GDF‐15 level, RFcsa loss, and % decrease in RFcsa on day 7 had predictive value for ICU‐AW diagnosis in mechanically ventilated patients. More specifically, the area under the ROC curve (AUC) of GDF‐15 was 0.904, the AUC of RFcsa loss was 0.873, and the AUC of % decrease in RFcsa was 0.886 (all P < 0.001). The 90‐day survival curve demonstrated that the survival rate of the high plasma GDF‐15 level group was 54.00%, while that of the low plasma GDF‐15 level group was 75.56%. The difference between the two groups was statistically significant (P < 0.05). Conclusion. The plasma GDF‐15 concentration level was significantly associated with skeletal muscle function and muscle wasting on day 7 in ICU patients with mechanical ventilation. Therefore, it can be concluded that the plasma GDF‐15 level on the 7th day has a high diagnostic yield for ICU‐acquired muscle weakness, and it can predict the 90‐day survival status of ICU mechanically ventilated patients.