Effects of ingesting large prey on the kinematics of rectilinear locomotion in Boa constrictor.

Large and stout snakes commonly consume large prey and use rectilinear crawling; yet, whether body wall distention after feeding impairs rectilinear locomotion is poorly understood. After eating large prey (30-37% body mass), all Boa constrictor tested could perform rectilinear locomotion in the region with the food bolus despite a greatly increased distance between the ribs and the ventral skin that likely lengthens muscles relevant to propulsion. Unexpectedly, out of 11 kinematic variables, only two changed significantly (P<0.05) after feeding: cyclic changes in snake height increased by more than 1.5 times and the longitudinal movements of the ventral skin relative to the skeleton decreased by more than 25%. Additionally, cyclic changes in snake width suggest that the ribs are active and mobile during rectilinear locomotion, particularly in fed snakes, but also in unfed snakes. These kinematic changes suggest that rectilinear actuators reorient more vertically and undergo smaller longitudinal excursions following large prey ingestion, both of which likely act to reduce elongation of these muscles that may otherwise experience substantial strain.

Prepared for landing: A simple activation strategy scales muscle force to landing height.

Before landing from a jump or fall, animals preactivate muscles to stiffen their limb joints but it is unclear how muscles tune limb stiffness and how collision forcefulness is anticipated. We measured electromyography and force from the lateral gastrocnemius muscle during landings in turkeys, an animal model that allows for direct measurements of muscle force. Many studies of landings in humans and other animals have found the duration of muscle preactivation to be constant, starting approximately 100 ms before impact, irrespective of fall duration. Therefore, we hypothesized a lack of relationship between fall duration (as dictated by drop height), muscle activity onset-time, and force at toe-down. Contrary to our expectations, both muscle activity and force rose from briefly after fall initiation until toe-down. Preactivation duration was proportional to fall height, while the rate of force rise was consistent across drop heights, resulting in force at landing and leg stiffness being proportional to fall height. Onset of muscle activity lagged 22 ± 7 ms (mean ± S.E.M.) from fall initiation, consistent with a reflex response initiation of the force ramp-up. Together, our results suggest that a constant (clock-like) rate of motor unit recruitment, initiated at fall initiation provides a preactivation that is proportional to drop height. The result is a tuning of pre-landing muscle force, providing a limb stiffening that is proportional to impact intensity, possibly without using information about fall distance.

The interaction of in vivo muscle operating lengths and passive stiffness in rat hindlimbs.

The operating length of a muscle is a key determinant of its ability to produce force in vivo. Muscles that operate near the peak of their force-length relationship will generate higher forces whereas muscle operating at relatively short length may be safe from sudden lengthening perturbations and subsequent damage. At longer lengths, passive mechanical properties have the potential to contribute to force or constrain operating length with stiffer muscle-tendon units theoretically being restricted to shorter lengths. Connective tissues typically increase in density during aging, thus increasing passive muscle stiffness and potentially limiting the operating lengths of muscle during locomotion. Here, we compare in vivo and in situ muscle strain from the medial gastrocnemius in young (7 months old) and aged (30-32 months old) rats presumed to have varying passive tissue stiffness to test the hypothesis that stiffer muscles operate at shorter lengths relative to their force-length relationship. We measured in vivo muscle operating length during voluntary locomotion on inclines and flat trackways and characterized the muscle force-length relationship of the medial gastrocnemius using fluoromicrometry. Although no age-related results were evident, rats of both age groups demonstrated a clear relationship between passive stiffness and in vivo operating length, such that shorter operating lengths were significantly correlated with greater passive stiffness. Our results suggest that increased passive stiffness may restrict muscles to operating lengths shorter than optimal lengths, potentially limiting force capacity during locomotion.

Architectural gear ratio depends on actuator spacing in a physical model of pennate muscle.

Pennate muscles are defined by the architectural arrangement of their muscle fibers, which run at an angle to the primary axis of muscle shortening. Pennation angles can vary dynamically over the course of individual contractions, influencing the speed and distance of muscle shortening. Despite their relevance to muscle performance, the physical mechanisms that drive dynamic changes in pennation angle remain poorly understood. Muscle fibers bulge radially as they shorten, a consequence of maintaining a constant internal fluid volume, and we hypothesized that radial interactions between tightly packed muscle fibers are essential to dynamic pennation angle changes. To explore this, we built physical models of pennate muscles in which the radial distance between fiber-like actuators could be experimentally altered. Models were built from pennate arrays of McKibben actuators, a type of pneumatic actuator that forcefully shortens and bulges radially when inflated with compressed air. Consistent with past studies of biological muscle and engineered pennate actuators, we found that the magnitude of pennation angle change during contraction varied with load. Importantly, however, we found that pennation angle changes were also strongly influenced by the radial distance between neighboring McKibben actuators. Increasing the radial distance between neighboring actuators reduced pennation angle change during contraction and effectively eliminated variable responses to load. Radial interactions between muscle fibers are rarely considered in theoretical and experimental analyses of pennate muscle; however, these findings suggest that radial interactions between fibers drive pennation angle changes and influence pennate muscle performance. Our results provide insight into the fundamental mechanism underlying dynamic pennation angle changes in biological muscle and highlight design considerations that can inform the development of engineered pennate arrays.

Evidence for multi-scale power amplification in skeletal muscle.

Many animals use a combination of skeletal muscle and elastic structures to amplify power output for fast motions. Among vertebrates, tendons in series with skeletal muscle are often implicated as the primary power-amplifying spring, but muscles contain elastic structures at all levels of organization, from the muscle tendon to the extracellular matrix to elastic proteins within sarcomeres. The present study used ex vivo muscle preparations in combination with high-speed video to quantify power output, as the product of force and velocity, at several levels of muscle organization to determine where power amplification occurs. Dynamic ramp-shortening contractions in isolated frog flexor digitorum superficialis brevis were compared with isotonic power output to identify power amplification within muscle fibers, the muscle belly, free tendon and elements external to the muscle tendon. Energy accounting revealed that artifacts from compliant structures outside of the muscle-tendon unit contributed significant peak instantaneous power. This compliance included deflection of clamped bone that stored and released energy contributing 195.22±33.19 W kg-1 (mean±s.e.m.) to the peak power output. In addition, we found that power detected from within the muscle fascicles for dynamic shortening ramps was 338.78±16.03 W kg-1, or approximately 1.75 times the maximum isotonic power output of 195.23±8.82 W kg-1. Measurements of muscle belly and muscle-tendon unit also demonstrated significant power amplification. These data suggest that intramuscular tissues, as well as bone, have the capacity to store and release energy to amplify whole-muscle power output.

Preventing Future Harm: Identifying the Drivers of an Unsafe Discharge to Improve Safety on an Inpatient Oncology Service.

Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.This article describes the care of a young patient with aggressive breast cancer, declining performance status, and multiple hospital admissions who died shortly after being discharged home without essential medications or an adequate plan for follow-up. The patient's death due to her malignancy was unavoidable, but she had inadequate resources before her death, leading to avoidable suffering. This outcome resulted from a series of minor errors attributable to inadequate handoffs, challenges establishing realistic goals of care, and hierarchy within and between medical teams that resulted in major lapses at the time of discharge. We explore these issues and discuss how this case led to the establishment of programs designed to empower health care providers and increase engagement of outpatient oncologists at critical points of patients' disease courses.

What good is a measure of muscle length? The how and why of direct measurements of skeletal muscle motion.

Over the past 50 years our understanding of the central role that muscle motion has in powering movement has accelerated significantly. Fundamental to this progress has been the development of methods for measuring the length of muscles and muscle fibers in vivo. A measurement of muscle fiber length might seem a trivial piece of information on its own. Yet when combined with knowledge of the properties of skeletal muscle it has proven a powerful tool for understanding the mechanics and energetics of locomotion and informing models of motor control. In this perspective we showcase the value of direct measurements of muscle fiber length from four different techniques: sonomicrometry, fluoromicrometry, magnetomicrometry, and ultrasound. For each method, we review its history and provide a high-level user's guide for researchers choosing tools for measuring muscle length in vivo. We highlight key insights that these measurements have provided, including the importance of passive elastic mechanisms and how skeletal muscle properties govern locomotor performance. The diversity of locomotor behaviors revealed across comparative studies has provided an important tool for discovering the rules for muscle function that span vertebrate locomotion more broadly, including in humans.

Practice-Level Variation in Molecular Testing and Use of Targeted Therapy for Patients With Non-Small Cell Lung Cancer and Colorectal Cancer.

Importance: All patients with newly diagnosed non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) should receive molecular testing to identify those who can benefit from targeted therapies. However, many patients do not receive recommended testing and targeted therapies. Objective: To compare rates of molecular testing and targeted therapy use by practice type and across practices. Design, Setting, and Participants: This cross-sectional study used 100% Medicare fee-for-service data from 2015 through 2019 to identify beneficiaries with new metastatic NSCLC or CRC diagnoses receiving systemic therapy and to assign patients to oncology practices. Hierarchical linear models were used to characterize variation by practice type and across practices. Data analysis was conducted from June 2019 to October 2022. Exposures: Oncology practice providing care. Outcomes: Primary outcomes were rates of molecular testing and targeted therapy use for patients with NSCLC and CRC. Secondary outcomes were rates of multigene testing for NSCLC and CRC. Results: There were 106 228 Medicare beneficiaries with incident NSCLC (31 521 [29.7%] aged 65-69 years; 50 348 [47.4%] female patients; 2269 [2.1%] Asian, 8282 [7.8%] Black, and 91 215 [85.9%] White patients) and 39 512 beneficiaries with incident CRC (14 045 [35.5%] aged 65-69 years; 17 518 [44.3%] female patients; 896 [2.3%] Asian, 3521 [8.9%] Black, and 32 753 [82.9%] White patients) between 2015 and 2019. Among these beneficiaries, 18 435 (12.9%) were treated at National Cancer Institute (NCI)-designated centers, 8187 (5.6%) were treated at other academic centers, and 94 329 (64.7%) were treated at independent oncology practices. Molecular testing rates increased from 74% to 85% for NSCLC and 45% to 65% for CRC. First-line targeted therapy use decreased from 12% to 8% among patients with NSCLC and was constant at 5% for patients with CRC. For NSCLC, molecular testing rates were similar across practice types while rates of multigene panel use (13.2%) and targeted therapy use (16.6%) were highest at NCI-designated cancer centers. For CRC, molecular testing rates were 3.8 (95% CI: 1.2-6.5), 3.3 (95% CI, 0.4-6.1), and 12.2 (95% CI, 9.1-15.3) percentage points lower at hospital-owned practices, large independent practices, and small independent practices, respectively. Rates of targeted therapy use for CRC were similar across practice types. After adjusting for patient characteristics, there was moderate variation in molecular testing and targeted therapy use across oncology practices. Conclusions and Relevance: In this cross-sectional study of Medicare beneficiaries, molecular testing rates for NSCLC and CRC increased in recent years but remained lower than recommended levels. Rates of targeted therapy use decreased for NSCLC and remained stable for CRC. Variation across practices suggests that where a patient was treated may have affected access to recommended testing and efficacious treatments.

Variation in Use of Lung Cancer Targeted Therapies Across State Medicaid Programs, 2020-2021.

Importance: Targeted therapies for EGFR (OMIM 131550)- and ALK (OMIM 105590)-altered metastatic non-small cell lung cancer (NSCLC) substantially improve outcomes for some patients. However, use of these therapies is lower among Medicaid patients, and access to oncology care varies across state Medicaid programs. Evidence is lacking on how use of targeted therapies for metastatic NSCLC varies across state Medicaid programs. Objectives: To characterize state-level variation in the use of targeted therapies among Medicaid patients with metastatic NSCLC and to describe factors associated with this variation. Design, Setting, and Participants: This cross-sectional study used publicly available data from the Medicaid Drug Utilization Database from 2020 and 2021 and peer-reviewed data on NSCLC incidence, the prevalence of EGFR and ALK alterations, and expected treatment durations to estimate expected use of targeted therapies for EGFR- and ALK-altered NSCLC in 33 states. Exposures: State-specific Medicaid programs and state policies and characteristics. Main Outcomes and Measures: The primary outcome was the estimated proportion of person-time of Medicaid patients with EGFR- or ALK-altered NSCLC associated with receipt of targeted therapy in each state Medicaid program. Nested linear regression models examined associations between the observed variation and state policies and characteristics. Results: There were an estimated 3461 person-years in which EGFR- and ALK-targeted therapies were indicated in 2020 and 2021. During these years, only 2281 person-years of EGFR- and ALK-targeted therapies were dispensed to Medicaid patients, suggesting that an estimated 66% of Medicaid patients with EGFR- and ALK-altered metastatic disease received indicated targeted therapies across all states. Rates of targeted therapy use ranged from 18% in Arkansas to 113% in Massachusetts; 30 of 33 states (91%) had lower rates of targeted therapy use than expected. The observed variation across state Medicaid programs was associated with Medicaid policies, the density of oncologists, and state gross domestic product per capita. Conclusions and Relevance: This study suggests that rates of targeted therapy use among Medicaid patients with EGFR- and ALK-altered NSCLC were lower than expected and varied across state Medicaid programs. State policies and characteristics were associated with the observed variation, indicating where interventions could improve access to treatment and outcomes for patients with NSCLC.

Care Fragmentation, Faulty Communication, and Documentation Lapses Derail a Treatment Plan.

This is the second Cancer Morbidity, Mortality, and Improvement Rounds, a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. This case describes the care of a patient who was diagnosed with locally advanced lung cancer during the COVID-19 pandemic; it highlights how gaps in communication and care coordination caused the patient to receive care that did not reflect the consensus of his multidisciplinary team. The discussion highlights the importance of multidisciplinary care, particularly for patients with stage III non-small-cell lung cancer, discusses factors that led to communication gaps, and examines how we should assign accountability across dispersed health care systems.Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.

Collagen type VI regulates TGFß bioavailability in skeletal muscle.

Collagen VI-related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes (COL6A1, COL6A2, and COL6A3). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalizatoion of collagen VI in the ECM underlies the non-cell autonomous dysfunction and dystrophic changes in skeletal muscle with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we conduct a comprehensive natural history and outcome study in a novel mouse model of COL6-RDs (Col6a2-/- mice) using standardized (Treat-NMD) functional, histological, and physiologic parameter. Notably, we identify a conspicuous dysregulation of the TGFß pathway early in the disease process and propose that the collagen VI deficient matrix is not capable of regulating the dynamic TGFß bioavailability at baseline and also in response to muscle injury. Thus, we propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGFß with downstream skeletal muscle abnormalities, paving the way for developing and validating therapeutics that target this pathway.

Untethered muscle tracking using magnetomicrometry.

Muscle tissue drives nearly all movement in the animal kingdom, providing power, mobility, and dexterity. Technologies for measuring muscle tissue motion, such as sonomicrometry, fluoromicrometry, and ultrasound, have significantly advanced our understanding of biomechanics. Yet, the field lacks the ability to monitor muscle tissue motion for animal behavior outside the lab. Towards addressing this issue, we previously introduced magnetomicrometry, a method that uses magnetic beads to wirelessly monitor muscle tissue length changes, and we validated magnetomicrometry via tightly-controlled in situ testing. In this study we validate the accuracy of magnetomicrometry against fluoromicrometry during untethered running in an in vivo turkey model. We demonstrate real-time muscle tissue length tracking of the freely-moving turkeys executing various motor activities, including ramp ascent and descent, vertical ascent and descent, and free roaming movement. Given the demonstrated capacity of magnetomicrometry to track muscle movement in untethered animals, we feel that this technique will enable new scientific explorations and an improved understanding of muscle function.

Clinical viability of magnetic bead implants in muscle.

Human movement is accomplished through muscle contraction, yet there does not exist a portable system capable of monitoring muscle length changes in real time. To address this limitation, we previously introduced magnetomicrometry, a minimally-invasive tracking technique comprising two implanted magnetic beads in muscle and a magnetic field sensor array positioned on the body's surface adjacent the implanted beads. The implant system comprises a pair of spherical magnetic beads, each with a first coating of nickel-copper-nickel and an outer coating of Parylene C. In parallel work, we demonstrate submillimeter accuracy of magnetic bead tracking for muscle contractions in an untethered freely-roaming avian model. Here, we address the clinical viability of magnetomicrometry. Using a specialized device to insert magnetic beads into muscle in avian and lagomorph models, we collect data to assess gait metrics, bead migration, and bead biocompatibility. For these animal models, we find no gait differences post-versus pre-implantation, and bead migration towards one another within muscle does not occur for initial bead separation distances greater than 3 cm. Further, using extensive biocompatibility testing, the implants are shown to be non-irritant, non-cytotoxic, non-allergenic, and non-irritating. Our cumulative results lend support for the viability of these magnetic bead implants for implantation in human muscle. We thus anticipate their imminent use in human-machine interfaces, such as in control of prostheses and exoskeletons and in closed-loop neuroprosthetics to aid recovery from neurological disorders.

A Perfect Storm Averted: Flawed Systems, a Dropped Ball, and Cognitive Biases Delay a Critical Diagnosis.

This is the first case of Cancer Morbidity, Mortality, and Improvement Rounds, a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. This case highlights how multiple overlapping factors contributed to a delay in diagnosing disseminated tuberculosis in a patient with lung cancer. The discussion focuses on the ways that cognitive biases contributed to the delayed diagnosis in a patient who, with the benefit of hindsight, exhibited several signs and symptoms suggesting tuberculosis.Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.1.

Relationship between gene expression networks and muscle contractile physiology differences in Anolis lizards.

Muscles facilitate most animal behavior, from eating to fleeing. However, to generate the variation in behavior necessary for survival, different muscles must perform differently; for instance, sprinting requires multiple rapid muscle contractions, whereas biting may require fewer contractions but greater force. Here, we use a transcriptomic approach to identify genes associated with variation in muscle contractile physiology among different muscles from the same individual. We measured differential gene expression between a leg and jaw muscle of Anolis lizards known to differ in muscle contractile physiology and performance. For each individual, one muscle was used to measure muscle contractile physiology, including contractile velocity (Vmax and V40), specific tension, power ratio, and twitch time, whereas the contralateral muscle was used to extract RNA for transcriptomic sequencing. Using the transcriptomic data, we found clear clustering of muscle type. Expression of genes clustered in gene ontology (GO) terms related to muscle contraction and extracellular matrix was, on average, negatively correlated with Vmax and slower twitch times but positively correlated to power ratio and V40. Conversely, genes related to the GO terms related to aerobic respiration were downregulated in muscles with higher power ratio and V40, and over-expressed as twitch time decreased. Determining the molecular mechanisms that underlie variation in muscle contractile physiology can begin to explain how organisms are able to optimize behavior under variable conditions. Future studies pursuing the effects of differential gene expression across muscle types in different environments might inform researchers about how differences develop across species, populations, and individuals varying in ecological history.

Lessons for Oncology From the COVID-19 Pandemic: Operationalizing and Scaling Virtual Cancer Care in Health Systems.

