Myosin-5 varies its step length to carry cargo straight along the irregular F-actin track.

Molecular motors employ chemical energy to generate unidirectional mechanical output against a track while navigating a chaotic cellular environment, potential disorder on the track, and against Brownian motion. Nevertheless, decades of nanometer-precise optical studies suggest that myosin-5a, one of the prototypical molecular motors, takes uniform steps spanning 13 subunits (36 nm) along its F-actin track. Here, we use high-resolution interferometric scattering microscopy to reveal that myosin takes strides spanning 22 to 34 actin subunits, despite walking straight along the helical actin filament. We show that cumulative angular disorder in F-actin accounts for the observed proportion of each stride length, akin to crossing a river on variably spaced stepping stones. Electron microscopy revealed the structure of the stepping molecule. Our results indicate that both motor and track are soft materials that can adapt to function in complex cellular conditions.

Closing the Chasm: Understanding and Addressing the Anesthesia Workforce Supply and Demand Imbalance.

The imbalance in anesthesia workforce supply and demand has been exacerbated post-COVID due to a surge in demand for anesthesia care, especially in non-operating room anesthetizing sites, at a faster rate than the increase in anesthesia clinicians. The consequences of this imbalance or labor shortage compromise healthcare facilities, adversely affect the cost of care, worsen anesthesia workforce burnout, disrupt procedural and surgical schedules, and threaten academic missions and the ability to educate future anesthesiologists. In developing possible solutions, one must examine emerging trends that are affecting the anesthesia workforce, new technologies that will transform anesthesia care and the workforce, and financial considerations, including governmental payment policies. Possible practice solutions to this imbalance will require both short- and long-term multifactorial approaches that include increasing training positions and retention policies, improving capacity through innovations, leveraging technology, and addressing financial constraints.

Comparing the quality of ChatGPT- and physician-generated responses to patients' dermatology questions in the electronic medical record.

BACKGROUND: ChatGPT is a free artificial intelligence (AI)-based natural language processing tool that generates complex responses to inputs from users. OBJECTIVES: To determine whether ChatGPT is able to generate high-quality responses to patient-submitted questions in the patient portal. METHODS: Patient-submitted questions and the corresponding responses from their dermatology physician were extracted from the electronic medical record for analysis. The questions were input into ChatGPT (version 3.5) and the outputs extracted for analysis, with manual removal of verbiage pertaining to ChatGPT's inability to provide medical advice. Ten blinded reviewers (seven physicians and three nonphysicians) rated and selected their preference in terms of 'overall quality', 'readability', 'accuracy', 'thoroughness' and 'level of empathy' of the physician- and ChatGPT-generated responses. RESULTS: Thirty-one messages and responses were analysed. Physician-generated responses were vastly preferred over the ChatGPT -responses by the physician and nonphysician reviewers and received significantly higher ratings for 'readability' and 'level of empathy'. CONCLUSIONS: The results of this study suggest that physician-generated responses to patients' portal messages are still preferred over ChatGPT, but generative AI tools may be helpful in generating the first drafts of responses and providing information on education resources for patients.

Clinical and Histopathologic Spectrum of Toxic Erythema of Chemotherapy: A Series of 56 Cases From a Single Institution.

INTRODUCTION: Although many individual cases and small series of toxic erythema of chemotherapy (TEC) have been described, the full spectrum of findings is not well understood. OBJECTIVE: To provide a comprehensive review of the clinical and histopathologic features of TEC with an emphasis on novel histopathologic findings. METHODS: We searched our electronic medical record for "toxic erythema of chemotherapy" or "neutrophilic eccrine hidradenitis." Fifty-six cases meeting clinical and histopathologic criteria were identified. The electronic medical record and accompanying hematoxylin and eosin-stained slides were retrospectively reviewed. RESULTS: The clinical findings were heterogeneous but included classic presentations such as intertriginous eruptions (34%) and acral erythema (25%). The most common histopathologic features were apoptotic keratinocytes (95%), basal vacuolar change (91%), and epithelial dysmaturation (79%). Eccrine squamous syringometaplasia was seen in over half of the cases (33/56; 59%), whereas neutrophilic eccrine hidradenitis was uncommon (16%). Interestingly, many cases showed prominent interstitial histiocytes (55%). Other novel findings included irregular orthohyperkeratosis (23%), irregular epidermal hyperplasia (14%), and acantholysis (9%). LIMITATIONS: As a retrospective study, it is subject to information bias. CONCLUSION: This is the largest reported series of TEC. In addition to confirming previously reported features, we identify novel histopathologic findings to add to the spectrum of TEC.

Resource-Efficient Dissipative Entanglement of Two Trapped-Ion Qubits.

We demonstrate a simplified method for dissipative generation of an entangled state of two trapped-ion qubits. Our implementation produces its target state faster and with higher fidelity than previous demonstrations of dissipative entanglement generation and eliminates the need for auxiliary ions. The entangled singlet state is generated in ∼7 ms with a fidelity of 0.949(4). The dominant source of infidelity is photon scattering. We discuss this error source and strategies for its mitigation.

High-Fidelity Indirect Readout of Trapped-Ion Hyperfine Qubits.

We propose and demonstrate a protocol for high-fidelity indirect readout of trapped ion hyperfine qubits, where the state of a ^{9}Be^{+} qubit ion is mapped to a ^{25}Mg^{+} readout ion using laser-driven Raman transitions. By partitioning the ^{9}Be^{+} ground-state hyperfine manifold into two subspaces representing the two qubit states and choosing appropriate laser parameters, the protocol can be made robust to spontaneous photon scattering errors on the Raman transitions, enabling repetition for increased readout fidelity. We demonstrate combined readout and back-action errors for the two subspaces of 1.2_{-0.6}^{+1.1}×10^{-4} and 0_{-0}^{+1.9}×10^{-5} with 68% confidence while avoiding decoherence of spectator qubits due to stray resonant light that is inherent to direct fluorescence detection.

Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization at Scale.

The development of accurate transferable force fields is key to realizing the full potential of atomistic modeling in the study of biological processes such as protein-ligand binding for drug discovery. State-of-the-art transferable force fields, such as those produced by the Open Force Field Initiative, use modern software engineering and automation techniques to yield accuracy improvements. However, force field torsion parameters, which must account for many stereoelectronic and steric effects, are considered to be less transferable than other force field parameters and are therefore often targets for bespoke parametrization. Here, we present the Open Force Field QCSubmit and BespokeFit software packages that, when combined, facilitate the fitting of torsion parameters to quantum mechanical reference data at scale. We demonstrate the use of QCSubmit for simplifying the process of creating and archiving large numbers of quantum chemical calculations, by generating a dataset of 671 torsion scans for druglike fragments. We use BespokeFit to derive individual torsion parameters for each of these molecules, thereby reducing the root-mean-square error in the potential energy surface from 1.1 kcal/mol, using the original transferable force field, to 0.4 kcal/mol using the bespoke version. Furthermore, we employ the bespoke force fields to compute the relative binding free energies of a congeneric series of inhibitors of the TYK2 protein, and demonstrate further improvements in accuracy, compared to the base force field (MUE reduced from 0.560.390.77 to 0.420.280.59 kcal/mol and R2 correlation improved from 0.720.350.87 to 0.930.840.97).

Exploration and validation of force field design protocols through QM-to-MM mapping.

The scale of the parameter optimisation problem in traditional molecular mechanics force field construction means that design of a new force field is a long process, and sub-optimal choices made in the early stages can persist for many generations. We hypothesise that careful use of quantum mechanics to inform molecular mechanics parameter derivation (QM-to-MM mapping) should be used to significantly reduce the number of parameters that require fitting to experiment and increase the pace of force field development. Here, we design and train a collection of 15 new protocols for small, organic molecule force field derivation, and test their accuracy against experimental liquid properties. Our best performing model has only seven fitting parameters, yet achieves mean unsigned errors of just 0.031 g cm-3 and 0.69 kcal mol-1 in liquid densities and heats of vaporisation, compared to experiment. The software required to derive the designed force fields is freely available at https://github.com/qubekit/QUBEKit.

Perioperative Brain Health in the Older Adult: A Patient Safety Imperative.

While people 65 years of age and older represent 16% of the population in the United States, they account for >40% of surgical procedures performed each year. Maintaining brain health after anesthesia and surgery is not only important to our patients, but it is also an increasingly important patient safety imperative for the specialty of anesthesiology. Aging is a complex process that diminishes the reserve of every organ system and often results in a patient who is vulnerable to the stress of surgery. The brain is no exception, and many older patients present with preoperative cognitive impairment that is undiagnosed. As we age, a number of changes occur in the human brain, resulting in a patient who is less resilient to perioperative stress, making older adults more susceptible to the phenotypic expression of perioperative neurocognitive disorders. This review summarizes the current scientific and clinical understanding of perioperative neurocognitive disorders and recommends patient-centered, age-focused interventions that can better mitigate risk, prevent harm, and improve outcomes for our patients. Finally, it discusses the emerging topic of sleep and cognitive health and other future frontiers of scientific inquiry that might inform clinical best practices.

Anesthesia Patient Safety: Next Steps to Improve Worldwide Perioperative Safety by 2030.

Patient safety is a core principle of anesthesia care worldwide. The specialty of anesthesiology has been a leader in medicine for the past half century in pursuing patient safety research and implementing standards of care and systematic improvements in processes of care. Together, these efforts have dramatically reduced patient harm associated with anesthesia. However, improved anesthesia patient safety has not been uniformly obtained worldwide. There are unique differences in patient safety outcomes between countries and regions in the world. These differences are often related to factors such as availability, support, and use of health care resources, trained personnel, patient safety outcome data collection efforts, standards of care, and cultures of safety and teamwork in health care facilities. This article provides insights from national anesthesia society leaders from 13 countries around the world. The countries they represent are diverse geographically and in health care resources. The authors share their countries' current and future initiatives in anesthesia patient safety. Ten major patient safety issues are common to these countries, with several of these focused on the importance of extending initiatives into the full perioperative as well as intraoperative environments. These issues may be used by anesthesia leaders around the globe to direct collaborative efforts to improve the safety of patients undergoing surgery and anesthesia in the coming decade.

Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear. Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied. Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2­1.6), 2.0 (95% CI, 1.6­2.4), and 3.4 (95% CI, 2.7­4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1­1.5), 1.6 (1.3­2.0), and 2.4 (1.9­3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome. Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

Quantum Harmonic Oscillator Spectrum Analyzers.

Characterization and suppression of noise are essential for the control of harmonic oscillators in the quantum regime. We measure the noise spectrum of a quantum harmonic oscillator from low frequency to near the oscillator resonance by sensing its response to amplitude modulated periodic drives with a qubit. Using the motion of a trapped ion, we experimentally demonstrate two different implementations with combined sensitivity to noise from 500 Hz to 600 kHz. We apply our method to measure the intrinsic noise spectrum of an ion trap potential in a previously unaccessed frequency range.

Anesthesiologists' Role in Value-based Perioperative Care and Healthcare Transformation.

Health care is undergoing major transformation with a shift from fee-for-service care to fee-for-value. The advent of new care delivery and payment models is serving as a driver for value-based care. Hospitals, payors, and patients increasingly expect physicians and healthcare systems to improve outcomes and manage costs. The impact of the coronavirus disease 2019 (COVID-19) pandemic on surgical and procedural practices further highlights the urgency and need for anesthesiologists to expand their roles in perioperative care, and to impact system improvement. While there have been substantial advances in anesthesia care, perioperative complications and mortality after surgery remain a key concern. Anesthesiologists are in a unique position to impact perioperative health care through their multitude of interactions and influences on various aspects of the perioperative domain, by using the surgical experience as the first touchpoint to reengage the patient in their own health care. Among the key interventions that are being effectively instituted by anesthesiologists include proactive engagement in preoperative optimization of patients' health; personalization and standardization of care delivery by segmenting patients based upon their complexity and risk; and implementation of best practices that are data-driven and evidence-based and provide structure that allow the patient to return to their optimal state of functional, cognitive, and psychologic health. Through collaborative relationships with other perioperative stakeholders, anesthesiologists can consolidate their role as clinical leaders driving value-based care and healthcare transformation in the best interests of patients.

The Evolution, Current Value, and Future of the American Society of Anesthesiologists Physical Status Classification System.

The American Society of Anesthesiologists (ASA) Physical Status classification system celebrates its 80th anniversary in 2021. Its simplicity represents its greatest strength as well as a limitation in a world of comprehensive multisystem tools. It was developed for statistical purposes and not as a surgical risk predictor. However, since it correlates well with multiple outcomes, it is widely used-appropriately or not-for risk prediction and many other purposes. It is timely to review the history and development of the system. The authors describe the controversies surrounding the ASA Physical Status classification, including the problems of interrater reliability and its limitations as a risk predictor. Last, the authors reflect on the current status and potential future of the ASA Physical Status system.

Implementation of the QUBE Force Field in SOMD for High-Throughput Alchemical Free-Energy Calculations.

The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein-ligand binding. To date, the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD. The implementation is validated by demonstrating the reproducibility of absolute hydration free energies computed with the QUBE force field across the SOMD and GROMACS software packages. We further demonstrate, by way of a case study involving two series of non-nucleoside inhibitors of HIV-1 reverse transcriptase, that the availability of QUBE in a modern simulation package that makes efficient use of graphics processing unit acceleration will facilitate high-throughput alchemical free-energy calculations.

Primary cutaneous malignant perivascular epithelioid cell tumor: Case of a rare tumor with review of the literature.

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epithelioid or spindled cytomorphology that typically grow around blood vessels. These tumors are phenotypically and immunohistochemically distinct, expressing markers of both melanocytic and smooth muscle differentiation. Herein, we describe a case of histopathologically malignant cutaneous PEComa without metastatic spread, with review of the pertinent literature. Telescoping punch biopsy demonstrated an epithelioid neoplasm with marked atypia, hypercellularity, and increased mitotic activity. Immunohistochemical stains for HMB-45, NK1-C3, PGP9.5, MiTF, CD10, and CD68 were positive within tumor cells. In addition, there was diffuse expression of caldesmon and focal cytoplasmic staining for smooth muscle actin on the excision specimen. The patient underwent treatment with surgical excision with adjuvant radiation and surveillance computed tomography (CT). The patient remains free of recurrence or metastatic disease after 10 months of follow-up. To our knowledge, this is only the third reported case of a malignant cutaneous PEComa reported in the literature to date.

A machine learning based intramolecular potential for a flexible organic molecule.

Quantum mechanical predictive modelling in chemistry and biology is often hindered by the long time scales and large system sizes required of the computational model. Here, we employ the kernel regression machine learning technique to construct an analytical potential, using the Gaussian Approximation Potential software and framework, that reproduces the quantum mechanical potential energy surface of a small, flexible, drug-like molecule, 3-(benzyloxy)pyridin-2-amine. Challenges linked to the high dimensionality of the configurational space of the molecule are overcome by developing an iterative training protocol and employing a representation that separates short and long range interactions. The analytical model is connected to the MCPRO simulation software, which allows us to perform Monte Carlo simulations of the small molecule bound to two proteins, p38 MAP kinase and leukotriene A4 hydrolase, as well as in water. We demonstrate that our machine learning based intramolecular model is transferable to the condensed phase, and demonstrate that the use of a faithful representation of the quantum mechanical potential energy surface can result in corrections to absolute protein-ligand binding free energies of up to 2 kcal mol-1 in the example studied here.

Bifunctional Hydrogen Bonding of Imidazole with Water Explored by Rotational Spectroscopy and DFT Calculations.

Laser vaporization of imidazole in the presence of an argon buffer gas has allowed the generation and isolation of two isomers of an imidazole monohydrate complex, denoted herein as imid···H2O and H2O···imid, within a gas sample undergoing supersonic expansion. Imidazole and water are respectively proton-accepting and proton-donating in imid···H2O, but these roles are reversed in the H2O···imid complex. Both isomers have been characterized by chirped-pulse Fourier transform microwave spectroscopy between 7.0 and 18.5 GHz. The ground-state rotational spectra of four isotopologues of imid···H2O and three isotopologues of H2O···imid have been measured. All spectra have been assigned and fitted to determine rotational (A0, B0, C0), centrifugal distortion (DJ, DJK), and nuclear quadrupole coupling constants (χaa(N1), [χbb(N1) - χcc(N1)], χaa(N3), and [χbb(N3) - χcc(N3)]). Structural parameters (r0 and rs) have been accurately determined from measured rotational constants for each isomer. The imid···H2O complex contains a nonlinear hydrogen bond (∠(O-Hb···N3) = 172.1(26)° in the experimentally determined, r0 geometry) between the pyridinic nitrogen of imidazole and a hydrogen atom of H2O. The DFT calculations find that the H2O···imid complex also contains a nonlinear hydrogen bond between the oxygen atom of water and the hydrogen attached to the pyrrolic nitrogen of imidazole (∠(O···H1-N1) = 174.7°). Two states observed in the spectrum of H2O···imid, assigned as 0- and 0+ states, confirm that large amplitude motions occur on the time scale of the molecular rotation. Density functional theory has been performed to characterize these large amplitude motions.

Targeting the unfolded protein response in head and neck and oral cavity cancers.

Many FDA-approved anti-cancer therapies, targeted toward a wide array of molecular targets and signaling networks, have been demonstrated to activate the unfolded protein response (UPR). Despite a critical role for UPR signaling in the apoptotic execution of cancer cells by many of these compounds, the authors are currently unaware of any instance whereby a cancer drug was developed with the UPR as the intended target. With the essential role of the UPR as a driving force in the genesis and maintenance of the malignant phenotype, a great number of pre-clinical studies have surged into the medical literature describing the ability of dozens of compounds to induce UPR signaling in a myriad of cancer models. The focus of the current work is to review the literature and explore the role of the UPR as a mediator of chemotherapy-induced cell death in squamous cell carcinomas of the head and neck (HNSCC) and oral cavity (OCSCC), with an emphasis on preclinical studies.

First-Year Results of the American Board of Anesthesiology's Objective Structured Clinical Examination for Initial Certification.

In 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate an Objective Structured Clinical Examination (OSCE) into its initial certification examination system. Previously, the ABA's staged examination system consisted of 2 written examinations (the BASIC and ADVANCED examinations) and the Standardized Oral Examination (SOE). The OSCE and the existing SOE are now 2 separate components of the APPLIED Examination. This report presents the results of the first-year OSCE administration. A total of 1410 candidates took both the OSCE and the SOE in 2018. Candidate performance approximated a normal distribution for both the OSCE and the SOE, and was not associated with the timing of the examination, including day of the week, morning versus afternoon session, and order of the OSCE and the SOE. Practice-based Learning and Improvement was the most difficult station, while Application of Ultrasonography was the least difficult. The correlation coefficient between SOE and OSCE scores was 0.35 ([95% confidence interval {CI}, 0.30-0.39]; P < .001). Scores for the written ADVANCED Examination were modestly correlated with scores for the SOE (r = 0.29 [95% CI, 0.25-0.34]; P < .001) and the OSCE (r = 0.15 [95% CI, 0.10-0.20]; P < .001). Most of the candidates who failed the SOE passed the OSCE, and most of the candidates who failed the OSCE passed the SOE. Of the 1410 candidates, 77 (5.5%) failed the OSCE, 155 (11.0%) failed the SOE, and 25 (1.8%) failed both. Thus, 207 (14.7%) failed at least 1 component of the APPLIED Examination. Adding an OSCE to a board certification examination system is feasible. Preliminary evidence indicates that the OSCE measures aspects of candidate abilities distinct from those measured by other examinations used for initial board certification.