Risk model for predicting mortality in patients with necrotizing soft tissue infections in the intensive care unit.

BACKGROUND: The goal of this study is to look into the factors that lead to death in patients with necrotizing soft tissue infections（NSTIs） in the intensive care unit and create a mortality risk model. METHODS: The clinical data of 106 patients with necrotizing soft tissue infections admitted to intensive care unit(ICU) of the First Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2021 were retrospectively analyzed. Univariate analysis and multivariate analysis were performed to evaluate the risk factors impacting patient mortality. The regression coefficient in binary logistic regression analysis was converted into the item score in the model, and then the model score of each patient was calculated. Finally, an ROC curve was constructed to evaluate the efficiency of the model for predicting mortality. Thirteen patients with NSTIs admitted to ICU between January 2022 and November 2022 were used to validate the model. RESULTS: The death group had 44 patients, while the survival group had 62 patients. The overall mortality was 41.5%. Binary logistic regression analysis showed that risk factors for mortality were age≥ 60 years(OR:4.419; 95%CI:1.093-17.862; P = 0.037), creatinine ≥ 132µmol/L(OR:11.166; 95%CI:2.234-55.816; P = 0.003), creatine kinase ≥ 1104 U/L(OR:4.019; 95%CI:1.134-14.250; P = 0.031), prothrombin time ≥ 24.4 s(OR:11.589; 95%CI:2.510-53.506; P = 0.002), and invasive mechanical ventilation (OR:17.404; 95%CI:4.586-66.052; P＜0.000). The AUC of the model for predicting mortality was 0.940 (95% CI:0.894-0.986). When the cut-off value for the model was 4 points, the sensitivity was 95.5% and the specificity was 83.9%. CONCLUSION: The death risk model in this study for NSTIs patients in the intensive care unit shows high sensitivity and specificity. Patients with a score of ≥ 4 points have a higher risk of mortality.

A New Nomogram for Predicting 30-Day In-Hospital Mortality Rate of Acute Cholangitis Patients in the Intensive Care Unit.

Purpose: Acute cholangitis (AC) is a widespread acute inflammatory disease and the main cause of septic shock, which has a high death rate in hospitals. At present, the prediction models for short-term mortality of AC patients are still not ideal. We aimed at developing a new model that could forecast the short-term mortality rate of AC patients. Methods: Data were extracted from the Medical Information Mart for Intensive Care IV version 2.0 (MIMIC-IV v2.0). There were a total of 506 cases of AC patients that were included. Patients were given a 7 : 3 split between the training set and the validation set after being randomly assigned to one of the groups. Multivariate logistic regression was used to create an AC patient predictive nomogram for 30-day mortality. The overall efficacy of the model is evaluated using the area under the receiver operating characteristic curve (AUC), the calibration curve, the net reclassification improvement (NRI), the integrated discrimination improvement (IDI), and a decision curve analysis (DCA). Results: Out of 506 patients, 14.0% (71 patients) died. The training cohort had 354 patients, and the validation cohort had 152 patients. GCS, SPO2, albumin, AST/ALT, glucose, potassium, PTT, and peripheral vascular disease were the independent risk factors according to the multivariate analysis results. The newly established nomogram had better prediction performance than other common scoring systems (such as SOFA, OASIS, and SAPS II). For two cohorts, the calibration curve demonstrated coherence between the nomogram and the ideal observation (P > 0.05). The clinical utility of the nomogram in both sets was revealed by decision curve analysis. Conclusion: The novel prognostic model was effective in forecasting the 30-day mortality rate for acute cholangitis patients.

Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons.

Immunotherapy has become established as major treatment modality for multiple types of solid tumors, including colorectal cancer. Identifying novel immunotherapeutic targets to enhance anti-tumor immunity and sensitize current immune checkpoint blockade (ICB) in colorectal cancer is needed. Here we report the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone methyl marks, as an essential mediator of immune escape. Ablation the function of PHF8 abrogates tumor growth, activates anti-tumor immune memory, and augments sensitivity to ICB therapy in mouse models of colorectal cancer. Strikingly, tumor PHF8 deletion stimulates a viral mimicry response in colorectal cancer cells, where the depletion of key components of endogenous nucleic acid sensing diminishes PHF8 loss-meditated antiviral immune responses and anti-tumor effects in vivo. Mechanistically, PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of the H3K9 methyltransferase SETDB1 in a demethylase-independent manner. Moreover, PHF8 expression is anti-correlated with canonical immune signatures and antiviral immune responses in human colorectal adenocarcinoma. Overall, our study establishes PHF8 as an epigenetic checkpoint, and targeting PHF8 is a promising viral mimicry-inducing approach to enhance intrinsic anti-tumor immunity or to conquer immune resistance.

A novel mechanism of Dimethyl ester of Alpha-ketoglutarate in suppressing Paraquat-induced BEAS-2B cell injury by alleviating GSDME dependent pyroptosis.

BACKGROUND: Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly, leading to high mortality; however, there is no specific antidote. Our limited knowledge of the pathogenic toxicological mechanisms of PQ has hindered the development of treatments against PQ exposure. PURPOSE: Pyroptosis is a form of programmed cell death recently identified as a novel molecular mechanism adopted by chemotherapeutic drugs for cancer therapy. However, the involvement of pyroptosis in PQ-induced lung injury has not been reported. Therefore, we investigated the effects of PQ on the lung tissues to elucidate the molecular mechanisms underlying its toxicity, especially its ability to induce pyroptosis. METHODS: To observe the morphological changes of BEAS-2B cells exposed to PQ, the plasma membrane damage of the cells was detected by LDH release assay, mitochondrial function and cell metabolism were detected by energy metabolism analysis. Western blotting was used to detect the protein levels of GSDMD, C-GSDMD, GSDME and N-GSDME in BEAS-2B cells. Metabolites of TCA cycle were detected by metabolomics, and the changes of TCA cycle metabolic enzymes in cells were detected by Western blotting. RESULTS: We observed that PQ induced proteolytic cleavage of gasdermin E (GSDME) with concomitant cleavage of caspase 3 in BEAS-2B cells. Knockout of GSDME attenuated PQ-induced cell death. Additionally, PQ induced ROS accumulation, mitochondrial depolarisation, and mitochondrial dysfunction in these cells. PQ activated the caspase 3/GSDME pathway and damaged the cytoplasmic membrane in cells, leading to pyroptosis. We demonstrated that DMK suppressed PQ-induced pyroptosis by blocking PQ-induced caspase 3/GSDME pathway activation, reducing cellular ROS levels, and improving mitochondrial function. CONCLUSION: These findings provide novel insights into the previously unrecognized mechanism of GSDME-dependent pyroptosis in PQ poisoning.

Orai1 overexpression improves sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction in mice.

Immune paralysis induced by sepsis, especially dysfunction of CD4+ T cells, leads to an increased risk of infection. In sepsis, abnormal differentiation of T lymphocytes is associated with multiorgan dysfunction syndrome. In T lymphocytes, the Orai1/nuclear factor of activated T Cells (NFAT) pathway is a critical mediator of infection, inflammation, and autoimmunity. In this study, we confirmed immunosuppression of splenic CD4+ T cells and abnormal differentiation of T lymphocytes in septic mice. Furthermore, we found that the Orai1/NFAT signaling pathway was inhibited in septic mice; however, the overexpression of Orai1 not only improved immune function of T cells in sepsis but also reduced the mortality and organ damage in septic mice. Moreover, the overexpression of Orai1 could reverse the increases in the numbers of T regulatory and T helper 17 cells in septic mice. These data suggest that the Orai1-mediated NFAT signaling pathway can improve sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction.

Development of a Novel Nomogram Incorporating Red Blood Cell Distribution Width-Albumin Ratio for the Prediction of 30-day Mortality in Acute Pancreatitis Patients.

Purpose: The available nomograms used to predict acute pancreatitis (AP) are not comprehensive. We sought to investigate the effect of red blood cell distribution width (RDW)-albumin ratio (RA) on prognosis of patients with AP and develop a new nomogram to identify AP patients at high risk for mortality. Methods: We used data from the Medical Information Mart for Intensive Care IV version 2.0 (MIMIC-IV v2.0). A total of 487 patients with acute pancreatitis were included. Patients enrolled in the study were randomly assigned to the training set and validation set at a 7 : 3 ratio. According to the 30-day mortality rate, the data were divided into a survival group and a death group. Multivariate logistic regression was used to establish a prognostic nomogram for predicting the 30-day mortality in AP patients. The area under the receiver operating characteristic curve (AUC), calibration curve, the net reclassification improvement (NRI), the integrated discrimination improvement (IDI), and a decision curve analysis (DCA) are used to verify the overall performance of the model. Results: Among 487 patients, 54 patients died (11.1%). 338 patients were assigned to the training cohort and 149 were assigned to the validation cohort. The multivariate analysis results showed that RA, age, heart rate, temperature, AST/ALT, BUN, hemoglobin, potassium, and bilirubin were independent risk factors. The prediction performance of the newly established nomogram was better than those of other common scoring systems (including SOFA, OASIS, and APSIII). The nomogram suggests that RA (OR = 1.706, 95% CI: 1.367-2.185) is the most significant laboratory test indicator influencing prognosis. Conclusion: The new nomogram incorporating RA performed well in predicting AP short-term mortality. A prospective study with a larger sample is needed to validate our findings.

Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction.

Acute lung injury (ALI) is the primary cause of death among patients with acute paraquat (PQ) poisoning, whereby peroxidative damage is an important mechanism underlying PQ-induced lung injury. There is a lack of effective interventional drugs for patients with PQ poisoning. Oxaloacetic acid (OAA) participates in multiple in vivo metabolic processes, whereby it facilitates the clearance of reactive oxygen species (ROS) and improves mitochondrial function. The study aimed to assess the protective effects of OAA on PQ-induced ALI and elucidate the underlying molecular mechanism. Our data demonstrated that OAA treatment significantly alleviated PQ-induced ALI and improved the survival rate of PQ-poisoned mice, and also alleviated PQ-induced cellular oxidative stress and mitochondrial dysfunction. OAA-mediated alleviation of PQ-induced mitochondrial dysfunction depends on the following mechanisms which may explain the above findings: 1) OAA effectively cleared intracellular ROS, inhibited ROS accumulation, and mitochondrial depolarization; 2) OAA inhibited the downregulation of L-OPA1 and MFN2 caused by PQ and promoted a dynamic balance of mitochondrial fusion and fission, and 3) the expression of PGC-1α, TFAM, COX2, and COX4I1, increased significantly following OAA intervention which improved mitochondrial respiratory functions and promoted its biogenesis and energy metabolism in damaged cells. In conclusion, OAA effectively cleared ROS and improved mitochondrial dysfunction, thereby significantly improving ALI caused by PQ poisoning and the animal survival rate. Therefore, OAA may be a potential drug for the treatment of PQ poisoning.

[Value of vascular endothelial-cadherin in evaluating the severity of patients with sepsis].

OBJECTIVE: To explore the value of vascular endothelial-cadherin (VE-cad) in evaluating the severity of sepsis. METHODS: A prospective study was conducted to select 85 patients with sepsis treated in the emergency ward of the First Affiliated Hospital of Wenzhou Medical University from June 1, 2015 to November 1, 2017. The gender, age, medical history, first infection site, number of affected organs, laboratory indexes, acute physiology and chronic health evaluation II (APACHE II), simplified acute physiology score II (SAPS II), sequential organ failure assessment (SOFA) and the total length of stay, emergency intensive care unit (EICU) length of stay, 28-day at admission and survival during hospitalization were measured, and the VE-cad level within 24 hours at admission was measured. The patients were divided into sepsis group and septic shock group according to the progress of the disease. The patients were divided into multiple organ dysfunction syndrome (MODS) group and non MODS group according to whether they were accompanied by MODS. The differences of the above indexes in patients with different disease progression, MODS and different prognosis were analyzed and compared. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the value of VE-cad in evaluating the severity of sepsis. RESULTS: A total of 85 patients were included, mainly respiratory tract infection. Among them, 38 cases were sepsis and 47 cases were septic shock, 39 cases had MODS, 46 cases had no MODS, 64 cases survived and 21 cases died within 28 days after admission. Compared with sepsis group, the number of affected organs in septic shock group was greater [3 (2, 4) vs. 1 (0, 2)], APACHE II score [13 (10, 21) vs. 7 (5, 12)], SAPS II score [35 (31, 55) vs. 7 (5, 12)], SOFA score [7.0 (5.0, 10.0) vs. 3.0 (0, 5.0)], blood lactic acid [Lac (mmol/L): 3.5 (2.4, 6.2) vs. 1.9 (1.2, 2.2)], C-reactive protein [CRP (mg/L): 90.0 (58.1, 90.0) vs. 50.5 (38.0,90.0)] and VE-cad levels [mg/L: 1.427 (1.141, 2.150) vs. 1.195 (0.901, 1.688)] were significantly increased, while platelet count [PLT (×109/L): 113.4±67.2 vs. 202.5±109.5] and hemoglobin (Hb) levels (g/L: 106.3±36.3 vs. 118.6±18.0) were significantly decreased (all P < 0.05). Compared with non MODS group, APACHE II score [14 (10, 22) vs. 8 (6, 13)], SAPS II score [36 (32, 56) vs. 29 (24, 35)], SOFA score (7.9±3.9 vs. 4.0±3.8), in-hospital mortality [53.8% (21/39) vs. 0% (0/46)], Lac [mmol/L: 3.1 (2.3, 6.3) vs. 2.1 (1.4, 4.6)] and VE-cad levels [mg/L: 1.427 (1.156, 1.937) vs. 1.195 (0.897, 1.776)] in MODS group were significantly higher, the length of stay in EICU was significantly longer [days: 6 (3, 12) vs. 3 (0, 7)], and the PLT level was significantly lower (×109/L: 118.2±80.0 vs. 182.5±104.0, all P < 0.05). Compared with the death group, the number of affected organs in the survival group was fewer [2 (1, 3) vs. 3 (1, 5)], APACHE II score [9 (6, 13) vs. 21 (13, 25)], SAPS II score [31 (25, 36) vs. 55 (35, 63)] and SOFA score (4.7±3.7 vs. 8.9±4.5) were significantly reduced, and the length of stay in EICU [days: 4 (1, 8) vs. 8 (3, 15)] was significantly shorter (all P < 0.05). ROC curve analysis showed that area under the ROC curve (AUC) of VE-cad, SOFA score and VE-cad combined with SOFA score in evaluating the severity of sepsis were 0.632 [95% confidence interval (95%CI) was 0.513-0.750], 0.830 (95%CI was 0.744-0.916) and 0.856 (95%CI was 0.779-0.933), respectively. When the cut-off value of VE-cad was 1.240 mg/L, the sensitivity was 68.1% and the specificity was 55.3%, the sensitivity of VE-cad combined with SOFA score was 85.1%, the specificity was 73.7%. CONCLUSIONS: VE-cad has a certain evaluation value for the severity of sepsis, and the evaluation value of VE-cad combined with SOFA score is better than that of VE-cad single index.

Red Blood Cell Membrane-Camouflaged PLGA Nanoparticles Loaded With Basic Fibroblast Growth Factor for Attenuating Sepsis-Induced Cardiac Injury.

Cardiac injury is recognized as a major contributor to septic shock and a major component of the multiple organ dysfunction associated with sepsis. Emerging evidence shows that regulation of the intramyocardial oxidative stress and inflammatory response has a promising prospect. Basic fibroblast growth factor (bFGF) exhibits anti-inflammatory and antioxidant properties. In this study, red blood cell membrane-camouflaged poly (lactide-co-glycolide) nanoparticles were synthesized to deliver bFGF (bFGF-RBC/NP) for sepsis-induced cardiac injury. The in vitro experiments revealed that bFGF-RBC/NP could protect cardiomyocytes from oxidative and inflammatory damage. In addition, the antioxidant and anti-inflammatory properties of bFGF-RBC/NP against cardiac injury were validated using data from in vivo experiments. Collectively, our study used bFGF for the treatment of sepsis-induced cardiac injury and confirmed that bFGF-RBC/NP has therapeutic benefits in the treatment of myocardial dysfunction. This study provides a novel strategy for preventing and treating cardiac injury in sepsis.

Activation of STIM1/Orai1­mediated SOCE in sepsis­induced myocardial depression.

Unbalanced Ca2+ homeostasis serves an essential role in the occurrence and development of septic myocardial injury. However, the mechanism of Ca2+ homeostasis in septic myocardial depression is poorly understood due to the complexity of Ca2+ transporters in excitable cells. It was therefore hypothesized that cardiac dysfunction, myocardial injury and cardiac apoptosis in septic myocardial depression are associated with elevated intracellular Ca2+ concentrations caused by stromal interaction molecule 1 (STIM1)/Orai calcium release­activated calcium modulator 1 (Orai1)­mediated store­operated Ca2+ entry (SOCE). A septic myocardial depression model was established using the cecal ligation and puncture operation (CLP) in mice and was simulated in H9C2 cells via lipopolysaccharide (LPS) stimulation. Cardiac function, myocardial injury, cardiac apoptosis and the expression levels of Bax, Bcl­2, STIM1 and Orai1 were quantified in vivo at 6, 12 and 24 h. Changes in the intracellular Ca2+ concentration, SOCE and the distribution of STIM1 were assessed in vitro within 6 h. The morphological changes of heart tissue were observed by hematoxylin­eosin staining. Myocardial cellular apoptosis was determined by TUNEL method. The expression of Bax, Bcl­2, STIM1 and Orai1 were visualized by western blot. Cytosolic calcium concentration and SOCE were evaluated by confocal microscopy. The results demonstrated that cardiac contractile function was significantly reduced at 6 h and morphological changes in cardiac tissues, as well as the myocardial apoptosis rate, were markedly increased at 6, 12 and 24 h following CLP. mRNA and protein expression levels of Bax/Bcl­2 were significantly enhanced at 6 and 12 h and glycosylation of Orai1 in the myocardium of septic mice was significantly increased at 6 h following CLP. The intracellular Ca2+ concentration, SOCE, was significantly increased at 1­2 h and the clustering and distribution of STIM1 were markedly changed in H9C2 cells at 1 and 2 h. These findings suggested that myocardial dysfunction, cardiac injury and myocardial depression may be related to increased intracellular Ca2+ concentration resulting from STIM1/Orai1­mediated SOCE, which may provide a potential method to alleviate septic myocardial depression.

Vesicle transport related protein Synaptotagmin-1 mediates paraquat transport to antagonize paraquat toxicity.

In this study, A549/PQ cells with moderate resistance to paraquat (PQ) were obtained by treating A549 cells with PQ, their growth rate was slowed down, the accumulation concentration of PQ and the levels of growth inhibition, injury and early apoptosis induced by PQ were significantly lower than those of parental A549 cells. Microarray screening and RT-qPCR detection found that Synaptotagmin-1 (SYT1) expression in drug-resistant cells was significantly increased, and PQ further enhanced its expression. After inhibiting SYT1 expression in A549/PQ cells, cell viability, intracellular PQ concentration and the expression of Bcl-2, SNAP25 and RAB26 were significantly reduced, while the mortality, early apoptosis rate and Bax expression were significantly increased. In vivo experiments also further showed that PQ promoted the expression of SYT1, SNAP25 and RAB26 in PQ-poisoned mice; when inhibiting SYT1 expression, PQ concentration in lung tissues was significantly increased, and the levels of lung injury and apoptosis were also significantly enhanced, while the expression of SNAP25 and RAB26 was significantly reduced. This indicates that PQ poisoning leads to compensatory up-regulation of vesicle transport related proteins such as SYT1 in vivo, thereby promoting PQ transmembrane transport, and then reducing the pulmonary accumulation of PQ and PQ-caused lung injury.

CD71+ Erythroid Cell Expansion in Adult Sepsis: Potential Causes and Role in Prognosis and Nosocomial Infection Prediction.

BACKGROUND: Immune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71+ erythroid cells had unappreciated immunosuppressive functions. This study aimed to investigate the values of CD71+ erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored. METHODS: In total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71+ cells, CD71+CD235a+ cells, and CD45+ CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis. RESULTS: The percentage of CD71+ cells, CECs, and CD45+ CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71+ cells, CECs, and CD45+ CECs were associated with NI development, while CD71+ cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71+ cells, CECs, and CD45+ CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45+ CECs. CONCLUSIONS: CECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis. TRIAL REGISTRATION: ChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645.

Ginkgolic acid promotes inflammation and macrophage apoptosis via SUMOylation and NF-κB pathways in sepsis.

Background: Excessive inflammation and increased apoptosis of macrophages contribute to organ damage and poor prognosis of sepsis. Ginkgolic acid (GA) is a natural constituent extracted from the leaves of Ginkgo biloba, that can regulate inflammation and apoptosis. The present study aims to investigate the potential effect of GA in treating sepsis and its possible mechanisms. Materials and methods: Here, a classic septic mice model and a lipopolysaccharide (LPS)-induced RAW 264.7 inflammation model were established. Cytokines in serum and culture supernatant were detected by ELISA, and the mRNA levels of them were examined by PCR. Hematoxylin and eosin (H&E) staining was performed to determine histopathological changes in liver, lung and kidney. Bacterial burden in the blood, peritoneal lavage fluids (PLFs) and organs were observed on Luria-Bertani agar medium. Flow cytometry and western blotting was used to detect apoptosis and the expression level of apoptosis related molecules, respectively. Moreover, the levels of SUMOylation were detected by western blotting. The activity of NF-κB p65 was assessed by immunofluorescence staining and western blotting. Results: The result showed that GA promoted inflammatory responses, reduced bacterial clearance, aggravated organ damage, and increased mortality in septic mice. GA increased apoptosis in peritoneal macrophages (PMs) and RAW 264.7 cells. Meanwhile, GA inhibited SUMOylation and increased the nuclear translocation of NF-κB p65 as well as its phosphorylation level. Conclusion: Collectively, GA promotes inflammation and macrophage apoptosis in sepsis, which may be mediated by inhibiting the SUMOylation process and increasing NF-κB p65 activity.

GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation.

Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1ß and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.

Plasma Concentration After the First Hemoperfusion has a High Predictive Value in Medium Level Acute Paraquat-Poisoned Patients.

BACKGROUND: Paraquat ( PQ) is very poisonous to humans and animals and there is no effective clinical antidote . The efficacy of hemoperfusion (HP) treatment for PQ poisoning remains controversial. To explore new ways to predict the prognosis of patients with acute PQ poisoning and assist in the development of better hemopurification treatment strategies. METHODS: The clinical data of patients who were intoxicated with PQ through contact were diagnosed with PQ poisoning by high-performance liquid chromatography. Samples were collected by the Emergency Intensive Care Unit of the First Affiliated Hospital of Wenzhou Medical University from January 2012 to November 2016. Based on the prognosis, the patients were grouped into survival and death groups. Comparisons of the differences in the clinical indexes were performed, including the initial concentration of PQ at admission, PQ concentration after first HP, the number of HP cartridges used for the first hemoperfusion, whether HP was combined with continuous renal replacement therapy, and the number of concurrent organ injuries between the 2 groups. In addition, data were analyzed using multivariate logistic regression models and receiver operating characteristic curves. Moreover, prognostic factors in patients with acute PQ poisoning were analyzed. RESULTS: Overall, 128 patients with acute PQ poisoning were enrolled in this study. The median plasma PQ concentrations of the patients at admission were 21 and 834 ng/mL (range: 50-1,099,118 ng/mL). The multiple logistic regression model revealed that the initial concentration of PQ and the PQ concentration after the first perfusion were independent risk factors for death in patients with acute PQ poisoning. The PQ concentration in the survival group after the first HP was <516 ng/mL and was mainly distributed at approximately 100 ng/mL. The percentage of patients whose concentration after the first HP was <516 ng/mL in the death group was only 19%. CONCLUSIONS: The initial plasma PQ concentration after admission and PQ concentration after the first HP are risk factors for death in patients with acute PQ poisoning. Moreover, PQ concentration after the first HP had a high predictive value for death. When the initial plasma PQ concentration after admission ranges from 50 ng/mL to 5000 ng/mL, the rapid reduction in plasma PQ concentration after HP treatment could improve the prognosis of patients with acute PQ poisoning.

