Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Efficacy and Safety of Ciprofol Sedation in ICU Patients Undergoing Mechanical Ventilation: A Multicenter, Single-Blind, Randomized, Noninferiority Trial.

OBJECTIVES: To determine the effectiveness and safety of ciprofol for sedating patients in ICUs who required mechanical ventilation (MV). DESIGN: A multicenter, single-blind, randomized, noninferiority trial. SETTING: Twenty-one centers across China from December 2020 to June 2021. PATIENTS: A total of 135 ICU patients 18 to 80 years old with endotracheal intubation and undergoing MV, who were expected to require sedation for 6-24 hours. INTERVENTIONS: One hundred thirty-five ICU patients were randomly allocated into ciprofol ( n = 90) and propofol ( n = 45) groups in a 2:1 ratio. Ciprofol or propofol were IV infused at loading doses of 0.1 mg/kg or 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol or propofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr, to achieve the target sedation range of Richmond Agitation-Sedation Scale (+1 to -2). Besides, continuous IV remifentanil analgesia was administered (loading dose: 0.5-1 µg/kg, maintenance dose: 0.02-0.15 µg/kg/min). MEASUREMENTS AND MAIN RESULTS: Of the 135 patients enrolled, 129 completed the study. The primary endpoint-sedation success rates of ciprofol and propofol groups were 97.7% versus 97.8% in the full analysis set (FAS) and were both 100% in per-protocol set (PPS). The noninferiority margin was set as 8% and confirmed with a lower limit of two-sided 95% CI for the inter-group difference of -5.98% and -4.32% in the FAS and PPS groups. Patients who received ciprofol had a longer recovery time ( p = 0.003), but there were no differences in the remaining secondary endpoints (all p > 0.05). The occurrence rates of treatment-emergent adverse events (TEAEs) or drug-related TEAEs were not significantly different between the groups (all p > 0.05). CONCLUSIONS: Ciprofol was well tolerated, with a noninferior sedation profile to propofol in Chinese ICU patients undergoing MV for a period of 6-24 hours.

The Role of MicroRNAs in Predicting the Neurological Outcome of Patients with Subarachnoid Hemorrhage: A Meta-analysis.

Subarachnoid hemorrhage (SAH) is a hemorrhagic cerebrovascular disease with an extremely poor prognosis. The molecular mechanism and biomarkers involved in neurological outcome after SAH still need to be explored. This study assessed the microRNA expression characteristics of SAH patients with different neurological outcomes by meta-analysis. Public databases were searched from database inception until December 2022. The study reported that microRNA expression data in SAH patients with different neurological outcomes were included in the analysis. The differential expression of miRNAs was evaluated by meta-analysis. Overrepresentation analysis was performed for the targeted genes of significant miRNAs. The XGBoost algorithm was used to assess the predictive ability for neurological outcomes with clinical characteristics and significantly expressed miRNAs. Seven studies were finally included in the meta-analysis. The results showed that the levels of miR-152-3p (SMD: - 0.230; 95% CI - 0.389, - 0.070; padj = 0.041), miR-221-3p (SMD: - 0.286; 95% CI - 0.446, - 0.127; padj = 0.007), and miR-34a-5p (SMD: - 0.227; 95% CI - 0.386, - 0.067; padj = 0.041) were significantly lower in SAH patients with good neurological outcomes than in those with poor neurological outcomes. The PI3K-AKT signaling pathway may have an important role in neurological recovery after SAH. Based on the XGBoost algorithm, the neurological outcome could be accurately predicted with clinical characteristics plus the three miRNAs. The expression levels of miR-152-3p, miR-221-3p, and miR-34a-5p were significantly lower in patients with good neurological outcomes than in those with poor outcomes. These miRNAs can serve as potential predictive biomarkers for neurological outcomes. The molecular mechanism and biomarkers involved in neurological outcome after SAH still need to be explored. Our study analyzed microRNA expression characteristics of SAH patients with different neurological outcomes by meta-analysis. After analyze studies reporting the microRNA expression data in SAH patients with different neurological outcomes, results show that the levels of miR-152-3p, miR-221-3p, and miR-34a-5p were significantly lower in SAH patients with good neurological outcomes than in those with poor neurological outcomes. The PI3K-AKT signaling pathway may have an important role in neurological recovery after SAH. Based on the XGBoost algorithm, the neurological outcome could be accurately predicted with clinical characteristics plus the three miRNAs.

