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Particle accelerators are complex systems that focus, guide, and accelerate intense charged particle beams to high energy. Beam diagnostics present a challenging problem due to limited non-destructive measurements, computationally demanding simulations, and inherent uncertainties in the system. We propose a two-step unsupervised deep learning framework named as Conditional Latent Autoregressive Recurrent Model (CLARM) for learning the spatiotemporal dynamics of charged particles in accelerators. CLARM consists of a Conditional Variational Autoencoder transforming six-dimensional phase space into a lower-dimensional latent distribution and a Long Short-Term Memory network capturing temporal dynamics in an autoregressive manner. The CLARM can generate projections at various accelerator modules by sampling and decoding the latent space representation. The model also forecasts future states (downstream locations) of charged particles from past states (upstream locations). The results demonstrate that the generative and forecasting ability of the proposed approach is promising when tested against a variety of evaluation metrics.
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Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.
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Understanding vapor intrusion (VI) temporal variability is key for the design of sampling strategies intended to assess reasonable maximum exposure of indoor air concentrations of volatile organic compounds (VOCs) as well as risk evaluation and mitigation planning. VI temporal variability has previously been shown to be dependent on the complex interactions of multiple independent variables-meteorological, hydrogeological, and human behavioral. Several meteorological variables, including barometric pressure, wind speed, and rainfall, are linked during tropical and extratropical storm events. High-frequency meteorological and indoor VOC data from a series of seven tropical storms and four extratropical storms were collected at a single industrial building with multiple heating, ventilation, and air conditioning (HVAC) zones. The storms and sampling zones showed a variety of effects on trichloroethylene (TCE) concentrations in indoor air. In one zone (supply room), increases in TCE concentrations often, but not always, closely coincided with decreasing barometric pressure, sustained wind speeds over 32 km/h (20 mph), and differential pressures indicating subslab to indoor flow. A second zone, in a restroom, did not show a consistent pattern of temporal correlation between meteorological factors and indoor air concentrations. While peak indoor air concentrations may be associated with the passage of cyclonic storms at some sampling locations, this does not appear to be generalizable to all sampling locations. The observed increase in indoor air concentration potentially attributable to these storms is typically less than an order of magnitude and the duration ranges from a day to a week.
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Per- and polyfluoroalkyl substances (PFASs) have been detected in an array of environmental media due to their ubiquitous use in industrial and consumer products as well as potential release from fluorochemical manufacturing facilities. During their manufacture, many fluorotelomer (FT) facilities rely on neutral intermediates in polymer production including the FT-alcohols (FTOHs). These PFAS are known to transform to the terminal acids (perfluoro carboxylic acids; PFCAs) at rates that vary with environmental conditions. In the current study on soils from a FT facility, we employed gas chromatography coupled with conventional- and high-resolution mass spectrometry (GC-MS and GC-HRMS) to investigate the profile of these precursor compounds, the intermediary secondary alcohols (sFTOHs), FT-acrylates (FTAcr), and FT-acetates (FTAce) in soils around the former FT-production facility. Of these precursors, the general trend in detection intensity was [FTOHs] > [sFTOHs] > [FTAcrs], while for the FTOHs, homologue intensities generally were [12:2 FTOH] > [14:2 FTOH] > [16:2 FTOH] > [10:2 FTOH] > [18:2 FTOH] > [20:2 FTOH] > [8:2 FTOH] â¼ [6:2 FTOH]. The corresponding terminal acids were also detected in all soil samples and positively correlated with the precursor concentrations. GC-HRMS confirmed the presence of industrial manufacturing byproducts such as FT-ethers and FT-esters and aided in the tentative identification of previously unreported dimers and other compounds. The application of GC-HRMS to the measurement and identification of precursor PFAS is in its infancy, but the methodologies described here will help refine its use in tentatively identifying these compounds in the environment.
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Fluorocarburos , Contaminantes del Suelo , Suelo , Contaminantes del Suelo/análisis , Suelo/química , Fluorocarburos/análisis , Cromatografía de Gases y Espectrometría de Masas , Monitoreo del Ambiente , Instalaciones Industriales y de FabricaciónRESUMEN
Quantitative diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is essential for the safe administration of 8-aminoquinoline based radical cure for the treatment of Plasmodium vivax infections. Here, we present the PreQuine Platform (IVDS, USA), a quantitative biosensor that uses a dual-analyte assay for the simultaneous measurement of Hemoglobin (Hgb) levels and G6PD enzyme activity within the same sample. The platform relies on a downloadable mobile application. The device requires 10µl of whole blood and works with a reflectance-based meter. Comparing the G6PD measurement normalized by Hgb of 12 samples from the PreQuine Platform with reference measurements methods (spectrophotometry, Pointe Scientific, USA and hemoglobin meter, HemoCue, Sweden) showed a positive and significant agreement with a slope of 1.0091 and an intercept of -0.0379 under laboratory conditions. Next steps will be to conduct field trials in Bangladesh, Cambodia, and the USA to assess diagnostic performance, user friendliness and acceptance.
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Deficiencia de Glucosafosfato Deshidrogenasa , Glucosafosfato Deshidrogenasa , Hemoglobinas , Humanos , Glucosafosfato Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/sangre , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Deficiencia de Glucosafosfato Deshidrogenasa/sangre , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Técnicas Biosensibles/métodos , Malaria Vivax/diagnóstico , Malaria Vivax/sangre , AminoquinolinasRESUMEN
Introduction: Clinical informatics is an important component of the AMA-endorsed third pillar of undergraduate medical education, health systems science. Discrete educational opportunities for clinical informatics and health systems science among early learners are lacking in medical school curricula. Methods: We developed and evaluated a multistep, 2.5-hour activity during the gastroenterology module to introduce these topics to preclerkship medical students. A didactic session introducing clinical informatics and clinical decision support and reviewing health promotion and screening concepts was followed by small-group activities. Students worked through a series of exercises culminating in the generation of a clinical decision support tool based on the United States Preventive Services Task Force (USPSTF) colorectal cancer screening recommendations. Results: Between 2022 and 2023, 326 first-year medical students participated in this workshop. Feedback was predictably mixed. In 2022, 88% of postclass survey respondents confirmed having a better clinical informatics understanding after the workshop. In 2023, students reported a statistically significant increase in their self-reported understanding of the role of clinical informatics, clinical decision support, and USPSTF colorectal cancer recommendations. Discussion: Clinical decision support is a viable pathway for introduction of clinical informatics, health systems science, and public health/prevention topics. Our educational approach offers an interactive introduction to this group of topics that can benefit future physicians. While colon cancer provides a robust option for the clinical situation, this activity could be modified to fit into many different clinical scenarios, allowing for interdisciplinary education during either undergraduate or graduate medical education.
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Neoplasias Colorrectales , Informática Médica , Humanos , Detección Precoz del Cáncer , Estudiantes , Curriculum , Neoplasias Colorrectales/diagnósticoRESUMEN
Per- and polyfluoroalkyl substances (PFAS) are used in various industrial products; however, they pose serious health risks. In this study, soil, soil gas, and groundwater samples were collected at a PFAS manufacturing facility in New Jersey, USA, to determine the presence and distribution of PFASs from the soil surface to groundwater and at various distances from the presumed source. Fluorotelomer alcohols (FTOHs) were detected in soil (< 0.26-36.15 ng/g) and soil gas (160-12,000 E µg/m3), while perfluorinated carboxylic acids (PFCAs) were found in soil (4.3-810 ng/g), soil gas (<0.10-180 µg/m3), and groundwater (37-49 µg/L). FTOH and PFCA concentrations decreased as the distance from the presumed source increased, suggesting that PFCAs are likely to migrate in groundwater, whereas FTOHs primarily move in the vapor phase. The presence of PFAS in the groundwater, soil, and soil gas samples indicate its potential for vapor intrusion; thus, some PFAS may contribute to indoor air inhalation exposure. To the best of our knowledge, this is the first report on the quantification of volatile PFAS in soil gas at a PFAS manufacturing facility.
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Management of deep-sea fisheries in areas beyond national jurisdiction by Regional Fisheries Management Organizations/Arrangements (RFMO/As) requires identification of areas with Vulnerable Marine Ecosystems (VMEs). Currently, fisheries data, including trawl and longline bycatch data, are used by many RFMO/As to inform the identification of VMEs. However, the collection of such data creates impacts and there is a need to collect non-invasive data for VME identification and monitoring purposes. Imagery data from scientific surveys satisfies this requirement, but there currently is no established framework for identifying VMEs from images. Thus, the goal of this study was to bring together a large international team to determine current VME assessment protocols and establish preliminary global consensus guidelines for identifying VMEs from images. An initial assessment showed a lack of consistency among RFMO/A regions regarding what is considered a VME indicator taxon, and hence variability in how VMEs might be defined. In certain cases, experts agreed that a VME could be identified from a single image, most often in areas of scleractinian reefs, dense octocoral gardens, multiple VME species' co-occurrence, and chemosynthetic ecosystems. A decision flow chart is presented that gives practical interpretation of the FAO criteria for single images. To further evaluate steps of the flow chart related to density, data were compiled to assess whether scientists perceived similar density thresholds across regions. The range of observed densities and the density values considered to be VMEs varied considerably by taxon, but in many cases, there was a statistical difference in what experts considered to be a VME compared to images not considered a VME. Further work is required to develop an areal extent index, to include a measure of confidence, and to increase our understanding of what levels of density and diversity correspond to key ecosystem functions for VME indicator taxa. Based on our results, the following recommendations are made: 1. There is a need to establish a global consensus on which taxa are VME indicators. 2. RFMO/As should consider adopting guidelines that use imagery surveys as an alternative (or complement) to using bycatch and trawl surveys for designating VMEs. 3. Imagery surveys should also be included in Impact Assessments. And 4. All industries that impact the seafloor, not just fisheries, should use imagery surveys to detect and identify VMEs.
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Conservación de los Recursos Naturales , Ecosistema , Conservación de los Recursos Naturales/métodos , Explotaciones PesquerasRESUMEN
Allogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin ( B2M ) expression is commonly employed to evade T cell-mediated rejection, although absence of B2M triggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligands CD54 and CD58 on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion of CD54 and CD58 in B2M -deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cells in vitro and in vivo without affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.
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Egg case nurseries of the boreal skate (Amblyraja hyperborea) and Richardson's skate (Bathyraja richardsoni) were defined and mapped on a bathyal seascape (c. 500-1900 m depths) south of Tasmania, Australia, using 99 towed-camera transects (157 linear km; N = 50,858 images). In total, 738 skate egg cases were observed (present in 240 images, absent in 50,618); among 113 egg cases examined to identify parent species, 70% were A. hyperborea, 10% B. richardsoni and 20% unidentified Bathyraja species. "Recently laid" egg cases were differentiated from "aged" ones by classifying their colour and condition. The great majority (98%) of egg cases were observed in c. 1100-1400 m depths on seamounts (15 of 36 surveyed), not seamount bases or adjacent continental slope. Egg cases were associated with reefs formed by accumulated skeletal matrix of the stony coral Solenosmilia variabilis, with >90% egg cases (including most of those recently laid) observed on living S. variabilis that characterises a "coral zone" in c. 950-1350 m depths. Water in the coral zone is warmer (+0.66 to 2.37°C) than at the deep distributional limits of adult A. hyperborea and B. richardsoni (2000 and 3000 m, respectively), potentially providing for accelerated embryonic development. Co-occurrence with living coral infers an energetically favourable local-scale hydrodynamic environment for egg cases, particularly on seamount peaks, where increased water flow over egg cases would avert smothering by suspended sediment, and compensate for lower oxygen concentration compared to deeper depths occupied by adult skates. Criteria identifying egg case nurseries are strongly met for A. hyperborea at Seamount Z110 (468 egg cases of varied ages, maximum density of 5.47 m-2 ) and to a lesser extent on five others (Seamounts K1, Z16, Hill U, Z5 and Hill V). An abundance (density) criterion for defining nurseries needs to be flexible because it is a spatially scale-dependent measure that differs between surveys according to the tools and design employed. Off Australia, coral reef egg case nursery habitat is restricted to a narrow depth range in temperate latitudes where it is scarce and impacted by historical bottom trawl fishing in many locations. There has been effective conservation of nursery habitat, however, because four of the six nursery sites identified here and extensive coral reef areas are protected within marine parks.
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Antozoos , Rajidae , Animales , Arrecifes de Coral , Ecosistema , Rajidae/crecimiento & desarrollo , AguaRESUMEN
BACKGROUND: Transfusion-related adverse events can be unrecognized and unreported. As part of the US Food and Drug Administration's Center for Biologics Evaluation and Research Biologics Effectiveness and Safety initiative, we explored whether machine learning methods, such as natural language processing (NLP), can identify and report transfusion allergic reactions (ARs) from electronic health records (EHRs). STUDY DESIGN AND METHODS: In a 4-year period, all 146 reported transfusion ARs were pulled from a database of 86,764 transfusions in an academic health system, along with a random sample of 605 transfusions without reported ARs. Structured and unstructured EHR data were retrieved, including demographics, new symptoms, medications, and lab results. In unstructured data, evidence from clinicians' notes, test results, and prescriptions fields identified transfusion ARs, which were used to extract NLP features. Clinician reviews of selected validation cases assessed and confirmed model performance. RESULTS: Clinician reviews of selected validation cases yielded a sensitivity of 67.9% and a specificity of 97.5% at a threshold of 0.9, with a positive predictive value (PPV) of 84%, estimated to 4.5% when extrapolated to match transfusion AR incidence in the full transfusion dataset. A higher threshold achieved sensitivity of 43% with specificity/PPV of 100% in our validation set. Essential features predicting ARs were recognized transfusion reactions, administration of antihistamines or glucocorticoids, and skin symptoms (e.g., hives and itching). Removal of NLP features decreased model performance. DISCUSSION: NLP algorithms can identify transfusion reactions from the EHR with a reasonable level of precision for subsequent clinician review and confirmation.
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Productos Biológicos , Hipersensibilidad , Reacción a la Transfusión , Algoritmos , Registros Electrónicos de Salud , Glucocorticoides , Humanos , Hipersensibilidad/epidemiología , Hipersensibilidad/etiología , Reacción a la Transfusión/epidemiología , Reacción a la Transfusión/etiologíaRESUMEN
Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCRαß- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications.
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Edición Génica , Nucleasas de los Efectores Tipo Activadores de la Transcripción , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/genética , Linfocitos TRESUMEN
INTRODUCTION: Hepatitis B is a potentially deadly infection that can be acquired by exposure to infectious human blood or body fluids. While service members and others at occupational risk are routinely vaccinated to prevent hepatitis B, non-responders to this vaccine are at continued risk. Heplisav-B is a newer vaccine that may offer additional protection to those at risk. MATERIALS AND METHODS: Cases of hepatitis B vaccine non-responders who were given Heplisav-B after receiving six or more doses of standard hepatitis B vaccine were collected from existing health records within the military health system after Uniformed Services University of the Health Sciences Institutional Review Board review. RESULTS: Twelve of thirteen (92%) prior non-responders who were tested at least 1 month after completing the recombinant Heplisav-B vaccine series demonstrated seroprotection against hepatitis B. CONCLUSIONS: Ideally, all service members and other at-risk workers should be protected from hepatitis B. This case series suggests that prior non-responders are likely to gain protection from hepatitis B with Heplisav-B vaccination. A prospective trial is warranted for further evaluation of this potential indication.
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Vacunas contra Hepatitis B , Hepatitis B , Hepatitis B/prevención & control , Anticuerpos contra la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Vacunas contra Hepatitis B/uso terapéutico , Humanos , Estudios ProspectivosRESUMEN
Publications abound on the physiology, biochemistry and molecular biology of "anaerobic" protozoal parasites as usually grown under "anaerobic" culture conditions. The media routinely used are poised at low redox potentials using techniques that remove O2 to "undetectable" levels in sealed containers. However there is growing understanding that these culture conditions do not faithfully resemble the O2 environments these organisms inhabit. Here we review for protists lacking oxidative energy metabolism, the oxygen cascade from atmospheric to intracellular concentrations and relevant methods of measurements of O2, some well-studied parasitic or symbiotic protozoan lifestyles, their homeodynamic metabolic and redox balances, organism-drug-oxygen interactions, and the present and future prospects for improved drugs and treatment regimes.
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Metabolismo Energético , Oxígeno , Oxidación-Reducción , Especies Reactivas de OxígenoRESUMEN
The peopling of Sahul (the combined continent of Australia and New Guinea) represents the earliest continental migration and settlement event of solely anatomically modern humans, but its patterns and ecological drivers remain largely conceptual in the current literature. We present an advanced stochastic-ecological model to test the relative support for scenarios describing where and when the first humans entered Sahul, and their most probable routes of early settlement. The model supports a dominant entry via the northwest Sahul Shelf first, potentially followed by a second entry through New Guinea, with initial entry most consistent with 50,000 or 75,000 years ago based on comparison with bias-corrected archaeological map layers. The model's emergent properties predict that peopling of the entire continent occurred rapidly across all ecological environments within 156-208 human generations (4368-5599 years) and at a plausible rate of 0.71-0.92 km year-1. More broadly, our methods and approaches can readily inform other global migration debates, with results supporting an exit of anatomically modern humans from Africa 63,000-90,000 years ago, and the peopling of Eurasia in as little as 12,000-15,000 years via inland routes.