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Adults are skilled at using language to construct/negotiate identity and to signal affiliation with others, but little is known about how these abilities develop in children. Clearly, children mirror statistical patterns in their local environment (e.g., Canadian children using "zed" instead of "zee"), but do they flexibly adapt their linguistic choices on the fly in response to the choices of different peers? To address this question, we examined the effect of group membership on 7- to 9-year-olds' labeling of objects in a trivia game, exploring whether they were more likely to use a particular label (e.g., "sofa" vs. "couch") if members of their "team" also used that label. In a preregistered study, children (N = 72) were assigned to a team (red or green) and were asked during experimental trials to answer questions--which had multiple possible answers (e.g., "blackboard" or "chalkboard")--after hearing two teammates and two opponents respond to the same question. Results showed that children were significantly more likely to produce labels less commonly used by the community (i.e., dispreferred labels) when their teammates had produced those labels. Crucially, this effect was tied to group membership, and could not be explained by children simply repeating the most recently used label. These findings demonstrate how social processes (i.e., group membership) can guide linguistic variation in children.

Low-grade inflammation and pathological endochondral ossification are key processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, we employed a multi-faceted approach, integrating publicly available datasets, in silico analyses, in vitro experiments and in vivo models to identify new therapeutic candidates targeting these processes. Data mining of transcriptomic datasets identified EPHA2, a receptor tyrosine kinase associated with cancer, as being linked to both inflammation and endochondral ossification in osteoarthritis. A computational model of cellular signaling networks in chondrocytes predicted that in silico activation of EPHA2 in healthy chondrocytes increases inflammatory mediators and induces hypertrophic differentiation, a hallmark of endochondral ossification. We then evaluated the effect of EPHA2 inhibition using the tyrosine kinase inhibitor ALW-II-41-27 in cultured human chondrocytes from individuals with osteoarthritis, demonstrating significant reductions in both inflammation and hypertrophy. Additionally, systemic subcutaneous administration of ALW-II-41-27 in a mouse osteoarthritic model attenuated joint degeneration by reducing local inflammation and pathological endochondral ossification. Collectively, this study demonstrates a novel drug discovery pipeline that integrates computational, experimental, and animal models, paving the way for the development of disease-modifying treatments for osteoarthritis.

Experiments have been conducted to benchmark DYSMAS computer code calculations for the dynamic interaction of water with cylindrical structures. Small explosive charges were suspended using hypodermic needle tubing inside Al tubes filled with distilled water. Pressures were measured during shock loading by tourmaline crystal, carbon resistor and ytterbium foil gages bonded to the tube using a variety of adhesives. Comparable calculated and measured pressures were obtained for the explosive charges used, with some gages surviving long enough to record results after cavitation with the tube wall.

B cells contribute to multiple aspects of autoimmune disorders, and B cell–targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti–human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell–dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell–targeting therapies in treatment of autoimmune conditions without causing B cell depletion.

ABSTRACT Purifying extracellular vesicles (EVs) has been challenging because EVs are heterogeneous in cargo yet share similar sizes and densities. Most surface marker‐based affinity separation methods are limited to research or diagnostic scales. We report that heparin chromatography can separate purified EVs into two distinct subpopulations as ascertained by MS/MS: a non‐heparin‐binding (NHB) fraction that contains classical EV markers such as tetraspanins and a heparin‐binding (HB) fraction enriched in fibronectins and histones. Both fractions were similarly fusogenic but induced different transcriptional responses in endothelial cells. While EVs that were purified by conventional, non‐affinity methods alone induced ERK1/2 phosphorylation and Ki67, the NHB fraction did not. This result suggests heparin chromatography as an additional novel fractionation step that is inherently scalable, does not lead to loss of material, and separates inflammatory and pyrogenic EVs from unreactive EVs, which will improve clinical applications.

Abstract Objectives Many payers and health care providers are either currently using or considering use of prior authorization schemes to redirect patient care away from hospital outpatient departments toward free-standing ambulatory surgical centers owing to the payment differential between these facilities. In this work we work with a medium size payer to develop and lay out a process for analysis of claims data that allows payers to conservatively estimate potential savings from such policies based on their specific case mix and provider network. Study Design We analyzed payment information for a medium-sized managed care organization to identify movable cases that can reduce costs, estimate potential savings, and recommend implementation policy alternatives. Methods We analyze payment data, including all professional and institutional fees over a 15-month period. A rules-based algorithm was developed to identify episodes of care with at least one alternate site for each episode, and potential savings from a site-of-service policy. Results Data on 64,884 episodes of care were identified as possible instances that could be subject to the policy. Of those, 7,679 were found to be attractive candidates for movement. Total projected savings was approximately $8.2 million, or over $1,000 per case. Conclusions Instituting a site-of-service policy can produce meaningful savings for small and medium payers. Tailoring the policy to the specific patient and provider population can increase the efficacy of such policies in comparison to policies previously established by other payers.