Emodin alleviates LPS-induced myocardial injury through inhibition of NLRP3 inflammasome activation.

Myocardial injury and cardiovascular dysfunction are serious consequences of sepsis and contribute to high mortality. Currently, the pathogenesis of myocardial injury in sepsis is still unclear, and therapeutic approaches are limited. In this study, we investigated the protective effect of emodin on septic myocardial injury and the underlying mechanism. Lipopolysaccharide (LPS)-induced C57BL/6 mice and cardiomyocytes were used as models of sepsis in vivo and in vitro, respectively. The results showed that emodin alleviated cardiac dysfunction, myocardial injury and improved survival rate in LPS-induced septic mice. Emodin attenuated the levels of inflammatory cytokines and cardiac inflammation induced by LPS. Emodin reduced NOD-like receptor protein 3 (NLRP3) and Gasdermin D (GSDMD) expression in the heart tissue of LPS-induced septic mice. In vitro, emodin alleviated LPS-induced cell injury and inflammation in cardiomyocytes by inhibiting NLRP3 inflammasome activation. In addition, an NLRP3 inhibitor was used to further confirm the function of the NLRP3 inflammasome in LPS-induced myocardial injury. Taken together, our findings suggest that emodin improves LPS-induced myocardial injury and cardiac dysfunction by alleviating the inflammatory response and cardiomyocyte pyroptosis by inhibiting NLRP3 inflammasome activation, which provides a feasible strategy for preventing and treating myocardial injury in sepsis.

Thyroid hormone levels as a predictor marker predict the prognosis of patients with sepsis.

BACKGROUND: Sepsis is a systemic inflammatory response syndrome with high mortality. There is an upward trend in sepsis prevalence and mortality worldwide. Early and accurate prediction of outcome in sepsis is important. There remains a great need to improve a reliable prognostic model for sepsis patients with widely available variables. The aim of this study was to explore the correlation between serum thyroid hormone levels and prognosis in sepsis patients. METHODS: Septic patients were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Factors that were found to contribute to the outcome in the uni-variate analysis at P value <0.1 were included in the multivariate. Multivariate analysis was performed by binary logistic regression analysis, which allows adjust for confounding factors. We combined an assessment of thyroid hormone and some variables together, which improve the accurate prediction of outcome. The accuracy of the test was assessed measuring the area under the ROC curve (AUROC). RESULTS: A total of 929 eligible septic patients were included in the data analysis. Seventy hundred and three patients had a good functional outcome, whereas 226 patients had a bad functional outcome. Thyroxin (T4) level was significantly decreased in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome (P < 0.01). Binary logistic regression analyses revealed that lower thyroxin concentrations on admission were associated with a risk for poor outcomes (OR 0.556, 95% CI 0.41-0.75; P < 0.01). In addition, in ROC curve analysis, the combined model AUROC was 0.82 for ICU survival, which was significantly higher than the AUROCs of original fT4 (0.65 and 0.65), T4 (0.71 and 0.71) and SAPSII (0.70 and 0.72) (all P < 0.05). CONCLUSIONS: Low serum thyroxin levels can be a predictive marker of short-term outcome after sepsis. A combined model (fT4, T4 and SAPSII score) can add significant additional predictive information to the clinical score of the SAPSII.

The Neuroprotective Effect of Short Chain Fatty Acids Against Sepsis-Associated Encephalopathy in Mice.

Short chain fatty acids (SCFAs) are known to be actively involved in multiple brain disorders, but their roles in sepsis-associated encephalopathy (SAE) remain unclear. Here, we investigated the neuroprotective effects of SCFAs on SAE in mice. Male C57BL/6 mice were intragastrically pretreated with SCFAs for seven successive days, and then subjected to SAE induced by cecal ligation and puncture. The behavioral impairment, neuronal degeneration, and levels of inflammatory cytokines were assessed. The expressions of tight junction (TJ) proteins, including occludin and zoula occludens-1 (ZO-1), cyclooxygenase-2 (COX-2), cluster of differentiation 11b (CD11b), and phosphorylation of JNK and NF-κB p65 in the brain, were measured by western blot and Immunofluorescence analysis. Our results showed that SCFAs significantly attenuated behavioral impairment and neuronal degeneration, and decreased the levels of IL-1ß and IL-6 in the brain of SAE mice. Additionally, SCFAs upregulated the expressions of occludin and ZO-1 and downregulated the expressions of COX-2, CD11b, and phosphorylation of JNK and NF-κB p65 in the brain of SAE mice. These findings suggested that SCFAs could exert neuroprotective effects against SAE in mice.

Arterial oxygen pressure targets in critically ill patients: Analysis of a large ICU database.

BACKGROUND: Providing supplemental oxygen is common in the management of critically ill patients, yet the optimal oxygen regimen remains unclear. OBJECTIVES: To explore the optimal range of PaO2 in critically ill patients. METHODS: This is a retrospective study conducted in the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients with a least 48 h of oxygen therapy were included. Nonlinear regression was used to analyze the association between PaO2 and mortality. We derived an optimal range of PaO2 and evaluated the association between the proportion of PaO2 measurements within this range and mortality. RESULTS: In total, 8401 patients were included in the study. A J-shaped relationship was observed between median PaO2 and hospital mortality. Compared with the reference group of 100-120 mmHg, patients with values of 80-100 mmHg and 120-140 mmHg had higher hospital mortality (adjusted odds ratio [aOR], 1.23; 95% CI, 1.05-1.43 and 1.29; 95%CI, 1.08-1.54, respectively). Similarly, mortality rates were significantly higher for PaO2 <80 mmHg and ≥140 mmHg (aOR, 1.97; 95%CI, 1.58-2.45 and 1.42; 95%CI, 1.19-1.69, respectively). Patients spent a greater proportion of time within 100-120 mmHg tended to have a lower mortality rate. CONCLUSION: Among critically ill patients, the relationship between median PaO2 and hospital mortality was J-shaped. The lowest rates of mortality was observed in those with PaO2 levels within 100 to 120 mmHg.

Plasma ZO-1 proteins predict the severity and outcome of sepsis: A prospective observational study.

BACKGROUND: We determined whether plasma concentrations of ZO-1 proteins may be used a predictor of sepsis severity and 30-day mortality. METHODS: A total of 143 patients with sepsis and 30 healthy controls were enrolled. Plasma ZO-1 proteins concentrations were measured. Various methods, including area under the curves (AUCs), Kaplan-Meier curve, Cox regression, net reclassification improvement (NRI) and integrated discrimination improvement (IDI), were carried out to determine the value of ZO-1 in predicting 30-day mortality. RESULTS: Plasma ZO-1 concentrations in patients with sepsis and septic shock were significantly higher than those in healthy controls and were associated with the number of organ failures. ZO-1 concentrations also correlated with APACHE II or SOFA score and predicted 30-day mortality in sepsis patients with an AUC of 0.754. Multivariable regression analyses showed that a ZO-1 concentration ≥2.60 ng/ml remained a significant predictor of 30-day mortality in sepsis patients. Kaplan-Meier survival plots showed that patients with ZO-1 concentrations <2.60 ng/ml had a clear survival benefit. Adding ZO-1 to the SOFA score significantly improved its prognostic accuracy. CONCLUSION: Plasma ZO-1 proteins appear to be a valuable prognostic biomarker for the severity of sepsis and a predictor of 30-day mortality for patients with sepsis.