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1.
Cells ; 10(5)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924933

RESUMO

Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor-ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of "catch bonds" and on the recent observations that B-cell synapses retract and pull antigen generating a "retracting force", and propose some testable predictions that can lead to future research.

2.
Sci Rep ; 11(1): 7845, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846408

RESUMO

Endosomes are intracellular vesicles that mediate the communication of the cell with its extracellular environment. They are an essential part of the cell's machinery regulating intracellular trafficking via the endocytic pathway. Many viruses, which in order to replicate require a host cell, attach themselves to the cellular membrane; an event which usually initiates uptake of a viral particle through the endocytic pathway. In this way viruses hijack endosomes for their journey towards intracellular sites of replication and avoid degradation without host detection by escaping the endosomal compartment. Recent experimental techniques have defined the role of endosomal maturation in the ability of enveloped viruses to release their genetic material into the cytoplasm. Endosome maturation depends on a family of small hydrolase enzymes (or GTPases) called Rab proteins, arranged on the cytoplasmic surface of its membrane. Here, we model endosomes as intracellular compartments described by two variables (its levels of active Rab5 and Rab7 proteins) and which can undergo coagulation (or fusion) and fragmentation (or fission). The key element in our approach is the "per-cell endosomal distribution" and its dynamical (Boltzmann) equation. The Boltzmann equation allows us to derive the dynamics of the total number of endosomes in a cell, as well as the mean and the standard deviation of its active Rab5 and Rab7 levels. We compare our mathematical results with experiments of Dengue viral escape from endosomes. The relationship between endosomal active Rab levels and pH suggests a mechanism that can account for the observed variability in viral escape times, which in turn regulate the viability of a viral intracellular infection.

3.
Genome Med ; 13(1): 66, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883027

RESUMO

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Assuntos
Brônquios , Mucosa Respiratória , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Expressão Gênica , Variação Genética , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/imunologia , Doença Pulmonar Obstrutiva Crônica/genética , Locos de Características Quantitativas , Fatores de Risco , Fumar/genética
4.
Artigo em Inglês | MEDLINE | ID: mdl-33667479

RESUMO

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

5.
Chemistry ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33780583

RESUMO

The surface-assisted hierarchical assembly of DNA origami nanostructures is a promising route to fabricate regular nanoscale lattices. In this work, the scalability of this approach is explored and the formation of a homogeneous polycrystalline DNA origami lattice at the mica-electrolyte interface over a total surface area of 18.75 cm2 is demonstrated. The topological analysis of more than 50 individual AFM images recorded at random locations over the sample surface showed only minuscule and random variations in the quality and order of the assembled lattice. The analysis of more than 450 fluorescence microscopy images of a quantum dot-decorated DNA origami lattice further revealed a very homogeneous surface coverage over cm2 areas with only minor boundary effects at the substrate edges. At total DNA costs of €â€…0.12 per cm2 , this large-scale nanopatterning technique holds great promise for the fabrication of functional surfaces.

6.
Sensors (Basel) ; 21(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671253

RESUMO

Mechatronics and robotics appeared particularly effective in students' education, allowing them to create non-traditional solutions in STEM disciplines, which have a direct impact and interaction with the world surrounding them. This paper presents the current state of the MiniCERNBot Educational Robotic platform for high-school and university students. The robot provides a comprehensive educative system with tutorials and tasks tuned for different ages on 3D design, mechanical assembly, control, programming, planning, and operation. The system is inspired to existing robotic systems and typical robotic interventions performed at CERN, and includes an education mock-up that follows the example of a previous real operation performed in CERN's Antimatter Factory. The paper describes the learning paths where the MiniCERNBot platform can be used by students, at different ages and disciplines. In addition, it describes the software and hardware architecture, presenting results on modularity and network performance during education exercises. In summary, the objective of the study is improving the way STEM educational and dissemination activities at CERN Robotics Lab are performed, as well as their possible synergies with other education institutions, such as High-Schools and Universities, improving the learning collaborative process and inspiring students interested in technical studies. To this end, a new educational robotic platform has been designed, inspired on real scientific operations, which allows the students practice multidisciplinary STEM skills in a collaborative problem-solving way, while increasing their motivation and comprehension of the research activities.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33779531

RESUMO

RATIONALE Androgens are potentially beneficial in asthma, but androgen receptor (AR) has not been studied in human airways. OBJECTIVES To measure whether AR and its ligands are associated with human asthma outcomes. METHODS We compared AR expression to lung function, symptom scores and fractional of exhaled nitric oxide (FENO) in adults enrolled in the Severe Asthma Research Program (SARP). Further, asthma exacerbations, and emergency department (ED) visits were also evaluated in the SARP, with validation studies in the Cleveland Clinic Health System (CCHS) and the National Health and Nutrition Examination Survey (NHANES). MEASUREMENTS AND MAIN RESULTS In SARP (n=128), AR gene expression from bronchoscopic epithelial brushings was positively correlated with FEV1/FVC ratio (R2=0.135, p=0.0002) and total AQLQ score (R2=0.056, p=0.016); and was negatively associated with FENO (R2=0.178, p=9.8e-06) and NOS2 gene expression (R2=0.281, p=1.2e-10). In SARP (n=1,659), CCHS (n=32,527) and NHANES (n=2,629), women had more asthma exacerbations and ED visits than men. Levels of the AR ligand precursor dehydroepiandrosterone sulfate (DHEA-S) correlated positively with FEV1 in both women and men. CONCLUSIONS Higher AR expression in bronchial epithelial cells, and higher androgen levels, are associated with better lung function, fewer symptoms and lower FENO in human asthma. The role of androgens should be considered in asthma management.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33577895

RESUMO

BACKGROUND: Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. OBJECTIVES: We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. METHODS: We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity. RESULTS: Greater baseline wall area percent (ß = -0.15 [95% CI = -0.26 to -0.05]; P < .01), hyperinflation percent (ß = -0.25 [95% CI = -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal ß = 10.64 [95% CI = 3.79-17.49]; P < .01; posterior-anterior ß = -9.14, [95% CI = -15.49 to -2.78]; P < .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P < .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires. CONCLUSIONS: Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

11.
Am J Respir Crit Care Med ; 203(7): 882-892, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545021

RESUMO

Rationale: Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma.Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.Methods: The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly <2%, eosinophils predominantly ≥2%, or highly variable eosinophil percentages (>2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point.Measurements and Main Results: The group with predominantly <2% sputum eosinophils had the highest lung function (prebronchodilator FEV1% predicted, P < 0.01; FEV1/FVC ratio, P < 0.001) at baseline and throughout 3 years compared with other eosinophil groups. Healthcare use did not differ, although the highly variable eosinophil group reported more asthma exacerbations at Year 3. Longitudinal neutrophil groups showed few differences. However, a combination of predominantly ≥2% eosinophil and ≥50% neutrophil groups resulted in the lowest prebronchodilator FEV1% predicted (P = 0.049) compared with the combination with predominantly <2% eosinophils and<50% neutrophils.Conclusions: Subjects with predominantly ≥2% sputum eosinophils in combination with predominantly ≥50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare use.


Assuntos
Asma/genética , Asma/fisiopatologia , Eosinófilos/química , Granulócitos/química , Inflamação/fisiopatologia , Pulmão/fisiopatologia , Escarro/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Testes de Função Respiratória , Índice de Gravidade de Doença
12.
Eur Respir J ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542055

RESUMO

Asthma is a complex respiratory disease that varies in severity and response to treatment. Several asthma phenotypes with unique clinical and inflammatory characteristics have been identified. Endotypes, based on distinct molecular profiles, help to further understand the heterogeneity within asthma. Type 2 inflammation, involving both the innate (type 2 innate lymphoid cell) and adaptive (T helper type 2 cells) immune systems, underpins the complex pathophysiology of chronic inflammation in asthma, as well as the presence of comorbid disease (such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and atopic dermatitis). Type 2 inflammation is characterised by upregulation of type 2 cytokines interleukin (IL)-4, IL-5, and IL-13, immunoglobulin E (IgE)-mediated release of immune mediators, and dysfunction of epithelial or epidermal barriers. Targeting these key proximal type 2 cytokines has shown efficacy in recent studies adopting a personalised approach to treatment using targeted biologics. Elevated levels of biomarkers downstream of type 2 cytokines, including fractional exhaled nitric oxide, serum IgE, and blood and sputum eosinophils, have been linked to mechanisms involved in type 2 inflammation, and have the potential to aid diagnosis, and predict and monitor response to treatment. The objective of this review is to summarise the current understanding of the biology of type 2 inflammation in asthma, examine its influence on type 2 inflammatory comorbidities, and discuss how type 2 inflammatory biomarkers can be harnessed to further personalise treatments in the age of biologic medicines.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33290668

RESUMO

RATIONALE: It is unclear why select patients with moderate to severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of severe decline in lung function. OBJECTIVE: To evaluate corticosteroid response phenotypes as longitudinal predictors of lung decline. METHODS: Adults with in the NHLBI Severe Asthma Research Program (SARP3; (1, 2)) who had undergone a course of intramuscular triamcinolone at baseline and ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/year; mild decline, >0.5 to 2.0% loss/year; no change, 0.5% loss/year to <1% gain/year; improve, ≥1% gain/year. Regression models were used to develop predictors of severe decline. MEASUREMENTS AND MAIN RESULTS: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (tdFEV1; derived by baseline subtraction) was related to the 4-yr change in lung function or slope category in univariable models (p < 0.001). For each 5% decrement in the tdFEV1, there was a 50% increase in the odds of being in the severe decline group (OR 1.5, 95% CI 1.3 to 1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and BMI. CONCLUSIONS: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk of severe decline in lung function.

15.
Br J Radiol ; : 20201133, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33242252

RESUMO

Quantitative imaging of the lung has proved to be a valuable tool that has improved our understanding of asthma. CT, MRI, and positron emission tomography have all been utilized in asthma with each modality having its own distinct advantages and disadvantages. Research has now demonstrated that quantitative imaging plays a valuable role in characterizing asthma phenotypes and endotypes, as well as potentially predicting future asthma morbidity. Nonetheless, future research is needed in order to minimize radiation exposure, standardize reporting, and further delineate how imaging can predict longitudinal outcomes. With future work, quantitative imaging may make its way into the clinical care of asthma and change our practice.

16.
Otolaryngol Head Neck Surg ; : 194599820965233, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33138725

RESUMO

Biologic agents, monoclonal antibodies that target highly-specific molecular pathways of inflammation, are becoming integrated into care pathways for multiple disorders that are relevant in otolaryngology and allergy. These conditions share common inflammatory mechanisms of so-called Type 2 inflammation with dysregulation of immunoglobulin E production and eosinophil and mast cell degranulation leading to tissue damage. Biologic agents are now available for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, eosinophilic granulomatosis with polyangiitis (EGPA), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). This paper summarizes the diagnosis and management of these conditions and critically reviews the clinical trial data that has led to regulatory approval of biologic agents for these conditions.

17.
PLoS Comput Biol ; 16(11): e1008248, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33141821

RESUMO

Successful mathematical modeling of biological processes relies on the expertise of the modeler to capture the essential mechanisms in the process at hand and on the ability to extract useful information from empirical data. A model is said to be structurally unidentifiable, if different quantitative sets of parameters provide the same observable outcome. This is typical (but not exclusive) of partially observed problems in which only a few variables can be experimentally measured. Most of the available methods to test the structural identifiability of a model are either too complex mathematically for the general practitioner to be applied, or require involved calculations or numerical computation for complex non-linear models. In this work, we present a new analytical method to test structural identifiability of models based on ordinary differential equations, based on the invariance of the equations under the scaling transformation of its parameters. The method is based on rigorous mathematical results but it is easy and quick to apply, even to test the identifiability of sophisticated highly non-linear models. We illustrate our method by example and compare its performance with other existing methods in the literature.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33098584

RESUMO

BACKGROUND: Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis. METHODS: In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5-16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV1 , FVC, and FEV1 /FVC z-scores and methacholine PC20 were analyzed. RESULTS: 55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV1 (P < .0001) FVC (P < .0001) and FEV1 /FVC (P < .0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10-16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P = .0003). CONCLUSIONS: Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.

19.
Respir Res ; 21(1): 254, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008396

RESUMO

BACKGROUND: Previous studies suggested that the prone position (PP) improves oxygenation and reduces mortality among patients with acute respiratory distress syndrome (ARDS). However, the mechanism of this clinical benefit of PP is not completely understood. The aim of the present study was to quantitatively compare regional characteristics of lung functions in the PP with those in the supine position (SP) using inspiratory and expiratory computed tomography (CT) scans. METHODS: Ninety subjects with normal pulmonary function and inspiration and expiration CT images were included in the study. Thirty-four subjects were scanned in PP, and 56 subjects were scanned in SP. Non-rigid image registration-based inspiratory-expiratory image matching assessment was used for regional lung function analysis. Tissue fractions (TF) were computed based on the CT density and compared on a lobar basis. Three registration-derived functional variables, relative regional air volume change (RRAVC), volumetric expansion ratio (J), and three-dimensional relative regional displacement (s*) were used to evaluate regional ventilation and deformation characteristics. RESULTS: J was greater in PP than in SP in the right middle lobe (P = 0 .025), and RRAVC was increased in the upper and right middle lobes (P < 0.001). The ratio of the TF on inspiratory and expiratory scans, J, and RRAVC at the upper lobes to those at the middle and lower lobes and that ratio at the upper and middle lobes to those at the lower lobes of were all near unity in PP, and significantly higher than those in SP (0.98-1.06 vs 0.61-0.94, P < 0.001). CONCLUSION: We visually and quantitatively observed that PP not only induced more uniform contributions of regional lung ventilation along the ventral-dorsal axis but also minimized the lobar differences of lung functions in comparison with SP. This may help in the clinician's search for an understanding of the benefits of the application of PP to the patients with ARDS or other gravitationally dependent pathologic lung diseases. TRIAL REGISTRATION: Retrospectively registered.

20.
Proc Natl Acad Sci U S A ; 117(42): 26190-26196, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33004629

RESUMO

Epidemic spread is characterized by exponentially growing dynamics, which are intrinsically unpredictable. The time at which the growth in the number of infected individuals halts and starts decreasing cannot be calculated with certainty before the turning point is actually attained; neither can the end of the epidemic after the turning point. A susceptible-infected-removed (SIR) model with confinement (SCIR) illustrates how lockdown measures inhibit infection spread only above a threshold that we calculate. The existence of that threshold has major effects in predictability: A Bayesian fit to the COVID-19 pandemic in Spain shows that a slowdown in the number of newly infected individuals during the expansion phase allows one to infer neither the precise position of the maximum nor whether the measures taken will bring the propagation to the inhibition regime. There is a short horizon for reliable prediction, followed by a dispersion of the possible trajectories that grows extremely fast. The impossibility to predict in the midterm is not due to wrong or incomplete data, since it persists in error-free, synthetically produced datasets and does not necessarily improve by using larger datasets. Our study warns against precise forecasts of the evolution of epidemics based on mean-field, effective, or phenomenological models and supports that only probabilities of different outcomes can be confidently given.


Assuntos
Infecções por Coronavirus/epidemiologia , Previsões , Pneumonia Viral/epidemiologia , Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Previsões/métodos , Humanos , Modelos Biológicos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Espanha/epidemiologia , Incerteza
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