ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Persistent high sepsis-induced coagulopathy and sequential organ failure assessment scores can predict the 28-day mortality of patients with sepsis: A prospective study.

BACKGROUND: The performance of the sepsis-induced coagulopathy (SIC) and sequential organ failure assessment (SOFA) scores in predicting the prognoses of patients with sepsis has been validated. This study aimed to investigate the time course of SIC and SOFA scores and their association with outcomes in patients with sepsis. METHODS: This prospective study enrolled 209 patients with sepsis admitted to the emergency department. The SIC and SOFA scores of the patients were assessed on days 1, 2, and 4. Patients were categorized into survivor or non-survivor groups based on their 28-day survival. We conducted a generalized estimating equation analysis to evaluate the time course of SIC and SOFA scores and the corresponding differences between the two groups. The predictive value of SIC and SOFA scores at different time points for sepsis prognosis was evaluated. RESULTS: In the non-survivor group, SIC and SOFA scores gradually increased during the first 4 days (P < 0.05). In the survivor group, the SIC and SOFA scores on day 2 were significantly higher than those on day 1 (P < 0.05); however, they decreased on day 4, dropping below the levels observed on day 1 (P < 0.05). The non-survivors showed higher SIC scores on days 2 (P < 0.05) and 4 (P < 0.001) than the survivors, whereas no significant differences were found between the two groups on day 1 (P > 0.05). The performance of SIC scores on day 4 for predicting mortality was more accurate than that on day 2, with areas under the curve of 0.749 (95% confidence interval [CI]: 0.674-0.823), and 0.601 (95% CI: 0.524-0.679), respectively. The SIC scores demonstrated comparable predictive accuracy for 28-day mortality to the SOFA scores on days 2 and 4. Cox proportional hazards models indicated that SIC on day 4 (hazard ratio [HR] = 3.736; 95% CI: 2.025-6.891) was an independent risk factor for 28-day mortality. CONCLUSIONS: The time course of SIC and SOFA scores differed between surviving and non-surviving patients with sepsis, and persistent high SIC and SOFA scores can predict 28-day mortality.

Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II-Induced Atrial Fibrillation by Reducing Peroxisome Proliferator-Activated Receptor α Activation in Mice.

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/ß-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-ß1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.

Sublingual microcirculation and internal environment changes as early indications of sepsis: A prospective observational study.

OBJECTIVE: This study aims to investigate the changes in microcirculation and internal environment before sepsis in patients with infectious diseases. METHODS: In this single-center prospective observational study, all patients did not meet the diagnostic criteria of sepsis 3.0 at admission. Blood samples and sublingual microcirculation were collected at admission, 24 and 48 h after admission. RESULTS: A total of 101 patients completed this study. In total, 46 patients met the diagnostic criteria of sepsis 3.0 within 5 days after admission, while the remaining 55 patients did not. The platelet (PLT) was significantly lower in the sepsis patients (195.17 ± 63.89 vs. 242.02 ± 68.59, p = .01), Microvascular Flow Index (MFI) (2.45 ± 0.33 vs. 2.70 ± 0.18, p = .00) and Proportion of Perfused Vessels (PPV) (92.44 ± 4.45 vs. 95.88 ± 3.20, p = .00) were significantly lower, while Flow Heterogeneity Index (FHI) (0.32 ± 0.13 vs. 0.22 ± 0.10, p = .00) was significantly higher in the in the sepsis patients at admission. Decreased levels of MFI (p = .00, OR 0.02, 95% CI: 0.00, 0.15) and PLT (p = .00, OR 0.99, 95% CI: 0.98, 1.00) were independent risk factors for sepsis. Additionally, the 24 h PLT change rate (AUC 0.85, Cutoff -0.17, sensitivity 0.70, specificity 0.93, and Youden index 0.63) suggested a potential early warning effect for sepsis. CONCLUSION: Changes in microcirculation disturbance and the internal environment occurred before sepsis. The MFI and PLT are independent risk factors for sepsis. Sublingual microcirculation and PLT deterioration can be used as early warning indicators before sepsis.

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway.

Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (ß1i/ß2i/ß5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

Erector spinae muscle-based nomogram for predicting in-hospital mortality among older patients with severe community-acquired pneumonia.

BACKGROUND: No multivariable model incorporating erector spinae muscle (ESM) has been developed to predict clinical outcomes in older patients with severe community-acquired pneumonia (SCAP). This study aimed to construct a nomogram based on ESM to predict in-hospital mortality in patients with SCAP. METHODS: Patients aged ≥ 65 years with SCAP were enrolled in this prospective observational study. Least absolute selection and shrinkage operator and multivariable logistic regression analyses were used to identify risk factors for in-hospital mortality. A nomogram prediction model was constructed. The predictive performance was evaluated using the concordance index (C-index), calibration curve, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis. RESULTS: A total of 490 patients were included, and the in-hospital mortality rate was 36.1%. The nomogram included the following independent risk factors: mean arterial pressure, peripheral capillary oxygen saturation, Glasgow Coma Scale score (GCS), lactate, lactate dehydrogenase, blood urea nitrogen levels, and ESM cross-sectional area. Incorporating ESM into the base model with other risk factors significantly improved the C-index from 0.803 (95% confidence interval [CI], 0.761-0.845) to 0.836 (95% CI, 0.798-0.873), and these improvements were confirmed by category-free NRI and IDI. The ESM-based nomogram demonstrated a high level of discrimination, good calibration, and overall net benefits for predicting in-hospital mortality compared with the combination of confusion, urea, respiratory rate, blood pressure, and age ≥ 65 years (CURB-65), Pneumonia Severity Index (PSI), Acute Physiology and Chronic Health Evaluation II (APACHEII), and Sequential Organ Failure Assessment (SOFA). CONCLUSIONS: The proposed ESM-based nomogram for predicting in-hospital mortality among older patients with SCAP may help physicians to promptly identify patients prone to adverse outcomes. TRIAL REGISTRATION: This study was registered at www.chictr.org.cn (registration number Chi CTR-2300070377).

Machine learning-based prediction model of acute kidney injury in patients with acute respiratory distress syndrome.

BACKGROUND: Acute kidney injury (AKI) can make cases of acute respiratory distress syndrome (ARDS) more complex, and the combination of the two can significantly worsen the prognosis. Our objective is to utilize machine learning (ML) techniques to construct models that can promptly identify the risk of AKI in ARDS patients. METHOD: We obtained data regarding ARDS patients from the Medical Information Mart for Intensive Care III (MIMIC-III) and MIMIC-IV databases. Within the MIMIC-III dataset, we developed 11 ML prediction models. By evaluating various metrics, we visualized the importance of its features using Shapley additive explanations (SHAP). We then created a more concise model using fewer variables, and optimized it using hyperparameter optimization (HPO). The model was validated using the MIMIC-IV dataset. RESULT: A total of 928 ARDS patients without AKI were included in the analysis from the MIMIC-III dataset, and among them, 179 (19.3%) developed AKI after admission to the intensive care unit (ICU). In the MIMIC-IV dataset, there were 653 ARDS patients included in the analysis, and among them, 237 (36.3%) developed AKI. A total of 43 features were used to build the model. Among all models, eXtreme gradient boosting (XGBoost) performed the best. We used the top 10 features to build a compact model with an area under the curve (AUC) of 0.850, which improved to an AUC of 0.865 after the HPO. In extra validation set, XGBoost_HPO achieved an AUC of 0.854. The accuracy, sensitivity, specificity, positive prediction value (PPV), negative prediction value (NPV), and F1 score of the XGBoost_HPO model on the test set are 0.865, 0.813, 0.877, 0.578, 0.957 and 0.675, respectively. On extra validation set, they are 0.724, 0.789, 0.688, 0.590, 0.851, and 0.675, respectively. CONCLUSION: ML algorithms, especially XGBoost, are reliable for predicting AKI in ARDS patients. The compact model maintains excellent predictive ability, and the web-based calculator improves clinical convenience. This provides valuable guidance in identifying AKI in ARDS, leading to improved patient outcomes.

Predictive nomogram for in-hospital mortality among older patients with intra-abdominal sepsis incorporating skeletal muscle mass.

BACKGROUND: Studies on prognostic factors for older patients with intra-abdominal sepsis are scarce, and the association between skeletal muscle mass and prognosis among such patients remains unclear. AIMS: To develop a nomogram to predict in-hospital mortality among older patients with intra-abdominal sepsis. METHODS: Older patients with intra-abdominal sepsis were prospectively recruited. Their demographics, clinical features, laboratory results, abdominal computed tomography-derived muscle mass, and in-hospital mortality were recorded. The predictors of mortality were selected via least absolute shrinkage and selection operator and multivariable logistic regression analyses, and a nomogram was developed. The nomogram was assessed and compared with Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, and Simplified Acute Physiology Score II. RESULTS: In total, 464 patients were included, of whom 104 (22.4%) died. Six independent risk factors (skeletal muscle index, cognitive impairment, frailty, heart rate, red blood cell distribution width, and blood urea nitrogen) were incorporated into the nomogram. The Hosmer-Lemeshow goodness-of-fit test and calibration plot revealed a good consistency between the predicted and observed probabilities. The area under the receiver operating characteristic curve was 0.875 (95% confidence interval = 0.838-0.912), which was significantly higher than those of commonly used scoring systems. The decision curve analysis indicated the nomogram had good predictive performance. DISCUSSION: Our nomogram, which is predictive of in-hospital mortality among older patients with intra-abdominal sepsis, incorporates muscle mass, a factor that warrants consideration by clinicians. The model has a high prognostic ability and might be applied in clinical practice after external validation.

Peripheral blood monocyte status is a predictor for judging occurrence and development on sepsis in older adult population: a case control study.

BACKGROUND: Peripheral blood monocytes are important immune modulatory cells that change during aging. Previous studies on sepsis and monocytes did not distinguish between age groups, especially in the older adult population. The mechanisms of monocyte subsets and function are not well-understood in the aging context with sepsis. METHODS: Monocyte subsets were measured using flow cytometry in 80 sepsis patients and 40 healthy controls. Plasma cytokine levels were measured using cytokine antibody arrays. RESULTS: The percentage of MO3 (CD14 + CD16 + +)/monocytes was higher in sepsis patients than in controls (P = 0.011), whereas the percentage of MO1 (CD14 + + CD16 -)/monocytes was higher in septic shock patients and 28-day death group than in those without shock and 28-day survival group (P = 0.034, 0.038). Logistic regression analysis showed that the percentage of MO3/monocytes (OR = 1.120, P = 0.046) and plasma level of monocyte chemoattractant protein (MCP)-1 (OR = 1.006, P = 0.023) were independently associated with the occurrence of sepsis, whereas the percentage of MO1/monocytes (OR = 1.255, P = 0.048) was independently associated with septic shock. The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of MO3/monocyte percentage in combination with MCP-1 plasma level (AUC = 0.799) for predicting sepsis was higher than that of each parameter alone (P < 0.001). The AUC of MO1/monocyte percentage with the value 0.706 (P = 0.003) was lower than the AUC of SOFA (sequential organ failure assessment) score with the value 0.966 (P < 0.001) for predicting septic shock, but the value of the two AUCs were similar for predicting 28-day mortality (AUC = 0.705, 0.827; P = 0.020, P < 0.001). The AUC of MO1/monocytes percentage in combination with SOFA score for predicting 28-day mortality was higher than that of each parameter alone (AUC = 0.867, P < 0.001). Using a cut-off of 58.5% (for MO1/monocytes determined by ROC) could discriminate between survivors and non-survivors on Kaplan-Meier curves for 28-day mortality with a positive predictive value of 77.4%. CONCLUSION: The MO3/monocyte percentage and plasma MCP-1 level were independent predictors of sepsis occurrence, whereas the percentage of MO1/monocytes was an independent predictor of prognosis in the Chinese Han older adult population. TRIAL REGISTRATION: Registration number: ChiCTR2200061490, date of registration: 2022-6-26 (retrospectively registered).

Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism.

Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury.

Correlations of Triglyceride with Type, Severity and Clinical Prognosis of Acute Pancreatitis.

BACKGROUND: The aim of this study was to explore the correlations of triglyceride (TG) with type, severity, and prognosis of acute pancreatitis (AP). METHODS: A total of 184 AP patients treated from January 2017 to June 2019 were selected. The severity and prognosis were assessed through modified computed tomography severity index (MCTSI) score and sequential organ failure assessment (SOFA) score, respectively. They were divided into biliary AP (BAP) and hyperlipidemic AP (HLAP) groups, and their blood lipid levels were compared. According to TG level, they were divided into normal and elevation groups (> 1.70 mmol/L), and the general data, severity, and prognosis were compared. The elevation group was further divided into mild, moderate, and severe elevation groups, and severity and prognosis were compared. Logistic regression analysis was performed with presence or absence of severe AP (SAP) and systemic inflammatory response syndrome (SIRS) as dependent variables. RESULTS: The levels of TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (Apo-A1), and Apo-B in the HLAP group were significantly higher than those in the BAP group (p < 0.05). Age, gender ratio, and body mass index had significant differences between normal and elevation groups (p < 0.05). Compared with the normal group, the numbers of cases of SAP, SIRS and pleural effusion, MCTSI score and SOFA score significantly rose, and the relief time of abdominal pain and length of hospital stay were significantly prolonged in the elevation group (p < 0.05). The number of cases of SAP, SIRS, and pleural effusion was significantly greater in the severe elevation group than that in the other three groups (p < 0.05), and the number of SIRS cases was significantly greater in the mild and moderate elevation groups than that in the normal group (p < 0.05). TG was an independent risk factor for SAP and SIRS (p < 0.05). CONCLUSIONS: Patients with TG elevation mostly suffer from HLAP. Higher TG level meant higher tendency of SAP, higher incidence rate of SIRS and worse prognosis of AP patients.

Ablation of Immunoproteasome ß5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice.

Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit ß2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit ß5i in regulating retinopathy and its underlying mechanisms. We induced a murine model of retinopathy by infusing Ang II (3,000 ng/kg/min) for 3 weeks into wild-type (WT) mice, ß5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing ß5i (Ad-ß5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The ß5i expression and chymotrypsin-like activity were most significantly elevated in Ang II-infused retinas and serum from patients with hypertensive retinopathy. Moreover, Ang II infusion-induced retinopathy was markedly attenuated in ß5i-KO mice but aggravated in Ad-ß5i-injected mice. Accordingly, ß5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-ß5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-ß5i-injected mice. This study found that ß5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.

Selective blocking of CXCR2 prevents and reverses atrial fibrillation in spontaneously hypertensive rats.

Atrial fibrillation (AF) is associated with inflammation and oxidative stress. Recently, we demonstrated that the chemokine-receptor CXCR2 plays a critical role in the recruitment of monocytes/macrophages and the development of hypertension and cardiac remodelling. However, the role of CXCR2 in the pathogenesis of hypertensive AF remains unclear. AF was induced in Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) administered with the CXCR2 inhibitor SB225002. Atrial remodelling, pathological changes and electrophysiology were examined. Our results showed that the chemokine CXCL1 and its receptor CXCR2 were markedly increased in atrial tissue of SHRs compared with WKYs. The administration of SB225002 to SHRs significantly reduced the elevation of blood pressure, AF inducibility and duration, atrial remodelling, recruitment of macrophages, superoxide production and conduction abnormalities compared with vehicle treatment. The administration of SB225002 to SHRs also reversed pre-existing AF development, atrial remodelling, inflammation and oxidative stress. These effects were associated with the inhibition of multiple signalling pathways, including TGF-ß1/Smad2/3, NF-κB-P65, NOX1, NOX2, Kir2.1, Kv1.5 and Cx43. In conclusion, this study provides new evidence that blocking CXCR2 prevents and reverses the development of AF in SHRs, and suggests that CXCR2 may be a potential therapeutic target for hypertensive AF.

Genetic ablation and pharmacological inhibition of immunosubunit ß5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice.

Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit ß5i (also named LMP7) is involved in angiotensin II-induced atrial fibrillation; however, its role in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. C57BL/6 J wild-type (WT) and ß5i knockout (ß5i KO) mice were subjected to uninephrectomy (sham) and DOCA-salt treatment for three weeks. Cardiac function, fibrosis, and inflammation were evaluated by echocardiography and histological analysis. Protein and gene expression levels were analyzed by quantitative real-time PCR and immunoblotting. Our results showed that after 21 days of DOCA-salt treatment, ß5i expression and chymotrypsin-like activity were the most significantly increased factors in the heart compared with the sham control. Moreover, DOCA-salt-induced elevation of blood pressure, adverse cardiac function, chamber and myocyte hypertrophy, interstitial fibrosis, oxidative stress, and inflammation were markedly attenuated in ß5i KO mice. These findings were verified in ß5i inhibitor PR-957-treated mice. Moreover, blocking of PTEN (the gene of phosphate and tensin homolog deleted on chromosome ten) markedly attenuated the inhibitory effect of ß5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of ß5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-ß1/Smad2/3, NOX, and NF-κB), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of ß5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of ß5i may be a promising therapeutic target for the treatment of hypertensive heart diseases.

Community-acquired bacterial co-infection predicts severity and mortality in influenza-associated pneumonia admitted patients.

BACKGROUND: Influenza is frequently complicated by bacterial co-infection, causing additional hospitalization and mortality. We determined the incidence, risk factors and outcomes of patients with influenza-associated community-acquired bacterial co-infection. METHOD: This was a retrospective, observational study. Influenza was diagnosed using the polymerase chain reaction. Co-infection had to be confirmed using standard bacteriological tests. The primary endpoint was presence of community-acquired co-infection, and the secondary endpoint was in-hospital mortality. RESULTS: During the 8 influenza seasons from 2010 to 2018, of the 209 influenza-associated pneumonia admitted patients, 41 (19.6%) were identified with community-acquired bacterial co-infections and Staphylococcus aureus was the predominant strain. Compared with patients without co-infection, patients with co-infection had similar demographic characteristics and co-morbidities, obtained a higher APACHE II score and a higher SOFA score, and had higher ratio of sepsis shock, invasive mechanical ventilation, and ICU requirement. In-hospital mortality independently associated with bacterial co-infection (adjusted hazard ratio (aHR) 2.619; 95%CI 1.252-5.480; p = 0.011); in subgroup S. aureus (aHR 6.267; 95%CI 2.679-14.662; p < 0.001) and other pathogens (aHR 2.964; 95%CI 1.160-7.577; p = 0.023); and in subgroup positive findings in bloodstream (aHR 7.420; 95%CI 2.712-20.302; p < 0.001) and positive findings in other site (aHR 3.427; 95%CI 1.514-7.757; p = 0.003). CONCLUSION: Community-acquired bacterial co-infection was frequent in influenza-associated pneumonia, without risk factor identified yet. Bacterial co-infection was likely to predict severity, and was an independent risk factor for in-hospital mortality. Co-infection of Staphylococcus aureus with influenza was identified as a lethal synergism, and should be targeted when developing clinical antibiotic strategies.

Risk stratification and prediction value of procalcitonin and clinical severity scores for community-acquired pneumonia in ED.

OBJECTIVE: Community-acquired pneumonia (CAP) is a common presentation to the emergency department (ED) and has high mortality rates. The aim of our study is to investigate the risk stratification and prognostic prediction value of precalcitonin (PCT) and clinical severity scores on patients with CAP in ED. METHODS: 226 consecutive adult patients with CAP admitted in ED of a tertiary teaching hospital were enrolled. Demographic information and clinical parameters including PCT levels were analyzed. CURB65, PSI, SOFA and qSOFA scores were calculated and compared between the severe CAP (SCAP) and non-severe CAP (NSCAP) group or the death and survival group. Receiver-operating characteristic (ROC) curves for 28-day mortality were calculated for each predictor using cut-off values. Logistic regression models and area under the curve (AUC) analysis were performed to compare the performance of predictors. RESULTS: Fifty-one patients were classified as SCAP and forty-nine patients died within 28days. There was significant difference between either SCAP and NSCAP group or death and survival group in PCT level and CURB65, PSI, SOFA, qSOFA scores (p < 0.001). The AUCs of the PCT and CURB65, PSI, SOFA and qSOFA in predicting SCAP were 0.875, 0.805, 0.810, 0.852 and 0.724, respectively. PCT is superior in predicting SCAP and the models combining PCT and SOFA demonstrated superior performance to those of PCT or the CAP severity score alone. The AUCs of the PCT and CURB65, PSI, SOFA and qSOFA in predicting 28-day mortality were 0.822, 0.829, 0.813, 0.913 and 0.717, respectively. SOFA achieved the highest AUC and the combination of PCT and SOFA had the highest superiority over other combinations in predicting 28-day mortality. CONCLUSION: Serum PCT is a valuable single predictor for SCAP. SOFA is superior in prediction of 28-day mortality. Combination of PCT and SOFA could improve the performance of single predictors. More further studies with larger sample size are warranted to validate our results.

Use of CRB-65 and quick Sepsis-related Organ Failure Assessment to predict site of care and mortality in pneumonia patients in the emergency department: a retrospective study.

BACKGROUND: The quick Sepsis-related Organ Failure Assessment (qSOFA) is a new screening system for sepsis that has prognostic performance equal to the full SOFA for patients with suspected infection outside the intensive care unit (ICU). The predictive value of qSOFA for mortality and site of care in patients with pneumonia is not clear. The present study was designed to investigate the predictive performance of qSOFA, CRB-65 (confusion, respiratory rate ≥30/minute, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg, age ≥65 years) and CRB (confusion, respiratory rate ≥30/minute, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg) for mortality, hospitalisation and ICU admission in patients with pneumonia in the emergency department (ED). METHODS: Retrospective analyses of published data on adult patients with pneumonia presenting between January 2012 and May 2014 were undertaken. The prevalence of 28-day mortality, hospitalisation and ICU admission were compared with regard to qSOFA, CRB and CRB-65 scores. The performance of these three systems for predicting outcomes was compared. RESULTS: Of 1641 patients, 861 (53 %) were hospitalised (38 % in a general ward, 15 % in the ICU), and the remaining 780 (47 %) were treated as outpatients or were observed in the ED. Within 28 days, 547 (33 %) of 1641 patients died. CRB-65, CRB and qSOFA scores of patients who died, were hospitalised and admitted to the ICU than those who survived and were not hospitalised or admitted to the ICU (P < 0.001). AUC values of qSOFA for prediction of 28-day mortality, hospitalisation and ICU admission were similar to those for CRB-65 and CRB. Patients with qSOFA scores of 0, 1, 2 and 3 were associated with, respectively, mortality of 16.3 %, 24.4 %, 48.2 % and 68.4 %; prevalence of hospitalisation of 37.2 %, 47.4 %, 61.6 % and 73.7 %; and prevalence of ICU admission of 9.3 %, 9.1 %, 22.4 % and 45.3 %. Patients with qSOFA scores of 2 and 3 had a significantly higher prevalence of mortality and ICU admission than patients with identical CRB-65 scores. CONCLUSIONS: qSOFA is better than CRB-65 for identification of a high risk of mortality and requirement of ICU admission.

Predictive performance of quick Sepsis-related Organ Failure Assessment for mortality and ICU admission in patients with infection at the ED.

OBJECTIVE: The objectives of this study are to investigate the performance of the quick Sepsis-related Organ Failure Assessment (qSOFA) in predicting mortality and intensive care unit (ICU) admission in patients with clinically diagnosed infection and to compare its performance with that of Mortality in Emergency Department Sepsis (MEDS), Acute Physiology and Chronic Health Evaluation (APACHE) II, and Sepsis-related Organ Failure Assessment (SOFA). METHODS: From July to December 2015, we retrospectively analyzed 477 patients clinically diagnosed with infection in the emergency department. We compared the performance of SOFA, MEDS, APACHE II, and qSOFA in predicting ICU admission and 28-day mortality. RESULTS: All scores were higher in nonsurvivors and ICU patients than in survivors and non-ICU patients (P< .001). The area under the receiver operating characteristic curve of qSOFA was lower than that of MEDS (0.666 vs 0.751; P< .05) and similar to that of SOFA (0.729) and APACHE II (0.732) in predicting 28-day mortality. The areas under the receiver operating characteristic curve of qSOFA, SOFA, MEDS, and APACHE II in predicting ICU admission were 0.636, 0.682, 0.661, and 0.640, respectively. There were no significant differences among the score systems. In patients with qSOFA scores less than 2 and greater than or equal to 2, 28-day mortality rates were 17.4% and 42.9% (P< .001), and ICU admission rates were 16.0% and 33.3% (P< .001). CONCLUSIONS: Quick SOFA predicted ICU admission with similar performance to that of SOFA, MEDS, and APACHE II. Its prognostic ability was similar to that of SOFA and APACHE II but slightly inferior to that of MEDS.