Investigation of the Maintenance of Activated Cd8+ T Cell Responses Induced by Persistent Adenovirus Vectors

Vaccines against some of the most pervasive pathogens, including HIV, TB, and malaria, are desperately needed. Available evidence suggests that both central memory and effector CD8+ T cells play a role in mediating protective immunity against many pathogens. Recombinant adenoviruses currently under development as vaccine carriers induce potent and sustained transgene product-specific CD8+ T cell responses. The transgene product-specific CD8+ T cell response remains activated and is delayed in transitioning to central memory. Here we investigate how this response is maintained. Adenoviral vectors persist and remain transcriptionally active in vivo. We investigated the role that continuous transgene expression plays in maintaining the effector memory-biased transgene product-specific CD8+ T cell response. Dual expression vectors based on AdC7 expressing transgenes that could be regulated temporally were generated. Vectors were unexpectedly unstable in vivo. Alternatively we inhibited the mTOR pathway, which is downstream of the T cell receptor and has recently been implicated in memory development, using a low dose of rapamycin. Rapamycin failed to enhance the quality of the transgene-product specific CD8+ T cells. Persisting transgene product could maintain the transgene product-specific CD8+ T cell response by continual recruitment of naïve CD8+ T cells, similar to some other persistent viruses. However, in an adoptive transfer model, we demonstrate that the response is primarily maintained by antigen-experienced cells that do not lose function over time. Pre-existing anti-adenovirus immunity is common, particularly for the human adenoviruses currently in development as vaccine carriers. Here we demonstrate that pre-existing anti-adenovirus neutralizing antibodies accelerate and enhance transgene product-specific CD8+ T cell differentiation into central memory. These cells were highly functional and responded robustly to booster immunization. Importantly, this may be due in part to a reduction the vector\u27s reservoir in T cells. These data suggest that further study of transgene product expression and its functional impact on immune responses is necessary. Further understanding this impact will allow manipulation of immune responses induced by the adenovirus vaccine platform such that they can be tailored to specific pathogens

The Enduring Value of Research in Medical Education

Evidence-based medicine (EBM) relies on scientific data to guide diagnosis and treatment and is recognized as the current paradigm in medicine. Accordingly, every current and future physician should be knowledgeable about its principles and methodologies. Embracing research and EBM is essential to modern clinical practice; however, trainees and physicians still struggle with the value of research-related courses and knowledge on epidemiology and research methodology is often poor. In this article we provide a cogent discussion of the importance of research as an indispensable discipline in medical education through a detailed analysis of the literature. We review the evolution of medicine towards EBM and discuss the myriad of benefits that research has on medical careers, leadership roles, mentoring relationships, social networking, and personal growth and development. Participation in research contributes to medicine, public health, and society while simultaneously allowing the achievement of a high level of personal satisfactio

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Comprensión de las dinámicas de relación de parejas del mismo sexo a partir de la intervención clínica sistémica

El objetivo de ésta investigación es comprender las dinámicas de relación de parejas del mismo sexo que acuden a terapia y proponer un modelo de abordaje desde la intervención clínica sistémica. Para ello, se revisaron los conceptos de pareja, terapia de pareja y diversidad sexual desde el enfoque sistémico y las premisas epistemológicas constructuvistas. Se utilizó una metodología de investigación-intervención y un diseño mixto que incluyó la revisión de historias clínicas de 98 personas (30 parejas y 38 consultantes) y el análisis del proceso terapéutico con 6 parejas. Los participantes fueron personas y parejas que solicitaron asesoría psicológica por dificultades de pareja. Se utilizaron como instrumentos el SPSS y las matrices categoriales. Como resultados se definieron dos tipos de parejas con características predominantes distintas en los cinco ejes analíticos asociados a la emergencia del conflicto conyugal. El modelo de abordaje terapéutico implica desarrollar una evaluación completa de la dinámica conyugal siguiendo los ejes de configuración de la relación, motivos para permanecer en la misma y fuentes de tensión, para establecer conexiones con el motivo de consulta y proponer estrategias interventivas que faciliten el posicionamiento de los miembros de la pareja y la exploración de las posibilidades de la relación.Magíster en Psicología ClínicaMaestrí