Phase Angle as a Reliable Biomarker of Frailty to Predict Postoperative Outcomes in Patients Undergoing Off-Pump Coronary Artery Grafting: A Prospective Observational Study.

OBJECTIVE: To elucidate the association between phase angle (PA) and a composite adverse outcome in patients requiring off-pump coronary artery bypass grafting (OPCAB). DESIGN: A prospective observational study. SETTING: High-volume single center. PARTICIPANTS: A total of 229 adult patients who underwent OPCAB from May 2019 to October 2020. INTERVENTIONS: Each patient underwent bioelectrical impedance analysis, including PA assessment before surgery (PApre), immediately postoperatively (PApost), and 1 day postoperatively (PAPOD1), using an Inbody S10. Frailty index and nutritional assessments also were obtained before surgery. MEASUREMENTS AND MAIN RESULTS: Patient outcomes were assessed using a composite adverse outcome comprising death, myocardial infarction, revascularization, new-onset atrial fibrillation, acute kidney injury, stroke, postoperative pulmonary complications, wound complications, sepsis, reoperation, and/or delirium occurring during hospitalization and over the following year. Patients for whom composite adverse outcomes were reported had lower PApre than those without complications (5.4 ± 0.9 v 6.0 ± 0.9, p < 0.001). The PA was significantly associated with in-hospital and 1-year composite postoperative outcomes. The odds ratios (OR, [95% confidence interval]) for PApre by time were in-hospital complications (0.435 [0.314, 0.604], p < 0.001; 1-year complications: 0.459 [0.330, 0.638], p < 0.001) and PAPOD1 (OR, in-hospital complications: 0.400 [0.277, 0.576], 1-year complications: 0.429 [0.298, 0.619], p < 0.001). The PApre was significantly associated with days alive and out of hospital until 1 year. The cut-off value of PApre for optimal prediction of in-hospital complications was 6.0 (area under the curve: 0.691 [0.623-0.758], p < 0.001). CONCLUSION: Low PA as an indicator of frailty is associated with adverse postoperative outcomes after OPCAB. Low PA may be employed as a noninvasive and practical tool for the prediction of prognosis in patients with coronary artery disease.

Renal injury from sevoflurane in noncardiac surgery: a retrospective cohort study.

BACKGROUND: Sevoflurane is metabolised into Compound A and fluoride that carry a hypothetical risk of nephrotoxicity. However, a clinically significant association between sevoflurane use and acute kidney injury (AKI) in humans has not been established. METHODS: We retrospectively reviewed 15 552 patients who underwent noncardiac surgery under general anaesthesia using a volatile agent lasting >3 h between July 2016 and May 2019 at a single centre. Patients were divided into a sevoflurane group or no sevoflurane group (desflurane or isoflurane). The primary outcome was incidence of postoperative AKI, which was defined based on the Kidney Disease: Improving Global Outcomes criteria using creatinine concentration within 48 h postoperatively. Propensity score analysis using inverse probability of treatment weighting and propensity score matching was designed to compare outcomes between groups. RESULTS: Amongst 13 701 included patients, 11 070 (80.8%) received sevoflurane during anaesthesia. The incidence of AKI was 2.3% (257/11 070) and 2.5% (66/2631) in the sevoflurane and no sevoflurane groups, respectvely (P=0.57). After inverse probability of treatment weighting adjustment, sevoflurane anaesthesia was not significantly associated with postoperative AKI (odds ratio [OR] 1.32; 95% confidence interval [CI]: 0.99-1.76; P=0.059). In the matched cohort, the incidence of AKI was 3.1% (81/2626) and 2.4% (62/2626) in the sevoflurane and no sevoflurane groups, respectively, and sevoflurane anaesthesia was not associated with postoperative AKI (OR 1.32; 95% CI: 0.94-1.86; P=0.11). CONCLUSIONS: Sevoflurane anaesthesia for >3 h was not associated with postoperative renal injury compared with anaesthesia using other volatile agents.

Nanoscale imaging of rat atrial myocytes by scanning ion conductance microscopy reveals heterogeneity of T-tubule openings and ultrastructure of the cell membrane.

In contrast to ventricular myocytes, the structural and functional importance of atrial transverse tubules (T-tubules) is not fully understood. Therefore, we investigated the ultrastructure of T-tubules of living rat atrial myocytes in comparison with ventricular myocytes. Nanoscale cell surface imaging by scanning ion conductance microscopy (SICM) was accompanied by confocal imaging of intracellular T-tubule network, and the effect of removal of T-tubules on atrial excitation-contraction coupling (EC-coupling) was observed. By SICM imaging, we classified atrial cell surface into 4 subtypes. About 38% of atrial myocytes had smooth cell surface with no clear T-tubule openings and intracellular T-tubules (smooth-type). In 33% of cells, we found a novel membrane nanostructure running in the direction of cell length and named it 'longitudinal fissures' (LFs-type). Interestingly, T-tubule openings were often found inside the LFs. About 17% of atrial cells resembled ventricular myocytes, but they had smaller T-tubule openings and a lower Z-groove ratio than the ventricle (ventricular-type). The remaining 12% of cells showed a mixed structure of each subtype (mixed-type). The LFs-, ventricular-, and mixed-type had an appreciable amount of reticular form of intracellular T-tubules. Formamide-induced detubulation effectively removed atrial T-tubules, which was confirmed by both confocal images and decreased cell capacitance. However, the LFs remained intact after detubulation. Detubulation reduced action potential duration and L-type Ca2+channel (LTCC) density, and prolonged relaxation time of the myocytes. Taken together, we observed heterogeneity of rat atrial T-tubules and membranous ultrastructure, and the alteration of atrial EC-coupling by disruption of T-tubules.

Evaluation of augmented pulse pressure variation using the Valsalva manoeuvre as a predictor of fluid responsiveness under open-chest conditions: A prospective observational study.

BACKGROUND: Pulse pressure variation (PPV) is a well known dynamic preload indicator of fluid responsiveness. However, its usefulness in open-chest conditions remains controversial. OBJECTIVE: We evaluated whether augmented PPV during a Valsalva manoeuvre can predict fluid responsiveness after sternotomy. DESIGN: A prospective, observational study. SETTING: Single-centre trial, study period from October 2014 to June 2015. PATIENTS: Forty-nine adult patients who underwent off-pump coronary arterial bypass grafting. INTERVENTION: After midline sternotomy, haemodynamic parameters were measured before and after volume expansion (6 ml kg of crystalloids). PPV was calculated both automatically (PPVauto) and manually (PPVmanual). For PPV augmentation, we performed Valsalva manoeuvres with manual holding of the rebreathing bag and constant airway pressure of 30 cmH2O for 10 s before fluid loading and calculated PPV during the Valsalva manoeuvre (PPVVM). MAIN OUTCOME MEASURES: The predictive ability of PPVVM for fluid responsiveness using receiver-operating characteristic curve analysis. Responders were identified when an increase in cardiac index of at least 12% occurred after fluid loading. RESULTS: Twenty-one patients were responders and 28 were nonresponders. PPVVM successfully predicted fluid responsiveness with an area under the curve (AUC) of 0.88 [95% confidence interval (95% CI) 0.75 to 0.95; sensitivity 91%, specificity 79%, P < 0.0001] and a threshold value of 55%. Baseline PPVauto and PPVmanual also predicted fluid responsiveness [AUC 0.75 (0.62 to 0.88); sensitivity 79%, specificity 75%; and 0.76 (0.61 to 0.87]; sensitivity 71%, specificity 71%, respectively). However, only PPVVM showed a significant AUC-difference from that of central venous pressure (P = 0.008) and correlated with the change of cardiac index induced by volume expansion (r = 0.6, P < 0.001). CONCLUSION: Augmented PPV using a Valsalva manoeuvre can be used as a clinically reliable predictor of fluid responsiveness under open-chest condition. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02457572.

Fibrinogen recovery and changes in fibrin-based clot firmness after cryoprecipitate administration in patients undergoing aortic surgery involving deep hypothermic circulatory arrest.

BACKGROUND: Cryoprecipitate may be used to treat bleeding in cardiac surgery. Its effects on plasma fibrinogen and fibrin clotting in this setting are poorly defined. STUDY DESIGN AND METHODS: Patients undergoing on-pump aortic surgery with deep hypothermic circulatory arrest (DHCA) were recruited prospectively. After protamine reversal, cryoprecipitate was administered to patients with bleeding, and fibrin deficit was indicated by thromboelastometry (ROTEM)-based FIBTEM test. Coagulation was assessed using ROTEM-based tests and standard laboratory tests before and after cryoprecipitate. RESULTS: Thirteen patients were included. Cryoprecipitate significantly elevated EXTEM A10 from (mean ± standard deviation) 29.4 ± 5.8 to 34.8 ± 5.9 mm (p = 0.01), FIBTEM A10 from 3.5 ± 0.9 to 5.8 ± 1.7 mm (p = 0.04), and plasma fibrinogen concentration from 154.2 ± 25.6 to 193.4 ± 30.5 mg/dL (p = 0.01). EXTEM clot elasticity at 10 minutes (CE10) increased from 42.5 ± 12.0 to 54.7 ± 14.9 mm after cryoprecipitate (30.0% increase). FIBTEM CE10 increased from 3.7 ± 0.9 to 6.2 ± 2.0 mm (53.0% increase). A fibrinogen dose of 13.2 ± 5.2 mg/kg was required to increase FIBTEM A10 by 1 mm. In vivo recovery of fibrinogen was 61.6 ± 31.2%. CONCLUSIONS: Cryoprecipitate increased plasma fibrinogen levels and fibrin-based clotting in bleeding patients undergoing aortic surgery with DHCA. In vivo recovery of fibrinogen was considerably below 100% and fibrinogen content varied between cryoprecipitate units. Trials are needed to assess whether cryoprecipitate impacts clinical outcomes and to evaluate its safety.

Effect of high-dose intravenous iron injection on hepatic function in a rat model of cirrhosis.

OBJECTIVE: To investigate the hepatic effects of high-dose intravenous (IV) iron, including those on liver function and the degree of fibrosis, in a rat model of cirrhosis. METHODS: We evenly allocated 25 Sprague-Dawley rats into five groups: normal rats (control group), cirrhotic rats receiving IV normal saline (liver cirrhosis [LC] group), and cirrhotic rats receiving 20, 40, or 80 mg/kg IV ferric carboxymaltose (LC-iron20, LC-iron40, and LC-iron80 group, respectively). Biochemical parameters were compared at 0, 7, 14, 21, and 28 days. The degrees of hepatic fibrosis and iron deposition were evaluated. Inflammatory and oxidative stress markers were also compared. RESULTS: There were no significant differences in the 28-day serum alanine aminotransferase levels among the LC-iron20, LC-iron40, and LC-iron80 groups (69 ± 7, 1003 ± 127, 1064 ± 309, 919 ± 346, and 820 ± 195 IU/L in the control, LC, LC-iron20, LC-iron40, and LC-iron80 groups, respectively). Hepatic iron accumulation increased in a dose-dependent manner, but the degree of hepatic fibrosis was comparable among the groups. The inflammatory and oxidative stress marker levels did not differ significantly according to the IV iron dose. CONCLUSIONS: Administration of IV iron at various high doses appears safe in our rat model of cirrhosis.

Preoperative C-reactive protein/albumin ratio and mortality of off-pump coronary artery bypass graft.

Background: We sought to investigate the prognostic value of preoperative C-reactive protein (CRP)-to-albumin ratio (CAR) for the prediction of mortality in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Methods: From January 2010 to August 2016, adult patients undergoing OPCAB were analyzed retrospectively. In a total of 2,082 patients, preoperative inflammatory markers including CAR, CRP, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were recorded. Receiver operating characteristic (ROC) curves were used to determine the optimal threshold and compare the predictive values of the markers. The patients were divided into two groups according to the cut-off value of CAR, and then the outcomes were compared. The primary end point was 1-year mortality. Results: During the 1-year follow-up period, 25 patients (1.2%) died after OPCAB. The area under the curve of CAR for 1-year mortality was 0.767, which was significantly higher than other inflammatory markers. According to the calculated cut-off value of 1.326, the patients were divided into two groups: 1,580 (75.9%) patients were placed in the low CAR group vs. 502 (24.1%) patients in the high CAR group. After adjustment with inverse probability weighting, high CAR was significantly associated with increased risk of 1-year mortality after OPCAB (Hazard ratio, 5.01; 95% Confidence interval, 2.01-12.50; p < 0.001). Conclusions: In this study, we demonstrated that preoperative CAR was associated with 1-year mortality following OPCAB. Compared to previous inflammatory markers, CAR may offer superior predictive power for mortality in patients undergoing OPCAB. For validation of our findings, further prospective studies are needed.

The effect of passive leg elevation and/or trendelenburg position on the cross-sectional area of the internal jugular vein in infants and young children undergoing surgery for congenital heart disease.

BACKGROUND: In this study we evaluated the effect of passive leg elevation (LE) and Trendelenburg (T) position on the cross-sectional area (CSA) of the internal jugular vein (IJV) in infants and young children undergoing surgery for congenital heart disease. A secondary aim was to compare the CSA of the IJV between subjects with right-to-left (RL) shunt and left-to-right (LR) shunt. METHODS: Ninety infants and small children from 10 days to 31 months old weighing from 1.5 to 9.7 kg were assigned to group RL (n = 48) or LR (n = 42). In both groups, the CSA, transverse, and vertical diameters of the IJV on both sides of the neck were measured using a 2-dimensional ultrasound transducer in the following positions: supine position, 15° of T position, supine position with 50° of LE, and 15° of Trendelenburg position with 50° of LE (TLE). A more than 25% increase in mean CSA of the IJV was considered clinically significant. RESULTS: In group LR, T, LE, and TLE significantly increased CSA of both right (at least 12.3%, 10.3%, and 18.3%, respectively, "at least" refers to the lower 95% confidence limits) and left (at least 15.8%, 15.0%, and 18.9%, respectively) IJVs, whereas only TLE increased the CSA of both IJVs significantly in group RL (at least 8.2% and 7.7% in the right and left, respectively). The increase in the CSA of the right IJV related to T and TLE was larger in group LR than in group RL (at least 12.3% vs 1.2% for T and at least 18.3% vs 8.2% for TLE, respectively). A clinically significant increase in CSA was achieved in both right and left IJVs with TLE in group LR (mean 28.6% and 26.3%, respectively). The CSA of the right IJV was larger than that of the left IJV in most (at least 69.2%) patients. CONCLUSIONS: Passive LE was as effective as T position to increase the CSA of the IJV, but there was no clinically significant increase in the CSA with any single maneuver. Only T position with passive LE achieved a clinically significant increase in the CSA of both IJVs in infants and young children with LR shunt, but not in the same age group with RL shunt.

Simplified clinical risk score to predict acute kidney injury after aortic surgery.

OBJECTIVE: The authors identified risk factors for acute kidney injury (AKI) defined by risk, injury, failure, loss, end-stage (RIFLE) criteria after aortic surgery with cardiopulmonary bypass and constructed a simplified risk score for the prediction of AKI. DESIGN: Retrospective and observational. SETTING: Single large university hospital. PARTICIPANTS: Patients (737) who underwent aortic surgery with cardiopulmonary bypass between 1997 and 2010. MAIN RESULTS: Multivariate logistic regression analysis was used to evaluate risk factors. A scoring model was developed in a randomly selected derivation cohort (n = 417), and was validated on the remaining patients. The scoring model was developed with a score based on regression ß-coefficient, and was compared with previous indices as measured by the area under the receiver operating characteristic curve (AUC). The incidence of AKI was 29.0%, and 5.8% required renal replacement therapy. Independent risk factors for AKI were age older than 60 years, preoperative glomerular filtration rate <60 mL/min/1.73 m(2), left ventricular ejection fraction <55%, operation time >7 hours, intraoperative urine output <0.5 mL/kg/h, and intraoperative furosemide use. The authors made a score by weighting them at 1 point each. The risk score was valid in predicting AKI, and the AUC was 0.74 [95% confidence interval (CI): 0.69 to 0.79], which was similar to that in the validation cohort: 0.74 (95% CI: 0.69 to 0.80; p = 0.97). The risk-scoring model showed a better performance compared with previously reported indices. CONCLUSIONS: The model would provide a simplified clinical score stratifying the risk of postoperative AKI in patients undergoing aortic surgery.

Days alive and out of hospital at 30 days and outcomes of off-pump coronary artery bypass grafting.

Days alive and out of hospital (DAOH) is a simple estimator based on the number of days not in hospital within a defined period. In cases of mortality within the period, DAOH is regarded as zero. It has not been validated solely in off-pump coronary artery bypass grafting (OPCAB). This study aimed to demonstrate a correlation between DAOH and outcome of OPCAB. We identified 2211 OPCAB performed from January 2010 to August 2016. We calculated DAOH at 30 and 60 days. We generated a receiver-operating curve and compared outcomes. The median duration of hospital stay after OPCAB was 6 days. The median DAOH values at 30 and 60 days were 24 and 54 days. The estimated thresholds for 3-year mortality for DAOH at 30 and 60 days were 20 and 50 days. Three-year mortality was higher for short DAOH (1.2% vs. 5.7% and 1.1% vs. 5.6% DAOH at 30 and 60 days). After adjustment, the short DAOH 30 group showed significantly higher mortality during 3-year follow-up (hazard ratio 3.07; 95% confidence interval 1.45-6.52; p = 0.004). DAOH at 30 days after OPCAB showed a correlation with 3-year outcomes. DAOH 30 might be a reliable long-term outcome measure that can be obtained within 30 days after surgery.

Vasoactive inotropic score as a predictor of long-term mortality in patients after off-pump coronary artery bypass grafting.

Increased vasoactive-inotropic score (VIS) is a reliable predictor of mortality and morbidity after cardiac surgery. Here, we retrospectively evaluated the association between VIS and adverse outcomes in adult patients after off-pump coronary artery bypass grafting (OPCAB). We included 2149 patients who underwent OPCAB. The maximal VIS was calculated for the initial 48 postoperative hours using standard formulae. The primary outcome was 1-year death. The composite adverse outcome was death, resuscitation or mechanical support, myocardial infarction, revascularization, new-onset atrial fibrillation, infection requiring antibacterial therapy, acute kidney injury, and stroke. Path-analysis was conducted using lactate and prognostic nutritional index (PNI). VIS was associated with 1-year death (odds ratio [OR] 1.07 [1.04-1.10], p < 0.001) and 1-year composite outcome (OR 1.02 [1.0-1.03], p = 0.008). In path-analysis, high VIS showed a direct effect on the increased risk of 1-year death and composite outcome. In the pathway using lactate as a mediating variable, VIS showed an indirect effect on the composite outcome but no significant effect on death. Low PNI directly affected the increased risk of 1-year death and composite outcome, and had an indirect effect on both outcomes, even when VIS was used as a mediating variable. In patients undergoing OPCAB, high VIS independently predicted morbidity and 1-year death. Patients with increased lactate levels following high VIS had an increased risk of postoperative complications, although not necessarily resulting in death. However, patients with poor preoperative nutritional status had an increased risk of unfavourable outcomes, including death, implying the importance of preoperative nutritional support.

Intravenous iron injection does not impair liver function in a rat model of cirrhosis.

BACKGROUND: There is a lack of convincing data concerning the safety of iron therapy in patients with advanced liver cirrhosis (LC). This study investigated the hepatic effects of ferric carboxymaltose, an intravenous iron supplement, in a rat model of cirrhosis. METHODS: In total, 45 Sprague-Dawley rats were allocated into three groups: normal rats (control group, n=15), cirrhotic rats receiving intravenous normal saline (LC group, n=15), and cirrhotic rats receiving 20 mg/kg intravenous ferric carboxymaltose (LC-iron group, n=15). LC was induced by twice-weekly intraperitoneal injection of carbon tetrachloride. Biochemical parameters were compared at 0, 2, 14, and 28 days. Additionally, liver tissue samples were extracted from five rats in each group at 2, 14, and 28 days for evaluation of the degrees of hepatic fibrosis and iron deposition. Inflammatory and oxidative stress markers were also compared among groups. RESULTS: Serum alanine transferase levels did not significantly differ between the LC and LC-iron groups at 0 (443±110 vs. 444±117 IU/L, P>0.99), 2 (453±117 vs. 479±136 IU/L, P=0.84), 14 (1,535±1,058 vs. 1,578±711 IU/L, P=0.55), or 28 days (2,067±641 vs. 2,533±914 IU/L, P=0.15). The degree of hepatic fibrosis was comparable between the groups, although hepatic iron accumulation was greater in the LC-iron group than in the LC group. The levels of inflammatory and oxidative stress markers were significantly lower in the LC-iron group than in the LC group. CONCLUSIONS: In our rat model of cirrhosis, the administration of intravenous iron appears safe. However, further preclinical and clinical studies are warranted to confirm the safety and efficacy of intravenous iron in patients with LC or end-stage liver disease.

Suppression of CFTR-mediated Cl secretion of airway epithelium in vitamin C-deficient mice.

Hyperoxic ventilation induces detrimental effects on the respiratory system, and ambient oxygen may be harmful unless compensated by physiological anti-oxidants, such as vitamin C. Here we investigate the changes in electrolyte transport of airway epithelium in mice exposed to normobaric hyperoxia and in gulonolacton oxidase knock-out (gulo[-/-]) mice without vitamin C (Vit-C) supplementation. Short-circuit current (I(sc)) of tracheal epithelium was measured using Ussing chamber technique. After confirming amiloride-sensitive Na(+) absorption (ΔI(sc,amil)), cAMP-dependent Cl(-) secretion (ΔI(sc,forsk)) was induced by forskolin. To evaluate Ca(2+)-dependent Cl(-) secretion, ATP was applied to the luminal side (ΔI(sc,ATP)). In mice exposed to 98% PO(2) for 36 hr, ΔI(sc,forsk) decreased, ΔI(sc,amil) and ΔI(sc,ATP) was not affected. In gulo(-/-) mice, both ΔI(sc,forsk) and ΔI(sc,ATP) decreased from three weeks after Vit-C deprivation, while both were unchanged with Vit-C supplementation. At the fourth week, tissue resistance and all electrolyte transport activities were decreased. An immunofluorescence study showed that the expression of cystic fibrosis conductance regulator (CFTR) was decreased in gulo(-/-) mice, whereas the expression of KCNQ1 K(+) channel was preserved. Taken together, the CFTR-mediated Cl(-) secretion of airway epithelium is susceptible to oxidative stress, which suggests that supplementation of the antioxidant might be beneficial for the maintenance of airway surface liquid.

The effect of patient-controlled intravenous analgesia on postoperative hypokalemia in patients undergoing laparoscopic cholecystectomy.

PURPOSE: We investigated whether hypokalemia developed during the postoperative period and whether the use of intravenous patient-controlled analgesia (IV-PCA) could decrease the incidence of postoperative hypokalemia in patients who underwent laparoscopic cholecystectomy. METHODS: Sixty patients undergoing laparoscopic cholecystectomy were randomly assigned to either IV-PCA (n = 30) or control (n = 30) groups. We measured serum potassium concentration at the outpatient department (T1), at 8:00 a.m. on the day of surgery (T2), at 6 h after the end of surgery (T3), and at 8:00 a.m. on the first (T4), second (T5), and third (T6) postoperative days. Serum potassium concentration, incidence of hypokalemia, mean blood pressure, heart rate, respiratory rate, and the patient-reported visual analogue scale score were compared within each group and between groups at each time point. RESULTS: Serum potassium concentrations in all patients showed a significant decrease at T2-T4 compared to the preoperative concentration (T1). Serum potassium concentrations at T3 and T4 in the IV-PCA group were significantly higher than those in the control group. Also, the incidence of hypokalemia at T3 and T4 was significantly lower in the IV-PCA group. Mean blood pressure and heart rate were significantly lower in the IV-PCA group than in controls at T3 and T4. CONCLUSIONS: The results show that hypokalemia developed during the perioperative period and the use of IV-PCA in patients undergoing laparoscopic cholecystectomy effectively decreased the degree and incidence of postoperative hypokalemia on the day of the operation and postoperative day one.

Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss.

Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

Effects of repeat bolus ethanol injections on cardiopulmonary hemodynamic changes during embolotherapy of arteriovenous malformations of the extremities.

PURPOSE: This study was designed to investigate the effects of repeat bolus absolute ethanol injections on cardiopulmonary hemodynamic changes during ethanol embolotherapy of inoperable congenital arteriovenous (AV) malformations in the extremities. MATERIALS AND METHODS: Thirty adult patients (14 male, 16 female; age range, 22-51 years) who underwent ethanol embolotherapy of extremity AV malformations were enrolled in the study. A pulmonary artery catheter was used to measure hemodynamic profiles at baseline (T(baseline)), immediately before (T(pre)) and after (T(post)) a bolus injection of absolute ethanol, at the time of the maximum mean pulmonary arterial pressure (PAP) value during a session (T(highest)), 10 minutes after the final injection (T(final)), and after restoration of spontaneous breathing (T(resp)). RESULTS: The systolic, mean, and diastolic PAP (P < .01, P < .01, and P < .01, respectively) and the systemic vascular resistance index (P < .05) and pulmonary vascular resistance index (PVRI; P < .05) of T(highest) and T(resp) were significantly higher than values for T(final). The volume of a single bolus injection of absolute ethanol from 0.023 to 0.175 mL/kg of body weight showed that the systolic PAP (P = .02), pulmonary capillary wedge pressure (P = .02), and PVRI (P < .01) significantly increased in accordance with the increased single volume of absolute ethanol. A significant increase of the right ventricular end-diastolic volume index and right ventricular end-systolic volume index were observed at a dose of more than 0.14 mL/kg of body weight for a single bolus injection of absolute ethanol. CONCLUSIONS: During ethanol embolotherapy of extremity AV malformations, significant hemodynamic changes can arise during a bolus injection of absolute ethanol. Cardiopulmonary hemodynamic profiles should be monitored closely after a bolus injection of more than 0.14 mL/kg of body weight of absolute ethanol.

Cardiovascular effects and predictability of cardiovascular collapse after repeated intravenous bolus injections of absolute ethanol in anesthetized pigs.

PURPOSE: To evaluate the effects of repeated intravenous bolus injections of absolute ethanol on cardiopulmonary hemodynamic changes and to investigate the predictability of ethanol-induced cardiovascular collapse in anesthetized pigs. MATERIALS AND METHODS: Twenty pigs aged 3-6 months and weighing 28-38 kg were enrolled in the study. Absolute ethanol (0.1 mL/kg of body weight) was repeatedly injected through the inferior vena cava central to the renal vein at 10-minute intervals up to a total volume of 1.0 mL/kg. The subjects were divided into a cardiovascular collapse group and a no-collapse group according to the development or absence of cardiac collapse. RESULTS: Among the 20 pigs, 12 died before the final injection. Hemodynamic parameters measured immediately before the injection of absolute ethanol did not differ between the cardiovascular collapse group and the no-collapse group except that among animals with cardiovascular collapse, the injection immediately before the one causing cardiovascular collapse resulted in significant increases in the following hemodynamic parameters: mean pulmonary arterial pressure (P < .01), pulmonary vascular resistance (P = .04), and right ventricular end-diastolic volume (P = .02). No such increases were observed in the no-collapse group. CONCLUSIONS: Hemodynamic profiles in pigs obtained immediately before intravenous injection of absolute ethanol did not predict the subsequent occurrence of cardiovascular collapse except after the injection immediately preceding the one resulting in cardiovascular collapse. In this animal model, significant increases in select hemodynamic parameters occurred after the injection immediately preceding the one resulting in cardiovascular collapse.

Ratchet-integrated pneumatic actuator (RIPA): a large-stroke soft linear actuator inspired by sarcomere muscle contraction.

Pneumatic artificial muscles (PAMs) have a wide range of robotics applications, especially in soft robots, for their ability to generate linear force and displacement with the soft, lightweight, compact, and safe characteristics as well as high power densities. However, the compressibility of the air causes a spring-like behavior of PAMs, resulting in several common issues of limited stroke, load-dependent stroke lengths, difficulty in maintaining their length against disturbance, and necessity of accurate pressure control system. To address these issues, this study borrows inspiration from a biological soft linear actuator, a muscle, and proposes a ratchet-integrated pneumatic actuator (RIPA). Utilizing two pawls integrated at both ends of a McKibben muscle and a flexible rack inserted in the middle of the muscle, the RIPA achieves a large stroke length by accumulating displacements from multiple small strokes of the McKibben muscle by repeating the cycle of pressurization and depressurization. This cycle mimics the cross-bridge model of a sarcomere, a basic unit of a skeletal muscle, in which a muscle accumulates nanoscale strokes of myosin head motors to generate large strokes. The synergy between a PAM and the inspiration from a sarcomere enabled a large-stroke soft linear actuator that can generate independent strokes from loads. The proposed actuator is not only capable of maintaining its length against unexpected mechanical disturbances but also controllable with a relatively simple system. In this paper, we describe the design of the RIPA and provide analytical models to predict the stroke length and the period per cycle for actuation. We also present experimental results for characterization and comparison with model predictions.

Effect of Intraoperative Sedation with Dexmedetomidine Versus Propofol on Acute Postoperative Pain Following Major Foot Surgery under Popliteal Sciatic Nerve Block: A Randomized Controlled Trial.

Intravenous (IV) dexmedetomidine is reported to prolong analgesia following peripheral nerve blocks. Popliteal sciatic nerve block provides effective postoperative analgesia, but some patients still experience severe pain during the early postoperative period. We aimed to evaluate the postoperative analgesic effects of IV dexmedetomidine versus propofol in patients undergoing foot surgeries under popliteal sciatic nerve block. Forty patients were enrolled and randomly assigned to receive either IV propofol (n = 20) or IV dexmedetomidine (n = 20) for intraoperative sedation. All the patients received continuous popliteal sciatic nerve block. The corresponding drug infusion rate was adjusted to achieve a modified observer's assessment of alertness/sedation score of 3 or 4. The primary outcome was postoperative cumulative opioid consumption during the first 24 h after surgery. Thirty-nine patients were analyzed. The median (interquartile ranges) postoperative cumulative opioid consumption during the first 24 h after surgery was significantly lower in the dexmedetomidine group (15 (7.5-16.9) mg) than in the propofol group (17.5 (15-25) mg) (p = 0.019). The time to first rescue analgesic request was significantly greater in the dexmedetomidine group than in the propofol group (11.8 ± 2.2 h vs. 10.0 ± 2.7 h, p = 0.030) without the prolonged motor blockade (p = 0.321). Intraoperative sedation with dexmedetomidine reduced postoperative opioid consumption and prolonged analgesic duration after a popliteal sciatic nerve block.

Intrathecal morphine combined with intravenous patient-controlled analgesia is an effective and safe method for immediate postoperative pain control in live liver donors.

The healthy condition of living donors makes their tolerance to pain particularly low, and clinicians are often challenged to come up with an analgesic technique that is effective yet ensures donor safety. This study compared, in donor right hepatectomy, the efficacy and safety of preoperative intrathecal morphine (ITM) combined with intravenous patient-controlled analgesia (IV-PCA) with IV-PCA alone. Forty adult patients were randomly allocated into 2 groups: ITM+IV-PCA group (n = 20) and IV-PCA-only group (n = 20). Patients in the ITM+IV-PCA group received morphine sulfate (400 microg). The visual analog scale (VAS) at rest and when coughing and supplementary meperidine and IV-PCA (fentanyl) consumption were assessed at 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 42, 48 56, 64, and 72 hours after surgery. Also, side effects such as sedation, dizziness, nausea, vomiting, pruritus, and respiratory depression were evaluated. The ITM+IV-PCA group showed significantly less pain at rest and when coughing for up to 30 hours and 24 hours, respectively. Cumulative postoperative consumption of meperidine and IV-PCA (fentanyl) were significantly less in the ITM+IV-PCA group. The incidence of side effects were comparable between the 2 groups except for pruritus; its incidence was significantly higher in the ITM+IV-PCA group during the first 24 hours, but no treatment was required due to its mild severity. The results of our study suggest that preoperative ITM combined with IV-PCA may be considered as an effective and safe pain management regimen in living liver donors who have characteristics of low tolerance to pain and postoperative coagulation derangement.