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Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia.Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers.Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001).Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.

Introducción: la educación médica basada en competencias (CBME) se ha ido adoptando ampliamente; en esta, las competencias se originan de las necesidades sociales de atención de salud y están articuladas en un marco claramente definido. El Royal College de Canadá (RCPSC) ha desarrollado el marco CanMEDS, que ha sido ampliamente utilizado en formación de especialistas. Métodos: la Dirección de Postgrado de la Pontificia Universidad Católica de Chile (DPG-UC) decidió adoptar el modelo CanMEDS de CBME, y se planteó la meta de integrarlo a nivel institucional y en sus programas de especialización médica. Se utilizó el modelo de Kotter de liderazgo en gestión del cambio para describir el proceso. Resultados: comenzamos estableciendo un sentido de urgencia de realizar el cambio, y se constituyó un equipo directivo sólido para liderar el proceso. Definimos nuestra visión: consolidar un Postgrado con estándares internacionales, y aportar especialistas de excelencia a la sociedad; diseminamos la visión con jefes de programas, docentes de primera línea y residentes, usando variadas estrategias para empoderarlos. Se fijaron metas: en DPG-UC se actualizaron procesos según estándares institucionales internacionales del RCPSC; y a nivel de programas, post mapeo curricular, estos se reescribieron por competencias, y se consolidó la enseñanza y evaluación de roles. El 2016, la UC logró el hito histórico de ser la primera institución no canadiense, acreditada por RCPSC. Discusión y conclusiones: preparar la acreditación internacional resultó un motor para impulsar cambios. formamos una comunidad de práctica UC-RCPSC, aprendimos a incorporar la mirada internacional del RCPSC, aplicada a nuestra realidad local. Nuestro desafío es mantener estándares internacionales, y seguir aportando especialistas de excelencia que aseguren una atención integral, experta y comprometida con la sociedad y nuestros pacientes.

Abstract Background The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. Methods By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. Results Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. Conclusion Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

Introduction: The consequences of the Covid-19 epidemic have been catastrophic for Latin America in 2021. This study explores experiences, lessons learned, and practice changes during this critical time in post-graduate medical education in Latin America. Methods: A panel of 53 post-graduate medical education leaders from 8 Latin American countries and Canada was invited to participate in the 2021 Latin American Medical Education Leaders Forum to share their experiences, lessons learned, and main educational practice changes given the Covid-19 pandemic scenario. Participants were selected following a snowball technique with the goal of obtaining a diverse group of experts. Small group discussions were conducted by bilingual facilitators based on a semi-structured questionnaire. The plenary session with the main conclusions of each group was recorded and fully transcribed for a thematic analysis using a framework methods approach. Results: Participants´ profiles included 13 experienced clinician-educators, 19 program directors, and 23 deans or organizational representatives. Seven specific themes emerged. They followed a pattern that went from an initial emotional reaction of surprise to a complex collective response. The responses highlighted the value of adaptability, the application of new digital skills, a renovated residents’ protagonism, the strengthening of humanism in medicine, the openness of new perspectives in wellness, and finally, an unresolved challenge of assessment in medical education in a virtual post-pandemic scenario. Conclusion: A diverse panel of medical educators from Latin America and Canada identified changes triggered by the Covid-19 pandemic that could transform postgraduate medical education in the region.

Resumen: Este artículo es continuación de la revisión iniciada en el número anterior sobre la utilidad de la ecografía clínica musculoesquelética en atención primaria, y completa los escenarios de lesiones musculares, artrosis, enfermedades reumatológicas y procesos ecoguiados. Abstract: This article is a continuation of the review initiated in the previous issue about the usefulness of musculoskeletal point of care ultrasound in Primary Care, completing the scenarios of muscle injuries, osteoarthritis, rheumatological diseases and eco-guided procedures. Palabras clave: Ecografía clínica, Medicina familiar, Utilidad, Fiabilidad, Keywords: Point of care ultrasound, Family Practice, Usefulness, Reliability

