Benefits of Accepting Infectious Diseases Pharmacist Recommendations: A 5-Year Outcome Study in a Multihospital System.

Background: Infectious diseases (ID) pharmacists are pivotal members of antimicrobial stewardship teams. Prospective audit and feedback is a strong recommendation by The Infectious Diseases Society of America Guidelines for Antimicrobial Stewardship Programs (ASP). Utilizing customized ASP intervention documentation tools known as "ivents" in Epic, we aimed to assess the impact of interventions by measuring outcomes that were accepted compared to those that were rejected in a multihospital health system over 5 years. Methods: A multicenter, retrospective cohort study was conducted to compare clinical outcomes among intensive care unit (ICU) and non-ICU patients with accepted and rejected ASP interventions over 5 years from October 2015 to December 2020. Outcomes measured included antibiotic days of therapy per 1000 patient days (DOT/1000 PD), antibiotic doses per 1000 patient days (doses/1000 PD), hospital length of stay (LOS), in-hospital mortality, hospital-acquired Clostridioides difficile infection (HA-CDI), community-onset C. difficile infection (CO-CDI) within 30 days, and hospital readmission within 30 days. Coarsened exact matching (CEM) was used as a non-parametric matching method to balance covariates between groups and to control for confounding. Results: ASP recommendations by ID pharmacists were well-received by providers in a multihospital system over 5 years as evidenced by an overall acceptance rate of 92%. Acceptance of ASP interventions was associated with substantial reductions in antibiotic utilization without adversely affecting mortality or hospital readmissions. While high-risk C. difficile antibiotic use increased significantly due to frequent de-escalation to ceftriaxone among non-ICU patients with accepted interventions, rates of HA-CDI and CO-CDI within 30 days did not worsen. Furthermore, hospital LOS was notably shorter by an average of 1 day for non-ICU patients with accepted interventions, which resulted in substantial cost avoidance of $7 631 400. Conclusion: Collaboration with ID pharmacists to optimize antimicrobial stewardship was associated with significant reductions in antibiotic utilization, costs, and hospital LOS without worsening patient outcomes.

Spermidine-Functionalized Injectable Hydrogel Reduces Inflammation and Enhances Healing of Acute and Diabetic Wounds In Situ.

The inflammatory response is a key factor affecting tissue regeneration. Inspired by the immunomodulatory role of spermidine, an injectable double network hydrogel functionalized with spermidine (DN-SPD) is developed, where the first and second networks are formed by dynamic imine bonds and non-dynamic photo-crosslinked bonds respectively. The single network hydrogel before photo-crosslinking exhibits excellent injectability and thus can be printed and photo-crosslinked in situ to form double network hydrogels. DN-SPD hydrogel has demonstrated desirable mechanical properties and tissue adhesion. More importantly, an "operando" comparison of hydrogels loaded with spermidine or diethylenetriamine (DETA), a sham molecule resembling spermidine, has shown similar physical properties, but quite different biological functions. Specifically, the outcomes of 3 sets of in vivo animal experiments demonstrate that DN-SPD hydrogel can not only reduce inflammation caused by implanted exogenous biomaterials and reactive oxygen species but also promote the polarization of macrophages toward regenerative M2 phenotype, in comparison with DN-DETA hydrogel. Moreover, the immunoregulation by spermidine can also translate into faster and more natural healing of both acute wounds and diabetic wounds. Hence, the local administration of spermidine affords a simple but elegant approach to attenuate foreign body reactions induced by exogenous biomaterials to treat chronic refractory wounds.

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.

Can ChatGPT assist authors with abstract writing in medical journals? Evaluating the quality of scientific abstracts generated by ChatGPT and original abstracts.

INTRODUCTION: ChatGPT, a sophisticated large language model (LLM), has garnered widespread attention for its ability to mimic human-like communication. As recent studies indicate a potential supportive role of ChatGPT in academic writing, we assessed the LLM's capacity to generate accurate and comprehensive scientific abstracts from published Randomised Controlled Trial (RCT) data, focusing on the adherence to the Consolidated Standards of Reporting Trials for Abstracts (CONSORT-A) statement, in comparison to the original authors' abstracts. METHODOLOGY: RCTs, identified in a PubMed/MEDLINE search post-September 2021 across various medical disciplines, were subjected to abstract generation via ChatGPT versions 3.5 and 4, following the guidelines of the respective journals. The overall quality score (OQS) of each abstract was determined by the total number of adequately reported components from the 18-item CONSORT-A checklist. Additional outcome measures included percent adherence to each CONOSORT-A item, readability, hallucination rate, and regression analysis of reporting quality determinants. RESULTS: Original abstracts achieved a mean OQS of 11.89 (95% CI: 11.23-12.54), outperforming GPT 3.5 (7.89; 95% CI: 7.32-8.46) and GPT 4 (5.18; 95% CI: 4.64-5.71). Compared to GPT 3.5 and 4 outputs, original abstracts were more adherent with 10 and 14 CONSORT-A items, respectively. In blind assessments, GPT 3.5-generated abstracts were deemed most readable in 62.22% of cases which was significantly greater than the original (31.11%; P = 0.003) and GPT 4-generated (6.67%; P<0.001) abstracts. Moreover, ChatGPT 3.5 exhibited a hallucination rate of 0.03 items per abstract compared to 1.13 by GPT 4. No determinants for improved reporting quality were identified for GPT-generated abstracts. CONCLUSIONS: While ChatGPT could generate more readable abstracts, their overall quality was inferior to the original abstracts. Yet, its proficiency to concisely relay key information with minimal error holds promise for medical research and warrants further investigations to fully ascertain the LLM's applicability in this domain.

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

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.

Nanoscale photobiotinylation, pulldown and sequencing of region-specific DNA from intact cells.

Femto-seq is a novel nanoscale optical method that can be used to obtain DNA sequence information from targeted regions around a specific locus or other nuclear regions of interest. Two-photon excitation is used to photobiotinylate femtoliter volumes of chromatin within the nucleus, allowing for subsequent isolation and sequencing of DNA, and bioinformatic mapping of any nuclear region of interest in a select set of cells from a heterogenous population.

Ameliorating the effects of multiple stresses on agronomic traits in crops: modern biotechnological and omics approaches.

While global climate change poses a significant environmental threat to agriculture, the increasing population is another big challenge to food security. To address this, developing crop varieties with increased productivity and tolerance to biotic and abiotic stresses is crucial. Breeders must identify traits to ensure higher and consistent yields under inconsistent environmental challenges, possess resilience against emerging biotic and abiotic stresses and satisfy customer demands for safer and more nutritious meals. With the advent of omics-based technologies, molecular tools are now integrated with breeding to understand the molecular genetics of genotype-based traits and develop better climate-smart crops. The rapid development of omics technologies offers an opportunity to generate novel datasets for crop species. Identifying genes and pathways responsible for significant agronomic traits has been made possible by integrating omics data with genetic and phenotypic information. This paper discusses the importance and use of omics-based strategies, including genomics, transcriptomics, proteomics and phenomics, for agricultural and horticultural crop improvement, which aligns with developing better adaptability in these crop species to the changing climate conditions.

Indigenous Australian grass seeds as grains: macrostructure, microstructure and histochemistry.

Utilization of grains of local grasses by Australia's First Nations people for food and connection to Country has largely been lost due to colonization. Native Australian grain production has the potential to deliver environmental, economic, nutritional and cultural benefits to First Nations people and the wider community. Revitalization of the native grain food system can only be achieved if relevant properties of the grains are elucidated. This study aimed to characterize the grain structure and histochemistry of four Australian native grasses: Dactyloctenium radulans (Button Grass), Astrebla lappacea (Curly Mitchell Grass), Panicum decompositum (Native Millet) and Microlaena stipoides (Weeping Grass). For these species, as well as wheat and sorghum, whole-grain images were obtained via stereo microscopy, starch and the embryo were visualized, and sections of fixed grains were imaged via bright-field and fluorescence microscopy. The shape, size and colour of the whole native grains varied between the species. The aleurone layer was one-cell thick in the native species, as in the domesticated grains, except for Weeping Grass, which had a two-cell-thick aleurone. In the native grains, endosperm cell walls appeared thinner than in wheat and sorghum. Starch granules in Button Grass, Curly Mitchell Grass and Native Millet were found mainly in the central region of the starchy endosperm, with very few granules in the sub-aleurone layer, whereas Weeping Grass had abundant starch in the sub-aleurone. Protein appeared most abundant in the aleurone and sub-aleurone layers of the native grains, although in Button Grass, the starchy endosperm was observed to be rich in protein, as in wheat and sorghum. As a proportion of the whole grain, the embryo was larger in the native species than in wheat. The differences found in the grain properties among the four native Australian species have important implications for the agri-food industry in a changing climate.

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.

EV-mediated promotion of myogenic differentiation is dependent on dose, collection medium, and isolation method.

Extracellular vesicles (EVs) have been implicated in the regulation of myogenic differentiation. C2C12 murine myoblast differentiation was reduced following treatment with GW4869 or heparin (to inhibit exosome biogenesis and EV uptake, respectively). Conversely, treatment with C2C12 myotube-conditioned medium enhanced myogenic differentiation. Ultrafiltration-size exclusion liquid chromatography (UF-SEC) was used to isolate EVs and non-EV extracellular protein in parallel from C2C12 myoblast- and myotube-conditioned medium. UF-SEC-purified EVs promoted myogenic differentiation at low doses (≤2 × 108 particles/mL) and were inhibitory at the highest dose tested (2 × 1011 particles/mL). Conversely, extracellular protein fractions had no effect on myogenic differentiation. While the transfer of muscle-enriched miRNAs (myomiRs) has been proposed to mediate the pro-myogenic effects of EVs, we observed that they are scarce in EVs (e.g., 1 copy of miR-133a-3p per 195 EVs). Furthermore, we observed pro-myogenic effects with undifferentiated myoblast-derived EVs, in which myomiR concentrations are even lower, suggestive of a myomiR-independent mechanism underlying the observed pro-myogenic effects. During these investigations we identified technical factors with profound confounding effects on myogenic differentiation. Specifically, co-purification of insulin (a component of Opti-MEM) in non-EV LC fractions and polymer precipitated EV preparations. These findings provide further evidence that polymer-based precipitation techniques should be avoided in EV research.

Therapeutic approaches for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.

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.

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.