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Abstract Direct observation of tumor-immune interactions is unlikely in tumors with currently available technology, but computational simulations based on clinical data can provide insight to test hypotheses. It is hypothesized that patterns of collagen evolve as a mechanism of immune escape, but the exact nature of immune-collagen interactions is poorly understood. Spatial data quantifying collagen fiber alignment in squamous cell carcinomas indicates that late-stage disease is associated with highly aligned fibers. Our computational modeling framework discriminates between two hypotheses: immune cell migration that moves (1) parallel or (2) perpendicular to collagen fiber orientation. The modeling recapitulates immune-extracellular matrix interactions where collagen patterns provide immune protection, leading to an emergent inverse relationship between disease stage and immune coverage. Here, computational modeling provides important mechanistic insights by defining a kernel cell-cell interaction function that considers a spectrum of local (cell-scale) to global (tumor-scale) spatial interactions. Short-range interaction kernels provide a mechanism for tumor cell survival under conditions with strong Allee effects, while asymmetric tumor-immune interaction kernels lead to poor immune response. Thus, the length scale of tumor-immune interaction kernels drives tumor growth and infiltration.

ABSTRACTIn the Staged Progression (SP) epidemic models, infected individuals are classified into a suitable number of states. The goal of these models is to describe as closely as possible the effect of differences in infectiousness exhibited by individuals going through the different stages. The main objective of this work is to study, from the methodological point of view, the behaviour of solutions of the discrete time SP models without reinfection and with a general incidence function. Besides calculating [Formula: see text], we find bounds for the epidemic final size, characterize the asymptotic behaviour of the infected classes, give results about the final monotonicity of the infected classes, and obtain results regarding the initial dynamics of the prevalence of the disease. Moreover, we incorporate into the model the probability distribution of the number of contacts in order to make the model amenable to study its effect in the dynamics of the disease.

Summary: Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are poorly understood. Here, loss of BMAL1 in the PVN results in arrhythmicity of processes controlling energy balance and alters peripheral diurnal gene expression. BMAL1 chromatin immunoprecipitation sequencing (ChIP-seq) and single-nucleus RNA sequencing (snRNA-seq) reveal its temporal regulation of target genes, including oxytocin (OXT), and restoring circulating OXT peaks in BMAL1-PVN knockout (KO) mice rescues absent activity rhythms. While glutamatergic neurons undergo day/night changes in expression of genes involved in cell morphogenesis, astrocytes and oligodendrocytes show gene expression changes in cytoskeletal organization and oxidative phosphorylation. Collectively, our findings show diurnal gene regulation in neuronal and non-neuronal PVN cells and that BMAL1 contributes to diurnal OXT secretion, which is important for systemic diurnal rhythms.

IntroductionMetabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches.MethodsHere, we present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. The model explores several immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1). We also explore the efficacy of anti-PD-L1 and sodium bicarbonate buffer agents for treatment. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed “meta-phenotypes”): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose.ResultsFomenting a stronger immune response leads to initial benefits (additional cytotoxicity), but this advantage is offset by increased cell turnover that leads to accelerated evolution and the emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. These constraints are dependent on heterogeneity in vascular context, microenvironmental acidification, and the strength of immune response.DiscussionThis model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.

Abstract The main aim of the work is to present a general class of two time scales discrete-time epidemic models. In the proposed framework the disease dynamics is considered to act on a slower time scale than a second different process that could represent movements between spatial locations, changes of individual activities or behaviors, or others. To include a sufficiently general disease model, we first build up from first principles a discrete-time susceptible–exposed–infectious–recovered–susceptible (SEIRS) model and characterize the eradication or endemicity of the disease with the help of its basic reproduction number R 0 $\mathcal{R}_{0}$ . Then, we propose a general full model that includes sequentially the two processes at different time scales and proceed to its analysis through a reduced model. The basic reproduction number R ‾ 0 $\overline{\mathcal{R}}_{0}$ of the reduced system gives a good approximation of R 0 $\mathcal{R}_{0}$ of the full model since it serves at analyzing its asymptotic behavior. As an illustration of the proposed general framework, it is shown that there exist conditions under which a locally endemic disease, considering isolated patches in a metapopulation, can be eradicated globally by establishing the appropriate movements between patches.

