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.

Sustained visual attention improves visuomotor timing.

Relative to audition, vision is considered much less trustworthy in sensorimotor timing such as synchronizing finger movements with a temporally regular sequence. Visuomotor timing requires maintaining attention over time, whereas the sustained visual attention may not be well held in conventional visuomotor timing task settings where flashing visual stimuli consisted of a briefly presented flash and a long blank period. In the present study, the potential attentional lapses in time due to the disappearance of the flash were carefully controlled in Experiment 1 by changing the color of the flash instead of its disappearance, or in Experiment 2 by adding an additional continuously presented fixation point serving as an external attentional cue when the flash disappeared. Improvement of visuomotor timing performance was found in both experiments. The finding suggests a role of enhanced sustained visual attention in improving visuomotor timing, by which vision could also be a trustworthy modality for processing temporal information in sensorimotor interactions.

Lipocalin 10 as a New Prognostic Biomarker in Sepsis-Induced Myocardial Dysfunction and Mortality: A Pilot Study.

INTRODUCTION: Sepsis-induced myocardial dysfunction (SIMD) is the most common complications of sepsis and septic shock with extremely high incidence and mortality. Lipocalin 10 (Lcn10) has recently been identified as a potential biomarker for heart failure, yet its relation to sepsis has not been investigated. The purpose of this study was to explore whether circulating Lcn10 could be used as a prognostic tool in patients with SIMD. METHODS: In this single-center observational pilot study, seventy-five sepsis patients were enrolled after sepsis diagnosis or ICU admission (45.3% female, median age 60 years), and 35 patients (46.7%) developed myocardial dysfunction. Serum Lcn10 levels of septic patients were measured using the enzyme-linked immunosorbent assay (ELISA) at the time of admission. Other biomarkers of cardiac function and Lcn10 concentration were compared between SIMD and non-SIMD groups. RESULTS: We observed that the median Lcn10 levels were 2.780 ng/mL in patients with SIMD and 2.075 ng/mL in patients without SIMD (P < 0.05). The area under the receiver operating characteristic (ROC) curve for the diagnosis of SIMD was 0.797 (P < 0.05). In addition, elevated serum Lcn10 levels at the time of admission were positively associated with 28-day mortality in septic patients. CONCLUSIONS: Our study indicates that circulating Lcn10 levels may serve as a novel biomarker for the diagnosis and prognosis of myocardial dysfunction induced by sepsis. An additional large multicenter study may be warranted to confirm the findings of this study.

Association of different Candida species with catheter-related candidemia, and the potential antifungal treatments against their adhesion properties and biofilm-forming capabilities.

BACKGROUND: To compare the adhesion properties and biofilm-forming capabilities of 27 Candida isolates obtained from catheter-related candidemia patients and to evaluate the inhibitory effects of antifungal agents on different Candida species. MATERIAL AND METHODS: Seven C. albicans, six C. parapsilosis, five C. guilliermondii, five C. tropicalis, and four C. glabrata clinical isolates were investigated. We quantified the adherence of these Candida species by flow cytometric method and evaluated the formation of biofilms by XTT reduction and crystal violet methods. Actions of micafungin (MF), fluconazole (FZ), and N-acetylcysteine (NAC) on the adhesion and biofilm formation of different Candida species were determined. RESULTS: Non-albicans Candida species were demonstrated to have stronger adhesion abilities compared with C. albicans. The biofilm-forming capabilities of different Candida species were varied considerably, and the degree of biofilm formation might be affected by different assay approaches. Interestingly, C. parapsilosis displayed the highest biofilm formation abilities, while C. glabrata exhibited the lowest total biomass and metabolic activity. Furthermore, the inhibitory activities of MF, FZ, and NAC on fungal adhesion and biofilm formation were evaluated, and the results indicated that MF could reduce the adhesion ability and biofilm metabolism more significantly (p < 0.05), and its antifungal activity was elevated in a dose-dependent manner. CONCLUSION: Non-albicans Candida species, especially C. guilliermondii, C. tropicalis, and C. parapsilosis, exhibited higher adhesion ability in catheter-related candidemia patients. However, these Candida species had varied biofilm-forming capabilities. MF tended to have stronger inhibitory effects against both adhesion and biofilm formation of different Candida species.

TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury.

OBJECTIVE: Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) has strong anti-inflammatory properties. However, it is unknown whether increased TIPE2 is protective against lipopolysaccharide (LPS)-induced ALI. In the current study, we aimed to investigate whether increased TIPE2 can exert protective effects in a mouse model of ALI induced by LPS. METHODS: We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Three weeks later, ALI was induced by intratracheal injection of LPS into BALB/c mice. Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. RESULTS: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. Moreover, TIPE2 overexpression markedly attenuated lung inflammation, as evidenced by the downregulation of polymorphonuclear neutrophils (PMNs) in the BALF, lung MPO activity, and pro-inflammatory cytokine levels in the serum. Moreover, TIPE2 overexpression not only dramatically prevented LPS-induced pulmonary cell apoptosis in mice but also blocked LPS-activated JNK phosphorylation and NF-κB p65 nuclear translocation. CONCLUSIONS: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI.

The Regulation of GluN2A by Endogenous and Exogenous Regulators in the Central Nervous System.

The NMDA receptor is the most widely studied ionotropic glutamate receptor, and it is central to many physiological and pathophysiological processes in the central nervous system. GluN2A is one of the two main types of GluN2 NMDA receptor subunits in the forebrain. The proper activity of GluN2A is important to brain function, as the abnormal regulation of GluN2A may induce some neuropsychiatric disorders. This review will examine the regulation of GluN2A by endogenous and exogenous regulators in the central nervous system.

N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats.

BACKGROUND: Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes. METHODS: Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R). RESULTS: NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2-, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-ß-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA. CONCLUSIONS: Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.

Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: role of the PI3K/Akt and JAK2/STAT3 pathways.

Patients with diabetes are vulnerable to MI/R (myocardial ischaemia/reperfusion) injury, but are not responsive to IPostC (ischaemic post-conditioning) which activates PI3K (phosphoinositide 3-kinase)/Akt (also known as PKB or protein kinase B) and JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathways to confer cardioprotection. We hypothesized that increased cardiac PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K/Akt, is responsible for the loss of diabetic heart sensitivity to IPostC cardioprotecton. In STZ (streptozotocin)-induced Type 1 diabetic rats subjected to MI/R (30 min coronary occlusion and 120 min reperfusion), the post-ischaemic myocardial infarct size, CK-MB (creatine kinase-MB) and 15-F2t-isoprostane release, as well as cardiac PTEN expression were significantly higher than those in non-diabetic controls, concomitant with more severe cardiac dysfunction and lower cardiac Akt, STAT3 and GSK-3ß (glycogen synthase kinase 3ß) phosphorylation. IPostC significantly attenuated post-ischaemic infarct size, decreased PTEN expression and further increased Akt, STAT3 and GSK-3ß phosphorylation in non-diabetic, but not in diabetic rats. Application of the PTEN inhibitor BpV (bisperoxovanadium) (1.0 mg/kg) restored IPostC cardioprotection in diabetic rats. HPostC (hypoxic post-conditioning) in combination with PTEN gene knockdown, but not HPostC alone, significantly reduced H/R (hypoxia/reoxygenation) injury in cardiac H9c2 cells exposed to high glucose as was evident from reduced apoptotic cell death and JC-1 monomer in cells, accompanied by increased phosphorylation of Akt, STAT3 and GSK-3ß. PTEN inhibition/gene knockdown mediated restoration of IPostC/HPostC cardioprotection was completely reversed by the PI3K inhibitor wortmannin, and partially reversed by the JAK2 inhibitor AG490. Increased cardiac PTEN, by impairing PI3K/Akt and JAK2/STAT3 pathways, is a major mechanism that rendered diabetic hearts not responsive to post-conditioning cardioprotection.

Cu-N dopants boost electron transfer and photooxidation reactions of carbon dots.

The broadband light-absorption ability of carbon dots (CDs) has inspired their application in photocatalysis, however this has been impeded by poor electron transfer inside the CDs. Herein, we report the preparation of Cu-N-doped CDs (Cu-CDs) and investigate both the doping-promoted electron transfer and the performance of the CDs in photooxidation reactions. The Cu-N doping was achieved through a one-step pyrolytic synthesis of CDs with Na2 [Cu(EDTA)] as precursor. As confirmed by ESR, FTIR, and X-ray photoelectron spectroscopies, the Cu species chelates with the carbon matrix through Cu-N complexes. As a result of the Cu-N doping, the electron-accepting and -donating abilities were enhanced 2.5 and 1.5 times, and the electric conductivity was also increased to 171.8 µs cm(-1) . As a result of these enhanced properties, the photocatalytic efficiency of CDs in the photooxidation reaction of 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate is improved 3.5-fold after CD doping.

Talaromycosis from Wuhan: two-case report and literature review.

Background: Talaromycosis is a serious opportunistic infectious disease caused by Talaromyces marneffei, which mostly occurs in immunocompromised patients. The disease is mainly prevalent in tropical countries and regions of Southeast Asia and South Asia, but non-endemic areas also have patients with Talaromycosis. The disease has no characteristic clinical manifestations and is difficult to diagnose. Delayed diagnosis often leads to death. Case presentation: Both patients had cellular immunodeficiency. Case 1 had a history of acquired immune deficiency syndrome, and case 2 had a history of renal transplantation and glucose-6-phosphate dehydrogenase deficiency. They all had fever, anemia, fatigue, and skin lesions. Case 1 had gastrointestinal bleeding, enlarged lymph nodes, and hepatosplenomegaly. Case 2 had cough and dyspnea. Both patients had thrombocytopenia and hypoalbuminemia; an increased neutrophil ratio, procalcitonin, and C-reactive protein; and abnormal liver function and coagulation dysfunction. Case 1 sputum culture, blood culture, and bronchoalveolar lavage fluid were positive for T. marneffei. T. marneffei was detected in the blood culture of case 2, with infection of Candida parapsilosis and Pneumocystis jirovecii. Chest computed tomography scan mainly showed pulmonary exudative lesions. Although these two patients were actively treated, they died of poor efficacy. Conclusion: Talaromycosis has an insidious onset, long course, atypical clinical symptoms, imaging performance and laboratory results, difficult diagnosis, and high mortality. Therefore, it is important to promptly consider and treat Talaromycosis in immunocompromised patients upon infection in order to reduce mortality.

The role of N-acetylcysteine on adhesion and biofilm formation of Candida parapsilosis isolated from catheter-related candidemia.

Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.

Use of Metagenomic Next-Generation Sequencing to Identify Pathogens Involved in Central Nervous System Infections.

Purpose: Application of metagenomic next-generation sequencing (mNGS) in identifying nosocomial central nervous system (CNS) infections in critical care units remains understudied. Methods: We conducted a retrospective analysis of microbiological results through both mNGS and routine examination of cerebrospinal fluid (CSF) samples from patients with nosocomial CNS infections. The aim of this study was to assess the clinical diagnostic effect of nosocomial mNGS in this population. Results: The study included 26 cases of nosocomial CNS infections in total. A total of 69.2% (18/26) of the samples tested positive for mNGS, which is substantially greater than the 7.7% (2/26; p<0.05) detected through conventional techniques. Administration of antibiotics before culture is most likely the cause of the low CSF culture rate. Twenty-five pathogenic strains that were missed by standard testing. Three pathogens that were consistent with the mNGS results were positive by routine tests. Eight cases were negative by mNGS due to low pathogen CSF titres. Compared to traditional testing, mNGS demonstrated 100% sensitivity and 33.3% specificity in diagnosing CNS infections. The thirty-day mortality rate was 26.9% (7/26). Conclusion: Routine microbiologic testing frequently falls short of detecting all neuroinvasive pathogens. Our research suggests that mNGS offers an alternative means of detecting nosocomial CNS infections. By applying mNGS to CSF samples from patients with meningitis or encephalitis, we were able to improve the ability to diagnose nosocomial neurologic infections.

Predictive Value of Multiple Scoring Systems in the Prognosis of Septic Patients with Different Infection Sites: Analysis of the Medical Information Mart for the Intensive Care IV Database.

