Rationale and Design of the IMPROVE Trial: A Multicenter, Randomized, Controlled, Open-label, Blinded-endpoint Trial Assessing the Efficacy of Remote Ischemic Conditioning in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting.

INTRODUCTION: Despite the appearance of off-pump coronary artery bypass grafting (CABG), ischemia-reperfusion injury (IRI) in the perioperative period still arouses concerns of clinicians. Remote ischemic conditioning (RIC) is the process of repeated ischemia and reperfusion in the peripheral vessels, which is proven to reduce IRI in vital organs. However, the effect of RIC in patients undergoing off-pump CABG is still unclear. METHODS: This IMPROVE trial is a national, multicenter, randomized, controlled, open-label, blinded-endpoint clinical trial designed to assess whether RIC intervention can improve short-term prognosis of patients undergoing off-pump CABG. It plans to enroll 648 patients who will be randomly assigned into a RIC group or control group. Patients in the RIC group will receive four cycles of 5 min of pressurization (about 200 mmHg) and 5 min of rest in the 3 days before and 7 days after the surgery. PLANNED OUTCOMES: The primary outcome is the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) within the 3-month follow-up. MACCE is defined as all-cause death, myocardial infarction, stroke, and coronary revascularization surgery. CLINICAL TRIAL REGISTRATION: NCT06141525 (ClinicalTrials.gov).

RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.

The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.

Prevalence and risk factors for colonisation and infection with carbapenem-resistant Enterobacterales in intensive care units: A prospective multicentre study.

OBJECTIVES: This study aimed to investigate the prevalence and risk factors for carbapenem-resistant Enterobacterales colonisation/infection at admission and acquisition among patients admitted to the intensive care unit. RESEARCH METHODOLOGY/DESIGN: A prospective and multicentre study. SETTING: This study was conducted in 24 intensive care units in Anhui, China. MAIN OUTCOME MEASURES: Demographic and clinical data were collected, and rectal carbapenem-resistant Enterobacterales colonisation was detected by active screening. Multivariate logistic regression models were used to analyse factors associated with colonisation/infection with carbapenem-resistant Enterobacterales at admission and acquisition during the intensive care unit stay. RESULTS: There were 1133 intensive care unit patients included in this study. In total, 5.9% of patients with carbapenem-resistant Enterobacterales colonisation/infection at admission, and of which 56.7% were colonisations. Besides, 8.5% of patients acquired carbapenem-resistant Enterobacterales colonisation/infection during the intensive care stay, and of which 67.6% were colonisations. At admission, transfer from another hospital, admission to an intensive care unit within one year, colonisation/infection/epidemiological link with carbapenem-resistant Enterobacterales within one year, and exposure to any antibiotics within three months were risk factors for colonisation/infection with carbapenem-resistant Enterobacterales. During the intensive care stay, renal disease, an epidemiological link with carbapenem-resistant Enterobacterales, exposure to carbapenems and beta-lactams/beta-lactamase inhibitors, and intensive care stay of three weeks or longer were associated with acquisition. CONCLUSION: The prevalence of colonisation/infection with carbapenem-resistant Enterobacterales in intensive care units is of great concern and should be monitored systematically. Particularly for the 8.5% prevalence of carbapenem-resistant Enterobacterales acquisition during the intensive care stay needs enhanced infection prevention and control measures in these setting. Surveillance of colonisation/infection with carbapenem-resistant Enterobacterales at admission and during the patient's stay represents an early identification tool to prevent further transmission of carbapenem-resistant Enterobacterales. IMPLICATIONS FOR CLINICAL PRACTICE: Carbapenem-resistant Enterobacterales colonization screening at admission and during the patient's stay is an important tool to control carbapenem-resistant Enterobacterales spread in intensive care units.

Serum CIRP increases the risk of acute kidney injury after cardiac surgery.

Introduction: Acute kidney injury (AKI) is a frequent perioperative complication. The underlying mechanisms of cardiac surgery-associated AKI are still not completely elucidated. Cold-induced RNA-binding protein (CIRP) has been subsequently found to be regulated by various stress conditions. During cardiac surgery and cardiopulmonary bypass (CPB), the host is subjected to hypothermia and inadequate organ perfusion, resulting in an upregulation of CIRP secretion. The aim of this study is to evaluate the role of elevated extracellular CIRP level as a contributing factor in the development of AKI. Methods: A total of 292 patients who underwent cardiac surgery were retrospectively enrolled and their serum samples were collected preoperative and postoperative. Demographic data, intraoperative data, in-hospital outcomes, and the occurrence of AKI were also collected for the patients. The correlation between CIRP and intraoperative procedures, as well as its association with postoperative outcomes were analyzed. Results: In multivariable analysis, higher ΔCIRP (p = 0.036) and body mass index (p = 0.015) were independent risk factors for postoperative AKI. Meanwhile, patients with postoperative AKI exhibited lower survival rate in 2-year follow-up (p = 0.008). Compared to off-pump coronary artery bypass grafting surgery, patients who underwent on-pump coronary artery bypass grafting, valve surgery, aortic dissection and other surgery showed higher ΔCIRP, measuring 1,093, 666, 914 and 258 pg/mL, respectively (p < 0.001). The levels of ΔCIRP were significantly higher in patients who underwent CPB compared to those who did not (793.0 ± 648.7 vs. 149.5 ± 289.1 pg/mL, p < 0.001). Correlation analysis revealed a positive correlation between ΔCIRP levels and the duration of CPB (r = 0.502, p < 0.001). Patients with higher CIRP levels are at greater risk of postoperative AKI (OR: 1.67, p = 0.032), especially the stage 2-3 AKI (OR: 2.11, p = 0.037). Conclusion: CIRP secretion increases with prolonged CPB time after cardiac surgery, and CIRP secretion is positively correlated with the duration of CPB. Cardiac surgeries with CPB exhibited significantly higher levels of CIRP compared to non-CPB surgeries. Elevation of CIRP level is an independent risk factor for the incidence of AKI, especially the severe AKI, and were associated with adverse in-hospital outcomes.

Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells.

Acute myeloid leukemia (AML) is a polyclonal and heterogeneous hematological malignancy. Relapse and refractory after induction chemotherapy are still challenges for curing AML. Leukemia stem cells (LSCs), accepted to originate from hematopoietic stem/precursor cells, are the main root of leukemogenesis and drug resistance. LSCs are dynamic derivations and possess various elusive resistance mechanisms. In this review, we summarized different primary resistance and remolding mechanisms of LSCs after chemotherapy, as well as the indispensable role of the bone marrow microenvironment on LSCs resistance. Through a detailed and comprehensive review of the spectacle of LSCs resistance, it can provide better strategies for future researches on eradicating LSCs and clinical treatment of AML.