Most Common Single-Nucleotide Polymorphisms Associated With Rheumatoid Arthritis in Persons of European Ancestry Confer Risk of Rheumatoid Arthritis in African Americans

Objective. Large-scale genetic association studies have identified \u3e20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population. Methods. Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We then calculated a composite genetic risk score (GRS) for each individual based on the sum of all risk alleles. Results. Overlap of the ORs and 95% CIs between the European and African American populations was observed for 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, and TNFAIP3 rs6920220) demonstrated ORs in the opposite direction from those reported for RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African American patients relative to control subjects were enriched for the risk alleles validated in European RA patients (P = 0.00005). Conclusion. The majority of RA risk alleles previously validated for RA patients of European ancestry showed similar ORs in our population of African Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel RA risk alleles in African Americans

The Diboson Excess: Experimental Situation and Classification of Explanations; A Les Houches Pre-Proceeding

We examine the `diboson' excess at $\sim 2$ TeV seen by the LHC experiments in various channels. We provide a comparison of the excess significances as a function of the mass of the tentative resonance and give the signal cross sections needed to explain the excesses. We also present a survey of available theoretical explanations of the resonance, classified in three main approaches. Beyond that, we discuss methods to verify the anomaly, determining the major properties of the various surpluses and exploring how different models can be discriminated. Finally, we give a tabular summary of the numerous explanations, presenting their main phenomenological features.Comment: 37 pages, 9 Figures, 1 Tabl

Estudio comparativo de las mejoras en las habilidades cognitivas y emocionales entre un currículo por objetivos y un currículo con enfoque por competencias en alumnos de la Facultad de Medicina Veterinaria y Zootecnia, UPCH, Perú

A comparative study of the improvements in cognitive and emotional skills is presented between an outcome-based curriculum, with innovation of active methodologies (2012-II), and a competency-based curriculum (2018-I), aiming to develop generic and specific competences by improving these skills. The evaluation of cognitive and emotional skills was done by adapting the Reuven’s Bar-On Emotional Quotient Inventory Survey (EQ-i). The survey was conducted twice in each semester. The results were compared to determine if there were improvements between the first and second surveys in each semester and between both curricula. Also, the results of academic indicators were compared. The number of students enrolled was 30 (2012-II) and 27 (2018-I) and the respondent rate exceeded 70%. The result referred to the improvement of cognitive skills, problem solving, showed an almost double improvement between the first and second surveys in both curricular proposals. In emotional skills, stress management, a negative impact was observed in the 2012-II semester, while in the 2018-I semester there was an improvement, possibly due to the greater support to the students in the activities carried out in the development, correction and feedback received in the competency-based curriculum. In academic achievements there was an improvement in the general grade average between the semesters and a significant decrease in the disapproval between the two semesters. It can be concluded that the implementation of a competence-based curriculum, with active teaching methodologies, allowed the improvement in cognitive and emotional skills, improvement of academic achievements and a significant decrease in the failure of the course.Se presenta un estudio comparativo de las mejoras en las habilidades cognitivas y emocionales entre un currículo diseñado por objetivos, con innovación de metodologías activas (2012-II), y un currículo con enfoque por competencias (2018-I), en búsqueda de desarrollar las competencias genéricas y específicas mediante la mejora de estas habilidades. La evaluación de las habilidades cognitivas y emocionales se hizo adaptando la Encuesta del Inventario de Cociente Emocional Bar-On (EQ-i) de Reuven. La encuesta fue realizada en dos ocasiones en cada semestre. Los resultados se compararon para determinar si hubo mejoras entre la primera y segunda encuesta en cada semestre y entre ambos currículos. Así mismo, se compararon los resultados de indicadores académicos. El número de alumnos matriculados fue de 30 (2012-II) y 27 (2018-I) y la tasa de encuestados superó el 70%. El resultado referido a la mejora de las habilidades cognitivas, solución de problemas, mostró una mejora de casi el doble entre la primera y segunda encuesta en ambas propuestas curriculares. En habilidades emocionales, manejo de estrés, se observó un impacto negativo en el semestre 2012-II, mientras que en el semestre 2018-I hubo una mejora, posiblemente debida al mayor acompañamiento al alumnado en las actividades realizadas en el currículo con enfoque por competencias. En logros académicos hubo una mejora en el promedio general entre los semestres y una disminución significativa de la desaprobación entre los semestres 2012-II y 2018- I. Se puede concluir que la implementación de un currículo con enfoque de competencias, con metodologías activas de enseñanza, permitió la mejora en las habilidades cognitivas y emocionales, de los logros académicos y una disminución significativa de la desaprobación en el curso

ESTRATEGIAS PEDAGÓGICAS PARA LA MEJORA DE LAS HABILIDADES COGNITIVAS Y EMOCIONALES DE LOS ALUMNOS DE LA FACULTAD DE MEDICINA VETERINARIA Y ZOOTECNIA, UPCH, PERÚ

The paper presents actions taken to modify the theoretical characteristics of the course of Medicine of Companion Animals, a mandatory course of the Veterinary Medi- cine and Animal Husbandry career at Universidad Peruana Cayetano Heredia, Lima, Peru. A practical-theoretical course was organized in pursuit of improving basic knowledge, skills and abilities in the veterinary field, and also for improving cognitive and emotional skills of students through innovative educational methodologies and technologies. These included resolution of clinical cases, critical thinking and creativity, revision, interpretation and analysis of scientific information, contextualized activities in actual practice, support of social activities and technology transfer of scientific information, all within a framework of university education by competences. The assessment of cognitive and emotional abilities was done by the Bar-On Emotional Quotient Inventory survey. A survey was conducted at the beginning and another at the end of the course involving 24 out of 30 registered students. The results show that the percentage of students with cognitive and emotional skills qualified as developed, adequate and to be improved was 25, 51 and 21% respectively in the first survey, and improving to 54, 33 and 13% respectively in the second survey.El documento presenta las acciones realizadas para modificar las características teóricas del curso de Medicina de Animales de Compañía, curso semestral obligatorio de la carrera de Medicina Veterinaria y Zootecnia de la Universidad Peruana Cayetano Heredia, Lima, Perú. Se organizó un curso práctico-teórico en búsqueda de mejorar los conocimientos básicos, habilidades y destrezas médico veterinarias; y asimismo, la me- jora de las habilidades cognitivas y emocionales de los estudiantes mediante la innovación de metodologías y tecnologías educativas. Estas comprendieron: resolución de casos clínicos, desarrollo del pensamiento crítico y de la creatividad, revisión, interpretación y análisis de información científica, actividades contextualizadas en la práctica real, actividades de apoyo social y tecnologías de transferencia de la información científica, todo ello dentro de un marco referencial de la formación universitaria por competencias. La evaluación de las habilidades cognitivas y emocionales se realizó con una adaptación del Inventario de Cociente Emocional de Reuver Bar-On. Se realizó una encuesta a inicios y otra a fines del curso, participando 24 de los 30 alumnos matriculados. Los resultados muestran que la proporción de alumnos con habilidades cognitivas y emocionales calificadas como desarrolladas, adecuadas y por mejorar fue de 25, 54 y 21%, respectivamente, en la primera encuesta, mejorando a 54, 33 y 13%, respectivamente, en la segunda encuesta

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

COVID-19-related absence among surgeons: development of an international surgical workforce prediction model

Background: During the initial COVID-19 outbreak up to 28.4 million elective operations were cancelled worldwide, in part owing to concerns that it would be unsustainable to maintain elective surgery capacity because of COVID-19-related surgeon absence. Although many hospitals are now recovering, surgical teams need strategies to prepare for future outbreaks. This study aimed to develop a framework to predict elective surgery capacity during future COVID-19 outbreaks. Methods: An international cross-sectional study determined real-world COVID-19-related absence rates among surgeons. COVID-19-related absences included sickness, self-isolation, shielding, and caring for family. To estimate elective surgical capacity during future outbreaks, an expert elicitation study was undertaken with senior surgeons to determine the minimum surgical staff required to provide surgical services while maintaining a range of elective surgery volumes (0, 25, 50 or 75 per cent). Results: Based on data from 364 hospitals across 65 countries, the COVID-19-related absence rate during the initial 6 weeks of the outbreak ranged from 20.5 to 24.7 per cent (mean average fortnightly). In weeks 7-12, this decreased to 9.2-13.8 per cent. At all times during the COVID-19 outbreak there was predicted to be sufficient surgical staff available to maintain at least 75 per cent of regular elective surgical volume. Overall, there was predicted capacity for surgeon redeployment to support the wider hospital response to COVID-19. Conclusion: This framework will inform elective surgical service planning during future COVID-19 outbreaks. In most settings, surgeon absence is unlikely to be the factor limiting elective surgery capacit

Opposing community assembly patterns for dominant and nondominant plant species in herbaceous ecosystems globally

Biotic and abiotic factors interact with dominant plants—the locally most frequent or with the largest coverage—and nondominant plants differently, partially because dominant plants modify the environment where nondominant plants grow. For instance, if dominant plants compete strongly, they will deplete most resources, forcing nondominant plants into a narrower niche space. Conversely, if dominant plants are constrained by the environment, they might not exhaust available resources but instead may ameliorate environmental stressors that usually limit nondominants. Hence, the nature of interactions among nondominant species could be modified by dominant species. Furthermore, these differences could translate into a disparity in the phylogenetic relatedness among dominants compared to the relatedness among nondominants. By estimating phylogenetic dispersion in 78 grasslands across five continents, we found that dominant species were clustered (e.g., co-dominant grasses), suggesting dominant species are likely organized by environmental filtering, and that nondominant species were either randomly assembled or overdispersed. Traits showed similar trends for those sites (\u3c50%) with sufficient trait data. Furthermore, several lineages scattered in the phylogeny had more nondominant species than expected at random, suggesting that traits common in nondominants are phylogenetically conserved and have evolved multiple times. We also explored environmental drivers of the dominant/nondominant disparity. We found different assembly patterns for dominants and nondominants, consistent with asymmetries in assembly mechanisms. Among the different postulated mechanisms, our results suggest two complementary hypotheses seldom explored: (1) Nondominant species include lineages adapted to thrive in the environment generated by dominant species. (2) Even when dominant species reduce resources to nondominant ones, dominant species could have a stronger positive effect on some nondominants by ameliorating environmental stressors affecting them, than by depleting resources and increasing the environmental stress to those nondominants. These results show that the dominant/nondominant asymmetry has ecological and evolutionary consequences fundamental to understand plant communities

Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort

Background β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (Type I) reactions mediated by antigen-specific IgE. Objective To identify genetic predisposing factors for immediate reactions to β-lactam antibiotics. Methods Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study (GWAS) was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. Results GWAS identified rs71542416 within the Class II HLA region as the top hit (P = 2x10-14); this was in linkage disequilibrium with HLA-DRB1*10:01 (OR = 2.93 P = 5.4x10-7) and HLA-DQA1*01:05 (OR=2.93, P=5.4x10-7). Haplotype analysis identified that HLA-DRB1*10:01 was a risk factor even without the HLA-DQA1*01:05 allele. The association with HLA-DRB1*10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1*10:01 increased the risk of immediate hypersensitivity at a genome-wide level (OR = 2.96 P=4.1x10-9). No association with HLA-DRB1*10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams. Conclusion HLA-DRB1*10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required. Clinical implications This novel insight into the mechanisms of immediate reactions associated with penicillins may be of use in risk stratifying patients where penicillin cannot be excluded as an etiological agent

Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

Background: Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies.// Results: To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules.// Conclusions: This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development