Sepsis is a fatal syndrome characterized by uncontrolled systemic inflammatory responses. Circular RNAs (circRNAs) are involved in the modulation of various pathophysiological processes, but their potential role in sepsis has largely been unexplored. In this study, we observed differential expression of circMLH3 between healthy volunteers and septic patients, and revealed the value of circMLH3 for sepsis diagnosis and prognostic prediction. Interestingly, we discovered a correlation between the expression level of circMLH3 and the degree of pyroptosis, a critical mechanism contributing to uncontrolled inflammation in sepsis patients. Knocking down circMLH3 alleviated macrophage pyroptosis whereas overexpressing circMLH3 aggravated pyroptosis. circMLH3 regulated macrophage pyroptosis by sponging miR-590-3p and subsequently modulating TAK1 expression. Furthermore, we found that the miR-590-3p/TAK1 axis inhibited the activation of pro-caspase-1 and the NLRP3 inflammasome. miR-590-3p overexpression had a protective effect by reducing macrophage pyroptosis, thereby alleviating sepsis-induced lung injury and systemic inflammatory responses. In conclusion, our study elucidated the circMLH3/miR-590-3p/TAK1 signaling pathway and identified its role in regulating mononuclear macrophage pyroptosis, thus providing potential novel targets and strategies for sepsis diagnosis and therapy. © 2024 The Authors

Early detection of acute kidney injury (AKI) may provide a crucial window of opportunity to prevent further injury, which helps improve clinical outcomes. This study aimed to develop a deep interpretable network for continuously predicting the 24-hour AKI risk in real-time and evaluate its performance internally and externally in critically ill patients. A total of 21,163 patients' electronic health records sourced from Beth Israel Deaconess Medical Center (BIDMC) were first included in building the model. Two external validation populations included 3025 patients from the Philips eICU Research Institute and 2625 patients from Zhongda Hospital Southeast University. A total of 152 intelligently engineered predictors were extracted on an hourly basis. The prediction model referred to as DeepAKI was designed with the basic framework of squeeze-and-excitation networks with dilated causal convolution embedded. The integrated gradients method was utilized to explain the prediction model. When performed on the internal validation set (3175 [15 %] patients from BIDMC) and the two external validation sets, DeepAKI obtained the area under the curve of 0.799 (95 % CI 0.791–0.806), 0.763 (95 % CI 0.755–0.771) and 0.676 (95 % CI 0.668–0.684) for continuousAKI prediction, respectively. For model interpretability, clinically relevant important variables contributing to the model prediction were informed, and individual explanations along the timeline were explored to show how AKI risk arose. The potential threats to generalisability in deep learning-based models when deployed across health systems in real-world settings were analyzed. © 2024

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury. © 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

Background: Sepsis is a life -threatening clinical syndrome caused by dysregulated host response to infection. The mechanism underlying sepsis -induced immune dysfunction remains poorly understood. Natural killer T (NKT) cells are cytotoxic lymphocytes that bridge the innate and adaptive immune systems, the role of NKT cells in sepsis is not entirely understood, and NKT cell cluster differences in sepsis remain unexplored. Methods: Mendelian randomization (MR) analyses were first conducted to investigate the causal relationship between side scatter area (SSC-A) on NKT cells and 28 -day mortality of septic patients. A prospective and observational study was conducted to validate the relationship between the percentage of NKT cells and 28 -day mortality of sepsis. Then, the single -cell RNA sequencing (scRNAseq) data of peripheral blood mononuclear cells (PBMCs) from healthy controls and septic patients were profiled. Results: MR analyses first revealed the protective roles of NKT cells in the 28 -day mortality of sepsis. Then, 115 septic patients were enrolled. NKT percentage was significantly higher in survivors (n = 84) compared to non -survivors (n = 31) (%, 5.00 +/- 3.46 vs 2.18 +/- 1.93, P < 0.0001). Patients with lower levels of NKT cells exhibited a significantly increased risk of 28 -day mortality. According to scRNA-seq analysis, NKT cell clusters exhibited multiple distinctive characteristics, including a distinguishing cluster defined as FOS + NKT cells, which showed a significant decrease in sepsis. Pseudo -time analysis showed that FOS + NKT cells were characterized by upregulated expression of crucial functional genes such as GZMA and CCL4 . CellChat revealed that interactions between FOS + NKT cells and adaptive immune cells including B cells and T cells were decreased in sepsis compared to healthy controls. Conclusion: Our findings indicate that NKT cells may protect against sepsis, and their percentage can predict 28 -day mortality. Additionally, we discovered a unique FOS + NKT subtype crucial in sepsis immune response, offering novel insights into its immunopathogenesis.

Current clinical approaches for septic shock increasingly incorporate bundle treatment, a multi-component approach that uses a collection of tests and agents to assist in the identification and treatment of infection. The present study analyzed completion rates of 3 h and 6 h bundle treatment among patients with septic shock in intensive care units (ICUs) of hospitals in Jiangsu Province from 2016 to 2020, using data from the Jiangsu Provincial Intensive Care Medical Quality Control Center. Current approaches and factors affecting treatment completion were assessed.The completion rates of 3 h and 6 h bundle treatment in ICUs of all medical units in Jiangsu Province and in ICUs of hospitals of different levels were recorded. Analyses show that the completion rate of 3 h and 6 h bundle treatment for patients with septic shock in ICUs in Jiangsu Province increased year by year from 2016 to 2020.The completion rate of 3 h bundle treatment increased from 69.82% (3 604/5 162) to 82.47% (8 915/10 775) (all P<0.001). The completion rate of 6 h bundle treatment increased from 62.69% (3 236/5 162) to 72.54% (7 816/10 775) (all P<0.001). In addition, year by year, the completion rate of 3 h bundle treatment in ICUs in tertiary hospitals increased, from 69.80% (3 596/5 152) to 82.23% (7 375/8 969), while the completion rate of 6 h bundle treatment increased from 62.69% (3 230/5 152) to 72.18% (6 474/8 969) (all P<0.001). Completion rates in secondary hospitals also increased year by year, from 80.00% (8/10) to 85.27% (1 540/1 806) for 3 h treatment and from 60.00% (6/10) to 74.31% (1 342/1 806) (all P<0.001) for 6 h treatment. Completion rates for 3 h treatment in first-tier cities (83.99% (2 099/2 499)) and second-tier cities (84.68% (3 952/4 667)) was higher than in third-tier cities (79.36% (2 864/3 609)). The completion rate of 6 h bundle treatment gradually decreased in first-line (77.19% (1 929/2 499)), second-line (74.37% (3 471/4 667)), and third-line (66.94% (2 416/3 609)) cities (all P<0.001). The data collectively show that from 2016 to 2020, the completion rate of bundle treatment in septic shock patients in ICUs in Jiangsu Province improved significantly.

BACKGROUND: Although the mean arterial pressure (MAP) target of 65mmHg was achieved, diastolic blood pressure (DBP) was still low in some septic shock patients. The effects of DBP on the prognosis and optimal target for patients with septic shock are unclear. We sought to investigate the relationship between DBP and 28-day mortalityin septic shock patients.; METHODS: In this retrospective observational study, we obtained data from the Chinese Database in Intensive Care (CDIC). We included patients with an admission diagnosis of septic shock and shock was controlled. DBP was measured every 1h, and the mean DBP during the first 24h (mDBP24h) was recorded. The primary outcome was 28-day mortality. Multivariable logistic regression determined the relationship between mDBP24h and 28-day mortality.; RESULTS: In total, 1251 patients were finally included. The 28-day mortality of included septic shock patients was 28.3%. The mDBP24h, not mSBP24h, was higher among 28-day survivors compared with non-survivors. 28-day mortality was inversely associated with mDBP24h (unadjusted OR 0.814 per 10mmHg higher mDBP24h, P=0.003), with a stepwise increase in 28-day mortality at lower mDBP24h. The 28-day mortality of patients with mDBP24h<59mmHg had an absolute risk reduction of 9.4% (P=0.001). And mDBP24h<59mmHg was the remaining high risk factor inversely associated with 28-day mortality after multivariable adjustment (adjusted OR 1.915, 95% CI 1.037-3.536, P=0.038), while mMAP24h and mSBP24h were not.; CONCLUSION: In patients with septic shock after initial resuscitation, we observed an inverse association between mDBP24h and 28-day mortality. The poor outcomes in patients with mDBP24h<59mmHg provide indirect evidence supporting a further DBP goal of 59mmHg for patients with septic shock after MAP of 65mmHg was achieved. © 2023. BioMed Central Ltd., part of Springer Nature.

Background:Pulmonary microvascular endothelial cells(PMVECs)were not complex,and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury(ALI)/acute respiratory distress syndrome(ARDS).P

PurposeAcute respiratory distress syndrome(ARDS)is a prevalent illness in intensive care units.Extracellular vesicles and particles released from activated alveolar macrophages(AMs)assist in ARDS lung injury and the inflammatory process through mechanisms that are unclear.This study investigated the role of AM-derived secretory autophagosomes(SAPs)in lung injury and microRNA(MiR)-199a-3p-regulated inflammation associated with ARDS in vitro and in a murine model.MethodsThe ARDS model in mouse was established by intratracheal LPS lipopolysaccharide(LPS)injection.The agomirs or antagomirs of MiR-199a-3p were injected into the caudal vein to figure out whether MiR-199a-3p could influence ARDS inflammation and lung injury,whereas the mimics or inhibitors of MiR-199a-3p,siRNA of Rab8a,or PAK4 inhibitor were transfected or applied to RAW264.7 cells to evaluate the mechanism of SAP release.Culture supernatants of RAW264.7 cells treated with LPS or bronchoalveolar lavage fluid from mice were collected for the isolation of SAPs.ResultsWe found that MiR-199a-3p was over-expressed in the lungs of ARDS mice.The MiR-199a-3p antagomir alleviated,whereas the MiR-199a-3p agomir exacerbated LPS-induced inflammation in mice by promoting AM-derived SAP secretion.In addition,MiR-199a-3p over-expression exacerbated LPS-induced ARDS via activating Rab8a,and Rab8a silencing significantly suppressed the promoting influence of the MiR-199a-3p mimic on SAP secretion.Furthermore,MiR-199a-3p mimic activated Rab8a by directly inhibiting PAK4 expression.ConclusionThe novel finding of this study is that MiR-199a-3p participated in the regulation of SAP secretion and the inflammatory process via targeting of PAK4/Rab8a,and is a potential therapeutic candidate for ARDS treatment.

目的系统评价肌松剂对急性呼吸窘迫综合征(ARDS)患者氧合的影响。方法联机检索“Medline”“EMBASE”“Web of science”“Cochrane central database”英文数据库及中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库、万方数据库