bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association of American Medical Colleges’ Local Area Physician Workforce Modeling Project
Authors: Dill Michael J. , Hirsch Gary B. 
Published: April 2021

Physician workforce planning must address multiple concerns such as having sufficient numbers and adequate geographic distribution of physicians and pressures for physicians to adapt to new models of care and payment. Though there are national workforce planning tools, planning tools for local areas have been scarce. This article describes a dynamic simulation model developed as a pilot project to support physician workforce planning in 2 metropolitan areas, Cleveland and Albuquerque (February 2014–June 2016). This model serves as a prototype for planning tools that could be used by medical educators and local health systems to project the effect of different policies on physician supply and demand.
System dynamics and group model building approaches were used to develop the model with the participation of local stakeholders to create the model’s causal structure. The model included determinants of the demand for primary and specialty care for the local population and projected the effects of births and deaths, aging, level of chronic illness present, and migration on demand. Physician supply was disaggregated by primary versus specialty care, age, sex, and work setting and projected based on completions of local residency programs, physician migration in and out of the area, and retirements. Feedback relationships between supply and demand (e.g., adequacy of care affecting the distribution of chronic illnesses, demand for care influencing in- and out-migration of physicians) were also included and had important effects on the results produced by the model.
Scenarios were simulated that projected increased demand for care (e.g., through expanded insurance coverage) and increased supply (e.g., through practice incentives to encourage in-migration) and a combination of these. An expanded advanced practice registered nurse and physician assistant capacity scenario was also simulated. In Albuquerque, the combination scenario yielded the greatest increases in local physician supply.
Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus
Authors: Trzupek Dominik , Lee Mercede , Hamey Fiona , Wicker Linda S. , Todd John A. , Ferreira Ricardo C. 
Published: April 2021

AbstractBackgroundThe characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients.MethodsWe designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFNhi), and an age- and sex- matched IFNlow SLE patient and healthy donor.ResultsWe confirmed the presence of a rare cytotoxic CD4+ T cell (CTL) subset, which was exclusively present in the IFNhi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57+ CD8+ T cell and CD16+ NKdim phenotypes, and the presence of a subset of recently-activated naïve CD4+ T cells.ConclusionsOur results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFNhi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57+ CD4+ CTLs.
A feasibility trial of a digital mindfulness-based intervention to improve asthma-related quality of life for primary care patients with asthma
Authors: Ainsworth Ben , Stanescu Sabina , Stuart Beth , Russell Daniel , Liddiard Megan , Djukanovic Ratko , Thomas Mike 
Published: April 2021

AbstractObjectiveAsthma outcomes remain suboptimal, despite effective pharmacotherapy. Psychological dysfunction (such as anxiety) is common, and associated with poorer outcomes. We evaluated a digital mindfulness programme as an intervention to improve asthma-related quality of life for primary care patients, in a prospectively registered randomized-controlled feasibility study.MethodsWe offered ‘Headspace’, a widely-used digital mindfulness intervention, to adults with asthma through 16 UK GP practices. Participants were randomised on a 2:1 basis to the mindfulness intervention, or waitlist control. Participants completed questionnaires (including asthma symptom control, asthma-related quality of life, anxiety, depression) at baseline, 6-week and 3-month follow-up.Results114 participants completed primary outcomes at 3-month follow-up (intervention 73 (71.6%), control 41 (70.7%)). Compared to baseline, the intervention group but not the control group reported significantly improved asthma-related quality of life, with a non-significant between-group difference favouring the intervention group (Mean difference = 0.16, 95%CI: - 0.11 – 0.44). Intervention use varied but was generally high.ConclusionsDigital mindfulness interventions are feasible and acceptable adjunct treatments for mild and moderate asthma to target quality of life. Further research should adapt ‘generic’ mindfulness-based stress-reduction to maximize effectiveness for asthma, and validate our findings in a fully-powered randomized controlled trial.Trial registrationProspectively registered: ISRCTN52212323
PodoCount: A robust, fully automated whole-slide podocyte quantification tool
Authors: Santo Briana A. , Govind Darshana , Daneshpajouhnejad Parnaz , Yang Xiaoping , Wang Xiaoxin X. , Myakala Komuraiah , Jones Bryce A. , Levi Moshe , Kopp Jeffrey B. , Niedernhofer Laura J. , Manthey David , Moon Kyung Chul , Han Seung Seok , Rosenberg Avi Z. , Sarder Pinaki 
Published: April 2021

ABSTRACTBackgroundPodocyte depletion is an established indicator of glomerular injury and predicts clinical outcomes. The semi-quantitative nature of existing podocyte estimation methods or podometrics hinders incorporation of such analysis into experimental and clinical pathologic workflows. Computational image analysis offers a robust approach to automate podometrics through objective quantification of cell and tissue structure. Toward this goal, we developed PodoCount, a computational tool for quantitative analysis of podocytes, and validated the generalizability of the tool across a diverse dataset.MethodsPodocyte nuclei and glomerular boundaries were labeled in murine whole kidney sections,n= 135, from six disease models and human kidney biopsies,n= 45, from diabetic nephropathy (DN) patients. Digital whole slide images (WSIs) of tissues were then acquired. Classical image analysis was applied to obtain podocyte nuclear and glomerular morphometrics. Statistically significant morphometric features, which correlated with each murine disease, were identified. Engineered features were also assessed for their ability to predict outcomes in human DN.PodoCounthas been disbursed for other researchers as an open-source, cloud-based computational tool.ResultsPodoCountoffers highly accurate quantification of podocytes. Engineered podometric features were benchmarked against routine glomerular histopathology and were found to be significant predictors of disease diagnosis, proteinuria level, and clinical outcomes.ConclusionsPodoCountoffers high quantification performance in diverse murine disease models as well as in human DN. Resultant podometric features offers significant correlation with associated metadata as well as outcome. Our cloud-based end-user tool will provide a standardized approach for podometric analysis from gigapixel size WSIs in basic research and clinical practice.
Transcriptomic encoding of sensorimotor transformation in the midbrain
Authors: Xie Zhiyong , Wang Mengdi , Liu Zeyuan , Shang Congping , Zhang Changjiang , Sun Le , Gu Huating , Ran Gengxin , Pei Qing , Ma Qiang , Huang Meizhu , Zhang Junjing , Zhang Jiyao , Zhao Miao , Wu Qian , Cao Peng , Wang Xiaoqun 
Published: April 2021

ABSTRACTSensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae express discrete marker genes. Of particular interest, Cbln2 and Pitx2 are key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediate behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.
The inhibition of Macrophage Migration Inhibitory Factor by ISO-1 attenuates trauma-induced multi organ dysfunction in rats
Authors: Martin Lukas , Patel Nikita Mayur , Yamada Noriaki , Borges Oliveira Filipe Rodolfo Moreira , Stiehler Lara , Zechendorf Elisabeth , Hinkelmann Daniel , Kraemer Sandra , Stoppe Christian , Collino Massimo , Collotta Debora , Alves Gustavo Ferreira , Ramos Hanna Pillmann , Sordi Regina , Marzi Ingo , Relja Borna , Marx Gernot , Thiemermann Christoph 
Published: April 2021

AbstractBackgroundMulti organ dysfunction syndrome caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine Migration Inhibitory Factor (MIF) is recognized as a modulator of inflammatory response, however, its role in trauma is unknown. The aim of this study was to investigate (a) the levels of MIF in serum of trauma patients and of rats after hemorrhagic shock, (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce multi organ dysfunction syndrome in an acute and chronic hemorrhagic shock rat model and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in hemorrhagic shock.MethodsThe serum MIF-levels in trauma patients and rats with hemorrhagic shock were measured by Enzyme-Linked Immunosorbent Assays. Acute and chronic hemorrhagic shock rat models were performed to determine the influence of ISO-1 on multi organ dysfunction syndrome. The activation of NF-κB and NLRP3 pathways were analyzed by western blot.ResultsWe demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after hemorrhagic shock, (b) hemorrhagic shock caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of hemorrhagic shock rats with ISO-1 attenuated organ injury and dysfunction in acute and chronic hemorrhagic shock rat models and (d) decreased the activation of NF-κB and NLRP3 pathways.ConclusionOur results point to a role of MIF in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that MIF tautomerase activity inhibitors may have potential in the therapy of the multi organ dysfunction syndrome after trauma and/or hemorrhage.
Pyridostigmine in the treatment of adults with severe SARS-CoV-2 infection (PISCO): a randomised, double-blinded, phase 2/3, placebo-controlled trial
Authors: Fragoso-Saavedra Sergio , Núñez Isaac , Audelo-Cruz Belem M. , Arias-Martínez Sarahi , Manzur-Sandoval Daniel , Quintero-Villegas Alejandro , Benjamín García-González H. , Carbajal-Morelos Sergio L. , de León-Rosales Sergio Ponce , Gotés-Palazuelos José , Maza-Larrea José A. , Caro-Vega Yanink , Batina Isabella , Islas-Weinstein León , Iruegas-Nunez David A. , Calva Juan J. , Belaunzarán-Zamudio Pablo F. , Sierra-Madero Juan , Crispín José C. , Valdés-Ferrer Sergio I. 
Published: April 2021

SummaryBackgroundHospitalised patients with severe COVID-19 have an increased risk of developing acute respiratory distress syndrome (ARDS) and death from severe systemic inflammatory response. Acetylcholine modulates the acute inflammatory response through a neuro-immune mechanism known as the inflammatory reflex. Pyridostigmine, an acetylcholine-esterase inhibitor, increases the half-life of endogenous ACh, reducing lung and systemic inflammation in murine sepsis. This trial aimed to evaluate whether pyridostigmine could decrease invasive mechanical ventilation (IMV) and death in patients with severe COVID-19.MethodsWe performed a parallel-group, multicentre, double-blinded, placebo-controlled, randomised clinical trial in two COVID-19-designated hospitals in Mexico City, Mexico. Adult (≥ 18-year-old), hospitalised patients with confirmed SARS-CoV-2 infection based on a positive RT-PCR test in a respiratory specimen, a computed tomography compatible with pneumonia, as well as requiring supplementary oxygen were included. Patients were randomly assigned (1:1) to receive oral pyridostigmine (60 mg per day) or placebo for a maximum of 14 days. The intention-to-treat analysis included all the patients who underwent randomisation. The primary endpoint was the composite outcome of initiation of IMV and 28-day all-cause mortality. The trial is registered in ClinicalTrials.gov, NCT04343963.FindingsBetween May 5, 2020, and Jan 29, 2021,188 participants were randomly assigned to placebo (n=94) or pyridostigmine (n=94). The composite outcome occurred in 22 (23·4%) vs. 11 (11·7%) participants, respectively (hazard ratio 0·46, 95% CI 0·22-0·96, p=0·03). The most frequent adverse event was diarrhoea (5 [5·3%] in the pyridostigmine group vs 3 [3·2%] in the placebo group). Most of the adverse events were mild to moderate, with no serious adverse events related to pyridostigmine.InterpretationOur data indicates that the addition of pyridostigmine to standard treatment reduces significantly the fatality rate among patients hospitalized for severe COVID-19.FundingConsejo Nacional de Ciencia y Tecnología, México.
Capturing site-to-site variability through Hierarchical Bayesian calibration of a process-based dynamic vegetation model
Authors: Fer Istem , Shiklomanov Alexey , Novick Kimberly A. , Gough Christopher M. , Altaf Arain M. , Chen Jiquan , Murphy Bailey , Desai Ankur R. , Dietze Michael C. 
Published: April 2021

AbstractProcess-based ecosystem models help us understand and predict ecosystem processes, but using them has long involved a difficult choice between performing data- and labor-intensive site-level calibrations or relying on general parameters that may not reflect local conditions. Hierarchical Bayesian (HB) calibration provides a third option that frees modelers from assuming model parameters to be completely generic or completely site-specific and allows a formal distinction between prediction at known calibration sites and “out-of-sample” prediction to new sites. Here, we compare calibrations of a process-based dynamic vegetation model to eddy-covariance data across 12 temperate deciduous Ameriflux sites fit using either site-specific, joint cross-site, or HB approaches. To be able to apply HB to computationally demanding process-based models we introduce a novel emulator-based HB calibration tool, which we make available through the PEcAn community cyberinfrastructure. Using these calibrations to make predictions at held-out tower sites, we show that the joint cross-site calibration is falsely over-confident because it neglects parameter variability across sites and therefore underestimates variance in parameter distributions. By showing which parameters show high site-to-site variability, HB calibration also formally gives us a structure that can detect which process representations are missing from the models and prioritize errors based on the magnitude of the associated uncertainty. For example, in our case-study, we were able to identify large site-to-site variability in the parameters related to the temperature responses of respiration and photosynthesis, associated with a lack of thermal acclimation and adaptation in the model. Moving forward, HB approaches present important new opportunities for statistical modeling of the spatiotemporal variability in modeled parameters and processes that yields both new insights and improved predictions.
LPMO-oxidized cellulose oligosaccharides evoke immunity in Arabidopsis conferring resistance towards necrotrophic fungusB. cinerea
Authors: Zarattini Marco , Corso Massimiliano , Kadowaki Marco Antonio , Monclaro Antonielle , Magri Silvia , Milanese Irma , Jolivet Sylvie , de Godoy Mariana Ortiz , Hermans Christian , Fagard Mathilde , Cannella David 
Published: April 2021

AbstractLytic Polysaccharide Monooxygenases (LPMOs) are powerful redox enzymes able to oxidatively cleave cellulose polymers. Widely conserved across biological kingdoms, LPMOs of the AA9 family are deployed by phytopathogens during necrotrophic attack of plant cell wall. In response, plants have evolved sophisticated mechanisms to sense cell wall damage and thus self-triggering Damage Triggered Immunity (DTI) responses. Here, we show that Arabidopsis plants exposed to LPMO products responds by activating the innate immunity ultimately leading to increased resistance to pathogenic fungus Botrytis cinerea. We demonstrated with microarray hybridization that plants undergo a deep transcriptional reprogramming upon elicitation with AA9 derived cellulose- or cello-oligosaccharides (AA9_COS). To decipher the specific effects of native and oxidized LPMO-generated cello-oligosaccharides, a pairwise comparison with cellobiose, the smallest non-oxidized unit constituting cellulose, is presented. Moreover, we identified two leucine-rich repeat receptor-like kinases, namely STRESS INDUCED FACTOR 2 and 4, playing a crucial role in signaling the AA9_COS-dependent responses such as camalexin production. We observed an increased production of ethylene, jasmonic and salicylic acid hormones, and finally deposition of callose in cell wall. Collectively, our data reveal that LPMOs might play a crucial role in plant-pathogen interactions.
Loss of SORCS2 is associated with neuronal DNA double-strand breaks
Authors: Gospodinova Katerina O. , Olsen Ditte , Kaas Mathias , Anderson Susan M. , Phillips Jonathan , Walker Rosie M. , Bermingham Mairead L. , Payne Abigail L. , Giannopoulos Panagiotis , Pandya Divya , Spires-Jones Tara L. , Abbott Catherine M. , Porteous David J. , Glerup Simon , Evans Kathryn L. 
Published: April 2021

AbstractSORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking outSORCS2in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaksin vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.
Differential tracking of linguistic vs. mental state content in naturalistic stimuli by language and Theory of Mind (ToM) brain networks
Authors: Paunov Alexander M. , Blank Idan A. , Jouravlev Olessia , Mineroff Zachary , Gallée Jeanne , Fedorenko Evelina 
Published: April 2021

AbstractLanguage and social cognition, especially the ability to reason about mental states, known as Theory of Mind (ToM), are deeply related in development and everyday use. However, whether these cognitive faculties rely on distinct, overlapping, or the same mechanisms remains debated. Some evidence suggests that, by adulthood, language and ToM draw on largely distinct—though plausibly interacting—cortical networks. However, the broad topography of these networks is similar, and some have emphasized the importance of social content / communicative intent in the linguistic signal for eliciting responses in the language areas. Here, we combine the power of individual-subjects functional localization with the naturalistic-cognition inter-subject correlation approach to illuminate the language-ToM relationship. Using fMRI, we recorded neural activity as participants (n=43) listened to stories and dialogs with mental state content (+linguistic, +ToM), viewed silent animations and live action films with mental state content but no language (-linguistic, +ToM), or listened to an expository text (+linguistic, -ToM). The ToM network robustly tracked stimuli rich in mental state information regardless of whether mental states were conveyed linguistically or non-linguistically, while tracking a +linguistic/-ToM stimulus only weakly. In contrast, the language network tracked linguistic stimuli more strongly than a) non-linguistic stimuli, and than b) the ToM network, and showed reliable tracking even for the linguistic condition devoid of mental state content. These findings suggest that in spite of their indisputably close links, language and ToM dissociate robustly in their neural substrates—and thus plausibly cognitive mechanisms—including during the processing of rich naturalistic materials.