GSDMD-mediated NETosis promotes the development of acute respiratory distress syndrome.

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.

How China anesthesiologists document and communicate difficult airway management.

BACKGROUND: According to the Chinese Society of Anesthesiology, it is recommended that patients with difficult airways be documented and notified, which will provide healthcare professionals with a direct reference when managing airways. However, compliance with this initiative remains unclear. This study was conducted to investigate the current status and need for difficult airway notification at Plastic Surgery Hospital and to explore the factors contributing to noncompliance. METHODS: Anesthesiologists, surgeons, and patients in Plastic Surgery Hospital were administered separate questionnaires regarding notification of difficult airway management. Participants were surveyed regarding their attitudes and current practices regarding difficult airway notification. In addition, questions were asked regarding the barriers that contribute to noncompliance. RESULTS: A total of 632 valid responses were obtained and analyzed, giving a response rate of 99.21%. 399 patients (89.46%) felt it was very important for anesthesiologists to inform them about their difficult airway, and 91.03% felt it was very important for them to receive a letter of their airway assessment. However, twenty-two anesthesiologists (64.7%) reported verbally informing less than 50% of patients about their difficult airway after surgery, and only four anesthesiologists informed all patients they encountered. Most surgeons (91.22%) and anesthesiologists (91.18%) believe that it is vital to inform patients verbally, while 114 surgeons (77.03%) and 31 anesthesiologists (91.18%) believe that it is essential to complete a difficult airway notification alert. Among the factors causing noncompliance, 17 (34.69%) believed that absence of mandatory rules, 9 (18.37%) believed that increased workload, and 8 (16.33%) believed that notification methods were lacking. CONCLUSIONS: The compliance to difficult airway notification remains low in Plastic Surgery Hospital despite the high incidence of difficult airways. Although anesthesiologists, surgeons, and patients are strongly in favor of it. Among the barriers to compliance were the absence of a well-developed notification system and a means of notification such as an alert form for difficult airways. This may spur the anesthesiology society to publish the notification system.

Effects of dexamethasone on the EC50 of remifentanil combined with dexmedetomidine achieving analgesia during pancreatic extracorporeal shockwave lithotripsy: a prospective, randomized and controlled study.

BACKGROUND: In addition to their classic genomic effects, glucocorticoids also manifest rapid non genomic effects. We speculate that dexamethasone has the potential prompt onset of analgesic effects. The objective of this study is to investigate the influence of a single preoperative dose of dexamethasone on the half maximal effective concentration (EC50) of remifentanil when combined with dexmedetomidine for pain relief during pancreatic extracorporeal shockwave lithotripsy (P-ESWL). METHODS: A total of 60 patients undergoing P-ESWL were enrolled and randomized at 1:1 ratio into the dexamethasone (DXM) group and the placebo group. Before anesthesia induction, patients in DXM group received an intravenous injection of 8 mg dexamethasone, while subjects in placebo group received an equal dose of physiological saline. Monitored anesthesia care (MAC) was performed based on remifentanil in combination with dexmedetomidine. Remifentanil was administered by TCI with an initial target concentration of 2.5 µg/mL for both groups. A positive response was defined as that VAS score > 3 by the patient at any time during the procedure. Subsequent target concentrations were adjusted by Dixon up-down sequential method, where dose modifications were performed by 0.3 ng/mL intervals, based on the response of the previous patient. The EC50 of remifentanil for pain relief during P-ESWL treatment was calculated using Dixon's up-and-down method. Hemodynamic variables, oxygen saturation and adverse events were also recorded. RESULTS: Dixon up-and-down method revealed that the EC50 of remifentanil was significantly higher in placebo group (2.65 ± 0.28 ng/mL) than in DXM group (2.02 ± 0.23 ng/ml) (P < 0.001). Hemodynamic parameter exhibited a significant decrease in mean arterial pressure (MAP) and heart rate (HR) before and after induction in placebo group; however, data of the two groups were comparable (P>0.05). Less adverse events occurred in DXM group, including the incidence of postoperative nausea and vomiting (PONV) and analgesia requirement with in the first 24 h following the procedure at ward. CONCLUSION: Dexamethasone exerted analgesic effects with a rapid onset, and patients received dexamethasone 8 mg preoperative had a lower required EC50 of remifentanil during P-ESWL. It is also associated with reduced PONV in addition to reduced postoperative analgesic consumption in the first postoperative 24 h. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry (ChiCTR2300078171) on 30/11/2023.

Does Increasing the Bend Angle of a Stylet to 90° Increase the Nasotracheal Intubation Success Rate?

BACKGROUND: Video-stylet-guided nasotracheal intubation (NTI) is an effective technique for airway management. However, the impact of the bend angle on the success rate of intubation remains unclear. PURPOSE: Does increasing the bend angle of a stylet to 90° increase NTI success rate?. STUDY DESIGN, SETTING, SAMPLE: This prospective randomized controlled trial was conducted in the operating room of a population-based hospital. Adult patients requiring NTI were recruited. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: The primary predictor variable is the choice of stylet bend angle (90° vs 70° bend) in NTI. MAIN OUTCOME VARIABLE(S): The primary outcome variables were success rates of NTI, defined as the proportion of successful intubation cases to total cases. COVARIATES: Demographics, intubation time, the distance from the thyroid prominence to the nostril, additional maneuvers applied during intubation, and cases of epistaxis were recorded. ANALYSES: The student's t-test was used to compare continuous variables between groups. Ordinal data (intubation attempts, head extension, and epistaxis) were analyzed using the Wilcoxon rank-sum test. As appropriate, frequency (external pharyngeal pressure) was analyzed using the χ2 test or Fisher's exact test. A P value of <.05 was considered statistically significant. RESULTS: Of the 103 subjects assessed for eligibility, 98 were enrolled in the study. The mean age (27.0 ± 6.9 years vs 27.0 ± 4.1 years, P = .972) and sex differences (male/female: 9/40 vs 7/42, P = .136) were comparable between groups. The overall success rate in the 70° group was significantly lower than that in the 90° group (91.8 vs 100%, P < .001). The intubation time in the 70° group was significantly longer than that in the 90° group (43.2 ± 15.8 s vs 33.7 ± 7.3 s, P < .001). CONCLUSIONS AND RELEVANCE: A 90° bend angle of the stylet significantly improves the likelihood of successful NTI.

High-dose ascorbic acid potentiates immune modulation through STAT1 phosphorylation inhibition and negative regulation of PD-L1 in experimental sepsis.

Sepsis is a complex, multifactorial syndrome characterized by a dysregulated host response to infection, leading to severe organ dysfunction and high mortality rates among critically ill patients. Hypovitaminosis C and vitamin C deficiency are frequently observed in septic patients, prompting interest in the potential therapeutic role of ascorbic acid. Although intravenous administration of ascorbic acid has been investigated in multiple clinical trials for sepsis treatment, the specific immunomodulatory mechanisms underlying its effects remain elusive. This study aimed to investigate the protective effects of high-dose ascorbic acid on experimental sepsis. Results show that intravenous administration of high-dose ascorbic acid (250 mg/kg) attenuated sepsis-induced organ dysfunctions in a cecal ligation and puncture (CLP)-induced septic mouse model. Ascorbic acid improved splenic cell apoptosis and increased the number of CD3+ T cells in septic mice induced by CLP. Furthermore, ascorbic acid downregulated PD-L1 expression in livers, reduced PD-1 expression in spleens, and inhibited the phosphorylation of STAT1 at Y701 in multiple organs of CLP-induced septic mice. The in vitro experiments also revealed that 800 µM ascorbic acid suppressed STAT1 phosphorylation and inhibited lipopolysaccharide (LPS) and IFN-γ-induced PD-L1 expression in macrophages. These findings suggest that ascorbic acid prevents sepsis-associated organ dysfunction through the p-STAT1/PD-L1 signaling pathway. Our study provides new insights into the potential therapeutic use of ascorbic acid in sepsis.

Identification of a novel cuproptosis-related gene signature for rheumatoid arthritis-A prospective study.

BACKGROUND: Rheumatoid arthritis (RA) is a multifactorial systemic autoimmune disease characterized by ongoing synovial inflammation, leading to the degradation of cartilage. Cuproptosis, as a newly characterized form of cell death, may influence RA progression by regulating immune cells and chondrocytes. This study sets out to identify the hub cuproptosis-related gene (CRG) associated with the pathogenesis of RA. METHODS: A series of bioinformatic analyses were performed to evaluate the expression score of CRGs and the immune infiltration landscape between RA and normal samples. The hub gene was screened through the correlation analysis of CRGs, and the interaction network between the hub gene and transcription factors (TFs) was constructed. Finally, the hub gene was validated through quantitative real-time polymerase chain reaction (qRT-PCR) of patient samples and cell experiments. RESULTS: Drolipoamide S-acetyltransferase (DLAT) was screened as the hub gene. Correlation analysis between the hub gene and immune microenvironment demonstrated that DLAT had the highest correlation with T follicular helper cells. Eight pairs of DLAT-TF interaction networks were constructed. Single-cell sequencing showed that CRGs were highly expressed in RA chondrocytes, and chondrocytes could be classified into three different subsets. qRT-PCR was used to validate the above results. Dlat knockdown in immortalized human chondrocytes led to significantly improved mitochondrial membrane potentials and reduced levels of intracellular reactive oxygen species (ROS), mitochondrial ROS and apoptosis. CONCLUSIONS: This study rudimentarily demonstrates the correlation between CRGs and immune cell infiltration in RA. The biomarker DLAT may provide comprehensive insights into the pathogenesis and drug targets of RA.

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Coimmunoprecipitation assays on control neutrophils challenged with interferon-γ and LPS showed that PD-L1 complexes with the p85 subunit of phosphatidyl 3-kinase (PI3K) to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared with wild-type animals, PD-L1-deficient animals presented lower levels of plasma tumor necrosis factor-α and interleukin-6 (IL-6) and higher levels of IL-10 after CLP, and reduced 7-day mortality in CLP PD-L1-knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.

Histone methyltransferase SETD2 inhibits M1 macrophage polarization and glycolysis by suppressing HIF-1α in sepsis-induced acute lung injury.

Sepsis is a severe syndrome caused by the imbalance of the host response to infection, accompanied by multiple organ damage, especially acute lung injury. SET Domain-Containing 2 (SETD2) is a methyltransferase catalyzing H3 lysine 36 trimethylation (H3K36me3) that regulates multiple biological processes. This study focused on explicating the action of SETD2 on macrophage function in sepsis and the precise mechanism involved. Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting were used to determine expression. Luciferase reporter assay and chromatin immunoprecipitation assay were conducted to detect the binding of SETD2 or H3K36me3 with the hypoxia-inducible factor 1, alpha subunit (Hif1a) gene. A sepsis-induced acute lung injury model was constructed via cecal ligation and puncture (CLP). SETD2 was decreased in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Besides, SETD2 suppressed M1 macrophage polarization and glycolysis caused by LPS. HIF-1α was enhanced in RAW 264.7 cells stimulated by LPS and inversely related to SETD2 expression. In addition, SETD2-catalyzed H3K36me3 bound to the Hif1a gene to modulate HIF-1α expression. Furthermore, Hif1a silencing suppressed Setd2 silencing-induced M1 macrophage polarization and glycolysis in RAW 264.7 cells. Moreover, overexpression of Setd2 inhibited CLP-induced lung injury and M1 macrophage polarization in mice. SETD2 suppressed M1 macrophage polarization and glycolysis via regulating HIF-1α through catalyzing H3K36me3 in sepsis.

Nicotinamide Mononucleotide Attenuates LPS-Induced Acute Lung Injury With Anti-Inflammatory, Anti-Oxidative and Anti-Apoptotic Effects.

INTRODUCTION: Nicotinamide mononucleotide (NMN) is a nucleotide that is commonly recognized for its role as an intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis with multiple pharmacological effects. The purpose of this study was to evaluate the protective effect of nicotinamide mononucleotide (NMN) against lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We investigated the effect of NMN on ALI-induced inflammatory response, oxidative stress, and cell apoptosis. The ALI mouse model was performed by injecting LPS intratracheally at a dose of 10 mg/kg in 50 µL saline. Flow cytometry was used to detect neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and ELISA was used to detect the contents of inflammatory cytokines TNF-α, IL-1ß and IL-6 in BALF. Oxidative stress was evaluated by determining the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in lung tissue. ROS formation was analyzed by immunofluorescence. Western blotting was performed to detect apoptotic levels and p38MAPK/NF-κB phosphorylation levels in lung tissue. RESULTS: In the ALI mouse model, NMN showed a significant therapeutic effect compared to the LPS group. NMN attenuated the pathological damage and cell apoptosis in lung tissue, decreased the levels of TNF-α, IL-1ß, and IL-6 in BALF, and reduced the number of total cells and neutrophils in BALF. In addition, NMN attenuated the LPS-induced elevation of dry-to-wet ratio, MDA content, p38 MAPK and p65 NF-κB phosphorylation levels, and the SOD activity was increased by NMN treatment. CONCLUSIONS: In conclusion, the present study showed that NMN exerted a protective effect on LPS-induced ALI with anti-inflammatory, antioxidative, and antiapoptotic effects.

Clinical observation of dexmedetomidine nasal spray in the treatment of sleep disorders on the first night after undergoing maxillofacial surgery: a single-center double-blind randomized controlled study.

Purpose: Dexmedetomidine exerts a sedative effect by promoting the sleep pathway endogenously and producing a state similar to N2 sleep. This study aimed to study the efficacy and safety of dexmedetomidine nasal spray in the treatment of postoperative sleep disturbance. Methods: This study enrolled 120 participants [men and women; age, 18-40 years; American Society of Anesthesiologists grade, I or II] who underwent maxillofacial surgery under general anesthesia through nasotracheal intubation. The participants were randomly divided into three groups: blank control group (BC group), 1.0 µg/kg dexmedetomidine group (1.0 Dex group), and 1.5 µg/kg dexmedetomidine group (1.5 Dex group), with 40 patients allocated to each group. At 21:30 on the night after the operation, the intervention groups were administered their corresponding doses of dexmedetomidine nasal spray. The Pittsburgh Sleep Quality Index (PSQI) scale was used to evaluate the baseline sleep status of participants 1 month preoperatively and on the night after the operation. Polysomnography (PSG) was used to record the sleep status on the night after the operation. We recorded the rescue times of sedative and analgesic drugs on the first night after surgery, adverse reactions, total hospital stay duration, and total costs. Results: Compared with patients in the BC group, those in 1.0 Dex and 1.5 Dex groups had longer N2 sleep duration, were awake for a shorter time after dose administration, woke up less often, and had significantly improved sleep efficiency (p < 0.05). Compared with the BC group, the PSQI scores of 1.0 Dex and 1.5 Dex groups were significantly lower on the night after operation, and the proportion of PSQI > 5 was significantly lower (p < 0.05). Compared with patients in the BC group and the 1.0 Dex group, those in the 1.5 Dex group had significantly prolonged N3 sleep, reduced frequency of requiring sufentanil rescue, lower incidence of sore throat after surgery, and shorter average length of hospital stay (all, p < 0.05). Conclusion: The sleep quality of participants on the night after having undergone maxillofacial surgery was safely and effectively improved by 1.0-1.5 µg/kg dexmedetomidine atomized nasal sprays. Notably, only the latter could prolong N3 sleep. Level of Evidence II: Evidence was obtained from at least one properly designed randomized controlled trial.

Preliminary evaluation of SaCoVLM video laryngeal mask-guided intubation in airway management for anesthetized children.

BACKGROUNDS: To preliminary evaluate the application of novel SaCoVLM video laryngeal mask -guided intubation for anesthetized children. METHODS: One hundred twenty-four children with microtia (ages 5-15 years,) who required general intubation anaesthesia, were enrolled in the study. After induction of general anesthesia,guided tracheal intubation under direct vision of the SaCoVLM was performed. Our primary outcome was first-pass success rate of guided tracheal tube placement. Secondary outcome included glottic visualization grades, the first-attempt success rate of LMA placement, the time for LMA placement and time to endotracheal intubation as well as the time for LMA removal after successful intubation, the fiberoptic grade of laryngeal view, the baseline and postinduction hemodynamic parameters were also recorded,and the incidence 24 h complications after operation. RESULTS: The first-pass success rate of guided tracheal tube placement was 91.1% (95%CI = 1.04-1.14), the status of glottic visualization was classified: grade 1 in 27cases, grade 2 in 36 cases, grade 3 in 41 cases and grade 4 in 20 cases. The first success rate of LMA placement was 92.7% (95%CI = 1.03-1.13), the time for LMA insertion was 15.7 (±9.1) s, intubation time was 30.9 (±17.6) s and withdrawl time was 24.9 (±9.3) s. The incidence of postoperative sore throat at 2 h was 29%, and 16.1% at 24 h, without dysphagia and hypoxia. CONCLUSION: The SaCoVLM video laryngeal mask-guided intubation is feasible in children, with a high success rate, could be a new promising device to guide intubation in airway management. TRIAL REGISTRATION: This study was approved by the University's Institutional Review Board and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (ChiCTR2200061481, http://www.chictr.org.cn . Principal investigator: Juan Zhi; Date of registration: 26/06/2022.

Intubation using video laryngeal mask airway SaCoVLM and laryngeal mask airway Ambu® Aura-i in anesthetized children with microtia: a randomized controlled study.

The Ambu Aura-i laryngeal mask is considered to be a device for blind intubation as well as for fiberoptic guided intubation. The novel video laryngeal airway mask SaCoVLM is a supraglottic airway device that allows intubation under direct vision. We hypothesized that success rates for device placement and tracheal intubation with the SaCoVLM would be comparable with the Ambu Aura-i mask. A prospective, randomized clinical trial was conducted from March 2021 to December 2021. One hundred and twenty patients were enrolled and randomized in the study. Direct intubation was performed with the SaCoVLM, and fiberoptic guided intubation was performed with the Ambu Aura-i mask. The primary outcome measure was the first success rate of LMA placement. Secondary outcome measures were the time from device placement and time from endotracheal intubation (as well as the time for LMA removal after successful intubation), differences in airway leak pressure, fiberoptic grade of the laryngeal view, and incidence of blood staining. The first success rate of LMA placement was similar for the two devices. There was no difference in the time for successful endotracheal intubation between the Ambu Aura-i and SaCoVLM groups (24.1 s ± 6.3 versus 25.7 s ± 2.1; p > 0.05). The time for removal was slower in the SaCoVLM group than in the Ambu Aura-i group (20.8 s ± 0.8 versus 14.7 s ± 6.1; p < 0.01). The airway leak pressure was higher in the SaCoVLM group than in the Ambu Aura-i group (27.0 s ± 1.0 versus 22.3 s ± 3.6; p < 0.01), and the incidence of blood staining was higher in the SaCoVLM group (16.7%). The SaCoVLM has an overall comparable performance to the Ambu Aura-i mask. However, the SaCoVLM is better relative to direct intubation without the assistance of a flexible intubation scope, which reduces the device's demand.

Ultrasound-guided Serratus Anterior Plane Block, Along with Improved Parasternal Block, is Superior to Serratus Anterior Plane Block Alone in Relieving Pain for Rhinoplasty with Autologous Costal Cartilage.

BACKGROUND: Rhinoplasty with autologous costal cartilage (ACC) is followed by severe pain in the chest. Ultrasound-guided (USG) serratus anterior plane block (SAPB), in combination with parasternal block (PSB), was earlier reported to be highly efficacious in relieving pain associated with thoracic anterior lateral surgery. However, it is unclear whether it is effective for pain relief after ACC harvest. METHODS: Sixty-four patients, aged 18 to 60, who received rhinoplasty with ACC, were randomly separated into a SAPB+PSB or SAPB group. The analyzed parameters of both groups included the rest and coughing numerical rating scale (NRS) pain scores of the chest and the NRS pain scores of the nose at postoperative 2, 4, 8, 12, 24, and 48 hours, oral rescue analgesic usage, side effect incidence and patient satisfaction, etc. RESULTS: Thirty patients per group were recruited for analysis. The rest and coughing NRS scores of the chest and the NRS scores of the nose at postoperative 2, 4, 8, 12 h were lower in the SAPB+PSB group, compared to the SAPB group (all P < 0.05). However, these scores were comparable between the two groups at postoperative 24 and 48 h (all P > 0.05). Additionally, relative to the SAPB group, the oral rescue analgesic usage was drastically lower (P < 0.05), the postoperative nausea and vomiting (PONV) incidence was diminished (P < 0.05), and the patient satisfaction was markedly higher (P < 0.001) in the SAPB+PSB group. CONCLUSION: USG-SAPB, in combination with improved PSB, is superior to SAPB alone in relieving pain after ACC harvest in rhinoplasty. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Combined Network Pharmacology and Cytology Experiments to Identify Potential Anti-Breast Cancer Targets and Mechanisms of Delphinidin.

Delphinidin is a type of anthocyanin monomer with antioxidant, anti-inflammatory, and anti-tumor effects. However, the biological mechanisms underlying its anti-breast cancer activity have not been thoroughly studied. We further studied the effect of delphinidin on breast cancer cells through comprehensive network pharmacology, cellular and molecular experiments. We acquired the know therapeutic targets of delphinidin and obtained differentially expressed genes (DEGs) of breast cancer using RTCGA. We used topological analysis to screen out the 106 core targets of delphinium anti-breast cancer and performed functional analysis. These genes were mainly enriched in the pathways in cancer, Progesterone-mediated oocyte maturation and cell cycle. Then, by taking the intersection of the three analyzed data sets, important core targets (EGFR, TOP2A and PTGS2) were obtained and molecular-docking was performed to validate the result. Additionally, In Vitro experiments, MCF-7 and BT-474 cell proliferation was inhibited in a dose-dependent manner by delphinidin and the expressions of EGFR, TOP2A and PTGS were reduced. Moreover, delphinidin influenced cell cycle, the expressions of cdk1 and cyclin B1 were reduced. Furthermore, delphinidin induced apoptosis by activating the MAPK-Signaling pathway. Collectively, our findings suggested that delphinidin may offer effective approaches in breast cancer prevention and therapy.Supplemental data for this article is available online at http://dx.doi.org/10.1080/01635581.2021.2012582.

Tim-3 Blockade Decreases the Apoptosis of CD8+ T Cells and Reduces the Severity of Sepsis in Mice.

INTRODUCTION: The T cell immunoglobulin and mucin domain 3 (Tim-3) mediated immunosuppressive pathway has been shown to play an essential role in the development of sepsis. However, the influence of Tim-3 blockade during sepsis and the possible effects on T cells' function remains largely unknown. Our study investigates the role of Tim-3 in cecal ligation and puncture (CLP)-induced sepsis in mice. METHODS: Sepsis was induced in C57BL/6 male mice via CLP. The expression of Tim-3 in CD8+ T cells after CLP challenge was measured. A dose of 50 µg anti-Tim-3 antibodies was injected intraperitoneally 30 min after surgery. Postoperative survival, bacterial clearance in the blood and peritoneal lavage fluid, cytokine secretion in the blood, and lung and liver histology were evaluated. In addition, the apoptosis of immune cells in the spleen and thymus was examined, respectively. RESULTS: Tim-3 expression was elevated in the splenic CD8+ T cells of septic mice. At the early stage of CLP-induced sepsis, blocking Tim-3 with anti-Tim-3 antibodies reduced the severity of sepsis. The anti-Tim-3 antibodies alleviated the morphology of lung and liver injuries in septic mice. The anti-Tim-3 antibodies also reduced the severity of the inflammatory responses and lymphocyte apoptosis in septic mice. CONCLUSIONS: Anti-Tim-3 antibodies might be a potential therapeutic strategy for sepsis.

Post-cardiopulmonary bypass hypoxaemia in paediatric patients undergoing congenital heart disease surgery: risk factors, features, and postoperative pulmonary complications.

BACKGROUND: Hypoxemia after cardiopulmonary bypass (CPB) is the quantifiable manifestation of pulmonary dysfunction. This retrospective study was designed to investigate the risk factors for post-cardiopulmonary bypass hypoxaemia and the features of hypoxaemia and pulmonary complications in paediatric congenital heart disease surgery involving CPB. METHODS: Data including demographics, preoperative pulmonary or cardiac parameters, and intraoperative interventions were retrospectively collected from 318 paediatric patients who underwent radical surgery with CPB for congenital heart disease. Among them, the factors that were significant by univariate analysis were screened for multivariate Cox regression. The lowest ratio of arterial oxygen tension and the inspiratory oxygen fraction (PaO2/FiO2), hypoxaemia (PaO2/FiO2 ≤ 300) insult time, duration of hypoxaemia, extubation time, and pulmonary complications were also analysed postoperatively. RESULTS: The morbidity of post-cardiopulmonary bypass hypoxaemia was 48.4% (154/318). Months (6 < months ≤ 12, 12 < months ≤ 36 and 36 < months compared with 0 ≤ months ≤ 6: HR 0.582, 95% CI 0.388-0.873; HR 0.398, 95% CI 0.251-0.632; HR 0.336, 95% CI 0.197-0.574, respectively; p < 0.01), preoperative intracardiac right-to-left shunting (HR 1.729, 95% CI 1.200-2.493, p = 0.003) and intraoperative pleural cavity entry (HR 1.582, 95% CI 1.128-2.219, p = 0.008) were identified as independent risk factors for the development of post-cardiopulmonary bypass hypoxaemia. Most hypoxaemia cases (83.8%, 129/154) occurred within 2 h, and the rate of moderate hypoxaemia (100 < PaO2/FiO2 ≤ 200) was 60.4% (93/154). CONCLUSION: The morbidity of post-cardiopulmonary bypass hypoxaemia in paediatric congenital heart disease surgery was considerably high. Most hypoxaemia cases were moderate and occurred in the early period after CPB. Scrupulous management should be employed for younger infants or children with preoperative intracardiac right-to-left shunting or intraoperative pleural cavity entry.

Effects of mandibular distraction osteogenesis on anesthetic implications in children with hemifacial microsomia.

BACKGROUND: Hemifacial microsomia (HFM) is a congenital craniofacial malformation, and its features include hypoplasia and asymmetry in skeletal tissue and soft tissue. These features are usually associated with a difficult airway. Mandibular distraction osteogenesis can achieve mandibular advancement, but its effect on the subsequent laryngoscopic views has not been adequately documented. AIM: The aim of this study was to determine the change in laryngoscopic views after mandibular distraction osteogenesis (MDO) in children with HFM and to examine the radiological changes after MDO by using computed tomography (CT)-based three-dimensional (3-D) airway reconstruction. METHODS: An observational prospective study was carried out in children with HFM undergoing MDO. All children underwent 3-D airway reconstruction preoperatively before the placement and removal of the distractor. The temporomandibular joint lesions in children were classified by the Pruzansky-Kaban classification. The Cormack-Lehane grade was assessed after induction under direct laryngoscopy. The relationship between difficult laryngoscopy and the Pruzansky-Kaban classification was assessed. Changes in the upper pharyngeal airway parameters and laryngoscopic views were analyzed. RESULTS: Forty children (ages ranging from 5 to 16 years, males = 26, females = 14) with HFM underwent 80 anesthesia for MDO. The incidence of difficult laryngoscopy before mandibular distraction was 5/12 (41.7%) in type IIa, 19/24 (79.2%) in type IIb and 1/4 (25%) in type III HFM. The mean difference in the incidence of difficult laryngoscopy before and after MDO was 33.3% (95% CI: -6.7% to 73.3%), 50.0% (95% CI: 8.4% to 91.6%), and 0% for type IIa, type IIb, and type III, respectively. In type IIb, 12/19 cases of difficult laryngoscopy became easy after mandibular distraction: this was associated with an increase in the palatopharyngeal and glossopharyngeal CT parameters (p < .05). In type IIa, 5/5 cases of difficult laryngoscopy became easy after mandibular distraction, and 1/7 cases of easy laryngoscopy became difficult laryngoscopy. However, there were no significant changes in the palatopharyngeal, glossopharyngeal, and hypopharyngeal CT parameters in type IIa and type III HFM (p > .05). CONCLUSIONS: MDO can improve the laryngoscopic views in children with HFM. According to the Pruzansky-Kaban classification, children with type IIb showed the highest incidence of difficult laryngoscopy before MDO. After MDO, the improvement in laryngoscopic views under direct laryngoscopy in type IIb was related to the increase in the palatopharyngeal and glossopharyngeal volume.

Ultrasound-guided Bilateral Serratus Anterior Plane Block for Postoperative Analgesia in Ear Reconstruction after Costal Cartilage Harvest: A Randomized Controlled Trial.

BACKGROUND: Costal cartilages harvest for ear reconstruction is accompanied by severe pain in chest. However, there is no perfect solution for reducing this chest pain. OBJECTIVE: Evaluate the efficacy and safety of analgesia using ultrasound-guided bilateral serratus anterior plane block (SAPB) in children receiving costal cartilage harvest for ear reconstruction. METHODS: Sixty children undergoing ear reconstruction using costal cartilage were randomized to an SAPB group (SAPB with 3 mg/kg 0.25% ropivacaine) or an incision infiltration (II) group (II with 3 mg/kg 0.75% ropivacaine), and 29 in each group completed the study. All children received patient-controlled intravenous analgesia (PCIA). The primary outcomes were numerical rating scale (NRS) scores of pain while rest and coughing at 1, 6, 12, 24, and 48 h after surgery. The secondary outcomes were sufentanil use within 24 h, duration of analgesia, use of oral rescue analgesics, first time out of bed, and incidence of treatment-related adverse effects. RESULTS: The SAPB group had lower rest and coughing NRS scores at 6 and 12 h after surgery (all P < 0.001), but the scores were similar at other times. The SAPB group used less sufentanil within 24 h, but had a longer duration of analgesia (both P < 0.001). The II group used more oral rescue analgesics within 48 h, had a longer time until first time out of bed, and had more opioid-related side effects (all P < 0.01). There were no SAPB-related complications. CONCLUSION: Ultrasound-guided SAPB can provide safe and effective regional pain relief after costal cartilage harvest for ear reconstruction. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

Comparison of the Sedative and Analgesic Effects of Dexmedetomidine-Remifentanil and Dexmedetomidine-Sufentanil for Liposuction: A Prospective Single-Blind Randomized Controlled Study.

BACKGROUND: Dexmedetomidine had sedative and analgesic effects and did not produce significant respiratory depression at therapeutic doses. AIMS: To compare the sedative and analgesic effects and safety of dexmedetomidine combined with remifentanil or sufentanil in patients undergoing liposuction. METHODS: A total of 100 subjects were randomized 1:1 to two groups: Group R and Group S. First, patients were administered midazolam 0.02 mg·kg-1. Anesthesia was induced with an intravenous infusion of dexmedetomidine 1 µg kg-1 (15 min) and remifentanil 0.1 µg kg-1 min-1 (Group R) or sufentanil 0.1 µg kg-1h-1 (Group S). Anesthesia was maintained with an intravenous infusion of dexmedetomidine 1.0 µg kg-1h-1, midazolam 0.015 mg kg-1h-1, remifentanil 0.1 µg kg-1min-1 (Group R), or sufentanil 0.1 µg kg-1h-1 (Group S). Hemodynamic and respiratory changes, modified OAA/S score and BIS values, postoperative Visual Analogue Scale pain scores, satisfaction of the patient and surgical team with the procedure, and adverse events and recovery time were recorded. RESULTS: Group R received significantly less midazolam and midazolam per hour compared to Group S (Group R vs. Group S: 3.4 ± 1.7 mg vs. 5.1 ± 2.0 mg, P < 0.0001; 1.5 ± 0.7 mg/h vs. 1.9 ± 0.6 mg/h, P = 0.002). The incidence of physical or verbal expressions of pain at the start of surgery was significantly lower in Group R compared to Group S (2 [4.3%] vs. 12 [26.7%], P = 0.003). Patient satisfaction with the procedure was significantly higher in Group R compared to Group S (3.9 ± 0.3 vs. 3.1 ± 0.3, P < 0.0001). CONCLUSION: Dexmedetomidine-remifentanil and dexmedetomidine-sufentanil were effective and safe sedative and analgesic agents for liposuction. Hemodynamic stability was maintained. Dexmedetomidine-remifentanil might be associated with improved analgesic effects compared to dexmedetomidine-sufentanil. LEVEL OF EVIDENCE II: Evidence was obtained from at least one properly designed randomized controlled trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury.

Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (also known as efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 mL/kg) for 4 h. On day 1 after mechanical ventilation, Tlr4+/+ or Tlr4-/- bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4+/+ BMDMs. Importantly, these proresolving effects by Tlr4+/+ BMDMs were abolished in mice receiving Tlr4-/- BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4-/- BMDMs than that in those receiving Tlr4+/+ BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4+/+ BMDMs, but not Tlr4-/- BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis.