Predicted Epitope Abundance Supports Vaccine-Induced Cytotoxic Protection Against SARS-CoV-2 Variants of Concern

The effect of emerging SARS-CoV-2 variants on vaccine efficacy is of critical importance. In this study, the potential impact of mutations that facilitate escape from the cytotoxic cellular immune response in these new virus variants for the 551 most abundant HLA class I alleles was analyzed. Computational prediction showed that most of these alleles, that cover >90% of the population, contain enough epitopes without escape mutations in the principal SARS-CoV-2 variants. These data suggest that the cytotoxic cellular immune protection elicited by vaccination is not greatly affected by emerging SARS-CoV-2 variants.This research was supported by grants from COV20_00679 (MPY 222-20), to MM, MPY 509/19 to AM-G, and MPY 388/18 to DL of “Acción Estratégica en Salud” from the ISCIII.S

Impacto en los resultados de salud cardiovascular de la implantación del contrato de Dirección Clínica en atención primaria de Tarragona

ObjetivoLos objetivos del presente estudio son: a) determinar la mejora en la salud cardiovascular de una población tras la implantación del contrato de Dirección Clínica en los profesionales de los Equipos de Atención Primaria de Tarragona-Reus y Terres de l’Ebre (provincia de Tarragona), y b) identificar los factores predictivos que determinan una mejor salud cardiovascular tras la implantación del contrato de Dirección Clínica. La implantación del contrato de Dirección Clínica (basada en el liderazgo profesional, feedback de la información asistencial, control de los indicadores de riesgo cardiovascular basados en la evidencia científica concretadas en guías de práctica clínica) mejorará los resultados de salud cardiovascular de la población de referencia.DiseñoSe trata de un estudio antes-después y multicéntrico.EmplazamientoAtención primaria de salud.ParticipantesParticipan 30 centros de salud (totalidad de los centros de salud del ámbito de atención primaria del Institut Català de la Salut).Mediciones principalesCaracterísticas del centro. Variables de proceso: indicadores de buena práctica asistencial, cálculo del riesgo cardiovascular, aplicación de la guía de práctica clínica (hipertensión arterial, diabetes, dislipemia, tabaquismo y factores de riesgo cardiovascular), estándares de calidad de la prescripción farmacológica. Variables de resultados: cifras de riesgo cardiovascular, número de visitas en atención continuada, urgencias hospitalarias e ingresos por angina, infarto agudo de miocardio y accidente cerebrovascular, y cribados poblacionales de factores de riesgo.DiscusiónEste estudio es útil, ya que la dirección clinica pretende ser un motor para que los profesionales lideren la gestión asistencial y, mediante el control de indicadores y la «retroalimentación» de estos resultados a los profesionales, se mejore la calidad asistencial. Con este trabajo se pretende demostrar que una estrategia de gestión puede mejorar la salud cardiovascular de la población. La originalidad de este proyecto se basa en el desarrollo de una nueva herramienta de evaluación basada en una novedosa estrategia de gestión para medir resultados en salud cardiovascular.ObjectiveThe objectives of this study are: 1) to determine the improvement in the cardiovascular health of the population after the introduction of the clinical governance contract for primary care team professionals in Tarragona-Reus and the Terres de l’Ebre area (Tarragona province, Spain); 2) to identify the factors predictive of better cardiovascular health after the introduction of the clinical governance contract. The introduction of the clinical governance contract, which is based on professional leadership, feed-back of care information, and monitoring of indicators of cardiovascular risk based on scientific evidence and concretised in clinical practice guidelines, will improve the cardiovascular health results of the reference population. Improvements in indicators of procedure and result are specified in “Material and methods.”DesignThis is a before-and-after, multicentre study.SettingPrimary health care.ParticipantsTirty health centres (all the primary care Centres in the area).Main measurementsCharacteristics of the centre. Variables in procedures: indicators of good care practice, calculation of cardiovascular risk, application of clinical practice guidelines (hypertension, diabetes, lipaemia, tobacco and cardiovascular risk) and quality standards for drug prescription. Result variables: cardiovascular risk figures, number of ongoing care visits, hospital emergencies and admissions for angina, heart attack or stroke, and risk factor screenings of the population.DiscussionThis study is useful, in that clinical governance aims to be a dynamic device to bring professionals into the leadership of health care management and, through monitoring indicators and feeding the findings back to the professionals, to improve health care quality. The study aims to show that management strategy can improve the populatiońs cardiovascular health. The originality of the study lies in the development of a new tool of evaluation based on a novel management strategy for measuring cardiovascular health findings

Predicted impact of the viral mutational landscape on the cytotoxic response against SARS-CoV-2

The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.This research was supported by Acción Estratégica en Salud from the ISCIII (https://www.isciii.es), grants MPY 380/18 (to MJM), 388/18 (to DL) and 509/19 (to AJM-G). AJM-G is the recipient of a Miguel Servet contract by the ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins

Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.This project has been financed through a) The ISCIII (Miguel Servet-I, 2015), co-financed by the European Regional Development Fund (ERDF), No CP15/00071. b) The European Union’s Horizon 2020 research and innovation program, under grant agreement No 634479. c) Regional Ministry of Economy, Innovation and Science of the Junta de Andalucía, No P09-CTS-04967.info:eu-repo/semantics/publishedVersio

How much are built environments changing, and where?: Patterns of change by neighborhood sociodemographic characteristics across seven U.S. metropolitan areas

Investments in neighborhood built environments could increase physical activity and overall health. Disproportionate distribution of these changes in advantaged neighborhoods could inflate health disparities. Little information exists on where changes are occurring. This paper aims to 1) identify changes in the built environment in neighborhoods and 2) investigate associations between high levels of change and sociodemographic characteristics. Using Geographic Information Systems, neighborhood land-use, local destinations (for walking, social engagement, and physical activity), and sociodemographics were characterized in 2000 and 2010 for seven U.S. cities. Linear and change on change models estimated associations of built environment changes with baseline (2000) and change (2010–2000) in sociodemographics. Spatial patterns were assessed using Global Moran’s I to measure overall clustering of change and Local Moran’s I to identify statistically significant clusters of high increases surrounded by high increases (HH). Sociodemographic characteristics were compared between HH cluster and other tracts using Analysis of Variance (ANOVA). We observed small land-use changes but increases in the destination types. Greater increases in destinations were associated with higher percentage non-Hispanic whites, percentage households with no vehicle, and median household income. Associations were present for both baseline sociodemographics and changes over time. Greater increases in destinations were associated with lower baseline percentage over 65 but higher increases in percentage over 65 between 2000 and 2010. Global Moran’s indicated changes were spatially clustered. HH cluster tracts started with a higher percentage non-Hispanic whites and higher percentage of households without vehicles. Between 2000 and 2010, HH cluster tracts experienced increases in percent non-Hispanic white, greater increases in median household income, and larger decreases in percent of households without a vehicle. Changes in the built environment are occurring in neighborhoods across a diverse set of U.S. metropolitan areas, but are patterned such that they may lead to increased health disparities over time

Towards a formal description of the collapse approach to the inflationary origin of the seeds of cosmic structure

Inflation plays a central role in our current understanding of the universe. According to the standard viewpoint, the homogeneous and isotropic mode of the inflaton field drove an early phase of nearly exponential expansion of the universe, while the quantum fluctuations (uncertainties) of the other modes gave rise to the seeds of cosmic structure. However, if we accept that the accelerated expansion led the universe into an essentially homogeneous and isotropic space-time, with the state of all the matter fields in their vacuum (except for the zero mode of the inflaton field), we can not escape the conclusion that the state of the universe as a whole would remain always homogeneous and isotropic. It was recently proposed in [A. Perez, H. Sahlmann and D. Sudarsky, "On the quantum origin of the seeds of cosmic structure," Class. Quant. Grav. 23, 2317-2354 (2006)] that a collapse (representing physics beyond the established paradigm, and presumably associated with a quantum-gravity effect a la Penrose) of the state function of the inflaton field might be the missing element, and thus would be responsible for the emergence of the primordial inhomogeneities. Here we will discuss a formalism that relies strongly on quantum field theory on curved space-times, and within which we can implement a detailed description of such a process. The picture that emerges clarifies many aspects of the problem, and is conceptually quite transparent. Nonetheless, we will find that the results lead us to argue that the resulting picture is not fully compatible with a purely geometric description of space-time.Comment: 53 pages, no figures. Revision to match the published versio

Built environment change and change in BMI and waist circumference: Multi‐ethnic S tudy of A therosclerosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109571/1/oby20873.pd

Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in singlecenter experience

We analyzed the efficacy and applicability of surgery guided by 5-aminolevulinic acid (ALA) fluorescence in consecutive patients with glioblastoma multiforme (GBM). Thirty-six patients with GBM were operated on using ALA fluorescence. Resections were performed using the fluorescent light to assess the right plane of dissection. In each case, biopsies with different fluorescent quality were taken from the tumor center, from the edges, and from the surrounding tissue. These samples were analyzed separately with hematoxylin-eosin examination and immunostaining against Ki67. Tumor volume was quantified with pre- and postoperative volumetric magnetic resonance imaging. Strong fluorescence identified solid tumor with 100% positive predictive value. Invaded tissue beyond the solid tumor mass was identified by vague fluorescence with 97% positive predictive value and 66% negative predictive value, measured against hematoxylin-eosin examination. All the contrast-enhancing volume was resected in 83.3% of the patients, all patients had resection over 98% of the volume and mean volume resected was 99.8%. One month after surgery there was no mortality, and new or increased neurological morbidity was 8.2%. The fluorescence induced by 5-aminolevulinic can help to achieve near total resection of enhancing tumor volume in most surgical cases of GBM. It is possible during surgery to obtain separate samples of the infiltrating cells from the tumor borde

Inequalities in life expectancy in six large Latin American cities from the SALURBAL study: an ecological analysis.

BACKGROUND: Latin America is one of the most unequal regions in the world, but evidence is lacking on the magnitude of health inequalities in urban areas of the region. Our objective was to examine inequalities in life expectancy in six large Latin American cities and its association with a measure of area-level socioeconomic status. METHODS: In this ecological analysis, we used data from the Salud Urbana en America Latina (SALURBAL) study on six large cities in Latin America (Buenos Aires, Argentina; Belo Horizonte, Brazil; Santiago, Chile; San José, Costa Rica; Mexico City, Mexico; and Panama City, Panama), comprising 266 subcity units, for the period 2011-15 (expect for Panama city, which was for 2012-16). We calculated average life expectancy at birth by sex and subcity unit with life tables using age-specific mortality rates estimated from a Bayesian model, and calculated the difference between the ninth and first decile of life expectancy at birth (P90-P10 gap) across subcity units in cities. We also analysed the association between life expectancy at birth and socioeconomic status at the subcity-unit level, using education as a proxy for socioeconomic status, and whether any geographical patterns existed in cities between subcity units. FINDINGS: We found large spatial differences in average life expectancy at birth in Latin American cities, with the largest P90-P10 gaps observed in Panama City (15·0 years for men and 14·7 years for women), Santiago (8·9 years for men and 17·7 years for women), and Mexico City (10·9 years for men and 9·4 years for women), and the narrowest in Buenos Aires (4·4 years for men and 5·8 years for women), Belo Horizonte (4·0 years for men and 6·5 years for women), and San José (3·9 years for men and 3·0 years for women). Higher area-level socioeconomic status was associated with higher life expectancy, especially in Santiago (change in life expectancy per P90-P10 change unit-level of educational attainment 8·0 years [95% CI 5·8-10·3] for men and 11·8 years [7·1-16·4] for women) and Panama City (7·3 years [2·6-12·1] for men and 9·0 years [2·4-15·5] for women). We saw an increase in life expectancy at birth from east to west in Panama City and from north to south in core Mexico City, and a core-periphery divide in Buenos Aires and Santiago. Whereas for San José the central part of the city had the lowest life expectancy and in Belo Horizonte the central part of the city had the highest life expectancy. INTERPRETATION: Large spatial differences in life expectancy in Latin American cities and their association with social factors highlight the importance of area-based approaches and policies that address social inequalities in improving health in cities of the region. FUNDING: Wellcome Trust

Capital humano y desigualdad territorial. El proceso de alfabetización en los municipios españoles desde la Ley Moyano hasta la Guerra Civil

El objetivo de este estudio es ofrecer nueva evidencia acerca de los niveles de alfabetización en España para el período 1860-1930. En particular, a lo largo de las siguientes páginas se presenta una base de datos que permite desgranar la evolución del proceso alfabetizador, con una desagregación territorial correspondiente a los municipios y distinguiendo entre hombres y mujeres. Con esta nueva información, se analiza la evolución y se apuntan algunos de los potenciales determinantes de la alfabetización desde los albores del período contemporáneo y a lo largo de la primera gran fase del proceso de desarrollo económico español, que transcurre durante la segunda mitad del siglo XIX y el primer tercio del siglo XX. En este contexto, el objetivo final del presente trabajo es contribuir a la comprensión de los determinantes profundos de la desigualdad económica territorial en España y, por extensión, de los países hoy desarrollados