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BACKGROUND: : The subjective experience of residual neuromuscular blockade after emergence from anesthesia has not been examined systematically during postanesthesia care unit (PACU) stays. The authors hypothesized that acceleromyography monitoring would diminish unpleasant symptoms of residual paresis during recovery from anesthesia by reducing the percentage of patients with train-of-four ratios less than 0.9. METHODS: : One hundred fifty-five patients were randomized to receive intraoperative acceleromyography monitoring (acceleromyography group) or conventional qualitative train-of-four monitoring (control group). Neuromuscular management was standardized, and extubation was performed when defined criteria were achieved. Immediately upon a patient's arrival to the PACU, the patient's train-of-four ratios were measured using acceleromyography, and a standardized examination was used to assess 16 symptoms and 11 signs of residual paresis. This examination was repeated 20, 40, and 60 min after PACU admission. RESULTS: : The incidence of residual blockade (train-of-four ratios less than 0.9) was reduced in the acceleromyography group (14.5% vs. 50.0% control group, with the 99% confidence interval for this 35.5% difference being 16.4-52.6%, P < 0.0001). Generalized linear models revealed the acceleromyography group had less overall weakness (graded on a 0-10 scale) and fewer symptoms of muscle weakness across all time points (P < 0.0001 for both analyses), but the number of signs of muscle weakness was small from the time of arrival in the PACU and did not differ between the groups at any time. CONCLUSION: : Acceleromyography monitoring reduces the incidence of residual blockade and associated unpleasant symptoms of muscle weakness in the PACU and improves the overall quality of recovery. [ABSTRACT FROM AUTHOR]

BACKGROUND: : The effect of dexamethasone on quality of recovery after discharge from the hospital after laparoscopic surgery has not been examined rigorously in previous investigations. We hypothesized that preoperative dexamethasone would enhance patient-perceived quality of recovery on postoperative day 1 in subjects undergoing laparoscopic cholecystectomy. METHODS: : One hundred twenty patients undergoing outpatient laparoscopic cholecystectomy were randomized to receive either dexamethasone (8 mg) or placebo-saline. A 40-item quality-of-recovery scoring system (QoR-40) was administered preoperatively and on postoperative day 1 to all subjects. Nausea, vomiting, fatigue, and pain scores were recorded at the time of discharge from the postanesthesia care unit and ambulatory surgical unit. Hospital length of stay was also assessed. RESULTS: : Global QoR-40 scores on postoperative day 1 were higher in the dexamethasone group (median [range], 178 [130-195]) compared with the control group (161 [113-194]) (median difference [99% CI], -18 [-26 to -8]; P < 0.0001). Postoperative QoR-40 scores in the dimensions of emotional state, physical comfort, and pain were all improved in the dexamethasone group compared with the control group (P < 0.001). Nausea, fatigue, and pain scores were all reduced in the dexamethasone group during the hospitalization, as were postoperative analgesic requirements (P < 0.05). Total hospital length of stay was also reduced in subjects administered steroids (P = 0.003). CONCLUSIONS: : Among patients undergoing outpatient laparoscopic cholecystectomy surgery, the use of preoperative dexamethasone enhanced postdischarge quality of recovery and reduced nausea, pain, and fatigue in the early postoperative period. [ABSTRACT FROM AUTHOR]

Background: Incomplete recovery from neuromuscular blockade in the postanesthesia care unit (PACU) may contribute to adverse postoperative respiratory events. This study determined the incidence and degree of residual neuromuscular blockade in patients randomized to conventional qualitative train-of-four (TOF) monitoring or quantitative acceleromyographic monitoring. The incidence of adverse respiratory events in the PACU was also evaluated. Methods: One hundred eighty-five patients were randomized to intraoperative acceleromyographic monitoring (acceleromyography group) or qualitative TOF monitoring (TOF group). Anesthetic management was standardized. TOF patients were extubated when standard criteria were met and no fade was observed during TOF stimulation. Acceleromyography patients had a TOF ratio of greater than 0.80 as an additional extubation criterion. Upon arrival in the PACU, TOF ratios of both groups were measured with acceleromyography. Adverse respiratory events during transport to the PACU and during the first 30 min of PACU admission were also recorded. Results: A lower frequency of residual neuromuscular blockade in the PACU (TOF ratio < or = 0.9) was observed in the acceleromyography group (4.5%) compared with the conventional TOF group (30.0%; P < 0.0001). During transport to the PACU, fewer acceleromyography patients developed arterial oxygen saturation values, measured by pulse oximetry, of less than 90% (0%) or airway obstruction (0%) compared with TOF patients (21.1% and 11.1%, respectively; P < 0.002). The incidence, severity, and duration of hypoxemic events during the first 30 min of PACU admission were less in the acceleromyography group (all P < 0.0001). Conclusions: Incomplete neuromuscular recovery can be minimized with acceleromyographic monitoring. The risk of adverse respiratory events during early recovery from anesthesia can be reduced by intraoperative acceleromyography use. [ABSTRACT FROM AUTHOR]

Rickettsial diseases have affected the military throughout history. Efforts such as those of the Joint U.S. Typhus Commission near the beginning of World War II and of military researchers since have reduced the impact of these diseases on U.S. and Allied forces. Despite the postwar development of effective antibiotic therapies, the newly emerging antibiotic-resistant scrub typhus rickettsial strains of the Asian Pacific region mandate continued research and surveillance. Similarly, tick-infested training areas in the United States and similar exposure abroad render the spotted fevers and the ehrlichioses problematic to deployed troops. The military continues to work on countermeasures to control the arthropod vectors, as well as actively participating in the development of rapid accurate diagnostic tests, vaccines, and improved surveillance methods. Several rickettsial diseases, including epidemic typhus, scrub typhus, the ehrlichioses, and the spotted fevers, are reviewed, with emphasis on the military historical significance and contributions. [ABSTRACT FROM AUTHOR]

In recent decades, biocatalysis has emerged as an important alternative to chemical catalysis in pharmaceutical manufacturing. Biocatalysis is attractive because enzymatic cascades can synthesize complex molecules with incredible selectivity, yield, and in an environmentally benign manner. Enzymes for pharmaceutical biocatalysis are typically used in their unpurified state, since it is time-consuming and cost-prohibitive to purify enzymes using conventional chromatographic processes at scale. However, impurities present in crude enzyme preparations can consume substrate, generate unwanted byproducts, as well as make the isolation of desired products more cumbersome. Hence, a facile, nonchromatographic purification method would greatly benefit pharmaceutical biocatalysis. To address this issue, here we have captured enzymes into membraneless compartments by fusing enzymes with an intrinsically disordered protein region, the RGG domain from LAF-1. The RGG domain can undergo liquid-liquid phase separation, forming liquid condensates triggered by changes in temperature or salt concentration. By centrifuging these liquid condensates, we have successfully purified enzyme-RGG fusions, resulting in significantly enhanced purity compared to cell lysate. Furthermore, we performed enzymatic reactions utilizing purified fusion proteins to assay enzyme activity. Results from the enzyme assays indicate that enzyme-RGG fusions purified by the centrifugation method retain enzymatic activity, with greatly reduced background activity compared to crude enzyme preparations. Our work focused on three different enzymes-a kinase, a phosphorylase, and an ATP-dependent ligase. The kinase and phosphorylase are components of the biocatalytic cascade for manufacturing molnupiravir, and we demonstrated facile co-purification of these two enzymes by co-phase separation. To conclude, enzyme capture by RGG tagging promises to overcome difficulties in bioseparations and biocatalysis for pharmaceutical synthesis., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan., (© 2024 Wiley-VCH GmbH.)

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence 1-3 . Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents 4,5 . Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic 6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Over the past five decades, quantitative neuromuscular monitoring devices have been used to examine the incidence of postoperative residual neuromuscular block in international clinical practices, and to determine their role in reducing the risk of residual neuromuscular block and associated adverse clinical outcomes. Several clinical trials and a recent meta-analysis have documented that the intraoperative application of quantitative monitoring significantly reduces the risk of residual neuromuscular blockade in the operating room and postanesthesia care unit. In addition, emerging data show that quantitative monitoring minimizes the risk of adverse clinical events, such as unplanned postoperative reintubations, hypoxemia, and postoperative episodes of airway obstruction associated with incomplete neuromuscular recovery, and may improve postoperative respiratory outcomes. Several international anesthesia societies have recommended that quantitative monitoring be performed whenever a neuromuscular blocking agent is administered. Therefore, a comprehensive review of the literature was performed to determine the potential benefits of quantitative monitoring in the perioperative setting., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

Molnupiravir (MK-4482) is an investigational antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand and urgency for this compound, it was critical to develop a short and sustainable synthesis from simple raw materials that would minimize the time needed to manufacture and supply molnupiravir. The route reported here is enabled through the invention of a novel biocatalytic cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase. These engineered enzymes were deployed with a pyruvate-oxidase-enabled phosphate recycling strategy. Compared to the initial route, this synthesis of molnupiravir is 70% shorter and approximately 7-fold higher yielding. Looking forward, the biocatalytic approach to molnupiravir outlined here is anticipated to have broad applications for streamlining the synthesis of nucleosides in general., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Study Objective: Comparison of the TetraGraph (TG) and TOFscan (TS) for monitoring recovery from neuromuscular blockade in the Post Anesthesia Care Unit (PACU)., Design: Randomized, multicenter trial., Setting: PACU in three tertiary care hospitals., Patients: 120 patients (40 per site) receiving neuromuscular blockade during elective surgery., Interventions: Patients were enrolled preoperatively and intraoperative neuromuscular blockade management was at the discretion of the anesthesiologist. Upon arrival to the PACU, patients were randomized to have either TG or TS placed on their dominant hand. The alternate device (TS or TG) was placed on the non-dominant hand. Following simultaneous ulnar nerve stimulation on each arm, the response of the adductor pollicis was measured., Measurements: Train-of-four ratios (TOFRs) were obtained upon arrival to the PACU (t = 0), after 5 min (t = + 5) and after +10 min (t = + 10)., Main Results: There was there was no significant difference in the mean TOFRs obtained with the TG and TS at t = 0 (0.97 ± 0.18 vs 0.94 ± 0.13, P = 0.06, respectively) and t = + 5 (0.96 ± 0.20 vs 0.95 ± 0.12, P = 0.29, respectively). At (t = + 10), there was a statistically significant difference in mean TOFRs obtained with the TG and TS, (0.99 ± 0.14 vs 0.94 ± 0.12, P < 0.001, respectively). The bias between devices at t = 0 was estimated to be 0.03 (95% CI, -0.29 to 0.35, P = 0.26); at t = + 5 min, it was estimated to be 0.02 (95% CI, -0.36 to 0.40, P = 0.54); and at t = +10 min, it was estimated to be 0.05 (95% CI, -0.25 to 0.36, P = 0.77)., Conclusions: TS and TG provide interchangeable quantitative measurements once the TOF ratio has returned to a value of 0.90 or greater in the PACU., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients undergoing thoracoscopic procedures may be at high-risk for incomplete neuromuscular recovery and associated complications. The aim of this clinical investigation was to assess the incidence of postoperative residual neuromuscular blockade in adult thoracic surgical patients administered neostigmine or sugammadex when optimal dosing and reversal strategies for these agents were used. The effect of choice of reversal agent on hypoxemic events and signs and symptoms of muscle weakness were also determined. Additionally, operative conditions in each group were graded by surgeons performing the procedures., Methods: Two hundred patients undergoing thoracoscopic surgical procedures were enrolled in this nonrandomized controlled trial. One hundred consecutive patients maintained at moderate levels of neuromuscular blockade were reversed with neostigmine (neostigmine group) followed by 100 consecutive patients given sugammadex to antagonize deeper levels of neuromuscular blockade (sugammadex group). Anesthetic and neuromuscular management were standardized. Surgeons rated operative conditions at the conclusion of the procedure on a 4-point scale (grade 1 = excellent to grade 4 = poor). Train-of-four ratios were measured immediately before extubation and at PACU admission (primary outcomes). Postoperatively, patients were assessed for adverse respiratory events and 11 signs and 16 symptoms of muscle weakness., Results: The 2 groups were similar in intraoperative management characteristics. The percentage of patients with residual neuromuscular blockade, defined as a normalized train-of-four ratio <0.9, was significantly greater in the neostigmine group than the sugammadex group at both tracheal extubation (80% vs 6%, respectively, P < .0001) and PACU admission (61% vs 1%, respectively, P < .0001). Patients in the neostigmine group had less optimal operative conditions (median score 2 [good] versus 1 [excellent] in the sugammadex group; P < .0001), and more symptoms of muscle weakness were present in these subjects (median number [interquartile range] 4 [1-8] vs 1 [0-2] in the sugammadex group, P < .0001). No differences between groups in adverse airway events were observed., Conclusions: Despite the application of strategies documented to reduce the risk of residual neuromuscular blockade, a high percentage of thoracoscopic patients whose neuromuscular blockade was reversed with neostigmine were admitted to the PACU with clinical evidence of residual paralysis. In contrast, muscle weakness was rarely observed in patients whose neuromuscular blockade was antagonized with sugammadex., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Background: Despite application of multimodal pain management strategies, patients undergoing spinal fusion surgery frequently report severe postoperative pain. Methadone and ketamine, which are N-methyl-d-aspartate receptor antagonists, have been documented to facilitate postoperative pain control. This study therefore tested the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those give methadone alone., Methods: In this randomized, double-blind, placebo-controlled trial, 130 spinal surgery patients were randomized to receive either methadone at 0.2 mg/kg (ideal body weight) intraoperatively and a 5% dextrose in water infusion for 48 h postoperatively (methadone group) or 0.2 mg/kg methadone intraoperatively and a ketamine infusion (0.3 mg · kg-1 · h-1 infusion [no bolus] intraoperatively and then 0.1 mg · kg-1 · h-1 for next 48 h [both medications dosed at ideal body weight]; methadone/ketamine group). Anesthetic care was standardized in all patients. Intravenous hydromorphone use on postoperative day 1 was the primary outcome. Pain scores, intravenous and oral opioid requirements, and patient satisfaction with pain management were assessed for the first 3 postoperative days., Results: Median (interquartile range) intravenous hydromorphone requirements were lower in the methadone/ketamine group on postoperative day 1 (2.0 [1.0 to 3.0] vs. 4.6 [3.2 to 6.6] mg in the methadone group, median difference [95% CI] 2.5 [1.8 to 3.3] mg; P < 0.0001) and postoperative day 2. In addition, fewer oral opioid tablets were needed in the methadone/ketamine group on postoperative day 1 (2 [0 to 3] vs. 4 [0 to 8] in the methadone group; P = 0.001) and postoperative day 3. Pain scores at rest, with coughing, and with movement were lower in the methadone/ketamine group at 23 of the 24 assessment times. Patient-reported satisfaction scores were high in both study groups., Conclusions: Postoperative analgesia was enhanced by the combination of methadone and ketamine, which act on both N-methyl-d-aspartate and μ-opioid receptors. The combination could be considered in patients having spine surgery., (Copyright © 2021, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Protein engineering is the discipline of developing useful proteins for applications in research, therapeutic, and industrial processes by modification of naturally occurring proteins or by invention of de novo proteins. Modern protein engineering relies on the ability to rapidly generate and screen diverse libraries of mutant proteins. However, design of mutant libraries is typically hampered by scale and complexity, necessitating development of advanced automation and optimization tools that can improve efficiency and accuracy. At present, automated library design tools are functionally limited or not freely available. To address these issues, we developed Mutation Maker, an open source mutagenic oligo design software for large-scale protein engineering experiments. Mutation Maker is not only specifically tailored to multisite random and directed mutagenesis protocols, but also pioneers bespoke mutagenic oligo design for de novo gene synthesis workflows. Enabled by a novel bundle of orchestrated heuristics, optimization, constraint-satisfaction and backtracking algorithms, Mutation Maker offers a versatile toolbox for gene diversification design at industrial scale. Supported by in silico simulations and compelling experimental validation data, Mutation Maker oligos produce diverse gene libraries at high success rates irrespective of genes or vectors used. Finally, Mutation Maker was created as an extensible platform on the notion that directed evolution techniques will continue to evolve and revolutionize current and future-oriented applications.

A subcommittee of the Hawaii Governor's Joint Task Force on Rat Lungworm Disease developed preliminary guidelines for the diagnosis and treatment of neuroangiostrongyliasis (NAS) in 2018 (Guidelines, 2018). This paper reviews the main points of those guidelines and provides updates in areas where our understanding of the disease has increased. The diagnosis of NAS is described, including confirmation of infection by real-time polymerase chain reaction (RTi-PCR) to detect parasite DNA in the central nervous system (CNS). The treatment literature is reviewed with recommendations for the use of corticosteroids and the anthelminthic drug albendazole. Long-term sequelae of NAS are discussed and recommendations for future research are proposed.

Angiostrongylus cantonensis is a metastrongylid lungworm of rats with a global distribution and the cause of neuroangiostrongyliasis in humans. In Hawai'i, neuroangiostrongyliasis cases have occurred sporadically since 1960; however, in 2001, the number of cases on Maui and Hawai'i Island began to increase significantly. Since most human treatment trials have been conducted in Thailand, where the disease is usually mild, there is a need to develop treatment protocols for Hawai'i, where there is a broader disease spectrum. In 2018, preliminary guidelines for the diagnosis and treatment of neuroangiostrongyliasis were developed for Hawai'i's physicians. This article summarizes those guidelines and provides additional recommendations for individuals who recently ingested an infected intermediate host., (©Copyright 2020 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Background: There is a need for easy to use, reliable neuromuscular monitors (NMMs). This multicenter, prospective, unblinded study compared the discomfort associated with neurostimulation in unmedicated healthy volunteers when using the new electromyography (EMG)-based TetraGraph and acceleromyography (AMG)-based TOF-Watch NMMs. The secondary aim was to compare the repeatability of the train-of-four (TOF) ratios (TOFRs) obtained with the 2 devices., Methods: The TOF measurements of 135 volunteers from 3 university hospitals were analyzed (age: 38.3 ± 12 years [mean ± standard deviation [SD]]; male/female ratio = 63:72). The left or right ulnar nerve was stimulated at the wrist in TOF mode with 20, 30, 40, and 50 mA stimulating current intensities with both devices in random order. The TOF-Watch used standard electrocardiography (ECG) electrodes (Red Dot; 3M Health Care) for nerve stimulation. The stimulating surface area of 1 ECG electrode is 113 mm. The piezoelectric probe was attached to the thumb, and a hand adapter was used to ensure consistency of AMG measurements. The TetraGraph uses proprietary surface strip electrodes for nerve stimulation and muscle action potential recording, whose stimulating surface area is roughly twice as big as that of standard ECG electrodes (228.5 mm). The volunteers were asked to rate the discomfort associated with neurostimulation on a 0-10 verbal numerical rating scale (VNRS) score anchored with 0 (no pain) and 10 (worst pain ever experienced). A linear mixed-effects model was used to evaluate the difference in VNRS scores between devices. P <.05 was accepted as the level of significance., Results: In the linear mixed-effects model, there were no differences in VNRS scores between devices at any of the stimulating current intensities, P = .38. The median (range) VNRS scores obtained with TOF-Watch and TetraGraph devices were 2 (0-7) vs 2 (0-8) at 20 mA, 3 (1-9) vs 3 (1-9) at 30 mA, 5 (1-10) vs 5 (1-10) at 40 mA, and 5 (1-10) vs 6 (1-10) at 50 mA stimulating current intensities. The mean of the 1469 TOFRs obtained with TetraGraph was 100.43% ± 7.74% (standard error = 0.2%). Due to technical difficulties, the repeatability of the TOFRs could not be determined., Conclusions: Despite the different size and design of the stimulating electrodes, the 2 NMMs caused the same level of discomfort in unmedicated healthy volunteers.

Background: Methadone is a long-acting opioid that has been reported to reduce postoperative pain scores and analgesic requirements and may attenuate development of chronic postsurgical pain. The aim of this secondary analysis of two previous trials was to follow up with patients who had received a single intraoperative dose of either methadone or traditional opioids for complex spine or cardiac surgical procedures., Methods: Preplanned analyses of long-term outcomes were conducted for spinal surgery patients randomized to receive 0.2 mg/kg methadone at the start of surgery or 2 mg hydromorphone at surgical closure, and for cardiac surgery patients randomized to receive 0.3 mg/kg methadone or 12 μg/kg fentanyl intraoperatively. A pain questionnaire assessing the weekly frequency (the primary outcome) and intensity of pain was mailed to subjects 1, 3, 6, and 12 months after surgery. Ordinal data were compared with the Mann-Whitney U test, and nominal data were compared using the chi-square test or Fisher exact probability test. The criterion for rejection of the null hypothesis was P < 0.01., Results: Three months after surgery, patients randomized to receive methadone for spine procedures reported the weekly frequency of chronic pain was less (median score 0 on a 0 to 4 scale [less than once a week] vs. 3 [daily] in the hydromorphone group, P = 0.004). Patients randomized to receive methadone for cardiac surgery reported the frequency of postsurgical pain was less at 1 month (median score 0) than it was in patients randomized to receive fentanyl (median score 2 [twice per week], P = 0.004)., Conclusions: Analgesic benefits of a single dose of intraoperative methadone were observed during the first 3 months after spinal surgery (but not at 6 and 12 months), and during the first month after cardiac surgery, when the intensity and frequency of pain were the greatest.

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Although uncommon, severe neurological events have been reported in patients undergoing shoulder surgery in the beach chair position. The presumed etiology of central nervous system injury is hypotension and subsequent cerebral hypoperfusion that occurs after alterations in positioning under general anesthesia. Most clinical trials have demonstrated that beach chair positioning results in reductions in regional brain oxygenation, cerebral blood flow, and jugular bulb oxygenation, as well as impairment in cerebral autoregulation and electroencephalographic/processed electroencephalographic variables. Further studies are needed to define the incidence of adverse neurological adverse events in the beach chair position, identify the best intraoperative neurological monitors that are predictive of neurocognitive outcomes, the lowest "safe" acceptable blood pressure during surgery for individual patients, and the optimal interventions to treat intraoperative hypotension.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Quantitative neuromuscular monitoring is required to ensure neuromuscular function has recovered completely at the time of tracheal extubation. The TOFscan (Drager Technologies, Canada) is a new three-dimensional acceleromyography device that measures movement of the thumb in multiple planes. The aim of this observational investigation was to assess the agreement between nonnormalized and normalized train-of-four values obtained with the TOF-Watch SX (Organon, Ireland) and those obtained with the TOFscan during recovery from neuromuscular blockade., Methods: Twenty-five patients were administered rocuronium, and spontaneous recovery of neuromuscular blockade was allowed to occur. The TOFscan and TOF-Watch SX devices were applied to opposite arms. A preload was applied to the TOF-Watch SX, and calibration was performed before rocuronium administration. Both devices were activated, and train-of-four values were obtained every 15 s. Modified Bland-Altman analyses were conducted to compare train-of-four ratios measured with the TOFscan to those measured with the TOF-Watch SX (when train-of-four thresholds of 0.2 to 1.0 were achieved)., Results: Bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at nonnormalized train-of-four ratios between 0.2 and 1.0 were 0.021 and -0.100 to 0.141, respectively. When train-of-four measures with the TOF-Watch SX were normalized, bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at ratios between 0.2 and 1.0 were 0.015 and -0.097 to 0.126, respectively., Conclusions: Good agreement between the TOF-Watch SX with calibration and preload application and the uncalibrated TOFscan was observed throughout all stages of neuromuscular recovery.

Purpose: The goal of this study was to assess compliance with a presurgical safety checklist before and after the institution of a surgical flight board displaying a surgical safety checklist with embedded real-time clinical decision support (CDS). We hypothesized that the institution of a surgical flight board with embedded real-time data support would improve compliance with the presurgical safety checklist., Methods: In this prospective, observational trial, surgeon-led procedural timeout compliance for 300 procedures was studied. In phase I (PI), procedural timeouts were performed using a simple paper checklist. In phase II (PII), an electronic surgical flight board with an embedded safety checklist was installed in each operating room, but the timeout procedure consisted of the same paper process as in PI. In phase III (PIII), the flight board safety checklist was used. Ten procedures each from 10 surgeons were evaluated in each phase. Compliance was scored on a 12-point scale with each point representing a different item on the checklist., Results: Timeout compliance in PI ranged from 4.5 to 8.6 and 8.75 to 12 in PIII. All 10 surgeons demonstrated statistically improved compliance from PI to PIII. Compliance was significantly improved in 8 of 12 safety check items. Decreased compliance was not seen with any checklist item. Of the items with CDS, compliance with procedure consent and special safety precautions improved from PI to PIII, as did compliance with display of essential imaging, critical events or concerns, and number of procedures (i.e., >1 surgeon performing procedures)., Conclusions: Using the electronic medical record with real-time CDS improves compliance with presurgical safety checklists.

Producing novel enzymes that are catalytically active in vitro and biologically functional in vivo is a key goal of synthetic biology. Here we describe Syn-F4, the first de novo protein that meets both criteria. Purified Syn-F4 hydrolyzes the siderophore ferric enterobactin, and expression of Syn-F4 allows an inviable strain of Escherichia coli to grow in iron-limited medium. These findings demonstrate that entirely new sequences can provide life-sustaining enzymatic functions in living organisms.

Neuromuscular monitoring devices were introduced into clinical practice in the 1970s. Qualitative neuromuscular monitors, or peripheral nerve stimulators, provide an electrical stimulus to a motor nerve and the response of corresponding muscle subjectively evaluated. A standard peripheral nerve stimulator provides several patterns of nerve stimulation, including train-of-four (TOF), double-burst, tetanic, and post-tetanic count. Qualitative (and quantitative) monitors are needed to determine onset of neuromuscular blockade, maintain the required depth of muscle relaxation during the surgical procedure, and assess an appropriate dose of reversal agent. However, absence of fade measured with a peripheral nerve stimulator does not exclude residual neuromuscular block; TOF ratios as low as 0.4-0.6 may be present when fade is no longer observed. In addition, the risk of incomplete neuromuscular recovery may be influenced by monitoring site. The adductor pollicis is more sensitive to the effects of neuromuscular blocking agents (compared to the muscles surrounding the eye), and monitoring at this site may more accurately reflect recovery of pharyngeal muscles (the last muscles to recover from the effects of neuromuscular blocking agents, in which dysfunction may persist even at a TOF ratio of 1.0). Quantitative monitors are devices that measure and quantify the degree of muscle weakness and display the results numerically. Several different technologies have been developed, including mechanomyography, electromyography, acceleromyography, kineograph, and phonomyography. Lower doses of anticholinesterases may be used to effectively reverse neuromuscular blockade at TOF ratios of 0.4-0.6; quantitative monitoring is required to determine that this level of neuromuscular recovery has occurred. As clinical tests of muscle strength, peripheral nerve stimulators are unable to determine whether full recovery of neuromuscular function is present at the end of the surgical procedure. The use of quantitative monitors is essential in excluding clinically important muscle weakness (TOF ratios <0.9 to 1.0) at the time of tracheal extubation.

Objective: To determine whether opioids during the first 24 postoperative hours were significantly altered when receiving intravenous (IV) acetaminophen during that time compared with those receiving placebo (normal saline)., Methods: One hundred forty patients undergoing any type of craniotomy were randomly assigned to receive either 1 g of IV acetaminophen or placebo upon surgical closure, and every 6 hours thereafter, up to 18 hours postoperatively. Analgesic requirements for the first 24 postoperative hours were recorded. Time to rescue medications in the postanesthesia care unit (PACU)/intensive care unit (ICU), amount of rescue medication, ICU and hospital lengths of stay, number of successful neurological examinations, sedation, delirium, satisfaction, and visual analog scale pain scores were also recorded., Results: Compared with the placebo group, more patients in the IV acetaminophen group (10/66 [15.2%] vs. 4/65 [6.2%] in the placebo group) did not require opioids within the first 24 postoperative hours, but this did not reach significance (odds ratio, -9.0%, 95% confidence interval -20.5% to 1.8%; P = 0.166). Both groups had similar times to rescue medications, amounts of rescue medications, ICU and hospital lengths of stay, numbers of successful neurological examinations, sedation, delirium, satisfaction scores, visual analog scale pain scores, and temperatures within the first 24 postoperative hours., Conclusions: The opioid requirements within the first 24 postoperative hours were similar in the placebo and acetaminophen groups. This study is informative for the design and planning of future studies investigating the management of postoperative pain in patients undergoing craniotomies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: When a muscle relaxant is administered to facilitate intubation, the benefits of anticholinesterase reversal must be balanced with potential risks. The aim of this double-blinded, randomized noninferiority trial was to evaluate the effect of neostigmine administration on neuromuscular function when given to patients after spontaneous recovery to a train-of-four ratio of 0.9 or greater., Methods: A total of 120 patients presenting for surgery requiring intubation were given a small dose of rocuronium. At the conclusion of surgery, 90 patients achieving a train-of-four ratio of 0.9 or greater were randomized to receive either neostigmine 40 μg/kg or saline (control). Train-of-four ratios were measured from the time of reversal until postanesthesia care unit admission. Patients were monitored for postextubation adverse respiratory events and assessed for muscle strength., Results: Ninety patients achieved a train-of-four ratio of 0.9 or greater at the time of reversal. Mean train-of-four ratios in the control and neostigmine groups before reversal (1.02 vs. 1.03), 5 min postreversal (1.05 vs. 1.07), and at postanesthesia care unit admission (1.06 vs. 1.08) did not differ. The mean difference and corresponding 95% CI of the latter were -0.018 and -0.046 to 0.010. The incidences of postoperative hypoxemic events and episodes of airway obstruction were similar for the groups. The number of patients with postoperative signs and symptoms of muscle weakness did not differ between groups (except for double vision: 13 in the control group and 2 in the neostigmine group; P = 0.001)., Conclusions: Administration of neostigmine at neuromuscular recovery was not associated with clinical evidence of anticholinesterase-induced muscle weakness., Visual Abstract: An online visual overview is available for this article.(Figure is included in full-text article.).

Purpose of Review: The aim of this review is to examine data relating to perioperative management of the patient with neuromuscular disorders RECENT FINDINGS: Patients with pre-existing neuromuscular disorders are at risk for a number of postoperative complications that are related to anesthetic drugs that are administered intraoperatively. Careful preoperative assessment is necessary to reduce morbidity and mortality. In particular, the risk of postoperative respiratory failure and need for long-term ventilation should be reviewed with patients. The use of succinylcholine should be avoided in muscular dystrophies, motor neuron diseases, and intrinsic muscle disease due to a risk of malignant hyperthermia, hyperkalemia, rhabdomyolysis, and cardiac arrest. The use of quantitative neuromuscular monitoring should be strongly considered whenever nondepolarizing neuromuscular blocking agents are administered. A number of case series and reports have been recently published demonstrating that sugammadex can be safely used in patients with neuromuscular disease; the risk of residual neuromuscular is nearly eliminated when this agent is administered intraoperatively., Summary: Careful assessment and management of patients with underlying neuromuscular diseases is required to reduce postoperative complications. This article reviews the anesthetic implications of patients undergoing surgery with neuromuscular disorder.

In this study, we examined anesthetic records before and after the implementation of an electronic anesthetic record documentation (AIMS) in a single surgical population. The purpose of this study was to identify any inconsistencies in anesthetic care based on handwritten documentation (paper) or AIMS. We hypothesized that the type of anesthetic record (paper or AIMS) would lead to differences in the documentation and management of hypotension. Consecutive patients who underwent esophageal surgery between 2009 and 2014 by a single surgeon were eligible for the study. Patients were grouped in to 'paper' or 'AIMS' based on the type of anesthetic record identified in the chart. Pertinent patient identifiers were removed and data collated after collection. Predetermined preoperative and intraoperative data variables were reviewed. Consecutive esophageal surgery patients (N = 189) between 2009 and 2014 were evaluated. 92 patients had an anesthetic record documented on paper and 97 using AIMS. The median number of unique blood pressure recordings was lower in the AIMS group (median (Q1,Q3) AIMS 30.0 (24.0, 39.0) vs. Paper 35.0 (28.5, 43.5), p < 0.01). However, the median number of hypotensive events (HTEs) was higher in the AIMS group (median (Q1,Q3) 8.0 (4.0, 18.0) vs. 4.0 (1.0, 10.5), p < 0.001), and the percentage of HTEs per blood pressure recording was higher in the AIMS group (30.4 ((Q1, Q3) (9.5, 60.9)% vs. 12.5 (2.4, 27.5)%), p < 0.01). Multivariable regression analysis identified independent predictors of HTEs. The incidence of HTEs was found to increase with AIMS (IRR = 1.88, p < 0.01). Preoperative systolic blood pressure, increased blood loss, and phenylephrine. A phenylephrine infusion was negatively associated with hypotensive events (IRR = 0.99, p = 0.03). We noted an increased incidence of HTEs associated with the institution of an AIMS. Despite this increase, no change in medical therapy for hypotension was seen. AIMS did not appear to have an effect on the management of intraoperative hypotension in this patient population.

Background: Patients undergoing spinal fusion surgery often experience severe pain during the first three postoperative days. The aim of this parallel-group randomized trial was to assess the effect of the long-duration opioid methadone on postoperative analgesic requirements, pain scores, and patient satisfaction after complex spine surgery., Methods: One hundred twenty patients were randomized to receive either methadone 0.2 mg/kg at the start of surgery or hydromorphone 2 mg at surgical closure. Anesthetic care was standardized, and clinicians were blinded to group assignment. The primary outcome was intravenous hydromorphone consumption on postoperative day 1. Pain scores and satisfaction with pain management were measured at postanesthesia care unit admission, 1 and 2 h postadmission, and on the mornings and afternoons of postoperative days 1 to 3., Results: One hundred fifteen patients were included in the analysis. Median hydromorphone use was reduced in the methadone group not only on postoperative day 1 (4.56 vs. 9.90 mg) but also on postoperative days 2 (0.60 vs. 3.15 mg) and 3 (0 vs. 0.4 mg; all P< 0.001). Pain scores at rest, with movement, and with coughing were less in the methadone group at 21 of 27 assessments (all P = 0.001 to < 0.0001). Overall satisfaction with pain management was higher in the methadone group than in the hydromorphone group until the morning of postoperative day 3 (all P = 0.001 to < 0.0001)., Conclusions: Intraoperative methadone administration reduced postoperative opioid requirements, decreased pain scores, and improved patient satisfaction with pain management.

Background: Opportunities for anesthesia research investigators to obtain consent for clinical trials are often restricted to the day of surgery, which may limit the ability of subjects to freely decide about research participation. The aim of this study was to determine whether subjects providing same-day informed consent for anesthesia research are comfortable doing so., Methods: A 25-question survey was distributed to 200 subjects providing informed consent for one of two low-risk clinical trials. While consent on the day of surgery was permitted for both studies, a preadmission telephone call was required for one. The questionnaire was provided to each subject at the time of discharge from the hospital. The questions were structured to assess six domains relating to the consent process, and each question was graded on a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree). Overall satisfaction with same-day consent was assessed using an 11-point scale with 0 = extremely dissatisfied and 10 = extremely satisfied., Results: Completed questionnaires were received from 129 subjects. Median scores for satisfaction with the consent process were 9.5 to 10. Most respondents reported that the protocol was well explained and comprehended and that the setting in which consent was obtained was appropriate (median score of 5). Most patients strongly disagreed that they were anxious at the time of consent, felt obligated to participate, or had regrets about participation (median score of 1). Ten percent or less of subjects reported negative responses to any of the questions, and no differences were observed between the study groups., Conclusion: More than 96% of subjects who provided same-day informed consent for low-risk research were satisfied with the consent process.

Designing and producing novel proteins that fold into stable structures and provide essential biological functions are key goals in synthetic biology. In initial steps toward achieving these goals, we constructed a combinatorial library of de novo proteins designed to fold into 4-helix bundles. As described previously, screening this library for sequences that function in vivo to rescue conditionally lethal mutants of Escherichia coli (auxotrophs) yielded several de novo sequences, termed SynRescue proteins, which rescued four different E. coli auxotrophs. In an effort to understand the structural requirements necessary for auxotroph rescue, we investigated the biophysical properties of the SynRescue proteins, using both computational and experimental approaches. Results from circular dichroism, size-exclusion chromatography, and NMR demonstrate that the SynRescue proteins are α-helical and relatively stable. Surprisingly, however, they do not form well-ordered structures. Instead, they form dynamic structures that fluctuate between monomeric and dimeric states. These findings show that a well-ordered structure is not a prerequisite for life-sustaining functions, and suggests that dynamic structures may have been important in the early evolution of protein function., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Elderly patients are at increased risk for anesthesia-related complications. Postoperative residual neuromuscular block (PRNB) in the elderly, defined as a train-of-four ratio less than 0.9, may exacerbate preexisting muscle weakness and respiratory dysfunction. In this investigation, the incidence of PRNB and associated adverse events were assessed in an elderly (70 to 90 yr) and younger cohort (18 to 50 yr)., Methods: Data were prospectively collected on 150 younger and 150 elderly patients. Train-of-four ratios were measured on arrival to the postanesthesia care unit (PACU). After tracheal extubation, patients were examined for adverse respiratory events during transport to the PACU, for 30 min after PACU admission, and during hospital admission. Postoperative muscle weakness was quantified using a standardized examination, and PACU and hospital lengths of stay were determined., Results: The incidence of PRNB was 57.7% in elderly and 30.0% in younger patients (difference, -27.7%; 99% CI, -41.2 to -13.1%; P < 0.001). Airway obstruction, hypoxemic events, signs and symptoms of muscle weakness, postoperative pulmonary complications, and increased PACU and hospital lengths of stay were observed more frequently in the elderly (all P < 0.01). Within each cohort, most adverse events were observed in patients with PRNB. Younger patients with PRNB received larger total doses of rocuronium than did those without it (60 vs. 50 mg, P < 0.01), but there were no differences in rocuronium dose between elderly patients with PRNB and those without it (both 50 mg)., Conclusion: The elderly are at increased risk for PRNB and associated adverse outcomes.

Background: Patients undergoing mastectomy and prosthetic breast reconstruction have significant acute postsurgical pain, routinely mandating inpatient hospitalization. Liposomal bupivacaine (LB) (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, N.J.) has been shown to be a safe and effective pain reliever in the immediate postoperative period and may be advantageous for use in mastectomy and breast reconstruction patients., Methods: Retrospective review of 90 immediate implant-based breast reconstruction patient charts was completed. Patients were separated into 3 groups of 30 consecutively treated patients who received 1 of 3 pain treatment modalities: intravenous/oral narcotic pain control (control), bupivacaine pain pump, or LB injection. Length of hospital stay, patient-reported Visual Analog Scale (VAS) pain scores, postoperative patient-controlled analgesia usage, and nausea-related medication use were abstracted and subjected to analysis of variance and multiple linear-regression analysis, as appropriate., Results: Subjects were well-matched for age (P = 0.24) regardless of pain-control modality. Roughly half (53%) of control and pain pump-treated subjects had bilateral procedures, as opposed to 80% of LB subjects. Mean length of stay for LB subjects was significantly less than control (1.5 days vs 2.00 days; P = 0.016). LB subjects reported significantly lower VAS pain scores at 4, 8, 12, 16, and 24 hours compared with pain pump and control (P < 0.01). There were no adverse events in the LB group., Conclusion: Use of LB in this group of immediate breast reconstruction patients was associated with decreased patient VAS pain scores in the immediate postoperative period compared with bupivacaine pain pump and intravenous/oral narcotic pain management and reduced inpatient length of stay.

Background: The intensity of pain after cardiac surgery is often underestimated, and inadequate pain control may be associated with poorer quality of recovery. The aim of this investigation was to examine the effect of intraoperative methadone on postoperative analgesic requirements, pain scores, patient satisfaction, and clinical recovery., Methods: Patients undergoing cardiac surgery with cardiopulmonary bypass (n = 156) were randomized to receive methadone (0.3 mg/kg) or fentanyl (12 μg/kg) intraoperatively. Postoperative analgesic requirements were recorded. Patients were assessed for pain at rest and with coughing 15 min and 2, 4, 8, 12, 24, 48, and 72 h after tracheal extubation. Patients were also evaluated for level of sedation, nausea, vomiting, itching, hypoventilation, and hypoxia at these times., Results: Postoperative morphine requirements during the first 24 h were reduced from a median of 10 mg in the fentanyl group to 6 mg in the methadone group (median difference [99% CI], -4 [-8 to -2] mg; P < 0.001). Reductions in pain scores with coughing were observed during the first 24 h after extubation; the level of pain with coughing at 12 h was reduced from a median of 6 in the fentanyl group to 4 in the methadone group (-2 [-3 to -1]; P < 0.001). Improvements in patient-perceived quality of pain management were described in the methadone group. The incidence of opioid-related adverse events was not increased in patients administered methadone., Conclusions: Intraoperative methadone administration resulted in reduced postoperative morphine requirements, improved pain scores, and enhanced patient-perceived quality of pain management.