Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNgamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNgamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found. Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFNgamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNgamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFNgamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer

Confianza de los estudiantes de medicina en el aprendizaje de la exploracion obstetrica con simuladores

Students' confidence in performing the procedures improved significantly (p≤0.001) after the interventio

La educación interprofesional en la universidad: retos y oportunidades

La educación interprofesional (EIP) es clave para garantizar el aprendizaje integrado de los alumnos de diferentes titulaciones, que ejercerán una labor profesional basada en el cuidado centrado en la persona, de manera conjunta. El proyecto de EIP de la Universidad de Navarra pretende dar a los alumnos de medicina, enfermería y farmacia los conocimientos, habilidades y actitudes necesarias para trabajar de manera interprofesional, centrándonos en trabajo en equipo, conocimiento y respeto de roles, resolución de conflictos y comunicación interprofesional. Para ello, el equipo de docentes implicados en este proyecto ha tenido que trabajar colaborativamente, experimentando las claves de este trabajo interprofesional, centrado en el alumno, constituyendo una experiencia enriquecedora, constructiva, y que ha aportado las claves del trabajo en equipo necesario para llevar a cabo un proyecto docente de EIP.Interprofessional Education is key to guarantee the integrated learning to different students, who will exercise together a professional work based on a person-centred care. The EIP project of the University of Navarra aims to provide to medical, nursing and pharmacy students with the knowledge, skills and attitudes necessary to work interprofessionally focu- sing on teamwork, knowledge and respect for roles, conflict resolution and interprofessional communication. To achieve this aim, the teachers from the different faculties involved in this project has worked collaboratively, experiencing the keys of this interprofessional work focused on the student, constituting an enriching, living a constructive experience and contributing to the cornerstone of the teamwork necessary to undertake an EIP teaching project

Educación interprofesional: una propuesta de la Universidad de Navarra

La asistencia sanitaria centrada en el paciente es la clave para una atención humana a la persona y a su familia. La práctica colaborativa en equipos interprofesionales resulta imprescindible para alcanzar una atención sanitaria de calidad. La universidad tiene la responsabilidad de preparar a sus graduados para trabajar en equipos interprofesionales. Una enseñanza/aprendizaje centrada en la persona, fundamentada en las competencias que definen la educación interprofesional, es clave para que nuestros estudiantes reconozcan la necesidad del trabajo colaborativo. Este artículo detalla un proyecto docente de educación interprofesional de la Universidad de Navarra, donde estudiantes de las facultades de medicina, enfermería y farmacia aprenden juntos y de manera gradual, las claves de cómo trabajar en equipo

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

Clinical phenotypes of acute heart failure based on signs and symptoms of perfusion and congestion at emergency department presentation and their relationship with patient management and outcomes

Objective To compare the clinical characteristics and outcomes of patients with acute heart failure (AHF) according to clinical profiles based on congestion and perfusion determined in the emergency department (ED). Methods and results Overall, 11 261 unselected AHF patients from 41 Spanish EDs were classified according to perfusion (normoperfusion = warm; hypoperfusion = cold) and congestion (not = dry; yes = wet). Baseline and decompensation characteristics were recorded as were the main wards to which patients were admitted. The primary outcome was 1-year all-cause mortality; secondary outcomes were need for hospitalisation during the index AHF event, in-hospital all-cause mortality, prolonged hospitalisation, 7-day post-discharge ED revisit for AHF and 30-day post-discharge rehospitalisation for AHF. A total of 8558 patients (76.0%) were warm+ wet, 1929 (17.1%) cold+ wet, 675 (6.0%) warm+ dry, and 99 (0.9%) cold+ dry; hypoperfused (cold) patients were more frequently admitted to intensive care units and geriatrics departments, and warm+ wet patients were discharged home without admission. The four phenotypes differed in most of the baseline and decompensation characteristics. The 1-year mortality was 30.8%, and compared to warm+ dry, the adjusted hazard ratios were significantly increased for cold+ wet (1.660; 95% confidence interval 1.400-1.968) and cold+ dry (1.672; 95% confidence interval 1.189-2.351). Hypoperfused (cold) phenotypes also showed higher rates of index episode hospitalisation and in-hospital mortality, while congestive (wet) phenotypes had a higher risk of prolonged hospitalisation but decreased risk of rehospitalisation. No differences were observed among phenotypes in ED revisit risk. Conclusions Bedside clinical evaluation of congestion and perfusion of AHF patients upon ED arrival and classification according to phenotypic profiles proposed by the latest European Society of Cardiology guidelines provide useful complementary information and help to rapidly predict patient outcomes shortly after ED patient arrival

Assessing the context of health care utilization in Ecuador: A spatial and multilevel analysis

<p>Abstract</p> <p>Background</p> <p>There are few studies that have analyzed the context of health care utilization, particularly in Latin America. This study examines the context of utilization of health services in Ecuador; focusing on the relationship between provision of services and use of both preventive and curative services.</p> <p>Methods</p> <p>This study is cross-sectional and analyzes data from the 2004 National Demographic and Maternal & Child Health dataset. Provider variables come from the Ecuadorian System of Social Indicators (SIISE). Global Moran's I statistic is used to assess spatial autocorrelation of the provider variables. Multilevel modeling is used for the simultaneous analysis of provision of services at the province-level with use of services at the individual level.</p> <p>Results</p> <p>Spatial analysis indicates no significant differences in the density of health care providers among Ecuadorian provinces. After adjusting for various predisposing, enabling, need factors and interaction terms, density of public practice health personnel was positively associated with use of preventive care, particularly among rural households. On the other hand, density of private practice physicians was positively associated with use of curative care, particularly among urban households.</p> <p>Conclusions</p> <p>There are significant public/private, urban/rural gaps in provision of services in Ecuador; which in turn affect people's use of services. It is necessary to strengthen the public health care delivery system (which includes addressing distribution of health workers) and national health information systems. These efforts could improve access to health care, and inform the civil society and policymakers on the advances of health care reform.</p

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE