The dual effects of dexmedetomidine on intestinal barrier and intestinal motility during sepsis.

BACKGROUND: Sepsis, characterized by dysregulated host responses to infection, remains a critical global health concern, with high morbidity and mortality rates. The gastrointestinal tract assumes a pivotal role in sepsis due to its dual functionality as a protective barrier against injurious agents and as a regulator of motility. Dexmedetomidine, an α2-adrenergic agonist commonly employed in critical care settings, exhibits promise in influencing the maintenance of intestinal barrier integrity during sepsis. However, its impact on intestinal motility, a crucial component of intestinal function, remains incompletely understood. METHODS: In this study, we investigated dexmedetomidine's multifaceted effects on intestinal barrier function and motility during sepsis using both in vitro and in vivo models. Sepsis was induced in Sprague-Dawley rats via cecal ligation and puncture. Rats were treated with dexmedetomidine post-cecal ligation and puncture, and various parameters were assessed to elucidate dexmedetomidine's impact. RESULTS: Our findings revealed a dichotomous influence of dexmedetomidine on intestinal physiology. In septic rats, dexmedetomidine administration resulted in improved intestinal barrier integrity, as evidenced by reduced mucosal hyper-permeability and morphological alterations. However, a contrasting effect was observed on intestinal motility, as dexmedetomidine treatment inhibited both the frequency and amplitude of contractions in isolated intestinal strips and decreased the distance of ink migration in vivo. Additionally, dexmedetomidine suppressed the secretion of pro-motility hormones while having no influence on hormones that inhibit intestinal peristalsis. CONCLUSION: The study revealed that during sepsis, dexmedetomidine exhibited protective effects on barrier integrity, although concurrently it hindered intestinal motility, partly attributed to its modulation of pro-motility hormone secretion. These findings underscore the necessity of a comprehensive understanding of dexmedetomidine's impact on multiple facets of gastrointestinal physiology in sepsis management, offering potential implications for therapeutic strategies and patient care.

Ductility Variation and Improvement of Strain-Hardening Cementitious Composites in Structural Utilization.

Strain-hardening cementitious composite (SHCC) has the obvious advantages of excellent material properties such as its high tensile and compressive strengths, high tensile strain capacity, and excellent durability against multi-cracking performance with very fine crack widths. In particular, the multi-cracking performance of SHCC during structural utilization is obviously reduced compared to that of SHCC in uniaxial tension tests using dumbbell-shaped specimens of small size. The corresponding tensile strain capacity of SHCC during structural utilization is, thus, significantly decreased compared to that of SHCC in uniaxial tension tests. However, the reduction in the ductility of SHCC during structural utilization has not been sufficiently understood, and further study is required. This paper presents an experimental investigation into the ductility variation of flexural-failed and shear-failed SHCC members as well as the ductility improvement of SHCC members with steel reinforcement compared with that of SHCC in uniaxial tension tests using small-sized specimens. This study focuses on not only the decrease in the crack elongation performance of the SHCC material during structural utilization but also the increase in the crack elongation performance of SHCC members with steel reinforcement. The results demonstrate that the crack elongation performance of flexural-failed and shear-failed SHCC members is significantly reduced compared to that of SHCC in the uniaxial tension tests. Moreover, it was confirmed that steel reinforcement can effectively improve the SHCC member, increasing the strain-hardening capacity and multi-cracking performance. The load-carrying capacity of the flexural-failed SHCC member with steel reinforcement seemed to increase linearly with an increase in the reinforcement ratio, accompanied by an increase in the distribution of multiple fine cracks in the flexural-failed SHCC member with steel reinforcement.

5-methylcytosine RNA modification regulators-based patterns and features of immune microenvironment in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease of the blood cell. The current therapies for AML are unsatisfactory and the molecular mechanisms underlying AML are unclear. 5-methylcytosine (m5C) is an important posttranscriptional modification of mRNA, and is involved in the regulation of mRNA stability, translation, and other aspects of RNA metabolism. However, based on our knowledge of published literature, the role of the m5C regulators has not been explored in AML till date. In this study, we clarified the expression and gene variants of m5C regulators in AML and found that most m5C regulators were differentially expressed and correlated with disease prognosis. We also found that the methylation status of certain m5C regulators (e.g., DNMT3A, DNMT3B) affects the survival of AML patients. Two m5C modification subtypes, and high- and low-risk subgroups identified based on the expression of m5C regulators showed significant differences in the prognosis as well as immune cell infiltration. In addition, most of the m5C regulators were found to be correlated with miRNA expression in AML, as well as IC50 values of many drugs. The miRNA and GSVA analysis were used to identify the different miRNAs and KEGG or hallmark pathways between high- and low-risk subgroups. We also built a prognostic model based on m5C regulators, which was validated by two GSE databases. To verify the reliability of our analysis and conclusions, qPCR was used to identify the expressions of m5C regulators between normal and AML. In summary, we comprehensively explored the molecular characteristics of m5C regulators and built a prognostic model in AML. We proposed new mechanistic insights into the role of m5C in multiple databases and clinical data, which may pave novel ways for the development of therapeutic strategies.

Performance of Single-Layer Lining Using Shotcrete and Reinforcement Ribs Employed for Supporting Large-Span Tunnel.

Single-layer tunnel lining using shotcrete has the significant advantages of reducing the tunnel excavation volume and saving construction materials, which has been gradually applied in tunnel construction. The high-performance concretes are generally adopted in single-layer tunnel lining for enhancing the bearing capacity of the tunnel lining, whereas the single-layer tunnel lining may still induce damages due to the adverse conditions such as shallow buried depth of the tunnel, and further study related to its application condition is thus required. This paper presents a study of the single-layer tunnel lining with shotcrete employed for supporting the large-span tunnel, in which the reinforcement ribs are also adopted in the single-layer lining for improving the lining stiffness and strength. The study is implemented using numerical simulation, focusing on the safety and performance variation of the single-layer tunnel lining influenced from the varied lining thicknesses and shallow buried depths of the tunnel. The results shows that the single-layer tunnel lining has the obvious advantage of toughness in significantly absorbing large deformation of surrounding rocks and improving the ability to resist lining cracking. The results also demonstrate that the single-layer tunnel lining with shotcrete and reinforcement ribs can safely support the large-span tunnel, in which the stability and safety of the large-span tunnel are confirmed from both the tunnel deformation and lining stresses. Moreover, the factors related to both the lining thickness and shallow buried depth of the tunnel have great influence on the single-layer tunnel lining with shotcrete and reinforcement ribs, in which the insufficient lining thickness and excessive shallow buried depth of the tunnel can induce the damages of the single-layer tunnel lining due to shotcrete stresses exceeding its strength. This study provides some references of employing the single-layer tunnel lining with shotcrete and reinforcement ribs for supporting large-span tunnel.

Performance Review of Strain-Hardening Cementitious Composites in Structural Applications.

Strain-hardening cementitious composites (SHCC) are an attractive construction material with obvious advantages of large strain capacity and high strength, as well as excellent workability and easy processing using conventional equipment. Moreover, SHCC can be designed with varied mix proportions in order to satisfy various requirements and expectations to overcome the shortages of existing construction materials. However, the behavior of SHCC in the structural application is varied from that of SHCC material, which is reviewed and presented in this paper, focusing on the flexural and shear behavior of the SHCC member and the SHCC layer used for strengthening reinforced concrete (RC). The reviewed results demonstrate that both the zero-span tensile behavior of the stress concentration and the uniaxial tensile behavior of the bending effect can influence the crack propagation patterns of multiple fine cracks in the SHCC strengthening layer, in which the crack distribution within the SHCC layer is limited near the existing crack in the RC substrate member in the zero-span tensile behavior. Moreover, the crack propagation patterns of the SHCC strengthening layer are changed with varied layer thicknesses, and the SHCC strengthening layer, even with a small thickness, can significantly increase the shear load carrying capacity of the shear strengthened RC member. This work provides the foundations for promoting SHCC material in the structural application of repairing or retrofitting concrete structures.

[Analysis of the incidence and related factors of hypothermia in patients with continuous renal replacement therapy].

OBJECTIVE: To investigate the incidence and risk factors of hypothermia in patients with acute renal injury (AKI) receiving continuous renal replacement therapy (CRRT), and to compare the effects of different heating methods on the incidence of hypothermia in patients with CRRT. METHODS: A prospective study was conducted. AKI patients with CRRT who were admitted to the department of critical care medicine of the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital) from January 2020 to December 2022 were enrolled as the study subjects. Patients were divided into dialysate heating group and reverse-piped heating group according to randomized numerical table method. Both groups were provided with reasonable treatment mode and parameter setting by the bedside physician according to the patient's specific condition. The dialysis heating group used the AsahiKASEI dialysis machine heating panel to heat the dialysis solution at 37 centigrade. The reverse-piped heating group used the Barkey blood heater from the Prismaflex CRRT system to heat the dialysis solution, and the heating line temperature was set at 41 centigrade. The patient's temperature was then continuously monitored. Hypothermia was defined as a temperature lower than 36 centigrade or a drop of more than 1 centigrade from the basal body temperature. The incidence and duration of hypothermia were compared between the two groups. Binary multivariate Logistic regression analysis was used to explore the influencing factors of hypothermia during CRRT in AKI patients. RESULTS: A total of 73 patients with AKI treated with CRRT were eventually enrolled, including 37 in the dialysate heating group and 36 in the reverse-piped heating group. The incidence of hypothermia in the dialysis heating group was significantly lower than that in the reverse-piped heating group [40.5% (15/37) vs. 69.4% (25/36), P < 0.05], and the hypothermia occurred later than that in the reverse-piped heating group (hours: 5.40±0.92 vs. 3.35±0.92, P < 0.01). Patients were divided into hypothermic and non-hypothermic groups based on the presence or absence of hypothermia, and a univariate analysis of all indicators showed a significant decrease in mean arterial pressure (MAP) in hypothermic patients (n = 40) compared with the non-hypothermic patients [n = 33; mmHg (1 mmHg ≈ 0.133 kPa): 77.45±12.47 vs. 94.42±14.51, P < 0.01], shock, administration of medium and high doses of vasoactive drug (medium dose: 0.2-0.5 µg×kg-1×min-1, high dose: > 0.5 µg×kg-1×min-1) and CRRT treatment were significantly increased [shock: 45.0% (18/40) vs. 6.1% (2/33), administration of medium and high doses of vasoactive drugs: 82.5% (33/40) vs. 18.2% (6/33), administration of CRRT (mL×kg-1×h-1): 51.50±9.38 vs. 38.42±10.97, all P < 0.05], there were also significant differences in CRRT heating types between the two groups [in the hypothermia group, the main heating method was the infusion line heating, which was 62.5% (25/40), while in the non-hypothermia group, the main heating method was the dialysate heating, which was 66.7% (22/33), P < 0.05]. Including the above indicators in a binary multivariate Logistic regression analysis, it was found that shock [odds ratio (OR) = 17.633, 95% confidence interval (95%CI) was 1.487-209.064], mid-to-high-dose vasoactive drug (OR = 24.320, 95%CI was 3.076-192.294), CRRT heating type (reverse-piped heating; OR = 13.316, 95%CI was 1.485-119.377), and CRRT treatment dose (OR = 1.130, 95%CI was 1.020-1.251) were risk factors for hypothermia during CRRT in AKI patients (all P < 0.05), while MAP was protective factor (OR = 0.922, 95%CI was 0.861-0.987, P < 0.05). CONCLUSIONS: AKI patients have a high incidence of hypothermia during CRRT treatment, and the incidence of hypothermia can be effectively reduced by heating CRRT treatment fluids. Shock, use of medium and high doses of vasoactive drug, CRRT heating type, and CRRT treatment dose are risk factors for hypothermia during CRRT in AKI patients, with MAP is a protective factor.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

A phosphatase-recruiting bispecific antibody-aptamer chimera for enhanced suppression of tumor growth.

The development of agents against abnormal activation of receptor tyrosine kinases (RTKs) for therapeutic interventions is in high demand. Using mesenchymal epithelial transition (Met) protein as a proof-of-concept RTK, here we developed a CD148-recruiting bispecific antibody-aptamer chimera for simultaneous inhibition of extra- and intra-cellular functions of Met in cancer cells. This chimera exhibited remarkable migration-suppressive and antiproliferative effects. This strategy is highly promising for developing kinase inhibitors for use in therapies of a broad range of cancers.

Targeted degradation of ABCG2 for reversing multidrug resistance by hypervalent bispecific gold nanoparticle-anchored aptamer chimeras.