During the expansion of adipose tissue adipocyte progenitor cells proliferate and undergo adipogenesis. Here, the authors show that adipocyte progenitor cell proliferation in visceral adipose tissue has a diurnal pattern, which is dependent on both energy intake and the circadian clock.

Abstract Aims The aim of this study was to evaluate the safety profile in terms of changes in renal function after co‐treatment with sacubitril/valsartan and empagliflozin in patients with type 2 diabetes (T2D) and heart failure with reduced ejection fraction (HFrEF). Methods and results This multicentre observational analysis included 108 patients with T2D and HFrEF treated with both agents: baseline sacubitril/valsartan (Group A; n = 43), baseline empagliflozin (Group B; n = 42), or both agents initiated simultaneously (Group C; n = 23). The primary endpoint was estimated glomerular filtration rate (eGFR) dynamics across treatment groups. A binary characterization of worsening renal function (WRF)/improved renal function (IRF) was included in the primary endpoint. WRF and IRF were defined as an increase/decrease in serum creatinine ≥ 0.3 mg/dL or GFR ≥ 20%. Changes in quantitative variables were evaluated using joint modelling of survival and longitudinal data (JM). Rates and their treatment differences were determined by Poisson regression. The mean left ventricle ejection fraction and eGFR were 32 ± 6% and 70 ± 28 mL/min/1.73 m2, respectively. At a median follow‐up of 1.01 years (inter‐quartile range 0.71–1.50), 377 outpatient visits were recorded. Although there were differences in GFR trajectories over time within each treatment, they did not achieve statistical significance (omnibus P = 0.154). However, when these differences were contrasted among groups, there was a significant decrease in GFR in Group A as compared with Group B (P = 0.002). The contrast between Groups C and B was not significant (P = 0.430). These differences were also reflected when the rates for WRF and IRF were contrasted among treatments. Conclusions The co‐administration of sacubitril/valsartan and empagliflozin in patients with HFrEF and concomitant T2D appears to be safe in terms of renal function.

Resumen: Las nuevas tecnologías de la información han transformado la manera de prestar la asistencia en los servicios de salud, impregnando casi todos los aspectos de la atención sanitaria. A medida que la complejidad del sistema aumenta, es más difícil trabajar de manera óptima sin la asistencia de las nuevas tecnologías. Su implantación supone un avance, bien por el adelanto que entraña el uso adecuado de cualquier nueva tecnología en el cuidado de la salud, bien por el desarrollo de aplicaciones específicas que mejoran la seguridad de la asistencia. Sin embargo, factores como un diseño incorrecto, implementación y mantenimiento deficientes, capacitación inadecuada, junto al exceso de confianza y dependencia, pueden hacer que las tecnologías comprometan, más que favorecer, la seguridad del paciente.Este artículo describe los efectos beneficiosos, y los que no lo son tanto, de la introducción en nuestro país de la historia clínica y la receta electrónicas en la calidad y la seguridad de la asistencia sanitaria. Abstract: New information technologies have transformed the way care is delivered within health services, permeating almost every aspect of health care. As the complexity of the system increases, it becomes more difficult to work optimally without the assistance of new technologies. Although its implementation represents a breakthrough, either because of the advancement involved in the proper use of any technology in health care, or because of the development of specific applications that improve patient safety, other factors such as incorrect design, implementation and poor maintenance, inadequate training, along with overconfidence and dependency, can make technologies compromise patient safety.This article describes the beneficial effects, and those that are not so, of the introduction in our country of the electronic medical record and the electronic prescription on the healthcare quality and safety.

Numerical modeling is a powerful tool to determine the stress-strain relationships of structures. However, for a reliable application, physical and mathematical models must be calibrated and validated. This paper presents an overview of numerical calibration through the finite element method and plate-load tests in an embankment. Additionally, an analysis of the constitutive models used in soils is performed, and the elastic-plastic constitutive model of Mohr-Coulomb was selected since it is the best suited for this study. The results from three test areas within a refinery project that the Cuban government undertook in the province of Cienfuegos are used. The numerical model used in this study was calibrated by means of the error theory and the non-parametric hypothesis tests from Mann-Whitney U. From the practical point of view, this study gives two procedures to calibrate the numerical model with experimental results.

Abstract In this work we present a reduction result for discrete-time systems with two time scales. In order to be valid, previous results in the field require some strong hypotheses that are difficult to check in practical applications. Roughly speaking, the iterates of a map as well as their differentials must converge uniformly on compact sets. Here, we eliminate the hypothesis of uniform convergence of the differentials at no significant cost in the conclusions of the result. This new result is then used to extend to non-linear cases the reduction of some population discrete models involving processes acting at different time scales. In practical cases, some processes that occur at a fast time scale are often only measured at slow time intervals, notably mortality. For a general class of linear models that include such a kind of processes, it has been shown that a more realistic approach requires the re-scaling of those processes to be considered at the fast time scale. We develop the same type of re-scaling in some non-linear models and prove the corresponding reduction results. We also provide an application to a particular model of a structured population in a two-patch environment.

Resumen: La actividad médica despliega un conjunto de competencias encaminadas a mejorar el estado de salud de las personas. En este camino se realizan diagnósticos, se hacen elecciones de pruebas y tratamientos y se toman decisiones sobre hacer y no hacer que afectan a la vida de los pacientes. En este artículo, proponemos una reflexión ante el sobrediagnóstico y sobretratamiento en relación con los factores que lo promueven y el impacto que tienen en la sociedad, en el funcionamiento del sistema sanitario y también directamente en los pacientes. Finalmente, realizamos unas propuestas de cómo redirigir este exceso considerando que la atención primaria es un lugar privilegiado para actuar en adecuar y minimizar el impacto de las actuaciones del sistema sanitario en la salud de los ciudadanos y reducir los incidentes de seguridad del paciente ligados al sobrediagnóstico y al uso inadecuado de pruebas y tratamientos que no aportan valor a la salud de los pacientes. Abstract: The medical activity displays a set of skills aimed at improving the health status of people. In this way, diagnoses are made, choices of tests and treatments are made, and decisions are made about what to do and what not to do that affect the lives of patients. In this article, we propose a reflection on overdiagnosis and overtreatment in relation to the factors that promote it and the impact they have on society, on the functioning of the health system and also directly on patients. Finally, we make some proposals on how to address this overuse considering that primary care is a privileged place to adapt and minimize the impact of the actions of the health system on the health of citizens and reduce the incidents of patient safety linked to the overdiagnosis and inappropriate use of tests and treatments that do not add value to the health of patients. Palabras clave: Sobrediagnostico, Sobretratamiento, Seguridad del paciente, Prevencion cuaternaria, Sistema sanitario, Keywords: Overdiagnosis, Overtreatment, Patient safety, Quaternary prevention, Healthcare system

Only a small body of literature exists on linking key marketing concepts in family business contexts and those studies that do exist show a significant bias towards brand management. Both the relevance of the subject and the lack of research assuming this challenge to date justify the interest and timeliness of this literature review. Based on this interest—and the existing research opportunities—this article presents the concept of brand, together with a framework for its analysis in family business contexts. The paper summarizes the six main lines of research proposed, three from the perspective of identity management, and three from the perspective of stakeholders. The last section presents a series of interesting aspects for carrying out future research.

La gestión de la identidad corporativa es un elemento clave para el éxito empresarial, especialmente en sectores muy competitivos como la banca. Dentro de este sector, el presente artículo responde a tres cuestiones relevantes: ¿Qué factores determinan la gestión de la identidad corporativa?, ¿Cómo se gestiona? y ¿Qué bene¿cios perciben los directivos de dicha gestión?. Para ello, se realizó una investigación cualitativa basada en la realización de entrevistas en profundidad a los encargados de la gestión de marca de siete de los principales bancos españoles. La información obtenida, categorizada mediante el software QSR-NVivo, indica que detrás de la gestión de la identidad existen motivaciones y barreras tanto de carácter interno como externo a la organización. También se encontró que los principales factores que los directivos asocian a la identidad corporativa son la cultura, estructura, estrategia, comportamiento, comunicaciones e identidad visual. Asimismo, los bene¿cios de la gestión también se reÀejan en el ámbito interno y externo, lo que lleva a la mejora de los resultados económico-¿nancieros. En general, los resultados corroboran la relevancia de la identidad, mostrando distintas variables que inciden directamente en la competitividad bancaria, y que deberían tenerse en cuenta tanto en el ámbito académico como en el empresarial.