Downregulation of miR-497-5p prevents liver ischemia-reperfusion injury in association with MED1/TIMP-2 axis and the NF-κB pathway.

Liver ischemia-reperfusion (I/R) injury is a common clinical pathological phenomenon, which is accompanied by the occurrence in liver transplantation. However, the underlying mechanism is not yet fully understood. MicroRNAs (miRNAs) play an important role in liver I/R injury. Therefore, the study of miRNAs function will contribute a new biological marker diagnosis of liver I/R injury. This study aims to evaluate effects of miR-497-5p in liver I/R injury in mice. The related regulatory factors of miR-497-5p in liver I/R injury were predicted by bioinformatics analysis. Vascular occlusion was performed to establish the liver I/R injury animal models. Hypoxia/reoxygenation (H/R) was performed to establish the in vitro models. Hematoxylin-eosin (HE) staining was conducted to assess liver injury. The inflammatory factors were evaluated by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was adopted to assess the cell apoptosis. The expression of miR-497b-5p was increased in liver I/R injury. Knockdown of miR-497b-5p inhibited the production of inflammatory factors and cell apoptosis. Overexpression of mediator complex subunit 1 (MED1) and tissue inhibitor of metalloproteinase 2 (TIMP2) inhibited cell apoptosis to alleviate liver I/R injury. miR-497b-5p could activate the nuclear factor kappa-B (NF-κB) pathway by inhibiting the MED1/TIMP-2 axis to promote liver I/R injury. This study may provide a new strategy for the treatment of liver I/R injury.

Characteristics of lymphocyte subsets and cytokine profiles of patients with COVID-19.

BACKGROUND: Abnormalities of lymphocyte subsets and cytokine profiles have been observed in most patients with coronavirus disease (COVID-19). Here, we explore the role of lymphocyte subsets and cytokines on hospital admission in predicting the severity of COVID-19. METHODS: This study included 214 patients with COVID-19 who were treated at Chongqing University Three Gorges Hospital from January 19, 2020 to April 30, 2020. Any mutants were not detected in the studied patients. Patients were divided into non-intensive care unit (ICU) (mild/moderate) group and ICU (severe/critical) group, according to the severity of the disease. Clinical and laboratory data, including peripheral lymphocyte subsets and cytokines, were analyzed and compared. Logistic regression was used to analyze the predictive factors for ICU admission. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of selected indicators for the severity of COVID-19. RESULTS: Of the 214 patients enrolled, 161 were non-ICU patients and 53 were ICU patients. Lymphopenia was observed in nearly all of ICU patients (96.2%) and 84.5% of non-ICU patients on hospital admission. The absolute number of lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and natural killer (NK) cells were lower in ICU group (659.00 × 106/L, 417.00 × 106/L, 261.00 × 106/L, 140.00 × 106/L, 109.00 × 106/L, 102.00 × 106/L, respectively) than in non-ICU group (1063.00 × 109/L, 717.00 × 106/L, 432.00 × 106/L, 271.00 × 106/L, 133.00 × 106/L, 143.00 × 106/L, respectively). Interleukin (IL)-6 was significantly higher in ICU patients than in non-ICU patients (18.08 pg/mL vs. 3.13 pg/mL, P < 0.001). Multivariate logistic regression analysis showed that age (odds ratio: 1.067 [1.034-1.101]), diabetes mellitus (odds ratio: 9.154 [2.710-30.926]), CD3+ T cells (odds ratio: 0.996 [0.994-0.997]), and IL-6 (odds ratio: 1.006 [1.000-1.013]) were independent predictors for the development of severe disease. ROC curve analysis showed that the area under the ROC curve (AUC) of CD3+ T cells and IL-6 was 0.806 (0.737-0.874) and 0.785 (0.705-0.864), respectively, and the cutoff values were 510.50 × 106/L (sensitivity, 71.7%; specificity, 79.5%) and 6.58 pg/mL (77.4%, 74.5%), respectively. There were no statistical differences among all tested indicators of lymphocyte subsets and cytokines between severe group (n = 38) and critical group (n = 15) on hospital admission or ICU admission, respectively. CONCLUSIONS: The levels of lymphocyte subsets decreased and the level of IL-6 increased significantly in ICU COVID-19 patients compared with non-ICU COVID-19 patients. Therefore, the number of CD3+ T cells and the level of IL-6 on hospital admission may serve as predictive factors for identifying patients with wild-type virus infection who will have severe disease.

Circulating expression and clinical significance of LncRNA ANRIL in diabetic kidney disease.

BACKGROUND: Long noncoding RNA ANRIL has been found to be involved in the pathogenesis of diabetic kidney disease (DKD) and is expected to be a new target for prevention of DKD. However, the circulating expression and clinical significance of ANRIL in DKD patients is uncertain. This study aims to explore this issue. METHODS: The study consisted of 20 healthy controls, 22 T2DM patients (normalbuminuria) and 66 DKD patients (grouped as follows: microalbuminuria, n = 23; macroalbuminuria, n = 22 and renal dysfunction, n = 21). The expressions of ANRIL in peripheral whole blood of all participants were measured by RT-qPCR. RESULTS: The expression of ANRIL was significantly up-regulated in DKD patients (microalbuminuria, macroalbuminuria and renal dysfunction groups) than that in healthy control group. ANRIL was also over-expressed in macroalbuminuria and renal dysfunction groups in comparison with normalbuminuria group. ANRIL expression was positively correlated with Scr, BUN, CysC, urine ß2-MG and urine α1-MG; while negatively correlated with eGFR in DKD patients. In addition, ANRIL was the risk factor for DKD with OR value of 1.681. The AUC of ANRIL in identifying DKD was 0.922, and the sensitivity and specificity of DKD diagnosis were 83.3% and 90.5%, respectively. CONCLUSION: Our results indicated that highly expressed ANRIL in peripheral blood is associated with progression of DKD. Circulating ANRIL is an independent risk factor of DKD and has a highly predictive value in identifying DKD.

Utilizing reclassification to explore characteristics and prognosis of KDIGOSCr AKI subgroups: a retrospective analysis of a multicenter prospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is widespread in the intensive care unit (ICU) and affects patient prognosis. According to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, the absolute and relative increases of serum creatinine (Scr) are classified into the same stage. Whether the prognosis of the two types of patients is similar in the ICU remains unclear. METHODS: According to the absolute and relative increase of Scr, AKI stage 1 and stage 3 patients were divided into stage 1a and 1b, stage 3a and 3b groups, respectively. Their demographics, laboratory results, clinical characteristics, and outcomes were analyzed retrospectively. RESULTS: Of the 345 eligible cases, we analyzed stage 1 because stage 3a group had only one patient. Using 53 or 61.88 µmol/L as the reference Scr (Scrref), no significant differences were observed in ICU mortality (P53=0.076, P61.88=0.070) or renal replacement therapy (RRT) ratio, (P53=0.356, P61.88=0.471) between stage 1a and 1b, but stage 1b had longer ICU length of stay (LOS) than stage 1a (P53<0.001, P61.88=0.032). In the Kaplan-Meier survival analysis, no differences were observed in ICU mortality between stage 1a and 1b (P53=0.378, P61.88=0.255). In a multivariate analysis, respiratory failure [HR = 4.462 (95% CI 1.144-17.401), p = 0.031] and vasoactive drug therapy [HR = 4.023 (95% CI 1.584-10.216), p = 0.003] were found to be independently associated with increased risk of death. CONCLUSION: ICU LOS benefit was more prominent in KDIGOSCr AKI stage 1a patients than in stage 1 b. Further prospective studies with a larger sample size are necessary to confirm the effectiveness of reclassification.

Intestinal barrier dysfunction following traumatic brain injury.

Traumatic brain injury (TBI) can cause non-neurological injuries to other organs such as the intestine. Newer studies have shown that paracellular hyperpermeability is the basis of intestinal barrier dysfunction following TBI. Ischemia-reperfusion injury, inflammatory response, abnormal release of neurotransmitters and hormones, and malnutrition contribute to TBI-induced intestinal barrier dysfunction. Several interventions that may protect intestinal barrier function and promote the recovery of TBI have been proposed, but relevant studies are still limited. This review is to clarify the established mechanisms of intestinal barrier dysfunction following TBI and to describe the possible strategies to reduce or prevent intestinal barrier dysfunction.

Effect of incubation with lipopolysaccharide and interferon-γ on reactive astrogliosis.

Sepsis associated encephalopathy is a common complication of sepsis, but its pathogenesis of sepsis-associated encephalopathy remains unclear. Astrocytes are the most abundant brain glial cells, and reactive astrogliosis, a pathological response to central nervous system diseases, has a clear disease and disease-stage specificity. Functional changes of astrocytes are of great significance for the detection and prognosis of sepsis-associated encephalopathy. The pathogenesis of sepsis-associated encephalopathy was explored at the cellular level by examining astrogliosis in an in vitro model of sepsis-associated encephalopathy. Astrocytes of Wistar neonatal rats were incubated with different concentrations of lipopolysaccharide combined with interferon-γ. Cell viability was assessed by levels of tumor necrosis factor-α, interleukin-6, nitric oxide, reactive oxygen species, glial fibrillary acidic protein, changes of astrocyte morphology, and prevalence of apoptosis and necrosis. Compared with the control group, the cell viability of treated groups was decreased. The levels of tumor necrosis factor-α, interleukin-6, nitric oxide, reactive oxygen species, and glial fibrillary acidic protein were increased, hypertrophy of astrocytes was observed, and apoptosis was increased. The pathogenic outcomes of astrogliosis in sepsis-associated encephalopathy is discussed and a new tool provided to explore the pathogenesis of sepsis-associated encephalopathy at the cellular level.

Does training improve diagnostic accuracy and inter-rater agreement in applying the Berlin radiographic definition of acute respiratory distress syndrome? A multicenter prospective study.

BACKGROUND: Poor inter-rater reliability in chest radiograph interpretation has been reported in the context of acute respiratory distress syndrome (ARDS), although not for the Berlin definition of ARDS. We sought to examine the effect of training material on the accuracy and consistency of intensivists' chest radiograph interpretations for ARDS diagnosis. METHODS: We conducted a rater agreement study in which 286 intensivists (residents 41.3%, junior attending physicians 35.3%, and senior attending physician 23.4%) independently reviewed the same 12 chest radiographs developed by the ARDS Definition Task Force ("the panel") before and after training. Radiographic diagnoses by the panel were classified into the consistent (n = 4), equivocal (n = 4), and inconsistent (n = 4) categories and were used as a reference. The 1.5-hour training course attended by all 286 intensivists included introduction of the diagnostic rationale, and a subsequent in-depth discussion to reach consensus for all 12 radiographs. RESULTS: Overall diagnostic accuracy, which was defined as the percentage of chest radiographs that were interpreted correctly, improved but remained poor after training (42.0 ± 14.8% before training vs. 55.3 ± 23.4% after training, p < 0.001). Diagnostic sensitivity and specificity improved after training for all diagnostic categories (p < 0.001), with the exception of specificity for the equivocal category (p = 0.883). Diagnostic accuracy was higher for the consistent category than for the inconsistent and equivocal categories (p < 0.001). Comparisons of pre-training and post-training results revealed that inter-rater agreement was poor and did not improve after training, as assessed by overall agreement (0.450 ± 0.406 vs. 0.461 ± 0.575, p = 0.792), Fleiss's kappa (0.133 ± 0.575 vs. 0.178 ± 0.710, p = 0.405), and intraclass correlation coefficient (ICC; 0.219 vs. 0.276, p = 0.470). CONCLUSIONS: The radiographic diagnostic accuracy and inter-rater agreement were poor when the Berlin radiographic definition was used, and were not significantly improved by the training set of chest radiographs developed by the ARDS Definition Task Force. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (registration number NCT01704066 ) on 6 October 2012.

The effect of trimetazidine treatment in patients with type 2 diabetes undergoing percutaneous coronary intervention for AMI.

PURPOSE: Trimetazidine (TMZ) improves clinical outcomes in patients with chronic heart failure and stable coronary artery disease. No study has yet evaluated the efficacy of TMZ in type 2 diabetes patients with acute myocardial infarction (AMI) undergoing Percutaneous Coronary Intervention (PCI). We performed this study to evaluate the efficacy TMZ in DM patients with AMI undergoing PCI, such as the effect on reductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function. METHODS: For this randomized study, we enrolled 173 AMI patients with type 2 diabetes undergoing PCI between January 1, 2014, and January 1, 2016. All patients received aspirin and ticagrelor upon admission and throughout their hospitalization. Patients in the experimental group were treated with a loading dose of 60mg TMZ at admission, and 20 mg TMZ three times a day thereafter. 89 patients were included in experimental group, and 84 patients were included in control group. All patients received PCI treatments. The endpoints evaluated were serum creatine kinase and its isoenzyme (CK and CK-MB), cardiac troponin I (cTNI), serum creatinine (Cr), serum urea, blood glucose, serum glutamic pyruvic transaminase (ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimension (LA), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), and cardiac output (CO). FINDINGS: Compared with the control group, TMZ treatment significantly reduced CK and CK-MB on the second day in hospital ([797±582] vs. [1092±1114]; [80±60] vs. [105±100]; p=0.029, p=0.041, respectively), and cTNI after one and six days in hospital ([13.5±12.7] vs. [19.8±19.2]; [3.3±3.2] vs. [4.8±4.7]; two-tailed p=0.012). In addition, TMZ significantly lowered liver enzymes (ALT, AST) at 6days ([29.0±11.6] vs. [42.4±24.5]; [39.8±17.3] vs. [69.2±70.0]; two-tailed p=0.000), lowered glucose after 6days ([6.80±2.12] vs. [7.59±2.24]; p=0.019), and increased LVEF after ten to fourteen days ([58.4±8.6] vs. [54.9±8.4]; p=0.008). There were no significant effect on Cr and serum urea (p=0.988, p=0.569, respectively), nor on LA, LVEDD, and CO ([36.3±4.5] vs. [37.0±4.1], p=0.264; [52.0±4.9] vs. [53.1±4.6], p=0.128; [5.4±0.9] vs. [5.4±0.9], p=0.929, respectively). IMPLICATIONS: Among type 2 diabetic patients with AMI undergoing PCI, TMZ significantly reduces serum myocardial enzyme, improves liver function, adjusts blood glucose and improves cardiac function.

Consensus development of core competencies in intensive and critical care medicine training in China.

BACKGROUND: The aim of this study is to develop consensus on core competencies required for postgraduate training in intensive care medicine. METHODS: We used a combination of a modified Delphi method and a nominal group technique to create and modify the list of core competencies to ensure maximum consensus. Ideas were generated modified from Competency Based Training in Intensive Care Medicine in Europe collaboration (CoBaTrICE) core competencies. An online survey invited healthcare professionals, educators, and trainees to rate and comment on these competencies. The output from the online survey was edited and then reviewed by a nominal group of 13 intensive care professionals to identify each competence for importance. The resulting list was then recirculated in the nominal group for iterative rating. RESULTS: The online survey yielded a list of 199 competencies for nominal group reviewing. After five rounds of rating, 129 competencies entered the final set defined as core competencies. CONCLUSIONS: We have generated a set of core competencies using a consensus technique which can serve as an indicator for training program development.

[Changes of miRNA-17-5p, miRNA-21 and miRNA-106a level during rat kidney ischemia-reperfusion injury].

OBJECTIVE: Ischemia-reperfusion (I/R) is a main cause of acute kidney injury (AKI). The renal expression profiles of microRNA (miRNA) and time course of their changes after renal I/R were explored to screen acute AKI prognostic-related microRNAs and biomarkers. METHODS: The expression profile of miRNA was analyzed for detecting miRNAs in kidney after renal I/R injury. Real-time polymerase chain reaction (PCR) was performed to validate the results of microarray. And the relationship was examined between kidney injury and time course of changes in selected miRNAs. RESULTS: Twenty-one miRNAs were differentially expressed in kidney of rats with renal I/R injury. And 5 miRNAs had prominent differences. miR-17-5p, miR-21 and miR-106a were selected for further confirmation by quantitative real-time-PCR. And the results were consistent with those of microarry. During early stage (4 h) after I/R, the expression level of miR-17-5p significantly increased (P < 0.05). And it occurred earlier than those of BUN level and plasma concentration of neutrophil gelatinase-associated lipocalin (NGAL). Renal expressions of miR-21 and miR-106a were significantly elevated in ischemia 20 min and 30 min groups at 12 h and 24 h post-reperfusion (P < 0.01). And the trend was in accordance with those of BUN and NGAL. CONCLUSIONS: miR-21, miR-17-5p and miR-106a are differentially expressed during different phases of renal I/R injury. And miR-17-5p is more sensitive than BUN and NGAL so that it is a more ideal biomarker for AKI.

[Construction and application of sepsis bundle therapy management and practice program].

OBJECTIVE: To construct a bundled therapy management and practice program for sepsis and explore its clinical application effect. METHODS: (1) Construction of sepsis bundled therapy management and practice program: a project team was established to conduct literature review, select experts, compile and distribute questionnaires, organize, analyze expert opinions, and ensure quality control throughout the research process. From October to November 2022, expert letter consultation was carried out, and questionnaires were distributed and collected by on-site filling and WeChat. The Likert 5-point scale was used to rate each item. (2) Clinical application of the protocol: ninety patients with sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Xinjiang Medical University from January to July 2022 were retrospectively selected as the control group, and routine bundle treatment and nursing strategy for sepsis were adopted. Ninety patients with sepsis admitted from January to July 2023 were prospectively selected as the intervention group. Based on the treatment and nursing strategy of the control group, sepsis bundled therapy management and practice program constructed using the Delphi inquiry method was implemented. The completion rate of 1-hour, 3-hour and 6-hour bundle, the levels of inflammatory indicators at 1, 3, 7 days of treatment, and prognostic indicators were compared between the two groups. RESULTS: (1) Construction of sepsis bundled therapy management and practice program: the final plan consists of 4 primary indicators, 15 secondary indicators and 34 tertiary indicators. The response rates for both rounds of inquiry questionnaires were 100%. The coefficients of expert authority value were 0.948 and 0.940, respectively. The coefficient of variation for each item was 0-0.287 and 0-0.187, respectively. Kendall's W coefficients were 0.242 and 0.249, respectively, with statistical significances (all P < 0.05). (2) Clinical application of the protocol: there were no statistically significant differences in baseline data such as age, gender, infection site, pathogen species, duration of mechanical ventilation, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II) between the two groups. The completion rate of 1-hour, 3-hour and 6-hour bundle in the intervention group were higher than those in the control group (1-hour bundle completion rate: 53.30% vs. 21.10%, 3-hour bundle completion rate: 92.20% vs. 80.00%, 6-hour bundle completion rate: 88.89% vs. 65.56%, all P < 0.05). The levels of C-reactive protein (CRP), white blood cell count (WBC), procalcitonin (PCT), and interleukin-6 (IL-6) in two groups of patients showed statistically significant differences at different time points, between groups, and in interaction effects. Compared with the control group, the length of ICU stay in the intervention group was significantly shortened [days: 7.00 (4.00, 14.00) vs. 8.00 (7.00, 20.00), P < 0.01], and the hospitalization cost of ICU was significantly reduced [ten thousand yuan: 4.63 (3.36, 6.19) vs. 6.46 (3.32, 11.34), P < 0.05]. The 28-day mortality in the intervention group was lower than that in the control group (33.33% vs. 46.67%), but the difference was not statistically significant (P > 0.05). CONCLUSIONS: The constructed bundled therapy management and practice program for sepsis can improve the completion rate of bundle treatment, shorten the length of ICU stay of sepsis patients, reduce the hospitalization cost in ICU, and have a tendency to reduce the 28-day mortality.

[Construction and analysis of early warning and prediction model for risk factors of sepsis-associated encephalopathy].

OBJECTIVE: To investigate the epidemiological characteristics of sepsis-associated encephalopathy (SAE) in patients with sepsis, analyze its risk factors and build a prediction model, which provides evidence for early clinical identification of SAE patients and improvement of clinical outcomes. METHODS: A retrospective observational study was conducted. Sepsis patients admitted to the critical care medical center of the First Affiliated Hospital of Xinjiang Medical University from February 2022 to February 2023 were enrolled. According to whether SAE occurred, the patients were divided into sepsis group and SAE group. The 24 patients without sepsis in the same period were used as controls (non-sepsis group). Demographic data, relevant scores and laboratory test indicators at admission to intensive care unit (ICU), and prognostic indicators were collected. Univariate and multivariate Logistic regression analysis was used to analyze the risk factors for sepsis and SAE. Receiver operator characteristic curve (ROC curve) was drawn. The predictive value of each risk factor for sepsis and SAE. RESULTS: A total of 130 patients with sepsis were included, of which 52 had SAE, and the incidence of SAE was 40.00%. There were significant differences in the length of ICU stay and total length of stay among all groups, while there were no significant differences in hospitalization cost and mechanical ventilation time. Multivariate Logistic regression analysis showed that pulmonary infection [odds ratio (OR) = 46.817, 95% confidence interval (95%CI) was 5.624-389.757, P = 0.000], acute physiology and chronic health evaluation II (APACHE II: OR = 1.184, 95%CI was 1.032-1.358, P = 0.016), sequential organ failure assessment (SOFA: OR = 9.717, 95%CI was 2.618-36.068, P = 0.001), Charson comorbidity index (CCI: OR = 4.836, 95%CI was 1.860-12.577, P = 0.001), hemoglobin (Hb: OR = 0.893, 95%CI was 0.826-0.966, P = 0.005), glutamyltranspeptidase (OR = 1.026, 95%CI was 1.008-1.045, P = 0.006) were independent risk factors for sepsis in ICU patients. Pulmonary infection (OR = 28.795, 95%CI was 3.296-251.553, P = 0.002), APACHE II score (OR = 1.273, 95%CI was 1.104-1.467, P = 0.001), SOFA score (OR = 8.670, 95%CI was 2.330-32.261, P = 0.001), CCI (OR = 5.141, 95%CI was 1.961-13.475, P = 0.001), Hb (OR = 0.922, 95%CI was 0.857-0.993, P = 0.031), glutamyltranspeptidase (OR = 1.020, 95%CI was 1.002-1.038, P = 0.030) were independent risk factors for SAE in sepsis patients. ROC curve analysis showed that the area under the curve (AUC) of pulmonary infection, APACHE II score, SOFA score, CCI, Hb, and glutamyltranspeptidase for predicting sepsis were 0.792, 0.728, 0.987, 0.933, 0.720, and 0.699, respectively; the AUC of the combined prediction of the above 6 variables for sepsis was 1.000, with a sensitivity of 100% and a specificity of 100%. The AUC predicted by pulmonary infection, APACHE II score, SOFA score, CCI, and Hb for SAE were 0.776, 0.810, 0.907, 0.917, and 0.758, respectively; the AUC of the combined prediction of the above 5 variables for SAE was 0.975, with a sensitivity of 97.3% and a specificity of 93.1%. CONCLUSIONS: Sepsis is more severe when accompanied by encephalopathy. Pulmonary infection, Hb, APACHE II score, SOFA score and CCI were independent risk factors of SAE. The combination of the above five indicators has good predictive value for early screening and prevention of the disease.