ABSTRACT: After several decades of slow expansion, the use of virtual care in oncology rapidly expanded during the COVID-19 pandemic. Data from cancer centers across the country show that most patients and providers were satisfied with components of virtual care, and virtual care may be able to improve access to care. However, the rapid implementation of programs during the pandemic worsened disparities in access to virtual care. Health systems must develop strategies to monitor quality, support patients and providers, promote health equity, and overcome regulatory challenges to successfully deliver care in hybrid systems that combine in-person and virtual care.

Gastrocnemius Muscle Structural and Functional Changes Associated with Domestication in the Turkey.

Selection for increased muscle mass in domestic turkeys has resulted in muscles twice the size of those found in wild turkeys. This study characterizes muscle structural changes as well as functional differences in muscle performance associated with selection for increased muscle mass. We compared peak isometric force production, whole muscle and individual fiber cross-sectional area (CSA), connective tissue collagen concentration and structure of the lateral gastrocnemius (LG) muscle in wild and adult domestic turkeys. We also explored changes with age between juvenile and adult domestic turkeys. We found that the domestic turkey's LG muscle can produce the same force per cross-sectional area as a wild turkey; however, due to scaling, domestic adults produce less force per unit body mass. Domestic turkey muscle fibers were slightly smaller in CSA (3802 ± 2223 µm2) than those of the wild turkey (4014 ± 1831 µm2, p = 0.013), indicating that the absolutely larger domestic turkey muscles are a result of an increased number of smaller fibers. Collagen concentration in domestic turkey muscle (4.19 ± 1.58 µg hydroxyproline/mg muscle) was significantly lower than in the wild turkeys (6.23 ± 0.63 µg/mg, p = 0.0275), with visible differences in endomysium texture, observed via scanning electron microscopy. Selection for increased muscle mass has altered the structure of the LG muscle; however, scaling likely contributes more to hind limb functional differences observed in the domestic turkey.

Passive skeletal muscle can function as an osmotic engine.

Muscles are composite structures. The protein filaments responsible for force production are bundled within fluid-filled cells, and these cells are wrapped in ordered sleeves of fibrous collagen. Recent models suggest that the mechanical interaction between the intracellular fluid and extracellular collagen is essential to force production in passive skeletal muscle, allowing the material stiffness of extracellular collagen to contribute to passive muscle force at physiologically relevant muscle lengths. Such models lead to the prediction, tested here, that expansion of the fluid compartment within muscles should drive forceful muscle shortening, resulting in the production of mechanical work unassociated with contractile activity. We tested this prediction by experimentally increasing the fluid volumes of isolated bullfrog semimembranosus muscles via osmotically hypotonic bathing solutions. Over time, passive muscles bathed in hypotonic solution widened by 16.44 ± 3.66% (mean ± s.d.) as they took on fluid. Concurrently, muscles shortened by 2.13 ± 0.75% along their line of action, displacing a force-regulated servomotor and doing measurable mechanical work. This behaviour contradicts the expectation for an isotropic biological tissue that would lengthen when internally pressurized, suggesting a functional mechanism analogous to that of engineered pneumatic actuators and highlighting the significance of three-dimensional force transmission in skeletal muscle.

The time course of calf muscle fluid volume during prolonged running.

Muscle fluid is essential for the biochemistry and the biomechanics of muscle contraction. Here, we provide evidence that muscle fluid volumes undergo significant changes during 75 min of moderate intensity (2.7 ± 0.4 m/s) running. Using MRI measurements at baseline and after 2.5, 5, 10, 15, 45 and 75 min, we found that the volumes of calf muscles (quantified through average cross-sectional area) in 18 young recreational runners increase (up to 9% in the gastrocnemii) at the beginning and decrease (below baseline levels) at later stages of running. However, the intensity of changes varied between analyzed muscles. We speculate that these changes are induced by muscle activity and dehydration-related changes in osmotic pressure gradients between intramuscular and extramuscular spaces. These findings highlight the complex nature of muscle fluid shifts during prolonged running exercise.