Relationship between muscle mass ratio and rocuronium dose required for maintaining deep neuromuscular blockade: A prospective observational study.

BACKGROUND: Deep neuromuscular blockade (NMB) has benefits in various surgical procedures, however, precise quantitative neuromuscular monitoring is crucial for its proper maintenance and recovery. Neuromuscular blocking agent dosage relies on actual body weight (ABW), but this varies among individuals. Therefore, this study hypothesizes that there is a correlation between the rocuronium requirement for deep NMB and muscle mass ratio measured by bioelectric impedance analysis. METHODS: Ninety adult female patients undergoing laparoscopic operation were enrolled in this study. Muscle and fat masses were assessed using a body composition analyser. Deep NMB, defined as a post-tetanic count of 1-2, was maintained through the continuous infusion of rocuronium. The primary outcome involves determining the correlation between the rocuronium dose required for deep NMB and the muscle mass ratio. Conversely, secondary outcomes included assessing the relationship between the rocuronium dose for deep NMB and fat mass ratio, and ABW. Additionally, we investigated their relationship with rocuronium onset time and profound blockade duration. RESULTS: No relationship was observed between the muscle mass ratio and rocuronium dose required for maintaining deep NMB (r = 0.059 [95% CI = 0.153-0.267], p = 0.586). Fat mass ratio and ABW showed no correlation with the rocuronium dose, whereas rocuronium onset time was positively correlated with muscle mass ratio (r = 0.327) and negatively correlated with fat mass ratio (r = -0.302), respectively. Profound blockade duration showed no correlation with any of the assessed variables. CONCLUSIONS: No correlation was detected between muscle mass ratio and the rocuronium dose required to achieve deep NMB.

Effects of an in vitro vitamin D treatment on the inflammatory responses in visceral adipose tissue from Ldlr-/- mice.

BACKGROUND/OBJECTIVES: Atherosclerosis is associated with increased inflammation in the visceral adipose tissue (VAT). Vitamin D has been reported to modulate the inflammatory responses of stromal vascular cells (SVCs) and adipocytes in adipose tissue, but the role of vitamin D in atherosclerosis biology is unclear. This study examined the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) treatment on the inflammatory responses of SVCs and adipocytes from atherosclerotic mice. MATERIALS/METHODS: C57BL/6J (B6) mice were divided randomly into 2 groups and fed a 10% kcal fat control diet (control group, CON) or 41% kcal fat, 0.21% cholesterol (high fat + cholesterol, HFC) diet (obese group, OB), and B6.129S7-Ldlrtm1Her/J (Ldlr-/-) mice were fed a HFC diet (obese with atherosclerosis group, OBA) for 16 weeks. SVCs and adipocytes isolated from VAT were pre-incubated with 1,25(OH)2D3 for 24 h and stimulated with lipopolysaccarides for the next 24 h. Proinflammatory cytokine production by adipocytes and SVCs, the immune cell population in SVCs, and the expression of the genes involved in the inflammatory signaling pathway in SVCs were determined. RESULTS: The numbers of total macrophages and SVCs per mouse were higher in OB and OBA groups than the CON group. The in vitro 1,25(OH)2D3 treatment significantly reduced macrophages/SVCs (%) in the OBA group. Consistent with this change, the production of interleukin-6 and monocyte chemoattractant protein 1 (MCP-1) by SVCs from the OBA group was decreased by 1,25(OH)2D3 treatment. The 1,25(OH)2D3 treatment significantly reduced the toll-like receptor 4 and dual-specificity protein phosphatase 1 (also known as mitogen-activated protein kinase phosphatase 1) mRNA levels in SVCs and MCP-1 production by adipocytes from all 3 groups. CONCLUSIONS: These findings suggest that vitamin D can attribute to the inhibition of the inflammatory response in VAT from atherosclerotic mice by reducing proinflammatory cytokine production.

HA N193D substitution in the HPAI H5N1 virus alters receptor binding affinity and enhances virulence in mammalian hosts.

During the 2021/2022 winter season, we isolated highly pathogenic avian influenza (HPAI) H5N1 viruses harbouring an amino acid substitution from Asparagine(N) to Aspartic acid (D) at residue 193 of the hemagglutinin (HA) receptor binding domain (RBD) from migratory birds in South Korea. Herein, we investigated the characteristics of the N193D HA-RBD substitution in the A/CommonTeal/Korea/W811/2021[CT/W811] virus by using recombinant viruses engineered via reverse genetics (RG). A receptor affinity assay revealed that the N193D HA-RBD substitution in CT/W811 increases α2,6 sialic acid receptor binding affinity. The rCT/W811-HA193N virus caused rapid lethality with high virus titres in chickens compared with the rCT/W811-HA193D virus, while the rCT/W811-HA193D virus exhibited enhanced virulence in mammalian hosts with multiple tissue tropism. Surprisingly, a ferret-to-ferret transmission assay revealed that rCT/W811-HA193D virus replicates well in the respiratory tract, at a rate about 10 times higher than that of rCT/W811-HA193N, and all rCT/W811-HA193D direct contact ferrets were seroconverted at 10 days post-contact. Further, competition transmission assay of the two viruses revealed that rCT/W811-HA193D has enhanced growth kinetics compared with the rCT/W811-HA193N, eventually becoming the dominant strain in nasal turbinates. Further, rCT/W811-HA193D exhibits high infectivity in primary human bronchial epithelial (HBE) cells, suggesting the potential for human infection. Taken together, the HA-193D containing HPAI H5N1 virus from migratory birds showed enhanced virulence in mammalian hosts, but not in avian hosts, with multi-organ replication and ferret-to-ferret transmission. Thus, this suggests that HA-193D change increases the probability of HPAI H5N1 infection and transmission in humans.

Reduced side effects and improved pain management by continuous ketorolac infusion with patient-controlled fentanyl injection compared with single fentanyl administration in pelviscopic gynecologic surgery: a randomized, double-blind, controlled study.

BACKGROUND: A combination of opioids and adjunctive drugs can be used for intravenous patient-controlled analgesia (PCA) to minimize opioid-related side effects. We investigated whether two different analgesics administered separately via a dual-chamber PCA have fewer side effects with adequate analgesia than a single fentanyl PCA in gynecologic pelviscopic surgery. METHODS: This prospective, double-blind, randomized, and controlled study included 68 patients who underwent pelviscopic gynecological surgery. Patients were allocated to either the dual (ketorolac and fentanyl delivered by a dual-chamber PCA) or the single (fentanyl alone) group. Postoperative nausea and vomiting (PONV) and analgesic quality were compared between the two groups at 2, 6, 12, and 24 h postoperatively. RESULTS: The dual group showed a significantly lower incidence of PONV during postoperative 2-6 h (P = 0.011) and 6-12 h (P = 0.009). Finally, only two patients (5.7%) in the dual group and 18 (54.5%) in the single group experienced PONV during the entire postoperative 24 h and could not maintain intravenous PCA (odds ratio: 0.056, 95% CI [0.007, 0.229], P < 0.001). Despite the administration of less fentanyl via intravenous PCA during the postoperative 24 h in the dual group than in the single group (66.0 ± 77.8 vs. 383.6 ± 70.1 µg, P < 0.001), postoperative pain had no significant intergroup difference. CONCLUSIONS: Two different analgesics, continuous ketorolac and intermittent fentanyl bolus, administered via dual-chamber intravenous PCA, showed fewer side effects with adequate analgesia than conventional intravenous fentanyl PCA in gynecologic patients undergoing pelviscopic surgery.

Phosphocode-dependent glutamyl-prolyl-tRNA synthetase 1 signaling in immunity, metabolism, and disease.

Ubiquitously expressed aminoacyl-tRNA synthetases play essential roles in decoding genetic information required for protein synthesis in every living species. Growing evidence suggests that they also function as crossover mediators of multiple biological processes required for homeostasis. In humans, eight cytoplasmic tRNA synthetases form a central machinery called the multi-tRNA synthetase complex (MSC). The formation of MSCs appears to be essential for life, although the role of MSCs remains unclear. Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is the most evolutionarily derived component within the MSC that plays a critical role in immunity and metabolism (beyond its catalytic role in translation) via stimulus-dependent phosphorylation events. This review focuses on the role of EPRS1 signaling in inflammation resolution and metabolic modulation. The involvement of EPRS1 in diseases such as cancer is also discussed.

SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility.

With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.

Secreted Akkermansia muciniphila threonyl-tRNA synthetase functions to monitor and modulate immune homeostasis.

Commensal bacteria are critically involved in the establishment of tolerance against inflammatory challenges, the molecular mechanisms of which are just being uncovered. All kingdoms of life produce aminoacyl-tRNA synthetases (ARSs). Thus far, the non-translational roles of ARSs have largely been reported in eukaryotes. Here, we report that the threonyl-tRNA synthetase (AmTARS) of the gut-associated bacterium Akkermansia muciniphila is secreted and functions to monitor and modulate immune homeostasis. Secreted AmTARS triggers M2 macrophage polarization and orchestrates the production of anti-inflammatory IL-10 via its unique, evolutionary-acquired regions, which mediates specific interactions with TLR2. This interaction activates the MAPK and PI3K/AKT signaling pathways, which converge on CREB, leading to an efficient production of IL-10 and suppression of the central inflammatory mediator NF-κB. AmTARS restores IL-10-positive macrophages, increases IL-10 levels in the serum, and attenuates the pathological effects in colitis mice. Thus, commensal tRNA synthetases can act as intrinsic mediators that maintain homeostasis.

The effect of intranasal dexmedetomidine administration on emergence agitation or delirium in pediatric patients after general anesthesia: A meta-analysis of randomized controlled trials.

BACKGROUND: Emergence agitation or delirium can occur in pediatric patients after anesthesia. Dexmedetomidine is known to reduce the impairment of postoperative cognitive function. AIMS: This study aimed to identify the role of intranasal administration of dexmedetomidine in lowering the development of emergence agitation or emergence delirium in pediatric patients after general anesthesia. METHODS: Electronic databases, including PubMed, EMBASE, CENTRAL, Scopus, and Web of Science, were searched to identify studies. The primary outcome was the proportion of patients who underwent emergence agitation or emergence delirium after the surgery. Secondary outcomes included emergence time and incidence of postoperative nausea and/or vomiting. We estimated the odds ratio and mean difference with 95% confidence intervals for the determination of effect size using a random-effects model. RESULTS: In total, 2103 pediatric patients from 20 randomized controlled trials were included in the final analysis. The incidence of emergence agitation or emergence delirium was 13.6% in the dexmedetomidine group and 33.2% in the control group. The pooled effect size revealed that intranasal dexmedetomidine administration significantly reduced the incidence of postoperative emergence agitation or emergence delirium in pediatric patients undergoing surgery under general anesthesia (odds ratio 0.25, 95% confidence interval 0.18-0.34; p = .0000; I2 = 37.74%). Additionally, significant difference was observed in emergence time between the two groups (mean difference 2.42, 95% confidence interval 0.37-4.46; p = .021; I2 = 98.40%). Children in the dexmedetomidine group had a significantly lower incidence of postoperative nausea and/or vomiting than those in the control group (odds ratio 0.39, 95% confidence interval 0.24-0.64; p = .0002; I2 = 0.00%). CONCLUSIONS: Intranasal dexmedetomidine reduced the incidence of emergence agitation or emergence delirium in pediatric patients after general anesthesia.

Risks and outcome of fatal respiratory events after lung cancer surgery: cohort study in South Korea.

Background: Severe complications such as acute respiratory distress syndrome or respiratory failure can occur after lung cancer surgery. However, the prevalence and risk factors have not been well identified. The aim of this study was to investigate the prevalence of and risk factors for fatal respiratory events after lung cancer surgery in South Korea. Methods: The National Health Insurance Service database in South Korea was used to extract data of all adult patients who were diagnosed with lung cancer and underwent lung cancer surgery from January 1, 2011, to December 31, 2018, for a population-based cohort study. Diagnosis of acute respiratory distress syndrome or respiratory failure after surgery was defined as postoperative fatal respiratory event. Results: A total of 60,031 adult patients who received lung cancer surgery were included in the analysis. Among them, 0.5% (285/60,031) experienced fatal respiratory events after the lung cancer surgery. In multivariable logistic regression, some risk factors (older age, male sex, higher Charlson comorbidity index score, underlying severe disability, bilobectomy, pneumonectomy, redo-case, lower case volume, and open thoracotomy) for developing postoperative fatal respiratory events were identified. Moreover, the development of postoperative fatal respiratory events was associated with high in-hospital mortality, 1-year mortality, longer length of hospital stays, and higher total hospitalization costs. Conclusions: Postoperative fatal respiratory events might worsen the clinical outcomes of lung cancer surgery. The knowledge of potential risk factors related to postoperative fatal respiratory events could enable earlier intervention to reduce the occurrence of these events and improve the postoperative clinical outcome.

The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway

Abstract Background The precise underlying mechanism of antioxidant effects of dexmedetomidine-induced neuroprotection against cerebral ischemia has not yet been fully elucidated. Activation of Nuclear factor erythroid 2-related factor (Nrf2) and Heme Oxygenase-1 (HO-1) represents a major antioxidant-defense mechanism. Therefore, we determined whether dexmedetomidine increases Nrf2/HO-1 expression after global transient cerebral ischemia and assessed the involvement of Protein Kinase C (PKC) in the dexmedetomidine-related antioxidant mechanism. Methods Thirty-eight rats were randomly assigned to five groups: sham (n = 6), ischemic (n = 8), chelerythrine (a PKC inhibitor; 5 mg.kg-1 IV administered 30 min before cerebral ischemia) (n = 8), dexmedetomidine (100 µg.kg-1 IP administered 30 min before cerebral ischemia (n = 8), and dexmedetomidine + chelerythrine (n = 8). Global transient cerebral ischemia (10 min) was applied in all groups, except the sham group; histopathologic changes and levels of nuclear Nrf2 and cytoplasmic HO-1 were examined 24 hours after ischemia insult. Results We found fewer necrotic and apoptotic cells in the dexmedetomidine group relative to the ischemic group (p< 0.01) and significantly higher Nrf2 and HO-1 levels in the dexmedetomidine group than in the ischemic group (p< 0.01). Additionally, chelerythrine co-administration with dexmedetomidine attenuated the dexmedetomidine-induced increases in Nrf2 and HO-1 levels (p< 0.05 and p< 0.01, respectively) and diminished its beneficial neuroprotective effects. Conclusion Preischemic dexmedetomidine administration elicited neuroprotection against global transient cerebral ischemia in rats by increasing Nrf2/HO-1 expression partly via PKC signaling, suggesting that this is the antioxidant mechanism underlying dexmedetomidine-mediated neuroprotection.

Change in glottic view during intubation using a KoMAC videolaryngoscope: A retrospective analysis.

Intubation with videolaryngoscopy has become popular in various clinical settings. However, despite the use of a videolaryngoscope, difficult intubation still exists and intubation failure has been reported. This retrospective study assessed the efficacy of the 2 maneuvers in improving the glottic view during videolaryngoscopic intubation. The medical records of patients who underwent videolaryngoscopic intubation and whose glottal images were stored in electronic medical charts were reviewed. The videolaryngoscopic images were divided into 3 categories according to the applied optimization techniques as follows: conventional method, with the blade tip located in the vallecular; backward-upward-rightward pressure (BURP) maneuver; and epiglottis lifting maneuver. Four independent anesthesiologists scored the visualization of the vocal folds using the percentage of glottic opening (POGO, 0-100%) scoring system. A total of 128 patients with 3 laryngeal images were analyzed. The glottic view was the most improved in the epiglottis lifting maneuver among all the techniques. The median POGO scores were 11.3, 36.9, and 63.1 in the conventional method, BURP, and epiglottis lifting maneuver, respectively (P < .001). There were significant differences in the distribution of POGO grades according to the application of BURP and epiglottis lifting maneuvers. In the POGO grades 3 and 4 subgroups, the epiglottis lifting maneuver was more effective than the BURP maneuver in improving the POGO score Inadequate visualization of the vocal folds occurred even when intubation was performed using a videolaryngoscope. The application of optimization maneuvers, such as BURP and epiglottis lifting by the blade tip, could improve the glottic view.

Intraoperative 5-HT3 receptor antagonists decrease the prevalence of postoperative delirium in older adults undergoing hip fracture surgery: a single-center retrospective study.

PURPOSE: Postoperative delirium (POD) occurs commonly in older adults, resulting in unfavorable outcomes. Several recent clinical studies have suggested that 5-hydroxytryptamine 3 (5-HT3) receptor antagonists can treat and prevent POD. In this retrospective study, the association between 5-HT3 receptor antagonists and POD was investigated in older adults who underwent hip fracture surgery. METHODS: The electronic medical records of older adults aged ≥ 65 years who underwent hip fracture surgery between January 2011 and June 2018 were reviewed retrospectively. Multivariable logistic regression analysis was used to investigate the association between 5-HT3 receptor antagonists and the occurrence of POD. In addition to the incidence of POD, anesthesia-, surgery-, and patient-related factors related to POD were evaluated. RESULTS: Of the 1025 patients included, 813 (79.3%) were administered 5-HT3 receptor antagonists intraoperatively; 471 (45.9%) were administered ramosetron, and 342 (33.4%) were administered palonosetron. POD was identified in 242 patients (23.6%). Ramosetron and palonosetron reduced the POD incidence by 53% (odds ratio [OR] 0.47; 95% confidence interval [CI] 0.32‒0.71; P < 0.001) and 41% (OR 0.59; 95% CI 0.39‒0.89; P = 0.011), respectively. Additionally, age, American Society of Anesthesiologists physical status class 4, and male were confirmed as risk factors for POD. CONCLUSION: Intraoperative 5-HT3 receptor antagonists may be associated with a reduced risk of POD and can be considered one of the preventive strategies for POD in older adults undergoing hip fracture surgery.

The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway.

BACKGROUND: The precise underlying mechanism of antioxidant effects of dexmedetomidine-induced neuroprotection against cerebral ischemia has not yet been fully elucidated. Activation of Nuclear factor erythroid 2-related factor (Nrf2) and Heme Oxygenase-1 (HO-1) represents a major antioxidant-defense mechanism. Therefore, we determined whether dexmedetomidine increases Nrf2/HO-1 expression after global transient cerebral ischemia and assessed the involvement of Protein Kinase C (PKC) in the dexmedetomidine-related antioxidant mechanism. METHODS: Thirty-eight rats were randomly assigned to five groups: sham (n...=...6), ischemic (n...=...8), chelerythrine (a PKC inhibitor; 5...mg.kg-1 IV administered 30...min before cerebral ischemia) (n...=...8), dexmedetomidine (100.....g.kg-1 IP administered 30...min before cerebral ischemia (n...=...8), and dexmedetomidine...+...chelerythrine (n...=...8). Global transient cerebral ischemia (10...min) was applied in all groups, except the sham group; histopathologic changes and levels of nuclear Nrf2 and cytoplasmic HO-1 were examined 24...hours after ischemia insult. RESULTS: We found fewer necrotic and apoptotic cells in the dexmedetomidine group relative to the ischemic group (p...<...0.01) and significantly higher Nrf2 and HO-1 levels in the dexmedetomidine group than in the ischemic group (p...<...0.01). Additionally, chelerythrine co-administration with dexmedetomidine attenuated the dexmedetomidine-induced increases in Nrf2 and HO-1 levels (p...<...0.05 and p...<...0.01, respectively) and diminished its beneficial neuroprotective effects. CONCLUSION: Preischemic dexmedetomidine administration elicited neuroprotection against global transient cerebral ischemia in rats by increasing Nrf2/HO-1 expression partly via PKC signaling, suggesting that this is the antioxidant mechanism underlying dexmedetomidine-mediated neuroprotection.

Postoperative Delirium after Dexmedetomidine versus Propofol Sedation in Healthy Older Adults Undergoing Orthopedic Lower Limb Surgery with Spinal Anesthesia: A Randomized Controlled Trial.

BACKGROUND: Delirium is a critical postoperative complication in older patients. Based on the hypothesis that intraoperative dexmedetomidine sedation would lower postoperative delirium than propofol sedation would, the authors compared the incidence of postoperative delirium in older adults, using the mentioned sedatives. METHODS: This double-blinded, randomized controlled study included 748 patients, aged 65 yr or older, who were scheduled for elective lower extremity orthopedic surgery, between June 2017 and October 2021. Patients were randomized equally into two groups in a 1:1 ratio according to the intraoperative sedative used (dexmedetomidine vs. propofol). The postoperative delirium incidence was considered the primary outcome measure; it was determined using the confusion assessment method, on the first three postoperative days. The mean arterial pressure and heart rate were evaluated as secondary outcomes. RESULTS: The authors enrolled 732 patients in the intention-to-treat analyses. The delirium incidence was lower in the dexmedetomidine group than in the propofol group (11 [3.0%] vs. 24 [6.6%]; odds ratio, 0.42; 95% CI, 0.201 to 0.86; P = 0.036). During sedation, the mean arterial pressure (median [interquartile range] mmHg) was higher in the dexmedetomidine group (77 [71 to 84]) than in the propofol group (74 [69 to 79]; P < 0.001); however, it significantly fell lower (74 [68 to 80]) than that of the propofol group (80 [74 to 87]) in the postanesthesia care unit (P < 0.001). Lower heart rates (beats/min) were recorded with the use of dexmedetomidine than with propofol, both during sedation (60 [55 to 66] vs. 63 [58 to 70]) and in the postanesthesia care unit (64 [58 to 72] vs. 68 [62-77]; P < 0.001). CONCLUSIONS: Dexmedetomidine showed a lower incidence of postoperative delirium than propofol in healthy older adults undergoing lower extremity orthopedic surgery.

Pre-existing and new-onset depression among patients undergoing esophageal cancer surgery: a nationwide cohort study in South Korea.

BACKGROUND: Esophageal cancer is believed to be related to psychological stress. This study aimed to examine the prevalence and risk factors for new-onset depression after esophageal cancer surgery among patients who had no pre-existing depression. In addition, we examined whether pre-existing depression affected postoperative 1-year mortality. METHODS: The National Health Insurance Service database in South Korea was used for data extraction in this population-based cohort study. This study included all adult patients diagnosed with esophageal cancer who underwent esophageal surgery between January 1, 2011, and December 31, 2018. RESULTS: A total of 7039 adult patients who underwent esophageal cancer surgery at 95 South Korean hospitals were included in the analyses. Of the total, 608 patients (8.6%) were diagnosed with new-onset depression within 1 year after esophageal cancer surgery. Female sex, adjuvant chemotherapy, increased Charlson comorbidity index, pre-existing anxiety disorder, and pre-existing insomnia disorder were potential risk factors for new-onset depression. In multivariable Cox regression analysis, the pre-existing depression group showed a 1.27-fold (hazard ratio: 1.27; 95% confidence interval: 1.08-1.48; P = 0.004) higher risk of 1-year all-cause mortality than those who had no pre-existing depression. CONCLUSION: In South Korea, 8.6% of patients are newly diagnosed with depression after esophageal cancer surgery, and some potential risk factors have been identified. Moreover, pre-existing depression was associated with increased 1-year all-cause mortality. Patients with esophageal cancer and pre-existing depression may be at high risk, requiring interventions after esophageal cancer surgery.

SARS-CoV-2 variants show temperature-dependent enhanced polymerase activity in the upper respiratory tract and high transmissibility.

With the convergent global emergence of SARS-CoV-2 variants of concern (VOC), a precise comparison study of viral fitness and transmission characteristics is necessary for the prediction of dominant VOCs and the development of suitable countermeasures. While airway temperature plays important roles in the fitness and transmissibility of respiratory tract viruses, it has not been well studied with SARS-CoV-2. Here we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmission. Specifically, SARS-COV-2 variants containing the P323L or P323L/G671S mutation in the NSP12 RNA-dependent RNA polymerase (RdRp) exhibited enhanced RdRp enzymatic activity at 33°C compared to 37°C and high transmissibility in ferrets. MicroScale Thermophoresis demonstrated that the NSP12 P323L or P323L/G671S mutation stabilized the NSP12-NSP7-NSP8 complex interaction. Furthermore, reverse genetics-derived SARS-CoV-2 variants containing the NSP12 P323L or P323L/G671S mutation displayed enhanced replication at 33°C, and high transmission in ferrets. This suggests that the evolutionarily forced NSP12 P323L and P323L/G671S mutations of recent SARS-CoV-2 VOC strains are associated with increases of the RdRp complex stability and enzymatic activity, promoting the high transmissibility.

Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling.

The AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylates Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. EPRS1 compartmentalizes AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembles an AKT signaling complex specific for anti-inflammatory activity. These events promote AKT activation-mediated GSK3ß phosphorylation, which increase anti-inflammatory cytokine production. EPRS1-deficient macrophages do not assemble the early endosomal complex and consequently exacerbate inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling.

Total intravenous anesthesia induced and maintained by a combination of remimazolam and remifentanil without a neuromuscular blocking agent: a prospective, observational pilot study.

BACKGROUND: A novel short-acting benzodiazepine, Remimazolam, has recently been approved for general anesthesia and sedation. Hence, we investigated the feasibility and safety of remimazolam during the induction and maintenance of general anesthesia without using a neuromuscular blocking agent (NMBA) in patients undergoing hysteroscopic surgery. METHODS: This prospective observational study included 38 patients undergoing hysteroscopic surgery. Remimazolam and remifentanil were the main anesthetic agents without an NMBA, and a supraglottic airway was inserted to protect the airway. The induction time, amount of each anesthetic agent used during anesthesia, intraoperative bispectral index (BIS) hemodynamic parameters, and recovery profiles were measured. RESULTS: General anesthesia was successfully administered to 37 patients using remimazolam and remifentanil without NMBA. The induction doses of remimazolam and remifentanil were 0.4 mg/kg (interquartile range [IQR] 0.34-0.47 mg/kg) and 1.07 µg/kg (IQR, 0.90-1.29 µg/kg), respectively. Additionally, the maintenance doses of remimazolam and remifentanil were 1.14 mg/kg/h (IQR, 0.88-1.55 mg/kg/h) and 0.06 µg/kg/min (IQR, 0.04-0.08 µg/kg/min), respectively. Intraoperative BIS values had risen temporarily > 60 in eight patients (21.6%) despite administration of 2 mg/kg/h of remimazolam; thus, they were treated with supplementary midazolam. The median recovery time was 7 min (IQR, 5-8 min) after 40 min (IQR, 40.0-57.5 min) of total mean anesthesia time. There was no correlation between the infusion dose of remimazolam and recovery profiles, such as recovery time, final BIS of anesthesia, modified observer assessment of alertness/sedation (OAA/S) scale or post-anesthesia recovery (PAR) score when arriving at the PACU, and length of stay in the PACU (all P > 0.05). CONCLUSION: Remimazolam can be combined with remifentanil without an NMBA in female patients who undergo hysteroscopic surgery, during which a supraglottic airway is a feasible method to protect the airway. TRIAL REGISTRATION: The study protocol was registered at ClinicalTrials.gov (NCT05025410) on 27/08/2021.

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1-/-) mouse models to study RARRES1 function in vivo. Rarres1-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of Rarres1 led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, Rarres1-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. Rarres1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). Rarres1 deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.

Standard digit-based versus 90° rotation technique for supraglottic airway device insertion: a meta-analysis of randomized controlled trials.

BACKGROUND: Prompt insertion and placement of supraglottic airway (SGA) devices in the correct position are required to secure the airway. This meta-analysis was performed to validate the usefulness of the 90° rotation technique as compared with the standard digit-based technique for the insertion of SGA devices in anesthetized patients in terms of insertion success rate, insertion time, and postoperative complications. METHODS: A literature search of PubMed, EMBASE, CENTRAL, CINAHL, Scopus, and Web of Science was conducted. Randomized controlled trials, without limitations on publication period, language, journal, or region, until July 2021, that compared the 90° rotation and the standard digit-based techniques for insertion of SGA devices in anesthetized patients were included. RESULTS: The first-attempt (risk ratio [RR]: 1.16, 95% CI [1.09, 1.25], P < 0.001) and overall success rates (RR: 1.06, 95% CI [1.03, 1.09], P < 0.001) were significantly higher in the 90° rotation group. The insertion time was shorter in the 90° rotation group (mean difference: -4.42 s, 95% CI [-6.70, -2.15 s], P < 0.001). The incidences of postoperative sore throat (RR: 0.63, 95% CI [0.49, 0.83], P < 0.001) and blood staining (RR: 0.28, 95% CI [0.20, 0.39], P < 0.001) were lower in the 90° rotation group. CONCLUSIONS: The use of the 90° rotation technique increases the success rate of SGA device insertion and decreases postoperative complications as compared with that of the standard digit-based technique in anesthetized patients.