MALAT1 DEREPRESSES MIR-433-3P-MEDIATED RPTOR SUPPRESSION TO IMPAIR AUTOPHAGY AND DRIVE PYROPTOSIS IN ENDOTOXEMIA.

ABSTRACT: Objective: Autophagy elevation in endotoxemia plays a protective role by negatively regulating the pyroptosis of vascular endothelial cells, but the molecular mechanisms are still poorly understood. The present study aimed to identify the mechanism underlying autophagy and pyroptosis in endotoxemia. Methods: Bioinformatics analysis and whole-gene transcriptome sequencing prediction were used to identify the endotoxemia-related lncRNA-miRNA-mRNA axis of interest. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) to mimic the inflammatory environment encountered in endotoxemia. Autophagy and pyroptosis of LPS-treated HUVECs were assessed in response to the knockdown of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1)/miR-433-3p (miRNA-433-3p)/RPTOR (regulatory-associated protein of mTOR). The binding affinity of MALAT1, miR-433-3p, and RPTOR was detected by RNA pull-down and luciferase activity assays. The endothelial cell-specific RPTOR knockout mice were developed and rendered septic using LPS induction to verify the role of RPTOR in autophagy, pyroptosis, and inflammatory response in vivo . Results: The in vitro experiments indicated that LPS could stimulate HUVECs to highly express RPTOR, and its knockdown enhanced cellular autophagy and restricted pyroptosis to curb inflammatory responses. Mechanically, MALAT1 is competitively bound to miR-433-3p to release RPTOR expression, thereby promoting pyroptosis and aggravating endotoxemia. In vivo experiments further confirmed that the knockdown of RPTOR activated autophagy and curtailed pyroptosis in septic mice. Conclusion: MALAT1 is highly expressed in endotoxemia. MALAT1 promotes RPTOR expression by competitively absorbing miR-433-3p, inhibits LPS-activated HUVEC cell autophagy, promotes cell death, enhances LPS-induced inflammatory activation of vascular endothelial cells, and ultimately promotes the progression of endotoxemia.

Characteristics of critically ill patients in ICUs in mainland China.

OBJECTIVES: We sought to describe the demographics, case mix, interventions, and clinical outcome of critically ill patients admitted to ICUs in Mainland China. DESIGN: A 2-month (July 1, 2009, to August 31, 2009) prospective, observational cohort study. SETTING: Twenty-two ICUs in Mainland China. PATIENTS: Adult patients admitted to participating ICUs during the study period with an ICU length of stay >24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, including demographics, underlying diseases, severity of illness, admission status, complications, intervention and treatment during ICU stay, and clinical outcome were recorded in case report form. The primary outcome measure was all-cause hospital mortality. Independent predictors for hospital mortality were determined with multivariate logistic regression analysis. One thousand two hundred ninety-seven patients met the inclusion criteria for the study, 821 (63.3%) were male, and mean age was 58.5 ± 19.2 yrs. Mean Acute Physiology and Chronic Health Evaluation II score was 18.0 ± 8.1, and mean Sequential Organ Failure Assessment score was 6.5 ± 3.8. One third of the patients were postoperative ICU admissions. Seven hundred sixty-five patients (59.0%) developed infections, followed by severe sepsis or septic shock (484, 37.3%), acute kidney injury (398, 30.7%), and acute lung injury/acute respiratory distress syndrome (351, 27.1%). Mechanical ventilation was used in almost three fourths of the patients, whereas any type of renal replacement therapy was used in 173 patients (13.3%). Hospital mortality was 20.3%. Multivariate logistic regression analysis found that Acute Physiology and Chronic Health Evaluation II score, solid tumor, severe sepsis/septic shock, acute lung injury/acute respiratory distress syndrome, and acute kidney injury were independent risk factors for hospital mortality. CONCLUSIONS: Critically ill patients in ICUs in Mainland China exhibited a case mix similar to those of Western countries, although there are significant differences in intensive care unit admission rates and disease severity between Western and Chinese ICUs.

[Research progress of sepsis-associated acute kidney injury based on Gut-Kidney axis].

Sepsis-associated acute kidney injury (SA-AKI), as a common renal dysfunction in sepsis, has become one of the major diseases threatening human health with increasing morbidity and mortality. Based on the theory of "gut-kidney axis", the intestine and kidney have a two-way synergistic relationship in sepsis. Intestinal flora imbalance, endogenous metabolite imbalance, and impaired endothelial barrier integrity are involved in renal injury, and the increase of renal inflammatory mediators interferes with the composition of intestinal microorganisms. Therefore, understanding the intestinal-renal crosstalk mechanism of SA-AKI will help to provide a potential basis for new treatment strategies for SA-AKI.

Dipeptidyl peptidase 3 is essential for maintaining osteoblastic differentiation under a high-glucose environment by inhibiting apoptosis, oxidative stress and inflammation through the modulation of the Keap1-Nrf2 pathway.

Dipeptidyl peptidase 3 (Dpp3) has emerged as a pivotal mediator of bone homeostasis and bone loss pathology. However, whether Dpp3 plays a role in diabetic osteoporosis has not been addressed. Therefore, this work explored the possible role of Dpp3 in osteoblast dysfunction evoked by high glucose (HG), a cellular model for studying diabetic osteoporosis in vitro. Dpp3 expression was decreased in the pre-osteoblast MC3T3-E1 during osteoblastic differentiation under the HG environment. The osteoblastic differentiation impaired by HG was reversed in Dpp3-overexpressing MC3T3-E1 cells. The migration and invasion of MC3T3-E1 cells impeded by HG were reversed by Dpp3 overexpression. Moreover, HG-evoked apoptosis, oxidative stress and inflammation were ameliorated in Dpp3-overexpressing MC3T3-E1 cells. A mechanistic study showed that Dpp3 up-regulated the activation of nuclear factor E2-related factor 2 (Nrf2) depending on Kelch-like ECH-associated protein 1 (Keap1). The blockade of Nrf2 reversed Dpp3-mediated effects on osteoblastic differentiation, apoptosis, oxidative stress and inflammation of HG-stimulated MC3T3-E1 cells. Therefore, Dpp3 plays an essential role in maintaining osteoblastic differentiation under a HG environment associated with the regulation of the Keap1-Nrf2 pathway. This work indicates a possible relationship between Dpp3 and diabetic osteoporosis.

Clinical Utility of the Sivelestat for the Treatment of ALI/ARDS: Moving on in the Controversy?

Acute respiratory distress syndrome (ARDS) is a serious condition that can arise following direct or indirect acute lung injury (ALI). It is heterogeneous and has a high mortality rate. Supportive care is the mainstay of treatment and there is no definitive pharmacological treatment as yet. In nonclinical studies, neutrophil elastase inhibitor sivelestat appears to show benefit in ARDS without inhibiting the host immune defense in cases of infection. In clinical studies, the efficacy of sivelestat in the treatment of ARDS remains controversial. The currently available evidence suggests that sivelestat may show some benefit in the treatment of ARDS, although large, randomized controlled trials are needed in specific pathophysiological conditions to explore these potential benefits.