The heterogeneity nature of sepsis is significantly impacted by the site of infection. This study aims to explore the predictive value of multiple scoring systems in assessing the prognosis of septic patients across different infection sites. Data for this retrospective cohort study were extracted from the Medical Information Mart for Intensive Care IV database (MIMIC-IV) (v2.2). Adult patients meeting the criteria for sepsis 3.0 and admitted to the intensive care unit (ICU) were enrolled. Infection sites included were pneumonia, urinary tract infection (UTI), cellulitis, abdominal infection, and bacteremia. The primary outcome assessed was 28-day mortality. The sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), and Logistic Organ Dysfunction System (LODS) score were compared. Binomial logistic regression analysis was conducted to evaluate the association between these variables and mortality. Additionally, differences in the area under the curve (AUC) of receiver operating characteristic (ROC) among the scoring systems were analyzed. A total of 4721 patients were included in the analysis. The average 28-day mortality rate was 9.4%. Significant differences were observed in LODS, OASIS, and SOFA scores between the 28-day survival and non-survival groups across different infection sites (p < 0.01). In the pneumonia group and abdominal infection group, both the LODS and OASIS scoring systems emerged as independent risk factors for mortality in septic patients (odds ratio [OR]: 1.165, 95% confidence interval [CI]: 1.109-1.224, p < 0.001; OR: 1.047, 95% CI: 1.028-1.065, p < 0.001) (OR: 1.200, 95% CI: 1.091-1.319, p < 0.001; OR: 1.060, 95% CI: 1.025-1.095, p < 0.001). For patients with UTI, the LODS, OASIS, and SOFA scoring systems were identified as independent risk factors for mortality (OR: 1.142, 95% CI: 1.068-1.220, p < 0.001; OR: 1.062, 95% CI: 1.037-1.087, p < 0.001; OR: 1.146, 95% CI: 1.046-1.255, p = 0.004), with the AUC of LODS score and OASIS significantly higher than that of the SOFA score (p = 0.006). Among patients with cellulitis, the OASIS and SOFA scoring systems were identified as independent risk factors for mortality (OR: 1.055, 95% CI: 1.007-1.106, p = 0.025; OR: 1.187, 95% CI: 1.005-1.403, p = 0.044), with no significant difference in prognosis prediction observed (p = 0.243). In the bacteremia group, the LODS scoring system was identified as an independent risk factor for mortality (OR: 1.165, 95% CI: 1.109-1.224, p < 0.001). The findings suggest that LODS scores offer better prognostic accuracy for predicting the mortality risk in septic patients with pneumonia, abdominal infections, bacteremia, and UTI compared to SOFA scores.

Sustaining attention in visuomotor timing is associated with location-based binding.

Maintaining focus of attention over prolonged periods can be challenging, especially when the target stimulus is absent from the temporal sequence. Prior research has shown that a temporal attentional cue filling in the temporal blank can improve sustained attention: in a sustained visual attention task requiring synchronizing finger tapping with a temporally regular sequence composed of brief flash disks interleaved with blank periods, task performance was improved when a continuous fixation point that served as a temporal attentional cue was presented superimposed on the disk stimulus. To test the hypothesis that binding the temporal attentional cue with the target temporal sequence by spatial overlapping is crucial for enhancing sustained attention, the present study conducted a series of three experiments that deconstructed the bound connection between the cue and the sequence stimulus. In Experiment 1, the cue was placed above or below a flash disk. In Experiment 2, the cue was between two vertically arranged flash disks. In Experiment 3, the cue was in a flash ring. No significant effect of sustained attention improvement was found in any of the three experiments. Experiment 4 further replicated these null results and the previously observed effect of sustained attention improvement when the temporal cue was superimposed on the sequence stimulus. Our finding demonstrates that binding by spatial overlapping during the temporal blank when the sequence stimulus is absent is critical for enhancing sustained attention, which should be beneficial for improving performance across a broader range of tasks that require prolonged maintenance of attention.

GDF3 Protects Mice against Sepsis-Induced Acute Lung Injury by Suppression of Macrophage Pyroptosis.

Sepsis-induced ALI is marked by physiological, pathological, and biochemical irregularities caused by infection. Growth differentiation factor 3 (GDF3) is closely associated with the inflammatory response. Accumulating evidence has demonstrated a close relationship between GDF3 expression and the severity and prognosis of sepsis. However, the precise mechanism by which GDF3 protects against ALI induced by sepsis is still unclear. Following the intravenous administration of GDF3 in this research, we noted a rise in the survival rate, a decrease in the severity of histopathological damage as evaluated through HE staining, a decline in the count of inflammatory cells in bronchoalveolar lavage fluid (BALF), a reduction in the ratio of lung wet/dry (W/D) weight, and a noteworthy decrease in the levels of pro-inflammatory cytokines in both serum and BALF when compared to septic mice who underwent cecal ligation and puncture (CLP). These collective findings unequivocally indicate the protective effects of GDF3 against sepsis-induced ALI. In addition, the GDF3 group showed a significant reduction in the mRNA expression of Caspase-1 and NLRP3 when compared to the CLP group. Following this, we performed in vitro tests to confirm these discoveries and obtained comparable outcomes, wherein the administration of GDF3 notably decreased the levels of Caspase-1 and NLRP3 mRNA and protein in macrophages in comparison to the LPS group. Furthermore, GDF3 exhibited the capacity to reduce the secretion of inflammatory molecules from macrophages. By illuminating the mechanism by which GDF 3 regulates macrophages, this offers a theoretical basis for preventing and treating sepsis-induced ALI.

Remimazolam tosylate's long-term sedative properties in ICU patients on mechanical ventilation: effectiveness and safety.

OBJECTIVE: This study compared remimazolam tosylate with propofol or midazolam to assess its safety and effectiveness for long-term sedation of intensive care unit (ICU) patients requiring mechanical ventilation. METHODS: Adult patients in the ICU receiving sedation and mechanical ventilation for longer than 24 h were included in this single-center, prospective, observational study. Depending on the sedatives they were given, they were split into two groups (midazolam or propofol group; remimazolam group). ICU mortality was the main result. Laboratory tests, adverse events, and the length of ICU stay were considered secondary outcomes. RESULTS: A total of 106 patients were involved (46 received propofol or midazolam versus 60 received remimazolam). Age (P = 0.182), gender (P = 0.325), and the amount of time between being admitted to the ICU and receiving medication infusion (P = 0.770) did not substantially differ between the two groups. Multivariate analysis revealed no statistically significant difference in ICU mortality between the two groups. The remimazolam group showed less variability in heart rate (P = 0.0021), pH (P = 0.048), bicarbonate (P = 0.0133), lactate (P = 0.0002), arterial blood gas analyses, liver, and kidney function. The Richmond Agitation and Sedation Scale scores, length of ICU stay, and occurrence of adverse events did not exhibit significant differences between the two groups. CONCLUSION: Remimazolam tosylate did not increase the total inpatient cost, the incidence of adverse events, and ICU mortality in patients with mechanical ventilation. These findings suggest that remimazolam may represent a promising alternative for sedation in the ICU setting.

NLRP3 inflammasome deficiency attenuates cerebral ischemia-reperfusion injury by inhibiting ferroptosis.

BACKGROUND: The role of ferroptosis in ischemic stroke has been hotly debated recently, but the mechanism is not clearly clarified. It has been reported that the NLRP3 inflammasome is essential for the progression of ischemic stroke. Whether the ferroptosis after ischemic stroke mediated by the activation of NLRP3 inflammasome is still not reported. In this study, we investigated the effect of NLRP3 deficiency on ferroptosis following cerebral ischemia-reperfusion injury (CIRI) in vivo and in vitro. MATERIALS: In vivo, we used C57BL/6J mice and NLRP3-/- mice to establish a model of middle cerebral artery occlusion (MCAO). After 3 days of reperfusion, we assessed neurological function and then performed TTC staining to measure the infarct volume. Besides, we measured the expression of NLRP3 inflammasome-related proteins and the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4) by western blotting (WB) and immunofluorescence (IF). Moreover, we evaluated the levels of ferroptosis-related factors (Fe2+, MDA and GSH) in the infarct area by using appropriate kits. Furthermore, we used WB to measure the expression of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), which participate in the progression of ischemic stroke. In vitro, we knocked down NLRP3 with small interfering RNAs (siRNAs) and established an oxygen glucose deprivation/Reperfusion (OGD/R) model in BV2 cells to simulate ischemic conditions. Next, we assessed the viability of BV2 cells by the Cell Counting Kit (CCK)-8 cytotoxicity assay. Moreover, we used WB to measure the expression of NLRP3, IL-1ß, GPX4, Keap1 and Nrf2 proteins which are involved in CIRI. RESULTS: Three days after MCAO, the NLRP3-/- mice exhibited smaller cerebral infarct volumes and lower neurological deficit scores. The expression of NLRP3 inflammasome-associated proteins (IL-18 and IL-1ß) and Keap1/Nrf2 signaling pathway moleculars (Keap1 and Nrf2) in mice brain tissue and BV2 cells were inhibited by NLRP3 knockout/knockdown, while the expression of GPX4, one of the ferroptosis-related factors was increased. Furthermore, the contents of Fe2+ and MDA in the brain tissues of NLRP3-/- mice were decreased, while the content of GSH were increased significantly. CONCLUSION: Inhibition of the NLRP3 inflammasome alleviates CIRI by inhibiting ferroptosis and inflammation, possibly through a mechanism of the Keap1-Nrf2 pathway.

Anti-CD1d treatment suppresses immunogenic maturation of lung dendritic cells dependent on lung invariant natural killer T cells in asthmatic mice.

Our previous findings show that invariant natural killer T (iNKT)cells can promote immunogenic maturation of lung dendritic cells (LDCs) to enhance Th2 cell responses in asthma. It has been accepted that recognition of glycolipid antigens presented by CD1d molecules by the T cell receptors of iNKT cells leads to iNKT cell activation. Therefore, we examine the immunoregulatory influences of anti-CD1d treatment on Th2 cell response and immunogenic maturation of LDCs and subsequently explored whether these influences were dependent on lung iNKT cells in asthmatic mice. We discoveredthat in wild-type mice sensitized and challenged with house dust mite or ovalbumin (OVA), anti-CD1d treatment inhibited Th2 cell response and immunogenic maturation of LDCs. LDCs from asthmatic mice with anti-CD1d treatment had a markedly decreased influence on Th2 cell responses in vivo and in vitro. Furthermore, anti-CD1d treatment reduced the abundance and activation of lung iNKT cells in asthmatic mice. Moreover, in asthmatic iNKT cell-deficient Jα18-/- mice, anti-CD1d treatment did not influence Th2 cell responses and immunogenic maturation of LDCs. Meanwhile, the quantity of CD40L+ iNKT cells in asthmatic mice was significant decreased by anti-CD1d treatment. Finally, the inhibition of anti-CD1d treatment on LDC immunogenic maturation and Th2 cell responses in asthmatic mice was reversed by anti-CD40 treatment. Our data suggest that anti-CD1d treatment can suppress Th2 cell responses through inhibiting immunogenic maturation of LDCs dependent on lung iNKT cells, which couldbe partially related to the downregulation of CD40L expression on lung iNKT cells in asthmatic mice.

The utilization of nanopore targeted sequencing proves to be advantageous in the identification of infections present in deceased donors.

Background: Nanopore Target Sequencing (NTS) represents a novel iteration of gene sequencing technology; however, its potential utility in the detection of infection in deceased donors has yet to be documented. The present study endeavors to assess the applicability of NTS in this domain. Methods: This retrospective study comprised a cohort of 71 patients who were under intensive care at Renmin Hospital of Wuhan University between June 2020 and January 2022. The specimens were subjected to microbiological tests utilizing NTS, culture, and other techniques, and subsequently, the diagnostic accuracy of NTS was compared with conventional methods. Results: Blood NTS exhibited a better agreement rate of 52.11% and a greater positive rate of pathogen detection than blood culture (50.70% vs. 5.63%, p < 0.001). In NTS of deceased donors, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii were the most frequently found bacteria, and Candida was the most frequently found fungus. Blood NTS had a considerably better sensitivity for detecting clinical bloodstream infection than blood culture (62.50%: 7.14%, p < 0.001). These findings were supported by comparisons between blood NTS and conventional microbial detection methods (such as blood culture, glucan testing, galactomannan testing, T cell spot testing for tuberculosis infection, smear, etc.). Conclusion: The pathogen detection technology NTS has a high sensitivity and positive rate. It can more accurately and earlier detect infection in deceased donors, which could be very important for raising the donation conversion rate.

Role of endoplasmic reticulum autophagy in acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the prime causes of morbidity and mortality in critically ill patients, are usually treated by general supportive treatments. Endoplasmic reticulum autophagy (ER-phagy) maintains cellular homeostasis by degrading damaged endoplasmic reticulum (ER) fragments and misfolded proteins. ER-phagy is crucial for maintaining ER homeostasis and improving the internal environment. ER-phagy has a particular role in some aspects, such as immunity, inflammation, cell death, pathogen infection, and collagen quality. In this review, we summarized the definition, epidemiology, and pathophysiology of ALI/ARDS and described the regulatory mechanisms and functions of ER-phagy as well as discussed the potential role of ER-phagy in ALI/ARDS from the perspectives of immunity, inflammation, apoptosis, pathogen infection, and fibrosis to provide a novel and effective target for improving the prognosis of ALI/ARDS.