Optimal risk in marketing resource allocation

Marketing resource allocation is increasingly based on the optimization of expected returns on investment. If the investment is implemented in a large number of repetitive and relatively independent simple decisions, it is an acceptable method, but risk must be considered otherwise. The Markowitz classical mean-deviation approach to value marketing activities is of limited use when the probability distributions of the returns are asymmetric (a common case in marketing). In this paper we consider a unifying treatment for optimal marketing resource allocation and valuation of marketing investments in risky markets where returns can be asymmetric, using coherent risk measures recently developed in finance. We propose a set of first order conditions for the solution, and present a numerical algorithm for the computation of the optimal plan. We use this approach to design optimal advertisement investments in sales response managementResource allocation, Coherent risk measures, Optimization, Sales response models

Mecanismo molecular implicado en la configuración del peptidoma de HLA-B*27 por variantes naturales de ERAP1 asociadas a la espondilitis anquilosante

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 15-04-2015HLA-B*27 is the main genetic risk factor for ankylosing spondylitis (AS), but its pathogenetic role remains unknown. As for any other MHC-I molecule, the canonic function of HLA-B*27 is to present peptides from viruses and other intracellular parasites for recognition by cytolytic T-lymphocytes. Genetic analyses have determined that ERAP1, a resident aminopeptidase of the endoplasmic reticulum whose function is to trim peptides to their optimal length for binding to MHC-I molecules, is associated with AS only among HLA-B*27+ individuals. Thus ERAP1 polymorphism may affect AS pathogenesis by altering peptide-dependent features of the HLA-B*27 molecule. The aim of this thesis was to characterize the nature and extent of the alterations induced by diseaseassociated ERAP1 polymorphism on the HLA-B*27 peptidome in live cells and to define the molecular basis for these effects. This was carried out by means of comparative analyses of the HLAB*27:04 and HLA-B*27:05 peptidomes from cell lines expressing distinct ERAP1 variants carrying disease-associated polymorphisms. The results indicated that ERAP1 polymorphism induced substantial alterations on the expression levels, molecular mass, length, sequence and affinity of many peptides. Polymorphisms associated with increased risk of disease, in particular K528, induced an optimization of the global affinity of the HLA-B*27:05 peptidome by influencing the sequence of the peptides. A combination of protective polymorphisms resulted in the generation of a suboptimal HLA-B*27:04 peptidome, in terms of length and affinity, that reduced the global stability of the molecule. The mechanism by with ERAP1 variants affected the HLA-B*27 peptidome was by altering the balance between epitope generation and destruction as a function of the susceptibility of the N-terminal flanking sequences and the P1 residues to trimming. These alterations were both variant and peptide-dependent. The magnitude and complexity of the effects of ERAP1 polymorphism on the nature and affinity of the peptidome was such that it could affect not only specific antigen presentation, but also other peptide-dependent features of HLA-B*27 potentially able to alter its pro-inflammatory and autoimmune potential. The susceptibility to ERAP1 trimming of the P1 residues in the peptidomes of HLA-B*27 subtypes differentially associated with AS was also examined. This analysis revealed that the relative frequency of P1 residues resistant and highly susceptible to this enzyme in AS-associated and non-AS-associated subtypes paralleled the pattern observed in the HLA-B*27:05 peptidome in the context of ERAP1 variants with high and low activity, respectively. This suggests that non-AS-associated HLA-B*27 subtypes are less influenced by ERAP1 polymorphism than AS-associated one

Espesura crítica y regeneración en un pinar natural de silvestre de elevada complejidad estructural (monte “Cabeza de Hierro”, Rascafría, Madrid)

El monte privado “Cabeza de Hierro” (Rascafría, Madrid), con 2.016,5 ha de superficie total y 1.886,4 ha de superficie arbolada, presenta una masa de pino silvestre de origen natural con abundante melojo, de elevado valor económico y ecológico, sobre la que se realizan aprovechamientos maderables desde hace al menos 150 años. La mayor parte del monte está incluido en la Zona Periférica de Protección del Parque Natural de la Cumbre, Circo y Lagunas de Peñalara. Ordenado desde 1957, se siguió primero el método de tramos permanentes, y después el de tramo móvil. Las cortas de regeneración aplicadas han sido de aclareo sucesivo. La gran variabilidad estacional, el intenso aprovechamiento pastoral y la competencia con melojo y matorral han generado una estructura de elevada complejidad, de modo que en general aparece un mosaico de bosquetes de tamaño variable, en cuyo interior la masa es regular o semirregular, generando una estructura irregular a escala de cantón. En este trabajo se estudia, mediante diversas técnicas de análisis multivariante y en especial mediante análisis discriminante, la relación entre la aparición de regeneración y diversos factores del medio y de la masa, con el objetivo principal de comprobar por debajo de qué espesura crítica es esperable la instalación de regeneración suficiente. La propuesta se realiza para diferentes situaciones presentes en el monte. Para ello se emplea la información recogida en el Estado Forestal de la Tercera Revisión del Proyecto de Ordenación (2007) para los cuarteles A y B, de 806,3 ha totales y 776,7 ha arboladas. Dicha información procede de un muestreo cuyas características se resumen a continuación: muestreo estratificado con afijación proporcional, parcelas circulares de radios concéntricos, distribución sistemática con lado de malla cuadrada de 160 m. Como resumen de los resultados se encuentra que: elevadas espesuras en pinar adulto no impiden la instalación del diseminado, aunque luego éste muere por falta de luz; la presencia abundante de otras especies (matorral, melojo o acebo) sí impide o dificulta la regeneración; como valor global aproximado, se propone un rango de valores de área basimétrica crítica total, suma de la de pinos mayores, melojos y acebos, de 16 a 30 m 2 /ha para permitir la regeneración suficiente de pino silvestre. El valor de espesura crítica se puede concretar para cada combinación de calidad de suelo, número de pies menores y fracción de cabida cubierta de especies acompañantes

ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies

Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies, and there is a connection between atherosclerosis and autoimmunity. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.Ministerio de Economía y Competitividad (SVP-2014-068289); P.D. was supported by an AECC grant (AIO 2012, Ayudas a Investigadores en Oncología 2012); A.S.-B. is a Juan de la Cierva researcher (IJC2018-035279-I); I.M.-F. was a fellow of the research training program funded by Ministerio de Economía y Competitividad (SVP-2014-068216); and A.R.R. and J.V. are supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC). The project leading to these results has received funding from la Caixa Banking Foundation under the project code HR17-00247 and from SAF2016-75511-R and PID2019-106773RB-I00 grants to A.R.R. (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–201

Multimorbidity Patterns and Their Association with Social Determinants, Mental and Physical Health during the COVID-19 Pandemic

Background: The challenge posed by multimorbidity makes it necessary to look at new forms of prevention, a fact that has become heightened in the context of the pandemic. We designed a questionnaire to detect multimorbidity patterns in people over 50 and to associate these patterns with mental and physical health, COVID-19, and possible social inequalities. Methods: This was an observational study conducted through a telephone interview. The sample size was 1592 individuals with multimorbidity. We use Latent Class Analysis to detect patterns and SF-12 scale to measure mental and physical quality-of-life health. We introduced the two dimensions of health and other social determinants in a multinomial regression model. Results: We obtained a model with five patterns (entropy = 0.727): ‘Relative Healthy’, ‘Cardiometabolic’, ‘Musculoskeletal’, ‘Musculoskeletal and Mental’, and ‘Complex Multimorbidity’. We found some differences in mental and physical health among patterns and COVID-19 diagnoses, and some social determinants were significant in the multinomial regression. Conclusions: We identified that prevention requires the location of certain inequalities associated with the multimorbidity patterns and how physical and mental health have been affected not only by the patterns but also by COVID-19. These findings may be critical in future interventions by health services and governments17 página

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

PurposeThe aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA.MethodsAdult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs.ResultsAdministration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity.ConclusionSubcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity

Nature of viruses and pandemics: Coronaviruses

Coronaviruses (CoVs) have the largest genome among RNA viruses and store large amounts of information without genome integration as they replicate in the cell cytoplasm. The replication of the virus is a continuous process, whereas the transcription of the subgenomic mRNAs is a discontinuous one, involving a template switch, which resembles a high frequency recombination mechanism that may favor virus genome variability. The origin of the three deadly human CoVs SARS-CoV, MERS-CoV and SARS-CoV-2 are zoonotic events. SARS-CoV-2 has incorporated in its spike protein a furine proteolytic site that facilitates the activation of the virus in any tissue, making this CoV strain highly polytropic and pathogenic. Using MERS-CoV as a model, a propagation-deficient RNA replicon was generated by removing E protein gene (essential for viral morphogenesis and involved in virulence), and accessory genes 3, 4a, 4b and 5 (responsible for antagonism of the innate immune response) to attenuate the virus: MERS-CoV-Δ[3,4a,4b,5,E]. This RNA replicon is strongly attenuated and elicits sterilizing protection after a single immunization in transgenic mice with the receptor for MERS-CoV, making it a promising vaccine candidate for this virus and an interesting platform for vector-based vaccine development. A strategy could be developed for the design of RNA replicon vaccines for other human pathogenic coronaviruses.This work was supported by grants from the Government of Spain (PID2019-107001RB-I00 AEI/FEDER, UE; SEV 2017-0712 and PIE_INTRAMURAL_LINEA 1-202020E079), the CSIC (PIE_INTRAMURAL-202020E043), the European Commission (ISOLDA_848166 H2020-SC1-2019-Two-Stage-RTD, RIA; MANCO_101003651 H2020-SC1-PHE-CORONAVIRUS-2020 RIA), and the U.S. National Institutes of Health (NIH_2P01AI060699).Peer reviewe

SARS-CoV-2-Mediated Lung Edema and Replication Are Diminished by Cystic Fibrosis Transmembrane Conductance Regulator Modulators

20 Pág.Coronaviruses (CoVs) of genera α, β, γ, and δ encode proteins that have a PDZ-binding motif (PBM) consisting of the last four residues of the envelope (E) protein (PBM core). PBMs may bind over 400 cellular proteins containing PDZ domains (an acronym formed by the combination of the first letter of the names of the three first proteins where this domain was identified), making them relevant for the control of cell function. Three highly pathogenic human CoVs have been identified to date: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. The PBMs of the three CoVs were virulence factors. SARS-CoV mutants in which the E protein PBM core was replaced by the E protein PBM core from virulent or attenuated CoVs were constructed. These mutants showed a gradient of virulence, depending on whether the alternative PBM core introduced was derived from a virulent or an attenuated CoV. Gene expression patterns in the lungs of mice infected with SARS-CoVs encoding each of the different PBMs were analyzed by RNA sequencing of infected lung tissues. E protein PBM of SARS-CoV and SARS-CoV-2 dysregulated gene expression related to ion transport and cell homeostasis. Decreased expression of cystic fibrosis transmembrane conductance regulator (CFTR) mRNA, essential for alveolar edema resolution, was shown. Reduced CFTR mRNA levels were associated with edema accumulation in the alveoli of mice infected with SARS-CoV and SARS-CoV-2. Compounds that increased CFTR expression and activity, significantly reduced SARS-CoV-2 growth in cultured cells and protected against mouse infection, suggesting that E protein virulence is mediated by a decreased CFTR expression. IMPORTANCE Three highly pathogenic human CoVs have been identified: SARS-CoV, MERS-CoV, and SARS-CoV-2. The E protein PBMs of these three CoVs were virulence factors. Gene expression patterns associated with the different PBM motifs in the lungs of infected mice were analyzed by deep sequencing. E protein PBM motif of SARS-CoV and SARS-CoV-2 dysregulated the expression of genes related to ion transport and cell homeostasis. A decrease in the mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR), which is essential for edema resolution, was observed. The reduction of CFTR mRNA levels was associated with edema accumulation in the lungs of mice infected with SARS-CoV-2. Compounds that increased the expression and activity of CFTR drastically reduced the production of SARS-CoV-2 and protected against its infection in a mice model. These results allowed the identification of cellular targets for the selection of antivirals.This work was supported by grants from the Government of Spain (BIO2016-75549-R; PID2019-107001RB-I00 AEI/FEDER, UE; SEV 2017-0712 and PIE_INTRAMURAL_LINEA 1- 202020E079), CSIC (PIE_INTRAMURAL-202020E043), the European Zoonotic Anticipation and Preparedness Initiative (ZAPI) (IMI_JU_115760), the European Commission (H2020-SC1- 2019, ISOLDA Project No. 848166-2), and the U.S. National Institutes of Health (NIH) (2P01AI060699). J.M.H. received a contract from Comunidad de Madrid (Y2020/BIO-6576, COVID-PREclinical-MODels-CM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In vivo experiments were performed at INIA-CISA (Madrid, Spain)Peer reviewe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality