UCHL1 regulates inflammation via MAPK and NF-κB pathways in LPS-activated macrophages.

Inflammation is a common pathophysiological process as well as a clinical threat that occurs in various diseases worldwide. It is well-documented that nuclear factor-κB (NF-κB) and mitogen-activated protein kinase pathways are involved in inflammatory reactions to microbial infections in lipopolysaccharide (LPS)-activated macrophages. The deubiquitinase ubiquitin carboxyl-terminal hydrolase-L1 (UCHL1) has been reported as an oncoprotein to promote the growth and progression of cancer cells. However, the regulatory mechanism of UCHL1 in inflammation is currently unclear. Here, we aimed to assess the effects of UCHL1 on LPS-associated inflammatory response in vitro and in vivo by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction, and western blot analysis. This study identified that inhibition or knockdown of UCHL1 decreased the amounts of the key pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α in macrophages. Additionally, inhibition of UCHL1 suppressed LPS-induced extracellular signal-regulated protein kinase 1/2 phosphorylation and NF-κB translocation by regulating the inhibitor of NF-κB. Mechanically, UCHL1 interacts with IκBα protein in THP-1. Meanwhile, inhibition of UCHL1 blocked the LPS-induced degradation of IκBα through the ubiquitin-proteasome system. Moreover, in vivo assay showed that suppression of UCHL1 notably reduced the LPS-induced animal death and release of pro-inflammatory cytokines. Overall, the current findings uncover that UCHL1 functions as a crucial regulator for inflammatory response via reversing the degradation of IκBα, representing a potential target for the treatment of inflammatory diseases.

Ubiquitin-specific protease 14 regulates LPS-induced inflammation by increasing ERK1/2 phosphorylation and NF-κB activation.

Persistent activation of nuclear factor B (NF-κB) is very important in the modulation of macrophages cellular response to microbial infections. The deubiquitinase USP14, which is critical for ubiquitin-mediated proteasomal degradation of proteins, is known to be involved in cancer, neurological diseases, and aging. However, the mechanism by which USP14 regulates inflammation remains unclear. Here, we demonstrated that decreasing the deubiquitinase activity of USP14 resulted in reduced lipopolysaccharides (LPS)-mediated tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 release in THP-1 and RAW264.7 cells. Meanwhile, USP14 knockdown by siRNA showed the same effects, with no cytotoxicity in THP-1 cells. Moreover, inhibiting the deubiquitinase activity of USP14 or USP14 knockdown resulted in decreased ERK1/2 and IκBα phosphorylation, increased amounts of the NF-κB inhibitor IκBα, and reduced NF-κB p65 transport from the cytoplasm into nucleus. These findings suggested that USP14 induces NF-κB activity and ERK1/2 phosphorylation triggered by microbial infection.

ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated (ECMO-RESCUE): study protocol for a prospective, multicentre, non-randomised cohort study.

INTRODUCTION: Severe septic cardiomyopathy (SCM) is one of the main causes of refractory septic shock (RSS), with a high mortality. The application of venoarterial extracorporeal membrane oxygenation (ECMO) to support the impaired cardiac function in patients with septic shock remains controversial. Moreover, no prospective studies have been taken to address whether venoarterial ECMO treatment could improve the outcome of patients with sepsis-induced cardiogenic shock. The objective of this study is to assess whether venoarterial ECMO treatment can improve the 30-day survival rate of patients with sepsis-induced refractory cardiogenic shock. METHODS AND ANALYSIS: ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated is a prospective, multicentre, non-randomised, cohort study on the application of ECMO in SCM. At least 64 patients with SCM and RSS will be enrolled in an estimated ratio of 1:1.5. Participants taking venoarterial ECMO during the period of study are referred to as cohort 1, and patients receiving only conventional therapy without ECMO belong to cohort 2. The primary outcome is survival in a 30-day follow-up period. Other end points include survival to intensive care unit (ICU) discharge, hospital survival, 6-month survival, quality of life for long-term survival (EQ-5D score), successful rate of ECMO weaning, long-term survivors' cardiac function, the number of days alive without continuous renal replacement therapy, mechanical ventilation and vasopressor, ICU and hospital length of stay, the rate of complications potentially related to ECMO treatment. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2020-hs-51). Participants will be screened and enrolled from ICU patients with septic shock by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. TRIAL REGISTRATION NUMBER: NCT05184296.

Association between the ß-blocker use and patients with sepsis: a cohort study.

Objective: This study aimed to assess whether ß-blockers are associated with mortality in patients with sepsis. Method: We conducted a retrospective cohort study of patients with sepsis using the Medical Information Market for Intensive Care (MIMIC)-IV and the emergency intensive care unit (eICU) databases. The primary outcome was the in-hospital mortality rate. The propensity score matching (PSM) method was adopted to reduce confounder bias. Subgroup and sensitivity analyses were performed to test the stability of the conclusions. Results: We included a total of 61,751 patients with sepsis, with an overall in-hospital mortality rate of 15.3% in MIMIC-IV and 13.6% in eICU. The inverse probability-weighting model showed that in-hospital mortality was significantly lower in the ß-blockers group than in the non-ß-blockers group [HR = 0.71, 95% CI: 0.66-0.75, p < 0.001 in MIMIC-IV, and HR = 0.48, 95% CI: 0.45-0.52, p < 0.001 in eICU]. In subgroups grouped according to sex, age, heart rate, APSIII, septic shock, and admission years, the results did not change. Conclusion: ß-blocker use is associated with lower in-hospital mortality in patients with sepsis, further randomized trials are required to confirm this association.

Critical Role Played by Interface Engineering in Weakening Thickness Dependence of Superconducting and Structural Properties of FeSe0.5Te0.5-Coated Conductors.

Increasing the thickness of a superconducting layer and simultaneously reducing the thickness effect in iron-based superconducting coated conductors are particularly essential for improving the critical current Ic. Here, for the first time, we have deposited high-performance FeSe0.5Te0.5 (FST) superconducting films up to 2 µm on LaMnO3-buffered metal tapes by pulsed laser deposition. An interface engineering strategy, alternating growth of a 10 nm-thick nonsuperconducting FST seed layer and a 400 nm-thick FST superconducting layer, was employed to guarantee the crystalline quality of the films with thicknesses of the order of micrometers, resulting in a highly biaxial texture with grain boundary misorientation angle less than the critical value θc ∼ 9°. Moreover, the thickness effect, that the critical current density (Jc) shows a clear dependence on thickness as in cuprates, is reduced by the interface engineering. Also, the maximum Jc was found for a 400 nm-thick film with 1.3 MA/cm2 in self-field at 4.2 K and 0.71 MA/cm2 (H∥ab) and 0.50 MA/cm2 (H∥c) at 9 T. Anisotropic Ginzburg-Landau scaling indicates that the major pinning centers vary from correlated to uncorrelated as the film thickness increases, while the thickness effect is most likely related to the weakening of flux pinning by the fluctuation of charge-carrier mean free path (δl) and strengthening of flux pinning caused by the variation of superconducting transition temperature (δTc) due to off-stoichiometry with thickness.

[Relationship of in-hospital mortality and using intra-aortic balloon pump with extracorporeal cardiopulmonary resuscitation in patients with cardiac arrest: a secondary analysis based on literature data].

OBJECTIVE: To assess the effect of intra-aortic balloon pump (IABP) on in-hospital mortality in patients with cardiac arrest undergoing extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: A retrospective study was performed on 696 patients with intra-hospital cardiac arrest undergoing ECPR from Samsung Medical Center in Korea between January 2004 and December 2013. According to whether IABP was used, the patients were divided into ECPR group and ECPR+IABP group. Cox regression and propensity score matching (PSM) were used to examine the correlation between IABP usage and in-hospital mortality, and standardized mean difference (SMD) was used to check the degree of PSM. Survival analysis of in-hospital mortality was performed by the Kaplan-Meier method, and further analyzed by the Log-Rank test. Using the propensity score as weights, multiple regression model and inverse probability weighting (IPW) model were used for sensitivity analysis. In-hospital mortality, extracorporeal membrane oxygenation (ECMO) withdrawal success rate and neurological function prognosis were compared between the two groups. RESULTS: A total of 199 patients with cardiac arrest undergoing ECPR were included, including 120 males and 79 females, and the average age was (60.0±16.8) years. Thirty-one patients (15.6%) were treated with ECPR and IABP, and 168 patients (84.4%) only received ECPR. The total hospitalized mortality was 68.8% (137/199). The 1 : 1 nearest neighbor matching algorithm was performed with the 0.2 caliper value. The following variables were selected to generate propensity scores, including age, gender, race, marital status, insurance, admission type, service unit, heart rate, mean arterial pressure, respiratory rate, pulse oxygen saturation, white blood cell count. After the propensity score matching, 24 pairs of patients were successfully matched, with the average age of (63.0±12.8) years, including 31 males and 17 females. The in-hospital mortality was 72.6% (122/168) and 48.4% (15/31) in the ECPR group and the ECPR+IABP group [hazard ratio (HR) = 0.48, 95% confidence interval (95%CI) was 0.28-0.82, P = 0.007]. Multiple regression model, adjusted propensity score, PSM and IPW model showed that the in-hospital mortality in the ECPR+IABP group was significantly lower compared with the ECPR group (HR = 0.44, 0.50, 0.16 and 0.49, respectively, 95%CI were 0.24-0.79, 0.28-0.91, 0.06-0.39 and 0.31-0.77, all P < 0.05). The combined application of IABP could improve the ECMO withdrawal success rate [odds ratio (OR) = 8.95, 95%CI was 2.72-29.38, P < 0.001] and neurological prognosis (OR = 4.06, 95%CI was 1.33-12.40, P = 0.014) in adult cardiac arrest patients. CONCLUSIONS: In patients with cardiac arrest using ECPR, the combination of IABP was independently associated with lower in-hospital mortality, higher ECMO withdrawal success rate and better neurological prognosis.

Association Between Wait Time of Central Venous Pressure Measurement and Outcomes in Critical Patients With Acute Kidney Injury: A Retrospective Cohort Study.

Background: Hemodynamic management is of paramount importance in patients with acute kidney injury (AKI). Central venous pressure (CVP) has been used to assess volume status. We intended to identify the optimal time window in which to obtain CVP to avoid the incidence of adverse outcomes in patients with AKI. Methods: The study was based on the Medical Information Mart for Intensive Care (MIMIC) IV database. The primary outcome was in-hospital mortality. Secondary outcomes included the number of ICU-free days and norepinephrine-free days at 28 days after ICU admission, and total fluid input and fluid balance during the first and second day. A time-dose-response relationship between wait time of CVP measurement and in-hospital mortality was implemented to find an inflection point for grouping, followed by propensity-score matching (PSM), which was used to compare the outcomes between the two groups. Results: Twenty Nine Thousand and Three Hundred Thirty Six patients with AKI were enrolled, and the risk of in-hospital mortality increased when the CVP acquisition time was >9 h in the Cox proportional hazards regression model. Compared with 8,071 patients (27.5%) who underwent CVP measurement within 9 h and were assigned to the early group, 21,265 patients (72.5%) who delayed or did not monitor CVP had a significantly higher in-hospital mortality in univariate and multivariate Cox regression analyses. After adjusting for potential confounders by PSM and adjusting for propensity score, pairwise algorithmic, overlap weight, and doubly robust analysis, the results were still stable. The HRs were 0.58-0.72, all p < 0.001. E-value analysis suggested robustness to unmeasured confounding. Conclusions: Among adults with AKI in ICU, increased CVP wait time was associated with a greater risk of in-hospital mortality. In addition, early CVP monitoring perhaps contributed to shortening the length of ICU stays and days of norepinephrine use, as well as better fluid management.

Association between Wait Time for Transthoracic Echocardiography and 28-Day Mortality in Patients with Septic Shock: A Cohort Study.

Background: the optimal timing of Transthoracic echocardiography (TTE) performance for patients with septic shock remains unexplored. Methods: a retrospective cohort study included patients with septic shock in the MIMIC-Ⅲ database. Risk-adjusted restricted cubic splines modeled the 28-day mortality according to time elapsed from ICU admission to receive TTE. The cut point when a smooth curve inflected was selected to define early and delayed group. We applied propensity score matching (PSM) to ensure our findings were reliable. Causal mediation analysis was used to assess the intermediate effect of fluid balance within 72 h after ICU admission. Results: 3264 participants were enrolled and the risk of 28-day mortality increased until the wait time was around 10 h (Early group) and then was relatively flat afterwards (Delayed group). A beneficial effect of early TTE in terms of the 28-day mortality was observed (HRs 0.73−0.78, all p < 0.05) in the PSM. The indirect effect brought by the fluid balance on day 2 and 3 was significant (both p = 0.006). Conclusion: early TTE performance might be associated with lower risk-adjusted 28-day mortality in patients with septic shock. Better fluid balance may have mediated this effect. A wait time within 10 h after ICU may represent a threshold defining progressively increasing risk.

[Comparative study of recruitment maneuver guided by pressure-volume curve on respiratory physiology and lung morphology between acute respiratory distress syndrome of pulmonary and extrapulmonary origin in canine models].

OBJECTIVE: To determine effects of recruitment maneuver (RM) guided by pressure-volume (P-V) curve on respiratory physiology and lung morphology in canine models of acute respiratory distress syndrome of pulmonary or extrapulmonary origin (ARDSp and ARDSexp). METHODS: Twenty-four healthy dogs were randomly divided into two groups with 12 dogs each: ARDSexp and ARDSp. Each dog in ARDSexp group was injected with oleic acid 0.1 ml/kg through femoral vein, and each dog in ARDSp group received hydrochloric acid 2 ml/kg via trachea. Subsequently, dogs with both models were randomly subdivided into lung protective ventilation strategy (LPVS) group and LPVS+RM group, respectively. Dogs in LPVS group were given LPVS only without RM. RM guided by P-V curve was performed in LPVS+RM group followed by LPVS and pressure controlled ventilation (PCV) mode was selected. Phigh was set at upper inflection point (UIP) of the P-V curve, positive end-expiratory pressure (PEEP) was set at lower inflection point (LIP)+2 cm H(2)O (1 cm H(2)O=0.098 kPa), and the duration of RM was 60 seconds. The duration of mechanical ventilation (MV) in both subgroups was 4 hours. The oxygenation index (PaO(2)/FiO(2)), relative lung mechanical indexes were measured in two ARDS models before establishment of ARDS model, and before and after RM. The UIP and LIP were calculated with P-V curve. The percentage of different volume in ventilation of lung accounting for total lung volume was compared by CT scan. RESULTS: The PaO(2)/FiO(2), UIP and LIP did not showed significant differences among all groups before ARDS and before RM. PaO(2)/FiO(2) and respiratory system compliance (Crs) were significantly elevated in LPVS+RM group of both models 4 hours after RM compared with corresponding LPVS group [PaO(2)/FiO(2) (mm Hg, 1 mm Hg=0.133 kPa) of ARDSexp model: 263.9±69.2 vs. 182.8±42.8, Crs (ml/cm H(2)O) of ARDSexp model: 11.3±4.2 vs. 9.7±3.7; PaO(2)/FiO(2) (mm Hg) of ARDSp model: 193.4±33.5 vs. 176.4±40.2, Crs (ml/cm H(2)O) of ARDSp model: 10.1±3.9 vs. 9.0±3.9, P<0.05 or P<0.01], and the airway pressure was significantly declined compared with corresponding LPVS group [peak inspiratory pressure (PIP), cm H(2)O ] of ARDSexp model: 24.1±7.4 vs. 30.2±8.5, plateau pressure (Pplat, cm H(2)O) of ARDSexp model: 19.1±7.3 vs. 25.6±7.7; PIP (cm H(2)O) of ARDSp model: 26.6±8.4 vs. 29.6±10.3, Pplat (cm H(2)O) of ARDSp model: 21.9±7.3 vs. 25.1±8.4, P<0.05 or P<0.01]. Moreover, PaO(2)/FiO(2), Crs, PIP and Pplat were improved better in ARDSexp model than ARDSp model (P<0.05 orP<0.01). Compared with LPVS maneuver, RM plus LPVS maneuver could significantly decrease the proportion of closure and hypoventilation region, and increase the proportion of normal ventilation region in both models [closure region of ARDSexp model: (9.9±3.1)% vs. (16.3±5.2)%, hypoventilation region of ARDSexp model: (10.2±4.2)% vs. (23.4±6.7)%, normal ventilation region of ARDSexp model: (76.2±12.3)% vs. (57.5±10.1)%; closure region of ARDSp model: (14.3±4.8)% vs. (18.2±5.1)%, hypoventilation region of ARDSp model: (17.4±6.3)% vs. (24.1±5.9)%, normal ventilation region of ARDSp model: (63.2±10.7)% vs. (54.6±11.3)%, P<0.05 or P<0.01]. All of the ventilation regions were better improved with ARDSexp model than ARDSp model (all P<0.05). CONCLUSION: RM guided by P-V curve could help obtain better oxygenation, improve pulmonary compliance and lung ventilation in ARDSexp and ARDSp, and better treatment effects are seen in ARDSexp dogs than ARDSp dogs.

[Establish the nomogram prediction model of septic cardiomyopathy based on the afterload-corrected cardiac performance].

OBJECTIVE: To establish a nomogram prediction model for the prognosis of patients with septic cardiomyopathy (SCM) based on afterload-corrected cardiac performance (ACP), in order to identify septic patients with poor outcomes and treatment. METHODS: The data of patients admitted to the department of critical medicine of the Second Affiliated Hospital of Guangzhou Medical University from June 2016 to June 2019 were analyzed. All patients were monitored by pulse indication continuous cardiac output (PiCCO) monitor more than 24 hours and diagnosed as SCM with ACP less than 80%. The predictors of 30-day death risk of SCM patients were screened by univariate Cox regression analysis. Multivariate Cox regression analysis was used to establish the prediction model for 30-day death risk of SCM patients, which was displayed by the nomogram. Finally, the discrimination and calibration of the model were analyzed by receiver operator characteristic curve (ROC curve) and consistency index (C-index). RESULTS: A total of 102 patients with SCM were included and the 30-day mortality was 60.8% (62 cases). Among 102 patients with SCM, 57 patients (55.9%) had mild impairment of cardiac function (60% ≤ ACP < 80%), and the 30-day mortality was 43.9% (25/57); 39 patients (38.2%) had moderate impairment of cardiac function (40% ≤ ACP < 60%), and the 30-day mortality was 79.5% (31/39); 6 patients (5.9%) had severe impairment of cardiac function (ACP < 40%), and the 30-day mortality was 100% (6/6). There was significantly difference in mortality among the three groups (χ2 = 24.156, P < 0.001). The potential risk factors for 30-day death of SCM patients screened by univariate Cox regression analysis were included in multivariate Cox regression analysis. The results showed that the independent risk factors for 30-day death of SCM patients were acute physiology and chronic health evaluation II [APACHE II, risk ratio (HR) = 1.031, 95% confidence interval (95%CI) was 1.002-1.061, P = 0.039], vasoactive inotropic score (VIS, HR = 1.003, 95%CI was 1.001-1.005, P = 0.012), continuous renal replacement therapy (CRRT; HR = 2.106, 95%CI was 1.089-4.072, P = 0.027), and ACP (HR = 0.952, 95%CI was 0.928-0.977, P < 0.001). The nomogram model was established based on the above independent risk factors and age, and the area under the curve (AUC) was 0.865 (95%CI was 0.795-0.935), P < 0.001; C-index was 0.797 (95%CI was 0.747-0.847), P > 0.05. CONCLUSIONS: The nomogram model based on age, APACHE II score, VIS score, CRRT and ACP has a certain clinical reference significance for the prediction of 30-day mortality of SCM patients. The discrimination and calibration are good, however, further verification is needed.

Relationship between Driving Pressure and Mortality in Ventilated Patients with Heart Failure: A Cohort Study.

Background: Heart failure (HF) is a leading cause of mortality and morbidity worldwide, with an increasing incidence. Invasive ventilation is considered to be essential for patients with HF. Previous studies have shown that driving pressure is associated with mortality in acute respiratory distress syndrome (ARDS). However, the relationship between driving pressure and mortality has not yet been examined in ventilated patients with HF. We assessed the association of driving pressure and mortality in patients with HF. Methods: We conducted a retrospective cohort study of invasive ventilated adult patients with HF from the Medical Information Mart for Intensive Care-III database. We used multivariable logistic regression models, a generalized additive model, and a two-piecewise linear regression model to show the effect of the average driving pressure within 24 h of intensive care unit admission on in-hospital mortality. Results: Six hundred and thirty-two invasive ventilated patients with HF were enrolled. Driving pressure was independently associated with in-hospital mortality (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.18; P < 0.001) after adjusted potential confounders. A nonlinear relationship was found between driving pressure and in-hospital mortality, which had a threshold around 14.27 cmH2O. The effect sizes and CIs below and above the threshold were 0.89 (0.75 to 1.05) and 1.17 (1.07 to 1.30), respectively. Conclusions: There was a nonlinear relationship between driving pressure and mortality in patients with HF who were ventilated for more than 48 h, and this relationship was associated with increased in-hospital mortality when the driving pressure was more than 14.27 cmH2O.

Association Between Preadmission Metformin Use and Outcomes in Intensive Care Unit Patients With Sepsis and Type 2 Diabetes: A Cohort Study.

Background: Sepsis is a deadly disease worldwide. Effective treatment strategy of sepsis remains limited. There still was a controversial about association between preadmission metformin use and mortality in sepsis patients with diabetes. We aimed to assess sepsis-related mortality in patients with type 2 diabetes (T2DM) who were preadmission metformin and non-metformin users. Methods: The patients with sepsis and T2DM were included from Medical Information Mart for Intensive Care -III database. Outcome was 30-day mortality. We used multivariable Cox regression analyses to calculate adjusted hazard ratio (HR) with 95% CI. Results: We included 2,383 sepsis patients with T2DM (476 and 1,907 patients were preadmission metformin and non-metformin uses) between 2001 and 2012. The overall 30-day mortality was 20.1% (480/2,383); it was 21.9% (418/1,907), and 13.0% (62/476) for non-metformin and metformin users, respectively. After adjusted for potential confounders, we found that preadmission metformin use was associated with 39% lower of 30-day mortality (HR = 0.61, 95% CI: 0.46-0.81, p = 0.007). In sensitivity analyses, subgroups analyses, and propensity score matching, the results remain stable. Conclusions: Preadmission metformin use may be associated with reduced risk-adjusted mortality in patients with sepsis and T2DM. It is worthy to further investigate this association.

Association between metformin use on admission and outcomes in intensive care unit patients with acute kidney injury and type 2 diabetes: A retrospective cohort study.

PURPOSE: Acute kidney injury (AKI) occurs in more than half of intensive care unit patients. Effective prevention and treatment strategies for AKI remain limited. We aimed to assess AKI-related mortality in patients with diabetes who were metformin and non-metformin users. MATERIALS AND METHODS: We included patients with AKI and type 2 diabetes (T2DM) from the Medical Information Mart for Intensive Care database. The 30-day mortality, neutrophil-to-lymphocyte ratio, and length of hospital stay were compared between patients with and without metformin prescriptions. We used multivariable Cox proportional hazards regression, propensity score analysis, and an inverse probability-weighting model to ensure the robustness of our findings. RESULTS: We included 4328 patients with AKI and T2DM (998 and 3330 patients were metformin and non-metformin users, respectively). The overall 30-day mortality was 14.2% (613/4328); it was 15.7% (523/3330) and 9.0% (90/998) for non-metformin and metformin users, respectively. In the inverse probability-weighting model, metformin use was associated with 37% lower 30-day mortality (HR = 0.63, 95% CI: 0.50-0.80, p < 0.0001). CONCLUSIONS: Metformin use may be associated with reduced risk-adjusted mortality in patients with AKI and T2DM. Further randomized controlled trials are needed to clarify this association.

The timing of continuous renal replacement therapy initiation in sepsis-associated acute kidney injury in the intensive care unit: the CRTSAKI Study (Continuous RRT Timing in Sepsis-associated AKI in ICU): study protocol for a multicentre, randomised controlled trial.

INTRODUCTION: Acute kidney injury (AKI) is one of the most common organ dysfunction in sepsis, and increases the risk of unfavourable outcomes. Renal replacement therapy (RRT) is the predominant treatment for sepsis-associated AKI (SAKI). However, to date, no prospective randomised study has adequately addressed whether initiating RRT earlier will attenuate renal injury and improve the outcome of sepsis. The objective of the trial is to compare the early strategy with delayed strategy on the outcomes in patients with SAKI in the intensive care unit (ICU). METHODS AND ANALYSIS: This is a large-scale, multicentre, randomised controlled trial about SAKI. In total, 460 patients with sepsis and evidence of AKI stage 2 of Kidney Disease Improving Global Outcomes (KDIGO) will be recruited and equally randomised into the early group and the delay group in a ratio of 1:1. In the early group, continuous RRT (CRRT) will be started immediately after randomisation. In the delay group, CRRT will initiated if at least one of the following criteria was met: stage 3 of KDIGO, severe hyperkalaemia, pulmonary oedema, blood urea nitrogen level higher than 112 mg/dL after randomisation. The primary outcome is overall survival in a 90-day follow-up period (90-day all-cause mortality). Other end points include 28-day, 60-day and 1-year mortality, recovery rate of renal function by day 28 and day 90, ICU and hospital length of stay, the numbers of CRRT-free days, mechanical ventilation-free days and vasopressor-free days, the rate of complications potentially related to CRRT, CRRT-related cost, and concentrations of inflammatory mediators in serum. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2017-31-ks-01). Participants will be screened and enrolled from patients in the ICU with SAKI by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. TRIAL REGISTRATION: NCT03175328.

[Relationship between "1-hour serum lactate" level and 30-day mortality in critical care patients in intensive care unit].

OBJECTIVE: To investigate the relationship between 1-hour lactate (1 h Lac) and 30-day mortality in critical care patients in intensive care unit (ICU). METHODS: A retrospective, observational cohort study was performed with adult critical patients (age ≥ 16 years old) having lactate records within 1 hour after ICU admission from Medical Information Mart for Intensive Care-III database (MIMIC-III). According to the 1 h Lac level, the patients were divided into three groups: < 2 mmol/L, 2-4 mmol/L, and > 4 mmol/L groups. The baseline characteristics were analyzed. Multivariable Logistic regression analysis was performed to assess the association between 1 h Lac and 30-day mortality. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of 1 h Lac for 30-day mortality, and Kaplan-Meier survival curve was performed according to the best cut-off value. In addition, sensitivity analysis was carried out for each classification variable. RESULTS: A total of 3 969 ICU patients were included, with 673 died in 30 days, and the total mortality was 16.95%. There were 1 664, 1 588, 717 patients in Lac < 2 mmol/L, 2-4 mmol/L and > 4 mmol/L group, respectively. There were significant differences in age, ICU duration, ICU type, heart rate, leukocyte count, hemoglobin, creatinine, sequential organ failure score (SOFA), ventilator application, vasoactive drug use and main diagnosis among the three groups. Multivariable Logistic regression analysis showed that a 1 mmol/L increment in Lac was associated with 0.24 times higher risk of 30-day mortality [odds ratio (OR) = 1.24, 95% confidence interval (95%CI) was 1.19-1.29, P < 0.000 1]. ROC curve analysis showed that the area under ROC curve (AUC) of 1 h Lac for predicting 30-day mortality of severe patients was 0.694 (95%CI was 0.669-0.718). The cut-off value was 3.35 mmol/L with sensitivity of 0.499 and specificity of 0.779, whilst positive likelihood ratio was 2.260, and negative likelihood ratio was 0.643. According to the cut-off value of 1 h Lac, the patients were divided into high lactate group (≥ 3.35 mmol/L) and low lactate group (< 3.35 mmol/L). In the two subgroups, 30-day mortality was 31.58% (336/1 064) and 11.60% (337/2 905), respectively. The Kaplan-Meier survival curve showed that the 30-day cumulative survival rate of high lactate group was significantly lower than that of low lactate group (Log-rank test: χ2 = 247.72, P < 0.000 1). Multiple Logistic regression analysis showed that the 30-day mortality rate of high lactate group was 2.34 times that the level of low lactate group (OR = 2.34, 95%CI was 1.90-2.88, P < 0.000 1), after the adjustment of age, time of admission, type of ICU, hemoglobin, leukocyte count, use of vasopressor, use of ventilator and main diagnosis of patients. Stratified analysis showed that the relationship between 1 h Lac and 30-day mortality was stable. CONCLUSIONS: 1 h Lac is associated with 30-day mortality in critical care patients. The risk of death was significantly increased in critically ill patients with 1 h Lac higher than 3.35 mmol/L.

[The interaction between soluble CD73 and 90-day mortality from patients with non-septic shock and sepsis shock: a secondary analysis from the prospective FINNAKI study].

OBJECTIVE: Fundamental researches have shown that soluble CD73 (sCD73) can inhibit inflammatory response and limit excessive tissue damage caused by continuous immune cell activation. A Finnish prospective, observational study of acute kidney injury (FINNAKI) showed no association between sCD73 and 90-day mortality in sepsis patients. Clinical data of this study was used for secondary analysis to explore whether the relationship between sCD73 and 90-day mortality was consistent in septic shock and non-septic shock patients. METHODS: The FINNAKI study was a prospective, observational cohort study conducted in 17 intensive care units (ICUs) in Finland from September 1st, 2011 to February 1st, 2012. Sepsis/septic shock was defined according to Sepsis-1 definition. Demographic characteristics, treatment, comorbidities and 90-day mortality of the patients were analyzed. To evaluate the difference (interaction test) between the relationship of sCD73 and 90-day mortality in septic shock and non-septic shock patients, likelihood ratio test was used to integrate the product term (sCD73×septic shock or non-septic shock) into multivariable Logistic regression. Sensitivity analysis was performed with the definition of Sepsis-3. The interaction between sCD73 and 90-day mortality in patients with septic shock and non-septic shock were verified by generalized additive model (GAM). RESULTS: A total of 588 patients with severe sepsis/septic shock were enrolled. 164 patients died in 90 days, and the 90-day mortality was 27.89%. Based on the Sepsis-1 definition, there were 159 non-septic shock patients and 429 septic shock patients. Compared with the non-septic shock patients, lactate (Lac) level, sequential organ failure assessment (SOFA) score, fluid balance on the first day, and ratio of mechanical ventilation, 12-hour acute kidney injury (AKI), renal replacement therapy (RRT), and postoperative ICU transition in the septic shock patients were significantly increased and the proportion of emergency admission to ICU was significantly decreased. Based on the Sepsis-3 definition, there were 383 non-septic shock patients and 205 septic shock patients; the results of clinical data analysis between the two groups were similar to those based on Sepsis-1. Based on Sepsis-1, there was no significant difference in 90-day mortality between non-septic shock and septic shock patients [23.90% (38/159) vs. 29.37% (126/429), P > 0.05]. However, based on Sepsis-3, the 90-day mortality of patients with septic shock was significantly higher than that of patients with non-septic shock [37.56% (77/205) vs. 22.72% (87/383), P < 0.01]. Multivariate Logistic regression analysis and interaction test showed that after adjusting all confounding factors (except the number of complications) in non-sepsis shock and sepsis shock patients, sCD73 and 90-day mortality were significantly different in both Sepsis-1 and Sepsis-3. The P values for interaction tests were 0.046 and 0.027, respectively. In patients with non-septic shock, sCD73 tended to be positively associated with 90-day mortality [Sepsis-1: odds ratio (OR) = 1.46, 95% confidence interval (95%CI) was 0.99-2.13, P = 0.053; Sepsis-3: OR = 1.34, 95%CI was 1.02-1.74, P = 0.034]. In septic shock patients, sCD73 tended to be negatively associated with 90-day mortality (Sepsis-1: OR = 0.91, 95%CI was 0.69-1.20, P = 0.494; Sepsis-3: OR = 0.80, 95%CI was 0.55-1.17, P = 0.249). The results of GAM model validation were consistent with the results of Logistic regression equation cross validation. CONCLUSIONS: The relationship between sCD73 and 90-day mortality is significantly different from patients with non-sepsis shock and sepsis shock. In patients with non-sepsis shock, sCD73 is trend to positively associated with 90-day mortality, and there is a negative trend between sCD73 and 90-day mortality in patients with septic shock.

[Role of macrophage migration inhibitory factor in mice with sepsis and after effect of its intervention].

OBJECTIVE: To investigate the expression profile of macrophage migration inhibitory factor (MIF) in serum and lung tissues of mice with sepsis, and to explore the effect of MIF antagonist ISO-1 on sepsis in a murine sepsis model. METHODS: Sepsis was reproduced in 40 mice by cecal ligation and puncture (CLP). Heart blood was obtained from 8 mice each at 12, 24, 36, 48 hours after CLP. The content of MIF in serum was determined by enzyme linked immunosorbent assay (ELISA). MIF mRNA and protein expressions in lung tissues of septic mice were assessed by reverse transcription-polymerase chain reaction (RT-PCR) or Western blotting. Another group of 40 mice were selected to investigate the role and the impact of MIF antagonist ISO-1 in septic mice. RESULTS: The content of MIF in serum was higher in septic mice than that in sham operation group, and it peaked at 36 hours, and decreased at 48 hours, but still higher than that in sham operation group (all P<0.01). The MIF mRNA and protein expression in lung tissues of septic mice were higher than those in sham operation group, beginning at 12 hours, and peaked at 48 hours (P<0.05 or P<0.01). ISO-1, which was the antagonist of MIF, could elevate the surviving rate of animals with sepsis [60% (12/20) vs. 25% (5/20), P<0.05]. CONCLUSION: MIF plays a role as a late mediator in sepsis, with a high expression of MIF in serum and lung tissue. ISO-1 can elevate the surviving rate in murine model of sepsis. It is concluded that MIF could be taken as a potential target of treatment of sepsis.

[Effects of continuous blood purification on extravascular lung water and respiratory function in patients with extrapulmonary acute respiratory distress syndrome].

OBJECTIVE: To assess the effects of continuous blood purification (CBP) on extravascular lung water and respiratory function in patients with extrapulmonary acute respiratory distress syndrome (ARDSexp). METHODS: The data of 31 patients with ARDSexp admitted in our department were retrospectively analyzed.Sixteen of the patients received CBP, and the other 15 patients did not (control group). The level of extravascular lung water index (EVLWI), pulmonary vascular permeability index (PVPI), and respiratory function were measured before and after CPB. RESULTS: The mortality rate was significantly lower in CBP group than in the control group (12.5% vs 33.3%, P<0.05). The patients in CPB group showed markedly earlier and significantly greater improvements in EVLWI, PVPI, PaO2/FiO, and respiratory function than the control patients (P<0.05). CONCLUSION: CBP can reduce EVLWI and PVPI, improve pulmonary compliance and oxygenation, and reduce mortality rate in patients with ARDSexp.

[Role of microRNA-141 in the regulation of synthesis of high mobility group protein B1 in THP-1 cells].

OBJECTIVE: To investigate the regulatory effect of microRNA-141 (miR-141) on expression of high mobility group protein B1(HMGB1) in human monocytes THP-1 cell line. METHODS: THP-1 cells were transfected with miR-141 mimic or inhibitor (100 nmol/L) for 48 hours with lipofectamine RNAi MAX. The levels of miR-141 and HMGB1 mRNA in the THP-1 cells were detected by real-time fluorescence quantitation reverse transcription-polymerase chain reaction (RT-PCR), and HMGB1 protein was determined with Western blotting. RESULTS: The levels of miR-141 could be up regulated (35.33±7.24 vs. 1.21±0.20, t=-8.408, P=0.010) or down regulated (0.55±0.12 vs 1.09±0.05, t=7.473, P=0.002) after being transfected with 100 nmol/L miR-141 mimic or inhibitor for 48 hours by lipofectamine RNAi MAX in THP-1, and the level of HMGB1 mRNA and protein decreased (mRNA: 0.43±0.06 vs. 0.97±0.08, t=9.760, P=0.001; protein: 0.63±0.12 vs. 1.00±0.11, t=2.991, P=0.040) or increased (mRNA: 2.13±0.11 vs. 1.16±0.13, t=-9.977, P=0.001; protein: 1.78±0.04 vs. 0.96±0.09, t=-13.778, P=0.000) simultaneously compared with the control group. CONCLUSIONS: miR-141 is involved in regulation of inflammation through HMGB1 gene and protein pathway, suggesting that miR-141 plays an important role in regulating immune cells during the inflammatory response.