A data generator for covid-19 patients’ care requirements inside hospitals

[EN] A Spanish version of the article is provided (see section before references). This paper presents the generation of a plausible data set related to the needs of COVID-19 patients with severe or critical symptoms. Possible illness’ stages were proposed within the context of medical knowledge as of January 2021. The parameters chosen in this data set were customized to fit the population data of the Valencia region (Spain) with approximately 2.5 million inhabitants. They were based on the evolution of the pandemic between September 2020 and March 2021, a period that included two complete waves of the pandemic. Contrary to expectation and despite the European and national transparency laws (BOE-A2013-12887, 2013; European Parliament and Council of the European Union, 2019), the actual COVID-19 pandemic-related data, at least in Spain, took considerable time to be updated and made available (usually a week or more). Moreover, some relevant data necessary to develop and validate hospital bed management models were not publicly accessible. This was either because these data were not collected, because public agencies failed to make them public (despite having them indexed in their databases), the data were processed within indicators and not shown as raw data, or they simply published the data in a format that was difficult to process (e.g., PDF image documents versus CSV tables). Despite the potential of hospital information systems, there were still data that were not adequately captured within these systems. Moreover, the data collected in a hospital depends on the strategies and practices specific to that hospital or health system. This limits the generalization of "real" data, and it encourages working with "realistic" or plausible data that are clean of interactions with local variables or decisions (Gunal, 2012; Marin-Garcia et al., 2020). Besides, one can parameterize the model and define the data structure that would be necessary to run the model without delaying till the real data become available. Conversely, plausible data sets can be generated from publicly available information and, later, when real data become available, the accuracy of the model can be evaluated (Garcia-Sabater and Maheut, 2021). This work opens lines of future research, both theoretical and practical. From a theoretical point of view, it would be interesting to develop machine learning tools that, by analyzing specific data samples in real hospitals, can identify the parameters necessary for the automatic prototyping of generators adapted to each hospital. Regarding the lines of research applied, it is evident that the formalism proposed for the generation of sound patients is not limited to patients affected by SARS-CoV-2 infection. The generation of heterogeneous patients can represent the needs of a specific population and serve as a basis for studying complex health service delivery systems.[ES] En este trabajo se presenta cómo se ha generado un conjunto de datos verosímiles relacionados con las necesidades de pacientes covid-19 con síntomas severe or critical. Se considerarán las etapas posibles con los conocimientos médicos a fecha de enero de 2021. Los parámetros elegidos en este data set están personalizados para adecuarse a los valores poblacionales de la región de Valencia (Spain), unos 2.5 Millones de habitantes y la evolución de la pandemia entre los meses de septiembre 2020 y marzo 2021, un periodo de tiempo que contemple dos olas completas de pandemia.En contra de lo que cabría esperar, a pesar de la ley de transparencia europea y nacional (BOE-A-2013-12887, 2013; Parlamento Europeo y del Consejo de la Unión Europea, 2019), los datos reales relacionados con la pandemia covid-19, al menos en España, tardan mucho en actualizarse y estar disponibles (normalmente una semana o más días). Además, algunos datos relevantes para trabajar los modelos de gestión de camas de hospital no están accesibles públicamente. Bien porque no se hayan recogido esos datos, o porque los organismos públicos no los ofrecen (a pesar de tenerlos indexados en sus bases de datos), o los ofrecen camuflados en indicadores procesados y no muestran los datos en bruto, o simplemente los publican en un formato de difícil reutilización (por ejemplo, en documentos PDF en lugar de en tablas CSV). A pesar de que los sistemas de información de los hospitales son bastante potentes, siguen existiendo datos que ni siquiera están recogidos adecuadamente en el sistema de información de salud.Por otra parte, los datos recogidos en un hospital dependen de las estrategias y practicas propias de ese hospital o sistema de salud. Este efecto limita la generalización de los datos “reales” y es necesario trabajar con datos “realistas” o verosímiles que están limpios de interacciones con variables o decisiones locales (Gunal, 2012; Marin-Garcia et al., 2020). Por un lado, se puede parametrizar el modelo y definir la estructura de datos que sería necesaria para ejecutar el modelo con datos reales. Por otro lado, se pueden generar conjuntos de datos verosímiles a partir de la información pública disponible y, posteriormente, cuando se disponga de los datos reales evaluar la bondad del modelo (Garcia-Sabater & Maheut, 2021).Marin-Garcia, JA.; Ruiz, A.; Julien, M.; Garcia-Sabater, JP. (2021). A data generator for covid-19 patients’ care requirements inside hospitals. WPOM-Working Papers on Operations Management. 12(1):76-115. https://doi.org/10.4995/wpom.1533276115121Alexander, G. L. (2007). The nurse-patient trajectory framework. Medinfo. MEDINFO, 12(Pt 2), 910- 914.Belciug, S., Bejinariu, S. I., & Costin, H. (2020). An artificial immune system approach for a multicompartment queuing model for improving medical resources and inpatient bed occupancy in pandemics. 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Role of endogenous cannabinoids in the control of basal ganglia activity

The cannabinoid system is a novel intercellular signaling system that plays a prominent role, among others, in the control of basal ganglia function. This finding can be concluded from the data obtained in different series of anatomical, biochemical, electrophysiological and pharmacological studies. These data demonstrated: (i) that the basal ganglia contain high levels of endocannabinoids and their receptors, mainly including the cannabinoid CB1 receptor subtype but also a related receptor type, the vanilloid TRPV1 receptor; (ii) that the activation or the blockade of this system produces important changes in motor behavior, changes that are originated as a consequence of interactions of the cannabinoid system with various classic neurotransmitters such as GABA, dopamine or glutamate; and (iii) the occurrence of marked changes in specific elements of the cannabinoid signaling system in various basal ganglia disorders, with emphasis in the induction/upregulation of the cannabinoid CB2 receptor subtype. This large evidence relating endocannabinoids and their receptors to the function of the basal ganglia, both in the healthy and the pathological brain, has provided support for the idea that cannabinoid-based medicines, with selectivity for different targets of the cannabinoid signaling system (synthetic enzymes, receptors, inactivation system), might have therapeutic potential to alleviate symptoms and/or provide neuroprotection in basal ganglia disorders, in particular Parkinson´s disease and Huntington´s chorea. The present chapter will review the knowledge on this issue trying to establish the future lines for the research on the therapeutic potential of the cannabinoid signaling system in basal ganglia disorders.peer-reviewe

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Durante la última década la investigación en nanomedicina ha generado gran cantidad de datos, heterogéneos, distribuidos en múltiples fuentes de información. El uso de las Tecnologías de la Información y la Comunicación (TIC) puede facilitar la investigación médica a escala nanométrica, proporcionando mecanismos y herramientas que permitan gestionar todos esos datos de una manera inteligente. Mientras que la informática biomédica comprende el procesamiento y gestión de la información generada desde el nivel de salud pública y aplicación clínica hasta el nivel molecular, la nanoinformática extiende este ámbito para incluir el “nivel nano”, ocupándose de gestionar y analizar los resultados generados durante la investigación en nanomedicina y desarrollar nuevas líneas de trabajo en este espacio interdisciplinar. En esta nueva área científica, la nanoinformática (que podría consolidarse como una auténtica disciplina en los próximos años), elGrupo de Informática Biomédica (GIB) de la Universidad Politécnica de Madrid (UPM) participa en numerosas iniciativas, que se detallan a continuación

Absolute Determination of the 22Na(p,g) Reaction Rate in Novae

Gamma-ray telescopes in orbit around the Earth are searching for evidence of the elusive radionuclide 22Na produced in novae. Previously published uncertainties in the dominant destructive reaction, 22Na(p,g)23Mg, indicated new measurements in the proton energy range of 150 to 300 keV were needed to constrain predictions. We have measured the resonance strengths, energies, and branches directly and absolutely by using protons from the University of Washington accelerator with a specially designed beamline, which included beam rastering and cold vacuum protection of the 22Na implanted targets. The targets, fabricated at TRIUMF-ISAC, displayed minimal degradation over a ~ 20 C bombardment as a result of protective layers. We avoided the need to know the stopping power, and hence the target composition, by extracting resonance strengths from excitation functions integrated over proton energy. Our measurements revealed that resonance strengths for E_p = 213, 288, 454, and 610 keV are stronger by factors of 2.4 to 3.2 than previously reported. Upper limits have been placed on proposed resonances at 198-, 209-, and 232-keV. We have re-evaluated the 22Na(p,g) reaction rate, and our measurements indicate the resonance at 213 keV makes the most significant contribution to 22Na destruction in novae. Hydrodynamic simulations including our rate indicate that the expected abundance of 22Na ejecta from a classical nova is reduced by factors between 1.5 and 2, depending on the mass of the white-dwarf star hosting the nova explosion.Comment: 20 pages, 18 figures; shortened paper, accepted in Phys. Rev.

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Sustainable territorial management requires reliable assessment of the impact of conservation policies on landscape structure and dynamics. Euro-Mediterranean regions present a remarkable biodiversity which is linked in part to traditional land use practices and which is currently threatened by global change. The effectiveness of one-decade conservation policies against land use changes was examined in Central Spain (Madrid Autonomous Community). A Markov model of landscape dynamics was parameterized with CORINE Land Cover information and transition matrices were obtained. The methods were applied in both protected and unprotected areas to examine whether the intensity and direction of key land use changes —urbanisation, agricultural intensification and land abandonment— differed significantly depending on the protection status of those areas. Protected areas experienced slower rates of agricultural intensification processes and faster rates of land abandonment, with respect to those which occurred in unprotected areas. It illustrates how simple mathematical tools and models —parameterized with available data— can provide to managers and policy makers useful indicators for conservation policy assessment and identification of land use transitions

Immunoanalytical Approach for Detecting and Identifying Ancestral Peptide Biomarkers in Early Earth Analogue Environments

Several mass spectrometry and spectroscopic techniques have been used in the search for molecular biomarkers on Mars. A major constraint is their capability to detect and identify large and complex compounds such as peptides or other biopolymers. Multiplex immunoassays can detect these com-pounds, but antibodies must be produced for a large number of sequence-dependent molecular targets. Ancestral Sequence Re-construction (ASR) followed by protein "resurrection" in the lab can help to narrow the selection of targets. Herein, we propose an immunoanalytical method to identify ancient and universally conserved protein/peptide sequences as targets for identifying ancestral biomarkers in nature. We have developed, tested, and validated this approach by producing antibodies to eight previously described ancestral resurrected proteins (three beta-lactamases, three thioredoxins, one Elongation Factor Tu, and one RuBisCO, all of them theoretically dated as Precambrian), and used them as a proxy to search for any potential feature of them that could be present in current natural environments. By fluorescent sandwich microarray immunoassays (FSMI), we have detected positive immunoreactions with antibodies to the oldest beta-lactamase and thioredoxin proteins (ca. 4 Ga) in samples from a hydrothermal environment. Fine epitope mapping and inhibitory immunoassays allowed the identification of well-conserved epitope peptide sequences that resulted from ASR and were present in the sample. We corroborated these results by metagenomic sequencing and found several genes encoding analogue proteins with significant matches to the peptide epitopes identified with the antibodies. The results demonstrated that peptides inferred from ASR studies have true counterpart analogues in Nature, which validates and strengthens the well-known ASR/protein resurrection technique and our immunoanalytical approach for investigating ancient environments and metabolisms on Earth and elsewhere

Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation

Bile acid; Inflammation; Oncostatin MÀcid biliar; Inflamació; Oncostatina MÁcido biliar; Inflamación; Oncostatina MBile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4α (HNF4α) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7α-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4α levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile.This study was supported by the CIBERehd (EHD15PI05/2016) and Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819, PI20/00189, and PI20/01663 co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”); Junta de Castilla y Leon (SA074P20); Fundació Marato TV3 (Ref. 201916/31), Spain; AECC Scientific Foundation (2017/2020), Spain; Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of Wuerzburg, Germany (Project A-E-384 to H.M.H.); grants PID2019-111669-RB-I00, PID2020-115055RB-I00 from Agencia Estatal de Investigación (AEI), Spain; the AGAUR of the Generalidad de Cataluña SGR-2017-1112, Spain; and European Cooperation in Science & Technology (COST) Action CA17112. R.E.E was recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). J.A. was recipient of a grant from Fundación Echebano (2020–2022)

Selection of extreme phenotypes: the role of clinical observation in translational research

Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology

Estimation of the real population and its impact on the utilisation of healthcare services in Mediterranean resort regions: an ecological study

BACKGROUND: The demographic structure has a significant influence on the use of healthcare services, as does the size of the population denominators. Very few studies have been published on methods for estimating the real population such as tourist resorts. The lack of information about these problems means there is a corresponding lack of information about the behaviour of populational denominators (the floating population or tourist load) and the effect of this on the use of healthcare services. The objectives of the study were: a) To determine the Municipal Solid Waste (MSW) ratio, per person per day, among populations of known size; b) to estimate, by means of this ratio, the real population in an area where tourist numbers are very significant; and c) to determine the impact on the utilisation of hospital emergency healthcare services of the registered population, in comparison to the non-resident population, in two areas where tourist numbers are very significant. METHODS: An ecological study design was employed. We analysed the Healthcare Districts of the Costa del Sol and the island of Menorca. Both are Spanish territories in the Mediterranean region. RESULTS: In the two areas analysed, the correlation coefficient between the MSW ratio and admissions to hospital emergency departments exceeded 0.9, with p < 0.001. On the basis of MSW generation ratios, obtained for a control zone and also measured in neighbouring countries, we estimated the real population. For the summer months, when tourist activity is greatest and demand for emergency healthcare at hospitals is highest, this value was found to be double that of the registered population. CONCLUSION: The MSW indicator, which is both ecological and indirect, can be used to estimate the real population in areas where population levels vary significantly during the year. This parameter is of interest in planning and dimensioning the provision of healthcare services

RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition

Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity may be the cause of aberrant innate immune activation in AGS. Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE-1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE-1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE-1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE-1-derived nucleic acids driving autoinflammation in AGS.M.B.-G. is funded by a “Formacion Profesorado Universitario” (FPU) PhD fellowship from the Government of Spain (MINECO, Ref FPU15/03294), and this paper is part of her thesis project (“Epigenetic control of the mobility of a human retrotransposon”). R.V.-A. is funded by a PFIS Fellowship from the Government of Spain (ISCiii, FI16/00413). O.M. is funded by an EMBO Long-Term Fellowship (ALTF 7-2015), the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and the Swiss National Science Foundation (P2ZHP3_158709). S.R.H. is funded by the Government of Spain (MINECO, RYC-2016-21395 and SAF2015-71589-P). A.P.J’s laboratory is supported by the UK Medical Research Council (MRC University Unit grant U127527202). J.L.G.P’s laboratory is supported by CICEFEDER- P12-CTS-2256, Plan Nacional de I+D+I 2008-2011 and 2013-2016 (FISFEDER- PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2) and by a private donation from Ms Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain)