Effective bolus dose of remimazolam for i-gel® insertion in nonparalyzed patients: a dose-finding study.

PURPOSE: Remimazolam is a recently developed ultra-short-acting benzodiazepine used for anesthesia induction and maintenance. Nevertheless, the effective bolus dose of remimazolam for i-gel® (Intersurgical Ltd., Wokingham, Berkshire, UK) insertion without the use of neuromuscular blocking agents (NMBAs) has not been well established. METHODS: This study included 25 adult patients scheduled for surgery under general anesthesia who were eligible for i-gel use. Anesthesia was induced with predetermined bolus doses of remimazolam, starting at 0.3 mg·kg-1 for the first patient, without the use of NMBAs. All patients concurrently received remifentanil using target-controlled infusion (TCI) at a fixed effect-site concentration (Ce) of 3.0 ng·mL-1. Insertion of the i-gel was attempted 90 sec after remimazolam administration, and insertion conditions were assessed. Subsequent doses of remimazolam were decreased or increased by 0.05 mg·kg-1, depending on the success or failure of i-gel insertion. RESULTS: The mean (standard deviation) 50% effective dose (ED50) of a remimazolam bolus for successful i-gel insertion as determined by the modified Dixon's up-and-down method was 0.100 (0.027) mg·kg-1. The ED50 and ED95 estimated by isotonic regression were 0.111 (83% confidence interval [CI], 0.096 to 0.131) mg·kg-1 and 0.182 (95% CI, 0.144 to 0.195) mg·kg-1, respectively. None of the patients required treatment for hypotension or bradycardia during anesthesia induction. CONCLUSION: Based on the ED95 of remimazolam bolus dose determined in our study, we recommend using 0.182 mg·kg-1 of remimazolam in combination with remifentanil TCI at a Ce of 3.0 ng·mL-1 for successful i-gel insertion without NMBAs in adult patients. This regimen seems effective with a low risk of hemodynamic instability during anesthesia induction. STUDY REGISTRATION: ClinicalTrials.gov ( NCT05298228 ); first submitted 6 March 2022.

RéSUMé: OBJECTIF: Le remimazolam est une benzodiazépine à action ultra-courte récemment mise au point et utilisée pour l'induction et le maintien de l'anesthésie. Toutefois, la dose efficace en bolus de remimazolam pour l'insertion de l'i-gel® (Intersurgical Ltd., Wokingham, Berkshire, Royaume-Uni) sans utiliser de bloqueurs neuromusculaires (BNM) n'a pas été bien établie. MéTHODE: Cette étude a inclus 25 adultes devant bénéficier d'une intervention chirurgicale sous anesthésie générale qui étaient éligibles à l'utilisation d'un i-gel. L'anesthésie a été induite avec des doses prédéterminées en bolus de remimazolam, à partir de 0,3 mg·kg−1 pour la première personne, sans utiliser de BNM. Toutes les personnes anesthésiées ont reçu en parallèle du rémifentanil en perfusion à objectif de concentration à une concentration au site effecteur (Ce) de 3,0 ng·mL−1. L'insertion de l'i-gel a été tentée 90 secondes après l'administration de remimazolam, et les conditions d'insertion ont été évaluées. Les doses subséquentes de remimazolam ont été diminuées ou augmentées de 0,05 mg·kg−1, en fonction du succès ou de l'échec de l'insertion de l'i-gel. RéSULTATS: La dose efficace moyenne (écart type) de 50 % (DE50) d'un bolus de remimazolam pour une insertion réussie de l'i-gel, telle que déterminée par la méthode « up-and-down ¼ de Dixon modifiée, était de 0,100 (0,027) mg·kg−1. Les DE50 et DE95 estimées par régression isotonique étaient de 0,111 (intervalle de confiance [IC] à 83 %, 0,096 à 0,131) mg·kg−1 et 0,182 (IC 95 %, 0,144 à 0,195) mg·kg−1, respectivement. Aucun·e patient·e n'a eu besoin de traitement pour une hypotension ou une bradycardie pendant l'induction de l'anesthésie. CONCLUSION: D'après la DE95 de la dose de remimazolam en bolus déterminée dans notre étude, nous recommandons d'utiliser 0,182 mg·kg−1 de remimazolam en association avec une perfusion à objectif de concentration de rémifentanil à une Ce de 3,0 ng·mL−1 pour réussir l'insertion de l'i-gel sans BNM chez la patientèle adulte. Ce schéma semble efficace avec un faible risque d'instabilité hémodynamique lors de l'induction de l'anesthésie. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05298228); première soumission le 6 mars 2022.