The structural use of timber coming from fast growing and low-grade species such as poplar is one of the current challenges in the wood value chains, through the development of engineering products. In this work, a qualitative comparison of the behavior of mixed glued laminated timber made of pine in their outer layers and of poplar in their inner layers is shown and discussed. Single-species poplar and pine laminated timber have been used as control layouts. The investigation includes destructive four-point bending tests and three non-destructive methodologies: finite elements numerical model; semi-analytical model based on the Parallel Axes theorem and acoustic resonance testing. An excellent agreement between experimental and numerical results is obtained. Although few number of samples have been tested, the results indicate that the use of poplar as a low-grade species in the inner layers of the laminated timber can be a promising technology to decrease the weight of the timber maintaining the good mechanical properties of pine. Likewise, the need for the use of the shear modulus in both experimental measurements and numerical analysis is suggested, as well as the need to reformulate the vibration methodology for non-destructive grading in the case of mixed timber.

Acoustic emission (AE) released by pine beams retrofitted with fiber reinforced plastic (FRP) and poplar planks in bending is analyzed. Basalt fabric (FB), carbon fabric (FC), and carbon pultruded laminate (LC) have been used as FRP. Experimental results and AE behavior are discussed based on an elastoplastic finite-element numerical model. The model demonstrates a strong strain concentration at the end of poplar planks, which causes high AE activity in these areas and acts as a precursor of the delamination of the poplar plank. Based on the experimental results, some AE criteria for predicting the onset of the delamination are tentatively proposed.

Tendencias pedagógicas

Brand identity management and corporate social responsibility have increased importance in both managerial practice and academic research. However, only a small number of studies have examined how these strategic tools influence employees’ attitudes and behaviours. The aim of this paper is, therefore, to analyse how employees’ perceptions of brand identity management and corporate social responsibility affect their attitudes and behaviours. An empirical study was undertaken among a sample of 297 front line employees working in the UK banking sector. Hypotheses were tested using partial least square regression. The results show that employees’ perceptions of brand identity management and corporate social responsibility determine their commitment towards their organisations, both directly and indirectly through perceived external prestige. Organisational commitment explains employees’ brand performance and brand citizenship behaviour. Age differences indicate higher impact of brand identity management on older employees, and higher effects of perceived corporate social responsibility in younger employees. The results extend existing knowledge and are informative for bank managers.

En este trabajo se analiza el efecto de las dimensiones de imagen corporativa sobre la satisfacción, compromiso y lealtad del cliente hacia su entidad bancaria, así como el efecto moderador de las variables sexo, edad y tipo de entidad en estas relaciones. A través de un estudio empírico se muestra que la dimensión relacionada con el personal es la que tiene un mayor efecto directo sobre la satisfacción y la lealtad. Asimismo, la dimensión de justicia en precios es la que tiene un mayor efecto directo sobre el compromiso. El análisis comparativo por grupos de sexo y edad señala diferencias en los efectos de algunas de las dimensiones de imagen, si bien no se observan diferencias significativas entre los bancos y las cajas de ahorros.

Se desarrolló un programa computacional mediante el método de elementos finitos, que permite predecir las frecuencias y modos transversales de vibración en el Ensamblaje de Fondo (BHA) de las sartas de perforación. Este modelo se puede aplicar tanto en la planificación como en tiempo real durante la operación de perforación, con la finalidad de evitar problemas de resonancia en el sistema. Este análisis se lleva a cabo en dos etapas. En la primera se resuelve el problema bidimensional y no lineal de la deformación estática de la sarta; esto proporciona su perfil deformado y las fuerzas en los puntos donde contacta las paredes del hoyo. De esta forma se determina la longitud efectiva del ensamblaje de fondo que está libre de vibrar lateralmente. La segunda, consiste en un análisis dinámico del sistema para obtener las frecuencias y modos de vibración transversales. El modelo fue validado con varias configuraciones de sartas de perforación utilizadas en otros estudios y en mediciones experimentales, obteniéndose excelentes resultados.A computer program based on the finite element method was developed to predict the lateral vibration modes and frequencies in the Bottom Hole Assembly (BHA) of a drillstring. This model is applicable in both a planning and a real time mode of operation to avoid resonance problems. The analysis used in this model proceeds in two stages. The first stage solves the two-dimensional nonlinear static deformation of the drillstring; this gives the deformed shape of the BHA and the side forces at points where the BHA touches the wellbore wall. In this way, the length of the BHA that is free to vibrate in the lateral direction is obtained. The second stage consists in a dynamic analysis of the system, to obtain the lateral vibration modes and frequencies. The model was compared with experimental and simulated results obtained from several BHA configurations, giving excellent results.

Traditional biomedical approaches treat diseases in isolation, but the importance of synergistic disease interactions is now recognized. As a first step we present and analyze a simple coinfection model for two diseases simultaneously affecting a population. The host population is affected by the primary disease, a long-term infection whose dynamics is described by a SIS model with demography, which facilitates individuals acquiring a second disease, secondary (or opportunistic) disease. The secondary disease is instead a short-term infection affecting only the primary infected individuals. Its dynamics is also represented by a SIS model with no demography. To distinguish between short- and long-term infection the complete model is written as a two-time-scale system. The primary disease acts at the slow time scale while the secondary disease does at the fast one, allowing a dimension reduction of the system and making its analysis tractable. We show that an opportunistic disease outbreak might change drastically the outcome of the primary epidemic process, although it does among the outcomes allowed by the primary disease. We have found situations in which either acting on the opportunistic disease transmission or recovery rates or controlling the susceptible and infected population size allows eradicating/promoting disease endemicity.

Sleep-wake circadian rhythm disturbances are a common problem associated to aging. Although this problem can be caused by several factors, low levels of the indol melatonin are related with these alterations. Our aim was to evaluate if the consumption of cereals enriched with tryptophan, the precursor of both serotonin and melatonin, can enhance sleep problems in elderly people. Participants (n=12; aged 55-67 yr) were selected from Elderly people University of The University of Extremadura. During all the assay participants wore a wrist actimeter and they filled every week an STAI anxiety test. Data were collected following this schedule: Control week: participants ingested a control cereal both at breakfast and dinner (22.5 mg tryptophan/ 30g product per dose); Treatment Week: volunteers consumed a tryptophan enriched cereal both at breakfast and dinner (60mg tryptophan/30g product per dose); Post-treatment week: participants ingested their habitual diet. We observed a decrease in sleep latency (p0.05) and sleep fragmentation (p

IntroductionThe hop (Humulus lupulus L.), a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the α-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter γ-aminobutyric acid (GABA), an inhibitory neurotransmitter acting in the central nervous system (CNS).ObjectivesTo analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population.MethodsThe experiment was conducted with healthy female nurses (n = 17) working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch®) after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0.0% alcohol) with supper for 14 days (treatment). Data were obtained in comparison with her own control group without consumption of beer during supper.ResultsActigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p≤0.05) in the Treatment group (12.01±1.19 min) when compared to the Control group (20.50±4.21 min), as also did Total Activity (p≤0.05; Treatment group = 5284.78±836.99 activity pulses vs Control = 7258.78±898.89 activity pulses). In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI) decreased in the Treatment group (State Anxiety 18.09±3.8 vs Control 20.69±2.14).ConclusionThe moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism.

A computer program based on the finite element method was developed to predict the lateral vibration modes and frequencies in the Bottom Hole Assembly (BHA) of a drillstring. This model is applicable in both a planning and a real time mode of operation to avoid resonance problems. The analysis used in this model proceeds in two stages. The first stage solves the two-dimensional nonlinear static deformation of the drillstring; this gives the deformed shape of the BHA and the side forces at points where the BHA touches the wellbore wall. In this way, the length of the BHA that is free to vibrate in the lateral direction is obtained. The second stage consists in a dynamic analysis of the system, to obtain the lateral vibration modes and frequencies. The model was compared with experimental and simulated results obtained from several BHA configurations, giving excellent results.

Se desarrolló un programa computacional mediante el método de elementos finitos, que permite predecir las frecuencias y modos transversales de vibración en el Ensamblaje de Fondo (BHA) de las sartas de perforación. Este modelo se puede aplicar tanto en la planificación como en tiempo real durante la operación de perforación, con la finalidad de evitar problemas de resonancia en el sistema. Este análisis se lleva a cabo en dos etapas. En la primera se resuelve el problema bidimensional y no lineal de la deformación estática de la sarta; esto proporciona su perfil deformado y las fuerzas en los puntos donde contacta las paredes del hoyo. De esta forma se determina la longitud efectiva del ensamblaje de fondo que está libre de vibrar lateralmente. La segunda, consiste en un análisis dinámico del sistema para obtener las frecuencias y modos de vibración transversales. El modelo fue validado con varias configuraciones de sartas de perforación utilizadas en otros estudios y en mediciones experimentales, obteniéndose excelentes resultados.