Objectives To assess the frequency of discharge against medical advice (DAMA) in a large UK teaching hospital, explore factors which increase the risk of DAMA and identify how DAMA impacts patient risk of mortality and readmission.Design Retrospective cohort study.Setting Large acute teaching hospital in the UK.Patients 36 683 patients discharged from the acute medical unit of a large UK teaching hospital between 1 January 2012 and 31 December 2016.Measurements Patients were censored on 1 January 2021. Mortality and 30-day unplanned readmission rates were assessed. Deprivation, age and sex were taken as covariates.Results 3% of patients discharged against medical advice. These patients were younger (median age (years) (IQR)): planned discharge (PD) 59 (40–77); DAMA 39 (28–51), predominantly of male sex (PD 48%; DAMA 66%) and were of greater social deprivation (in three most deprived quintiles PD 69%; DAMA 84%). DAMA was associated with increased risk of death in patients under the age of 33.3 years (adjusted HR 2.6 (1.2–5.8)) and increased incidence of 30-day readmission (standardised incidence ratio 1.9 (1.5–2.2)).Limitations Readmission to acute hospitals outside of the local health board may have been missed. We were unable to include information regarding comorbidity or severity of presentation.Conclusions These data highlight the vulnerability of younger patients who DAMA, even in a free-at-the-point-of-delivery healthcare setting.

Abstract Extracellular vesicles (EVs) are secreted from all cell types and are intimately involved in tissue homeostasis. They are being explored as vaccine and gene therapy platforms, as well as potential biomarkers. As their size is below the diffraction limit of light microscopy, direct visualizations have been daunting and single‐particle studies under physiological conditions have been hampered. Here, direct stochastic optical reconstruction microscopy (dSTORM) was employed to visualize EVs in three‐dimensions and to localize molecule clusters such as the tetraspanins CD81 and CD9 on the surface of individual EVs. These studies demonstrate the existence of membrane microdomains on EVs. These were confirmed by Cryo‐EM. Individual particle visualization provided insights into the heterogeneity, structure, and complexity of EVs not previously appreciated

Abstract Background Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence‐based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. Methods We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. Results Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence‐based care guidelines. Conclusion Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease‐modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Using real-time eye-movement measures, we asked how a fantastical discourse context competes with stored representations of real-world events to influence the moment-by-moment interpretation of a story by 7-year-old children and adults. Seven-year-olds were less effective at bypassing stored real-world knowledge during real-time interpretation than adults. Our results suggest that children privilege stored semantic knowledge over situation-specific information presented in a fictional story context. We suggest that 7-year-olds' canonical semantic and conceptual relations are sufficiently strongly rooted in statistical patterns in language that have consolidated over time that they overwhelm new and unexpected information even when the latter is fantastical and highly salient.

Micro/nano-plastics (MNPs) have been found within many environments and organisms including humans, making them a significant and growing concern. Initial research into the potential detrimental effects these MNPs both from acute and chronic exposure has been ongoing but still requires substantially more data to clarify. This research presents the response of nano-polystyrene (NPS) on Raphidocelis subcapitata, a freshwater alga, under an existing acute toxicity test along with additional analytical techniques to try identifying possible sources of toxicity. R. subcapitata cells were exposed for 72 h to a concentration range of 0–100 mg/l NPS. Growth Inhibition (GI) testing showed the R. subcapitata demonstrated statistically distinct reductions in growth over 72 h at all NPS exposure concentrations while not suffering culture collapse. By the 100 mg/l NPS exposure the R. subcapitata has suffered almost a 33.7% reduction in cell concentration after 72 h compared to control samples. Confocal imaging showed the NPS wasn't permeating into the algal plasma membrane or individual organelles but agglomerated onto the algal cell wall. The agglomeration was irregular but increased in total surface area covered as NPS concentration increases. UV–Vis fluorimetry testing produced a linear response of emission intensities to algae exposed to the 0–100 mg/l range of NPS. However, comparisons of emission intensity values of algae exposed to NPS to emission intensities of pure NPS at identical concentrations showed consistent intensity reduction. This response further indicated NPS agglomerating within the media and onto the alga cells seen from confocal imaging. Finally, Raman spectroscopy on R. subcapitata attempted to distinguish the key 1001 cm−1 peak or other crucial identifier peaks of polystyrene from overall Raman spectra. This was not successful as emissions from algal component (e.g. phenylaniline) completely suppressed the signal region.

Purpose: To identify a comprehensive list of outcome measures previously used in the literature to evaluate clinical outcomes after reconstruction of the anterior cruciate ligament (ACL) in patients 18 years of age or younger. Methods: A literature search was performed by querying MEDLINE, Embase and Cochrane computerized databases for relevant articles that reported clinical outcomes in pediatric patients undergoing ACL reconstruction. Studies that were nonclinical, that reported on patients older than 19 years, that were not available in English, or that included fewer than 10 patients were excluded. Outcome measures of all eligible studies were recorded. Results: We identified 77 studies published between 1986 and 2018 in 20 peer-reviewed journals. The mean age of the patients was 13.9 years. The ACL rerupture rate was reported in 60% of studies; 32 studies (42%) reported a rate of return to preinjury activity or sports. The use of adult-validated patient-reported outcome measures were reported in 63 (82%) articles. The Lysholm (64%), International Knee Documentation Committee (IKDC) (56%) and Tegner (37%) scores were the most commonly reported. Two patient-reported outcome measures designed for pediatric patients (the Pedi-IKDC and Hospital for Special Surgery Pediatric Functional Activity Brief Scale (Pedi-FABS) were employed in 5 (6%) recent studies. Conclusions: There is variability across studies in the metrics used to assess clinical outcomes following ACL reconstruction in children and adolescents. Validated pediatric-specific instruments were used infrequently. Clinical Relevance: A large body of existing pediatric ACL-reconstruction literature relies on a variable set of outcome measures that have not been developed or validated for children and adolescents. More recently, contemporary studies have begun to employ pediatric- and adolescent-specific validated measures, yet their use remains uncommon.

BAFF is an important cytokine for B cell survival, and is a therapeutic target for autoimmune disorders. Here the authors show that a 'flap' region of BAFF converts BAFFR binding events into survival signals and, with structural data, that this ‘flap’ differentially modulates binding of drugs such as belimumab or atacicept.

Iron storage proteins are essential for cellular iron homeostasis and redox balance. Ferritin proteins are the major storage units for bioavailable forms of iron. Some organisms lack ferritins, and it is not known how they store iron. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from Quasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo and show interactions underlying cargo-shell co-assembly. This compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. Our results reveal a new approach for survival in diverse habitats with limited or fluctuating iron availability via an iron storage system able to store 10 to 20 times more iron than ferritin.

The threats posed by neonicotinoid insecticides to bee populations have been the focus of considerable research. Previous work has shed new light on the effects of neonicotinoids on bees by uncovering pathways through which neonicotinoids affect bee population dynamics and the potential interactions they have with exogenous stressors. Yet, little is known about whether these effects translate in a field-relevant setting to substantial losses in honey yields for commercial beekeepers. Here, we used data from a 6-year survey of 60 apiaries in Greece and economic modelling to assess at the field level the effects of neonicotinoid insecticides on honey production. Based on production function estimates, we found that sub-lethal concentrations of two widely used neonicotinoid insecticides (imidacloprid and thiamethoxam) detected in the nectar of flowers resulted in substantial losses in honey production for commercial beekeepers in our sample. By simulating a scenario with ideal pathogenic and environmental conditions, we found that the magnitude of the neonicotinoid effects decreases significantly under ideal conditions providing evidence for possible synergies at the field between neonicotinoids and environmental and pathogenic factors. Moreover, in a replicated study with grouped apiaries, we found evidence that the marginal effects of neonicotinoids on honey production vary across apiaries facing different conditions.

An eye-tracking methodology was used to explore adults’ and children’s use of two utterance-based cues to overcome referential uncertainty in real time. Participants were first introduced to two characters with distinct color preferences. These characters then produced fluent (“Look! Look at the blicket.”) or disfluent (“Look! Look at thee, uh, blicket.”) instructions referring to novel objects in a display containing both talker-preferred and talker-dispreferred colored items. Adults (Expt 1, n = 24) directed a greater proportion of looks to talker-preferred objects during the initial portion of the utterance (“Look! Look at…”), reflecting the use of indexical cues for talker identity. However, they immediately reduced consideration of an object bearing the talker’s preferred color when the talker was disfluent, suggesting they infer disfluency would be more likely as a talker describes dispreferred objects. Like adults, 5-year-olds (Expt 2, n = 27) directed more attention to talker-preferred objects during the initial portion of the utterance. Children’s initial predictions, however, were not modulated when disfluency was encountered. Together, these results demonstrate that adults, but not 5-year-olds, can act on information from two talker-produced cues within an utterance, talker preference, and speech disfluencies, to establish reference.