A comparative study using gastric ultrasound to evaluate the safety of shortening the fasting time before pediatric echocardiography: a randomized controlled non-inferiority study.

PURPOSE: The objective of this study was to demonstrate that the gastric cross-sectional area (CSA) in the right lateral decubitus position (RLDP) during a 2-h fasting period is not larger than that during a conventional 4-h fasting period prior to pediatric echocardiography. METHODS: 93 patients aged under 3 years scheduled for echocardiography under sedation were enrolled and randomly allocated into two groups; 2-h fasting vs 4-h fasting. For group 4 h (n = 46), the patients were asked to be fasted for all types of liquid for more than 4 h, while group 2 h (n = 47) were asked to be fasted for all types of liquid for 2 h before echocardiography. Gastric ultrasound was performed before echocardiography, and CSARLDP was measured. We compared CSARLDP, incidence of at-risk stomach, fasting duration, and the incidence of major (pulmonary aspiration, aspiration pneumonia) and minor complications (nausea, retching, and vomiting, apnea, and bradycardia) between two groups. RESULTS: The mean difference of CSARLDP (group 2 h-group 4 h) was 0.49 (- 0.18 to 1.17) cm2, and it was within the non-inferiority margin (Δ = 2.1 cm2). There was no difference in the incidence of at-risk stomach (P = 0.514). There was no significant difference in the incidence of major and minor complications between the two groups. CONCLUSION: Two-hour fasting in pediatric patients who need an echocardiography did not increase major and minor complications and CSA significantly.

Association between body composition and chronic low back pain in Korean adults aged over 50 years: The Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2011.

Background The relationship between overweight or obesity and low back pain (LBP) has previously been investigated. Several recent studies have focused on the relationship between other indicators of obesity, particularly indicators of fat and the risk of LBP. However, the results of body composition and LBP have been inconsistent. Methods All data for the present retrospective, cross-sectional study was extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) versions V-1 and 2 conducted in 2010 and 2011 by the Korean Centers for Disease Control and Prevention. In KNHANES V-1 (2010) and V-2 (2011), those over 50 years of age completed the surveys on LBP, body weight, and body composition assessed using dual-energy X-ray absorptiometry (DXA) were included. The multivariable logistic regression analysis was used to examine the relationship between the presence of chronic LBP and body composition adjusting for confounders. Results We analyzed 3,579 persons who completed the question. In the multivariable analyses adjusting for age and sex, none of the variables, including fat mass and fat-free mass, remained positively or negatively associated with LBP. Additionally, when depression, smoking, alcohol intake, physical activity, diabetes mellitus, and fat or lean tissue mass were included in the multivariable logistic model, no significant associations were found between all measures of fat mass, fat-free mass, and LBP Conclusion This study is contrary to previous studies that concluded that there is a correlation between obesity and fat mass and LBP. LBP is not associated with increased levels of obesity and fat mass.

Body Map of Droplet Distributions During Oropharyngeal Suction to Protect Health Care Workers From Airborne Diseases.

PURPOSE: Health care workers (HCWs), and in particular anesthesia providers, often must perform aerosol-generating medical procedures (AGMPs). However, no studies have analyzed droplet distributions on the bodies of HCWs during AGMPs. Therefore, the purpose of this study was to assess and analyze droplet distributions on the bodies of HCWs during suction of oral cavities with and without oral airways and during extubations. DESIGN: Using a quasi-experiemental design, we assumed the HCWs perform suction and extubation on intubated patients, and we prepared an intubated mannequin mimicking a patient. This study performed the oral suction and extubation on the intubated mannequin (with or without oral airways in place) and analyzed the droplet distributions. METHODS: We prepared a mannequin intubated with an 8.0 mm endotracheal tube, assuming the situation of general anesthesia. We designed the body mapping gown, and divided it into 10 areas including the head, neck, chest, abdomen, upper arms, forearms, and hands. We classified experiments into group O when suctions were performed on the mannequin with an oral airway, and into group X when the suctions were performed on the mannequin without an oral airway. An experienced board-certified anesthesiologist performed 10 oral suctions on each mannequin, and 10 extubations. We counted the droplets on the anesthesiologist's gown according to the divided areas after each procedure. FINDINGS: The mean droplet count after suction was 6.20 ± 2.201 in group O and 13.6 ± 4.300 in group X, with a significant difference between the two groups (P < .001). The right and left hands were the most contaminated areas in group O (2.8 ± 1.033 droplets and 2.0 ± 0.943 droplets, respectively). The abdomen, right hand, left forearm, and left hand showed many droplets in group X. (1.3 ± 1.337 droplets, 3.1 ± 1.792 droplets, 3.2 ± 3.910 droplets, and 4.3 ± 2.214 droplets, respectively). The chest, abdomen, and left hand presented significantly more droplets in group X than in group O. The trunk area (chest and abdomen) was exposed to more droplets during extubations than during suctions. CONCLUSIONS: During suctions, more droplets are splattered from mannequins without oral airways than from those with oral airways. The right and left hands were the most contaminated areas in group O. Moreover, the abdomen, right hand, left forearm, and left hand presented a lot of droplets in group X. In addition, extubations contaminate wider areas (the head, neck, chest and abdomen) of an HCW than suctions.

Dynamic Arterial Elastance as a Predictor of Supine-to-Prone Hypotension (SuProne Study): An Observational Study.

Background and Objectives: Supine-to-prone hypotension is caused by increased intrathoracic pressure and decreased venous return in the prone position. Dynamic arterial elastance (Eadyn) indicates fluid responsiveness and can be used to predict hypotension. This study aimed to investigate whether Eadyn can predict supine-to-prone hypotension. Materials and Methods: In this prospective, observational study, 47 patients who underwent elective spine surgery in the prone position were enrolled. Supine-to-prone hypotension is defined as a decrease in Mean Arterial Pressure (MAP) by more than 20% in the prone position compared to the supine position. Hemodynamic parameters, including systolic blood pressure (SAP), diastolic blood pressure, MAP, stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index, cardiac index, dP/dt, and hypotension prediction index (HPI), were collected in the supine and prone positions. Supine-to-prone hypotension was also assessed using two different definitions: MAPprone < 65 mmHg and SAPprone < 100 mmHg. Hemodynamic parameters were analyzed to determine the predictability of supine-to-prone hypotension. Results: Supine-to-prone hypotension occurred in 13 (27.7%) patients. Eadyn did not predict supine-to-prone hypotension [Area under the curve (AUC), 0.569; p = 0.440]. SAPsupine > 139 mmHg (AUC, 0.760; p = 0.003) and dP/dtsupine > 981 mmHg/s (AUC, 0.765; p = 0.002) predicted supine-to-prone hypotension. MAPsupine, SAPsupine, PPVsupine, and HPIsupine predicted MAPprone <65 mm Hg. MAPsupine, SAPsupine, SVVsupine, PPVsupine, and HPIsupine predicted SAPprone < 100 mm Hg. Conclusions: Dynamic arterial elastance did not predict supine-to-prone hypotension in patients undergoing spine surgery. Systolic arterial pressure > 139 mmHg and dP/dt > 981 mmHg/s in the supine position were predictors for supine-to-prone hypotension. When different definitions were employed (mean arterial pressure < 65 mmHg in the prone position or systolic arterial pressure < 100 mmHg in the prone position), low blood pressures in the supine position were related to supine-to-prone hypotension.

Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation.

RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RA-PH module of RIAM interacts with GTP-bound RAP1 and phosphoinositol 4,5 bisphosphate but this interaction is inhibited by the N-terminal segment of RIAM. Here we report the structural basis for the autoinhibition of RIAM by an intramolecular interaction between the IN region (aa 27-93) and the RA-PH module. We solved the crystal structure of IN-RA-PH to a resolution of 2.4-Å. The structure reveals that the IN segment associates with the RA segment and thereby suppresses RIAM:RAP1 association. This autoinhibitory configuration of RIAM can be released by phosphorylation at Tyr45 in the IN segment. Specific inhibitors of focal adhesion kinase (FAK) blocked phosphorylation of Tyr45, inhibited stimulated translocation of RIAM to the plasma membrane, and inhibited integrin-mediated cell adhesion in a Tyr45-dependent fashion. Our results reveal an unusual regulatory mechanism in small GTPase signaling by which the effector molecule is autoinhibited for GTPase interaction, and a modality of integrin activation at the level of RIAM through a FAK-mediated feedforward mechanism that involves reversal of autoinhibition by a tyrosine kinase associated with integrin signaling.

Gastric Ultrasound Assessing Gastric Emptying of Preoperative Carbohydrate Drinks: A Randomized Controlled Noninferiority Study.

BACKGROUND: Tools for the evaluation of gastric emptying have evolved over time. The purpose of this study was to show that the risk of pulmonary aspiration is not increased with carbohydrate drink, by demonstrating that the gastric antral cross-sectional area (CSA) of the NO-NPO group is either equivalent to or less than that of the NPO (nil per os) group. METHODS: Sixty-four patients scheduled for elective laparoscopic benign gynecologic surgery were enrolled and randomly assigned to the NPO group (n = 32) or the NO-NPO group (n = 32). After having a regular meal until midnight before surgery, the NPO group fasted until surgery, while the NO-NPO group ingested 400 mL of a carbohydrate drink at midnight and freely up to 2 hours before anesthesia. The primary outcome was the gastric antral CSA by gastric ultrasound in right lateral decubitus position (RLDP). Noninferiority was defined as a mean difference of CSA <2.8 cm2. Secondary outcomes included CSA in supine position, gastric volume (GV), GV per weight (GV/kg), GV/kg >1.5 mL/kg, and Perlas grade. RESULTS: CSA in RLDP was not different between the NPO group (6.25 ± 3.79 cm2) and the NO-NPO group (6.21 ± 2.48 cm2; P = .959). The mean difference of CSA in RLDP (NO-NPO group - NPO group) was 0.04 (95% confidence interval [CI], -1.56 to 1.64), which was within the noninferiority margin of 2.8 cm2. CSA was not different between the 2 groups (4.17 ± 2.34 cm2 in NPO group versus 4.28 ± 1.23 cm2 in NO-NPO group; P = .828). GV in NPO group (70 ± 56 mL) was not different from NO-NPO group (66 ± 36 mL; mean difference, 3.66; 95% CI, -20 to 27; P = .756). GV/kg in the NPO group (1.25 ± 1.00 mL/kg) was not different from the NO-NPO group (1.17 ± 0.67 mL/kg; P = .694). The incidence of GV/kg > 1.5 mL/kg was not different between NPO (31.3%) and NO-NPO group (21.9%; P = .768). The median (interquartile range) of the Perlas grade was 1 (0-1) in NPO group and 0.5 (0-1) in NO-NPO group (P = .871). CONCLUSIONS: Preoperative carbohydrates ingested up to 2 hours before anesthesia do not delay gastric emptying compared to midnight fasting, as evaluated with gastric ultrasound.

Preoperative Oral Carbohydrate Loading in Laparoscopic Gynecologic Surgery: A Randomized Controlled Trial.

STUDY OBJECTIVE: To determine whether carbohydrate loading improves the postoperative quality of recovery (QoR) better than the midnight fasting policy in laparoscopic gynecologic surgeries. DESIGN: Randomized, parallel-group trial. SETTING: Tertiary university hospital. PATIENTS: Female patients scheduled for laparoscopic gynecologic surgery for nonmalignant gynecologic diseases. INTERVENTIONS: Eighty-eight women were randomly assigned to the midnight fasting group (nil per os, NPO group) or the carbohydrate loading group (carbohydrate group). Patients in both groups adhered to the enhanced recovery after surgery protocol except for carbohydrate intake in the carbohydrate group. MEASUREMENTS AND MAIN RESULTS: The postoperative QoR was evaluated using the QoR 15-item questionnaire on postoperative day 2. The times to readiness for discharge of the groups were compared. The QoR 15-item questionnaire scores were 97.7 ± 23.0 in the NPO group and 99.6 ± 22.4 in the carbohydrate group; they were not statistically different (p = .702). The times to readiness for discharge of both groups were also not different: 36.8 ± 12.2 hours in the NPO group and 37.6 ± 11.8 hours in the carbohydrate group (p = .684). CONCLUSION: The benefit of carbohydrate beverage intake was not significant in laparoscopic gynecologic surgeries when following the enhanced recovery after surgery protocol.

Machine Learning Approaches to Predict Chronic Lower Back Pain in People Aged over 50 Years.

Background and Objectives: Chronic lower back pain (LBP) is a common clinical disorder. The early identification of patients who will develop chronic LBP would help develop preventive measures and treatment. We aimed to develop machine learning models that can accurately predict the risk of chronic LBP. Materials and Methods: Data from the Sixth Korea National Health and Nutrition Examination Survey conducted in 2014 and 2015 (KNHANES VI-2, 3) were screened for selecting patients with chronic LBP. LBP lasting >30 days in the past 3 months was defined as chronic LBP in the survey. The following classification models with machine learning algorithms were developed and validated to predict chronic LBP: logistic regression (LR), k-nearest neighbors (KNN), naïve Bayes (NB), decision tree (DT), random forest (RF), gradient boosting machine (GBM), support vector machine (SVM), and artificial neural network (ANN). The performance of these models was compared with respect to the area under the receiver operating characteristic curve (AUROC). Results: A total of 6119 patients were analyzed in this study, of which 1394 had LBP. The feature selected data consisted of 13 variables. The LR, KNN, NB, DT, RF, GBM, SVM, and ANN models showed performances (in terms of AUROCs) of 0.656, 0.656, 0.712, 0.671, 0.699, 0.660, 0.707, and 0.716, respectively, with ten-fold cross-validation. Conclusions: In this study, the ANN model was identified as the best machine learning classification model for predicting the occurrence of chronic LBP. Therefore, machine learning could be effectively applied in the identification of populations at high risk of chronic LBP.

Comparison of vasodilatory properties between desflurane and sevoflurane using perfusion index: a randomised controlled trial.

BACKGROUND: The perfusion index (PI), calculated from the photoplethysmographic waveform, reflects peripheral vasomotor tone. As such, the PI serves as a surrogate for quantitative measures of drug-induced vasoconstriction or vasodilation. This study aimed to compare the effect on the PI of desflurane and sevoflurane at equi-anaesthetic concentrations in patients undergoing single-agent inhalation anaesthesia, where equi-anaesthetic dose was based on the known minimum alveolar concentration of these agents. METHODS: We randomly allocated patients scheduled for arthroscopic knee surgery to receive either desflurane or sevoflurane general anaesthesia after target-controlled induction of anaesthesia with propofol. Anaesthesia was maintained at age-corrected minimum alveolar concentration 1.0, under neuromuscular block (rocuronium). The PI and haemodynamic data were recorded every minute for 35 min after induction of anaesthesia and after standardised nociceptive stimulation. The primary outcome was PI, compared between the groups over time (repeated-measures analysis of variance). Secondary outcomes included MAP and HR. RESULTS: Sixty-nine participants (mean [range] age: 42 yr [19-65 yr]; 49% females) were assigned to either desflurane (n=34) or sevoflurane (n=35). The PI remained higher under desflurane compared with sevoflurane, both before (mean difference [MD]: 3.3; 95% confidence intervals [CIs]: 2.0-4.7; P<0.001) and after tetanic stimulation (MD: 2.8; 95% CI: 2.0-3.7; P<0.001). Higher PI paralleled lower MAP in participants assigned to desflurane anaesthesia (P<0.001), both before (MD: 8 mm Hg; 95% CI: 4-12) and after nociceptive stimulation (MD: 14 mm Hg; 95% CI: 7-22). HR was similar throughout. CONCLUSIONS: These findings suggest that at equipotent doses, desflurane exerts more potent vasodilatory properties and lowers blood pressure by a magnitude potentially associated with harm. CLINICAL TRIAL REGISTRATION: NCT03570164.

Comparison of single minimum dose administration of dexmedetomidine and midazolam for prevention of emergence delirium in children: a randomized controlled trial.

PURPOSE: Emergence delirium (ED) is common in children after sevoflurane anesthesia and should be prevented for patient safety. A prospective, double-blind, randomized, controlled study was performed to compare the efficacy of minimal dosage of midazolam versus dexmedetomidine to prevent ED in children undergoing tonsillectomy. METHODS: Seventy children aged 24 months to 12 years were allocated to receive midazolam (0.03 mg/kg) or dexmedetomidine (0.3 µg/kg) 5 min before the end of surgery. The incidence and severity of ED were assessed using a four-point scale and the pediatric anesthesia emergence delirium scale, respectively. The emergence time and postoperative pain scores were also evaluated. RESULTS: The incidence of ED was 31.3% in the midazolam group and 26.5% in the dexmedetomidine group (P = 0.668). The severity of ED was similar in both groups (9.6 ± 5.8 in the midazolam group, vs. 8.1 ± 5.9 in the dexmedetomidine group, P = 0.299). The emergence time was comparable in the two groups [11.0 (8.3-13.8) min in midazolam group vs. 12.0 (10.0-13.5) min in dexmedetomidine group (P = 0.218)]. Postoperative pain score was higher in the midazolam group [0 (0-1)] than in the dexmedetomidine group [0 (0-0)] (P = 0.011). CONCLUSION: Dexmedetomidine and midazolam at single minimum dosages had equal effectiveness to prevent ED in children without delaying emergence time, when administered at the end of surgery. With regards to postoperative analgesic efficacy, although dexmedetomidine showed statistically significant higher analgesic effect than midazolam, further clinical investigations are needed to validate our findings.

Comparison of impacts of intraperitoneal saline instillation with and without pulmonary recruitment maneuver on post-laparoscopic shoulder pain prevention: a randomized controlled trial.

BACKGROUND: Intraperitoneal isotonic saline instillation (SI) and pulmonary recruitment maneuver (RM) were indicated to alleviate post-laparoscopic shoulder pain (PLSP) effectively. The aim of this study was to compare the effects of the single strategy using SI alone and the combined strategy using SI and RM on PLSP reduction. METHODS: Subjects undergoing elective gynecologic laparoscopy were randomly allocated to a control group (no intervention, n = 48) and two intervention groups (single strategy of SI alone, n = 48; combined strategy of SI and RM, n = 48). In the control group, carbon dioxide was removed only via passive evacuation through the port sites at the completion of the laparoscopic procedure. In the saline instillation group, 20-mL/kg of body weight SI was performed. In the combined strategy group, RM using five pulmonary inflations was performed, in addition to SI. The PLSP scores, which were the primary outcome, were recorded using a visual analog scale postoperatively. RESULTS: The PLSP scores 24 and 48 h after surgery were significantly lower in the two intervention groups than in the control group (P = 0.014 and P = 0.001, respectively), while no significant differences were observed between the two intervention groups. CONCLUSIONS: The single strategy using SI alone is as effective as the combined strategy of SI and RM for removing residual carbon dioxide and consequently preventing PLSP. Therefore, considering the potential risks of pulmonary or hemodynamic complications associated with RM, the single strategy using SI alone might be a better choice than the combined strategy.

Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells.

Auranofin is a gold complex categorized as an anti-rheumatic agent. Recently, several investigators suggested that auranofin may act as a potent anti-cancer drug for breast tumors. Nutlin-3a is a cis-imidazoline analog which prevents interaction between mouse double minute 2 homolog (MDM2) and the tumor suppressor p53. The aim of this study was to examine cell growth inhibition mediated by auranofin or nutlin-3a individually as well as in combination with MCF-7 and MDA-MB-231 cells. To assess any potential synergistic effects between auranofin and nutlin-3a, low concentrations of auranofin and nutlin-3a were simultaneously incubated with MCF-7 and MDA-MB-231 cells. Cell viability assay, caspase-3/7 assay, and poly (ADP-ribose) polymerase cleavage revealed that auranofin and nutlin-3a exerted a synergistic effect on cancer cell apoptosis. Isobologram analysis of MCF-7 and MDA-MB-231 cells noted evident synergism between auranofin and nutlin-3a. The combined treatment increased the expression of mitochondrial pro-apoptotic factors such as Bcl-2 associated X protein and Bcl-2 homologous antagonist/killer. Further, combination treatment significantly enhanced reactive oxygen species (ROS) generation in MCF-7 and MDA-MB-231 cells. In conclusion, data demonstrated that combined treatment with auranofin and nutlin-3a exhibited a synergistic action on breast cancer cells and this combination may be considered for use as a novel therapeutic strategy for breast cancer.

Efficacy of Palonosetron-Dexamethasone Combination Versus Palonosetron Alone for Preventing Nausea and Vomiting Related to Opioid-Based Analgesia: A Prospective, Randomized, Double-blind Trial.

Background: The efficacy of dexamethasone plus palonosetron for postoperative nausea and vomiting (PONV) prophylaxis is not firmly established. This randomized, double-blind, controlled study evaluated whether the combination was superior to palonosetron alone in preventing PONV in patients receiving intravenous patient-controlled analgesia (IV-PCA) after upper extremity surgery. Methods: A total of 202 patients undergoing upper extremity surgery were randomly assigned to group P (palonosetron alone) or group PD (palonosetron plus dexamethasone). Group P patients received palonosetron 0.075 mg and normal saline 1.6 mL; group PD patients received palonosetron 0.075 mg and dexamethasone 8 mg. In both groups, palonosetron was added to the IV-PCA opioid infusion, which was continued for 48 h postoperatively. Incidence and severity of nausea, incidence of vomiting, rescue antiemetic requirements, pain intensity, and rescue analgesic requirements were evaluated for 72 h postoperatively. Quality of recovery was assessed using the quality of recovery-15 (QoR-15) questionnaire. Results: The incidence of PONV was significantly lower in group PD than in group P at 0-48 h postoperatively (61.5% vs 77.1%; p = 0.019). Severity of nausea at 0-6 h postoperatively was significantly less in group PD compared with group P (none/mild/moderate/severe: 49/22/15/10 vs. 36/16/25/19, p = 0.008). The incidence of vomiting and rescue antiemetic requirements were similar between groups. Pain intensity was significantly less in group PD than in group P at 0-48 h and 48-72 h postoperatively. Global QoR-15 was similar 24 h postoperatively between groups. Conclusions: Dexamethasone-palonosetron combination therapy reduced PONV incidence and postoperative pain in patients receiving opioid-based analgesia after upper extremity surgery.

Flavimarina flava sp. nov., isolated from Salicornia herbacea.

A Gram-stain-negative, motile-by-gliding, aerobic, non-spore-forming, rod-shaped and yellow-pigmented bacterium was isolated from Salicornia herbacea in the Yellow Sea and designated as strain MBLN091T. It belonged to the family Flavobacteriaceae. The 16S rRNA gene sequence of this isolated strain was similar to that of Flavimarina pacifica IDSW-73T with 94.8 % similarity, and with 92.3-92.8 % similarities to those of other closely related species of the genus Leeuwenhoekiella. The similarities of the RNA polymerase subunit B gene between this strain and F. pacifica KCTC 32466T and Leeuwenhoekiella marinoflava DSM 3653T were 80.5 and 80.2 %, respectively. Growth of strain MBLN091T was observed in the presence of 0.5‒15.0 % (w/v) NaCl at 4‒35 °C and pH 6.0-8.0, with optimal growth in the presence of 2.5‒5.0 % (w/v) NaCl at 20‒25 °C and pH 7.0. This isolate was able to hydrolyse gelatin. The only respiratory quinone was MK-6. The major polar lipids were phosphatidylethanolamine, an unidentified aminolipid and two unidentified lipids. Major fatty acids of the isolate were iso-C15 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), iso-C17 : 0 3-OH and iso-C15 : 1 G. The genomic DNA G+C content was 39.6 mol%. The physiological features were closely related to F. pacifica. Therefore, strain MBLN091T is considered to represent a novel species within the genus Flavimarina, for which the name Flavimarina flava sp. nov. is proposed. The type strain is MBLN091T (=KCTC 52527T=JCM 31731T).

ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex.

To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that, in nulliparous Wap-Cre;EN females, committed alveolar bipotent or CD61(+) luminal progenitors are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given the increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of preclinical models.

cAMP signaling inhibits radiation-induced ATM phosphorylation leading to the augmentation of apoptosis in human lung cancer cells.

BACKGROUND: The ataxia-telangiectasia mutated (ATM) protein kinase plays a central role in coordinating the cellular response to radiation-induced DNA damage. cAMP signaling regulates various cellular responses including metabolism and gene expression. This study aimed to investigate the mechanism through which cAMP signaling regulates ATM activation and cellular responses to ionizing radiation in lung cancer cells. METHODS: Lung cancer cells were transfected with constitutively active stimulatory G protein (GαsQL), and irradiated with γ-rays. The phosphorylation of ATM and protein phosphatase 2A was analyzed by western blotting, and apoptosis was assessed by western blotting, flow cytometry, and TUNNEL staining. The promoter activity of NF-κB was determined by dual luciferase reporter assay. BALB/c mice were treated with forskolin to assess the effect in the lung tissue. RESULTS: Transient expression of GαsQL significantly inhibited radiation-induced ATM phosphorylation in H1299 human lung cancer cells. Treatment with okadaic acid or knock down of PP2A B56δ subunit abolished the inhibitory effect of Gαs on radiation-induced ATM phosphorylation. Expression of GαsQL increased phosphorylation of the B56δ and PP2A activity, and inhibition of PKA blocked Gαs-induced PP2A activation. GαsQL enhanced radiation-induced cleavage of caspase-3 and PARP and increased the number of early apoptotic cells. The radiation-induced apoptosis was increased by inhibition of NF-κB using PDTC or inhibition of ATM using KU55933 or siRNA against ATM. Pretreatment of BALB/c mice with forskolin stimulated phosphorylation of PP2A B56δ, inhibited the activation of ATM and NF-κB, and augmented radiation-induced apoptosis in the lung tissue. GαsQL expression decreased the nuclear levels of the p50 and p65 subunits and NF-κB-dependent activity after γ-ray irradiation in H1299 cells. Pretreatment with prostaglandin E2 or isoproterenol increased B56δ phosphorylation, decreased radiation-induced ATM phosphorylation and increased apoptosis. CONCLUSIONS: cAMP signaling inhibits radiation-induced ATM activation by PKA-dependent activation of PP2A, and this signaling mechanism augments radiation-induced apoptosis by reducing ATM-dependent activation of NF-κB in lung cancer cells.

Inhibition of talin-induced integrin activation by a double-hit stapled peptide.

Integrins are ubiquitously expressed cell-adhesion proteins. Activation of integrins is triggered by talin through an inside-out signaling pathway, which can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two distinct sites. A helical talin-binding segment (TBS) in RIAM interacts with both sites in talin, leading to integrin activation. The bispecificity inspires a "double-hit" strategy for inhibiting talin-induced integrin activation. We designed an experimental peptidomimetic inhibitor, S-TBS, derived from TBS and containing a molecular staple, which leads to stronger binding to talin and inhibition of talin:integrin interaction. The crystallographic study validates that S-TBS binds to the talin rod through the same interface as TBS. Moreover, the helical S-TBS exhibits excellent cell permeability and effectively suppresses integrin activation in cells in a talin-dependent manner. Our results shed light on a new class of integrin inhibitors and a novel approach to design multi-specific peptidomimetic inhibitors.

Predicting the risk of inappropriate depth of endotracheal intubation in pediatric patients using machine learning approaches.

Endotracheal tube (ET) misplacement is common in pediatric patients, which can lead to the serious complication. It would be helpful if there is an easy-to-use tool to predict the optimal ET depth considering in each patient's characteristics. Therefore, we plan to develop a novel machine learning (ML) model to predict the appropriate ET depth in pediatric patients. This study retrospectively collected data from 1436 pediatric patients aged < 7 years who underwent chest x-ray examination in an intubated state. Patient data including age, sex, height weight, the internal diameter (ID) of the ET, and ET depth were collected from electronic medical records and chest x-ray. Among these, 1436 data were divided into training (70%, n = 1007) and testing (30%, n = 429) datasets. The training dataset was used to build the appropriate ET depth estimation model, while the test dataset was used to compare the model performance with the formula-based methods such as age-based method, height-based method and tube-ID method. The rate of inappropriate ET location was significantly lower in our ML model (17.9%) compared to formula-based methods (35.7%, 62.2%, and 46.6%). The relative risk [95% confidence interval, CI] of an inappropriate ET location compared to ML model in the age-based, height-based, and tube ID-based method were 1.99 [1.56-2.52], 3.47 [2.80-4.30], and 2.60 [2.07-3.26], respectively. In addition, compared to ML model, the relative risk of shallow intubation tended to be higher in the age-based method, whereas the risk of the deep or endobronchial intubation tended to be higher in the height-based and the tube ID-based method. The use of our ML model was able to predict optimal ET depth for pediatric patients only with basic patient information and reduce the risk of inappropriate ET placement. It will be helpful to clinicians unfamiliar with pediatric tracheal intubation to determine the appropriate ET depth.

Differences in preoperative gastric ultrasound findings in elderly compared to the mid-aged surgical patients: A retrospective observational study.

This study aimed to compare gastric ultrasound assessments between young and elderly patients, to determine whether the cross-section area (CSA) cutoff values for elderly and young patients should be different, and to suggest CSA cutoff values for elderly patients. This study evaluated the data of 120 patients who underwent elective surgery under general anesthesia between July 2019 and August 2020. Demographic and gastric ultrasound assessment data were retrieved. Patients were divided into the elderly group (n = 58, age: ≥65 years) and young group (n = 62, age: <65 years). The CSAs in the supine and right lateral decubitus positions (RLDP), semiquantitative 3-point Perlas grade (grades 0, 1, and 2), and gastric volume (GV) were determined. CSAs according to different Perlas grades were compared between the 2 groups. To compare normally and non-normally distributed continuous data, Student t test and the Mann-Whitney U test were used, respectively. Categorical data were compared using the chi-square test or Fisher exact test, as appropriate. The receiver operating characteristic (ROC) curves were built for the CSAs to predict pulmonary aspiration. The CSA cutoff values for predicting a high risk of pulmonary aspiration in both the groups were determined. Among patients with Perlas grade 0, the CSAsupine (P = .002) and CSARLDP (P = .002) were greater in the elderly group than in the young group. The specificity, positive predictive value, and accuracy of the CSA decreased when the CSA cutoff value for the young group was applied to the elderly group. The CSA cutoff values for the elderly group were: CSAsupine, 6.92 cm2 and CSARLDP, 10.65 cm2. The CSA of the empty stomach was greater in elderly patients than in young patients. We suggest that the following CSA cutoff values should be used for predicting pulmonary aspiration risk in elderly patients: CSAsupine, 6.92 cm2 and CSARLDP, 10.65 cm2.