Hypervalent bispecific gold nanoparticle-anchored aptamer chimeras (AuNP-APTACs) were designed as a new tool of lysosome-targeting chimeras (LYTACs) for efficient degradation of the ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) to reverse multidrug resistance (MDR) of cancer cells. The AuNP-APTACs could effectively increase the accumulation of drugs in drug-resistant cancer cells and provide comparable efficacy to small-molecule inhibitors. Thus, this new strategy provides a new way to reverse MDR, holding great promise in cancer therapy.

The Polo-Like Kinase 1-Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis.

The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms in vivo and in vitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated intestinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability in vitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in intestinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.

PLK1 protects intestinal barrier function in sepsis: A translational research.

BACKGROUND: Sepsis and its related complications are very challenging in the intensive care unit, among which intestinal barrier injury is a general manifestation. Polo-like kinase 1 (PLK1) is widely studied in cancer, while its role in sepsis is poorly understood. In this study, the efficiency of PLK1 as a marker of intestinal barrier function as well as a predictor of mortality in sepsis was evaluated. METHODS: The level of serum PLK1 was measured in septic patients (n = 51) and controls (n = 20); subsequently, its correlation with serum diamine oxidase (DAO), d-lactate, and endotoxin levels and its ability topredict mortality were analysed. The survival rate and barrier injury degree were also assessed in septic mice. RESULTS: Serum PLK1 levels were elevated in septic patients, were negatively correlated with serum DAO, d-lactate, and endotoxin levels, and had a high predictive value for 28-day mortality in patients. The serum PLK1 level in non-survivors was lower. The expression of PLK1 in the intestine was decreased in septic mice, and overexpression or inhibition of PLK1 alleviated or aggravated intestinal barrier injury, respectively, as evaluated by Chiu's score, serum levels of DAO and d-lactate, and expression of tight junction proteins. Overexpressing PLK1 also decreased the 72-hour death rate of septic mice. Further study also revealed the negative correlation of PLK1 and IL-6 in patients, and increasing or interfering with PLK1 expression reduced or increased the serum IL-6 level in mice. CONCLUSIONS: PLK1 plays a critical role in intestinal barrier function during sepsis, providing a novel perspective for sepsis therapy in the clinic.

ALTERATION IN SHEAR WAVE ELASTOGRAPHY IS ASSOCIATED WITH ACUTE KIDNEY INJURY: A PROSPECTIVE OBSERVATIONAL PILOT STUDY.

ABSTRACT: Background: Kidney stiffness could change during kidney disease. We hypothesize that acute kidney injury (AKI) would increase renal stiffness. Therefore, evaluating kidney Young's modulus (YM; a measure of tissue stiffness) using shear wave elastography (SWE) might help to diagnose AKI. Methods: This research was divided into two studies. Study A: Male C57BL/6 mice were used to observe kidney YM changes induced by sepsis-associated AKI, which was established by cecal ligation and puncture (CLP). Study B included 54 consecutive critically ill patients with or without AKI. Changes in renal YM were observed. Results: Study A: CLP mice showed a significantly higher kidney YM compared with the sham group. The YM gradually increased from CLP 0 hours to CLP 24 hours, and presented a fair relationship with the renal tubular injury score ( R2 = 0.71) and serum creatinine ( R2 = 0.73). Study B: YM was easily accessible, and the intraclass correlation coefficient ranged from 0.62 to 0.84. Kidney YM was higher in AKI patients and gradually increased from non-AKI to AKI III patients. Furthermore, the YM in the upper, middle, and lower poles of the renal cortex presented a fair relationship with kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin ( R2 ranging from 0.4 to 0.58), and the areas under the curve of the above five indicators for the diagnosis of AKI were 0.7, 0.73, 0.70, 0.74, and 0.79, respectively. Conclusion: SWE-derived estimates of renal stiffness are higher in AKI patients and sepsis-associated AKI mice. However, it has no advantage over NGAL and KIM-1. Trial Registration: Chinese Clinical Trial Registry No: ChiCTR2200061725. Retrospectively registered July 1, 2022, https://www.chictr.org.cn/showproj.aspx?proj=169359 .

SPECKLE TRACKING QUANTIFICATION PARASTERNAL INTERCOSTAL MUSCLE LONGITUDINAL STRAIN TO PREDICT WEANING OUTCOMES: A MULTICENTRIC OBSERVATIONAL STUDY.

ABSTRACT: Background: The purpose of this study was to determine the feasibility, reliability, and reproducibility of parasternal intercostal muscle longitudinal strain (LSim) quantification by speckle tracking and the value of maximal LSim to predict weaning outcomes. Methods: This study was divided into three phases. Phases 1 and 2 comprehended prospective observational programs to evaluate the feasibility, reliability, and repeatability of speckle tracking to assess LSim in healthy subjects and mechanically ventilated patients. Phase 3 was a multicenter retrospective study to evaluate the value of maximal LSim, intercostal muscle thickening fraction (TFim), diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index to predict weaning outcomes. Results: A total of 25 healthy subjects and 20 mechanically ventilated patients were enrolled in phases 1 and 2, respectively. Maximal LSim was easily accessible, and the intraoperator reliability and interoperator reliability were excellent in eupnea, deep breathing, and mechanical ventilation. The intraclass correlation coefficient ranged from 0.85 to 0.96. Moreover, 83 patients were included in phase 3. The areas under the receiver operating characteristic curve of maximal LSim, TFim, diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index were 0.91, 0.79, 0.71, 0.70, and 0.78 for the prediction of successful weaning, respectively. The best cutoff values of LSim and TFim were >-6% (sensitivity, 100%; specificity, 64.71%) and <7.6% (sensitivity, 100%; specificity, 50.98%), respectively. Conclusions: The quantification of LSim by speckle tracking was easily achievable in healthy subjects and mechanically ventilated patients and presented a higher predictive value for weaning success compared with conventional weaning parameters. Trial registration no. ChiCTR2100049817.

Comparison of assessment of diaphragm function using speckle tracking between patients with successful and failed weaning: a multicentre, observational, pilot study.

BACKGROUND: Diaphragmatic ultrasound has been increasingly used to evaluate diaphragm function. However, current diaphragmatic ultrasound parameters provide indirect estimates of diaphragmatic contractile function, and the predictive value is controversial. Two-dimensional (2D) speckle tracking is an effective technology for measuring tissue deformation and can be used to measure diaphragm longitudinal strain (DLS) to assess diaphragm function. The purpose of this study was to determine the feasibility and reproducibility of DLS quantification by 2D speckle tracking and to determine whether maximal DLS could be used to predict weaning outcomes. METHODS: This study was performed in the intensive care unit of two teaching hospitals, and was divided into two studies. Study A was a prospective study to evaluate the feasibility, reliability, and repeatability of speckle tracking in assessing DLS in healthy subjects and mechanically ventilated patients. Study B was a multicentre retrospective study to assess the use of maximal DLS measured by speckle tracking in predicting weaning outcomes. RESULTS: Twenty-five healthy subjects and twenty mechanically ventilated patients were enrolled in Study A. Diaphragmatic speckle tracking was easily accessible. The intra- and interoperator reliability were good to excellent under conditions of eupnoea, deep breathing, and mechanical ventilation. The intraclass correlation coefficient (ICC) ranged from 0.78 to 0.95. Ninety-six patients (fifty-nine patients were successfully weaned) were included in Study B. DLS exhibited a fair linear relationship with both the diaphragmatic thickening fraction (DTF) (R2 = 0.73, p < 0.0001) and diaphragmatic excursion (DE) (R2 = 0.61, p < 0.0001). For the prediction of successful weaning, the areas under the ROC curves of DLS, diaphragmatic thickening fraction DTF, RSBI, and DE were 0.794, 0.794, 0.723, and 0.728, respectively. The best cut-off value for predicting the weaning success of DLS was less than -21%, which had the highest sensitivity of 89.19% and specificity of 64.41%. CONCLUSIONS: Diaphragmatic strain quantification using speckle tracking is easy to obtain in healthy subjects and mechanically ventilated patients and has a high predictive value for mechanical weaning. However, this method offers no advantage over RSBI. Future research should assess its value as a predictor of weaning. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Register (ChiCTR), ChiCTR2100049816. Registered 10 August 2021. http://www.chictr.org.cn/showproj.aspx?proj=131790.

PLK1 protects intestinal barrier function during sepsis by targeting mitochondrial dynamics through TANK-NF-κB signalling.

BACKGROUND: Intestinal barrier integrity in the pathogenesis of sepsis is critical. Despite an abundance of evidence, the molecular mechanism of the intestinal barrier in sepsis pathology remains unclear. Here, we report a protective role of polo-like kinase 1 (PLK1) in intestinal barrier integrity during sepsis. METHODS: Mice with PLK1 overexpression (CAG-PLK1 mice) or PLK1 inhibition (BI2536-treated mice) underwent caecal ligation and puncture (CLP) to establish a sepsis model. The intestinal barrier function, apoptosis in the intestinal epithelium, mitochondrial function and NF-κB signalling activity were evaluated. To suppress the activation of NF-κB signalling, the NF-κB inhibitor PDTC, was administered. The Caco-2 cell line was chosen to establish an intestinal epithelial injury model in vitro. RESULTS: Sepsis destroyed intestinal barrier function, induced excessive apoptosis in the intestinal epithelium, and disrupted the balance of mitochondrial dynamics in wild-type mice. PLK1 overexpression alleviated sepsis-induced damage to the intestinal epithelium by inhibiting the activation of NF-κB signalling. PLK1 colocalized and interacted with TANK in Caco-2 cells. Transfecting Caco-2 cells with TANK-SiRNA suppressed NF-κB signalling and ameliorated mitochondrial dysfunction, apoptosis and the high permeability of cells induced by lipopolysaccharide (LPS). Furthermore, TANK overexpression impaired the protective effect of PLK1 on LPS-induced injuries in Caco-2 cells. CONCLUSION: Our findings reveal that the PLK1/TANK/NF-κB axis plays a crucial role in sepsis-induced intestinal barrier dysfunction by regulating mitochondrial dynamics and apoptosis in the intestinal epithelium and might be a potential therapeutic target in the clinic.

[Effect of different connection schemes of continuous renal replacement therapy and extracorporeal membrane oxygenation on arterial and venous pressure: an in vitro and in vivo study].

OBJECTIVE: To investigate the effects of different connection schemes of continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) on arterial pressure (PA), venous pressure (PV), and transmembrane pressure (TMP), and to provide a theoretical basis for choosing a suitable connection scheme. METHODS: (1) In vitro study: the different connection schemes of CRRT and ECMO were simulated and divided into 6 schemes according to the connection between CRRT and ECMO circuits at different positions. Scheme A: connected to the front and back points of the oxygenator; scheme B: connected to the points behind and in front of the oxygenator; scheme C: connected to the points in front of the oxygenator and in front of the centrifugal pump; scheme D: connected to the points behind the oxygenator and in front of the centrifugal pump; scheme E: connected to the points in front of the oxygenator and the return catheter; scheme F: connected to the points after the oxygenator and the return catheter. Each set of ECMO circuits was measured 5 times under each connection scheme and different flow rates (2, 3, 4, 5, 5.5 L/min). Six ECMO circuits for a total of 30 measurements, and the PA, PV, and TMP of the 6 schemes were compared. (2) In vivo study: the patients who were treated with ECMO combined with CRRT in the department of critical care medicine of the First Affiliated Hospital of Wannan Medical College from August 2017 to August 2021 changed the connection scheme due to high PA or PV (from scheme A or B to scheme E or F) were retrospectively analyzed. The changes of PA and PV before and after changing the scheme were compared. RESULTS: (1) In vitro study results: there was no significant difference in PA between schemes A and B, C and D, E and F under different ECMO blood flow (2-5.5 L/min). The PA of schemes C and D was the lowest, followed by schemes E and F. PV of scheme B was higher than that of scheme A under different ECMO blood flow (2-5.5 L/min). There was no significant difference in PV between schemes C and D, E and F under high ECMO blood flow (3-5.5 L/min), and the absolute value of PV was lowest in schemes E and F. Compared with schemes A and B [partial PA > 300 mmHg (1 mmHg ≈ 0.133 kPa) at high flow rate], C and D (partial PV > 350 mmHg at high flow rate), schemes E and F were more reasonable connection schemes. TMP was negative in schemes C and D at ECMO blood flow of 5 L/min and 5.5 L/min (mmHg; 5 L/min: scheme C was -29.14±11.42, scheme D was -42.45±15.70; 5.5 L/min: scheme C was -35.75±13.21, scheme D was -41.58±15.42), which indicated the presence of dialysate reverse filtration. Most of the differences in TMP among schemes A, B, E, and F under different ECMO blood flow (2-5.5 L/min) were statistically significant, and the absolute value of mean fluctuation was 9.89-49.55 mmHg, all within the normal range. (2) In vivo study results: a total of 10 patients who changed the connection scheme (from scheme A or B to E or F) due to high PA or PV were enrolled, including 8 males and 2 females; 7 cases of venous-arterial ECMO (VA-ECMO) and 3 cases of venous-venous ECMO (VV-ECMO), all used continuous veno-venous hemodiafiltration (CVVHDF) mode. After changing the scheme, both PA and PV decreased significantly as compared with those before changing [PA (mmHg): 244.00±22.58 vs. 257.20±21.92, PV (mmHg): 257.20±18.43 vs. 326.40±15.41, both P < 0.01], and PV decreased more significantly than PA [difference (mmHg): 69.20±6.55 vs. 13.20±5.45, P < 0.01]. CONCLUSION: For patients treated with ECMO in combination with CRRT, the scheme of connecting the access line of CRRT to the pre-oxygenator or post-oxygenator and connecting the return line to the point of the return catheter can significantly reduce PA and PV and maintains normal CRRT operation even running high-flow ECMO.

Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial.

PURPOSE: Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP. METHODS: We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission. RESULTS: A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI - 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%). CONCLUSION: The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

Effect of Dexmedetomidine on Intestinal Barrier in Patients Undergoing Gastrointestinal Surgery-A Single-Center Randomized Clinical Trial.

INTRODUCTION: Gastrointestinal failure results in death in critically ill patients. This study aimed to explore the effect of dexmedetomidine (DEX) on intestinal barrier function and its mechanism in critically ill patients undergoing gastrointestinal surgery. METHODS: Patients undergoing gastrointestinal surgery were randomized into the DEX group (n = 21) or midazolam (MID) group (n = 21). Sufentanil was used for analgesia in both groups. In the DEX group, DEX was loaded (1 µg/kg) before sedation and infused (0.7 µg/kg/h) during sedation. In the MID group, MID was loaded (0.05 mg/kg) before sedation and infused (0.1 mg/kg/h) during sedation. The mean arterial pressure , heart rate , borborygmus resumption time , first defecation time, length of intensive care unit stay, and length of hospital stay were observed. The diamine oxidase (DAO), D-lactate , TNF-α, IL-6, and α7nAChR levels in plasma or hemocytes were detected before the start of sedation (0 h) and after sedation (24 h). RESULTS: No significant differences in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were noted (P > 0.05). The mean arterial pressure between 0 h and 24 h showed no significant difference between the groups (P > 0.05), but the heart rate was significantly lower in the DEX group (P = 0.042). The borborygmus resumption time was significantly earlier in the DEX group (P = 0.034). The lengths of intensive care unit stay (P = 0.016) and hospital stay (P = 0.031) were significantly shorter in the DEX group. The TNF-α level in the DEX group was lower at 24 h than 0 h. The D-lactate level was significantly lower in the DEX group than the MID group at 24 h (P = 0.016). The expression of α7nAChR in the DEX group was significantly higher at 24 h than 0 h (P < 0.05). CONCLUSIONS: DEX maintained intestinal barrier integrity in patients undergoing gastrointestinal surgery through the cholinergic anti-inflammatory pathway.

Development of a nomogram for prediction of postoperative sore throat in patients under general anaesthesia: a single-centre, prospective, observational study.

OBJECTIVES: Postoperative sore throat (POST) is very common in patients under general anaesthesia. However, there is no effective clinical predictive model for reducing its occurrence. The objective of this study was to estimate the risk factors for POST in patients after general anaesthesia by designing a nomogram. DESIGN: A prospective study. SETTING: This study was conducted in a large tertiary hospital. PARTICIPANTS: Patients aged 18-85 years old who received general anaesthesia with either an endotracheal tube or supraglottic airway and of American Society of Anesthesiologists classification level Ⅰ-III. RESULTS: A total of 442 patients were enrolled in this study, with a POST incidence of 44.1%. The results showed that younger age (≤55 years), surgical site (head and neck surgery), duration of anaesthesia (≥4 hours) and history of chronic pharyngitis were independent risk factors for POST in general anaesthesia patients. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the nomogram. The area under the ROC curve was 0.784 and the C-index was 0.779. CONCLUSION: A nomogram combining age, surgical site, duration of anaesthesia and history of chronic pharyngitis is potentially useful in predicting POST under general anaesthesia. TRIAL REGISTRATION NUMBER: ChiCTR-ROC-17013258; Post-results.