Resumen: La ecografía musculoesquelética (EME) es una técnica que se ha extendido en los últimos años a la práctica totalidad de las especialidades médicas que abarcan esta parte de la patología. El médico de familia (MF) no ha sido ajeno a este proceso por su amplísimo espectro de competencias, usándola en gran cantidad de situaciones de su práctica habitual en las cuales obtiene rentabilidad de ella de modo fiable, eficiente y eficaz.La dotación de ecografía en los centros de Atención Primaria (AP) es una realidad creciente, aportando elevadas cotas de accesibilidad, inmediatez y capacidad de manejo clínico, lo que, unido a la elevada prevalencia de problemas del aparato locomotor en este ámbito, convierten a la EME en una acción estratégica de mejora de la capacidad resolutiva y de la calidad de la atención sanitaria.Para asegurar la competencia de quienes la practican, se hace necesario definir los beneficios y los potenciales riesgos que su uso puede generar, así como sus escenarios de aplicación, evitar exploraciones innecesarias y optimizar la inversión que supone dotar de este recurso al nivel de AP. Este artículo pretende resumir el estado actual de la ecografía clínica musculoesquelética y su utilidad para el MF en aquellos escenarios en los que resulta fiable y eficaz. Abstract: Musculoskeletal ultrasound (MSU) is a technique which has been extended to practically all medical specialties that comprise this pathology. Family Doctor (FD) has not been away from this process due to its great wide of competences, using it in different scenarios inside his common practice in which he can get profits in a reliable, efficient and effective way.Ultrasound equipment incorporation in Primary Care (PC) centers is an increasing reality, contributing to high ranges of accessibility, immediacy and clinic handle capability, and thus, together with the high prevalence in this area in locomotor apparatus, turns MSU into an strategic action for the improvement of the resolving capacity and consequently for the health care.To ensure proficiency among users, it's being necessary to define the benefits and potential risks its use can cause, as well as its different scenarios, avoiding unnecessary explorations and optimizing the investment of this resource at PC level. This paper pretends to summarize the state of the art of the musculoskeletal ultrasound and its benefits for the FD into this efficient and effective scenarios. Palabras clave: Ecografía clínica, Medicina familiar, Utilidad, Fiabilidad, Keywords: Point of care ultrasound, Family practice, Usefulness, Reliability

CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.

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[This corrects the article DOI: 10.1371/journal.pone.0158863.].

PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.

NK cell effector functions are controlled by a combination of inhibitory receptors, which modulate NK cell activation initiated by stimulatory receptors. Most of the canonical NK cell inhibitory receptors recognize allelic forms of classical and non-classical MHC class I molecules. Furthermore, high expression of MHC-I molecules on effector immune cells is also associated with reverse signaling, giving rise to several immune-regulatory functions. Consequently, the inhibitory function of MHC class I expressed on a human NKL cell line and activated primary NK and T cells on different activating receptors are analyzed in this paper. Our results reveal that MHC-I molecules display specific patterns of "selective" inhibition over cytotoxicity and cytokine production induced by ITAM-dependent receptors and 2B4, but not on NKG2D. This contrasts with the best known "canonical" inhibitory receptors, which constitutively inhibit both functions, regardless of the activating receptor involved. Our results support the existence of a new fine-tuner inhibitory function for MHC-I molecules expressed on cytotoxic effector cells that could be involved in establishing self-tolerance in mature activated NK cells, and could also be important in tumor and infected cell recognition.

En los programas de especialización médica, "competencias" se refiere a un grupo de cualidades o capacidades generales que todo especialista debe tener o adquirir. El Consejo de Acreditación de Educación Médica de Posgrado americano (ACGME) ha definido que en todo programa de posgrado en medicina hay que desarrollar la adquisición de seis competencias fundamentales: el manejo clínico de los pacientes, la aplicación del conocimiento médico, la capacidad para aprender de la práctica clínica y mejorarla, el profesionalismo, habilidades interpersonales y de comunicación y la capacidad para manejarse dentro de los sistemas de salud de los pacientes y usar adecuadamente los recursos. Utilizando este modelo, hemos desarrollado recientemente una pauta de evaluación para nuestros residentes, con doce ítems enfocados a evaluar desempeños mesurables a través de rúbricas de apreciación global relacionados a las 6 competencias mencionadas. Hemos aprovechado para esto el concepto de actividad profesional a cargo, ya que conecta muy bien lo que es educación basada en competencias con la realidad de la práctica clínica de los programas de especialización o de residencia. En este sistema de evaluación de residentes, la evaluación se enfoca a la observación de actividades clínicas concretas y desde ellas se infiere el grado de adquisición de competencias.

Lomas formations or "fog oases" are islands of vegetation in the desert belt of the west coast of South America, with a unique vegetation composition among the world's deserts. However, plant diversity and conservation studies have long been neglected, and there exists a severe gap in plant DNA sequence information. To address the lack of DNA information, we conducted field collections and laboratory DNA sequencing to establish a DNA barcode reference library of Lomas plants from Peru. This database provides 1,207 plant specimens and 3,129 DNA barcodes data corresponding with collections from 16 Lomas locations in Peru, during 2017 and 2018. This database will facilitate both rapid species identification and basic studies on plant diversity, thereby enhancing our understanding of Lomas flora's composition and temporal variation, and providing valuable resources for conserving plant diversity and maintaining the stability of the fragile Lomas ecosystems., (© 2023. The Author(s).)

The case analysis of five patients with post-ampullary adenocarcinoma of the duodenum showed this to be a tumor which favors local extension into surrounding organs, instead of lymphatic or hepatic metastasis. This justifies and aggressive resectional approach to treatment, pancreaticoduodenectomy being the basic operation to be applied. Proximity to the superior mesenteric vessels involving them in four out of five of our tumors, is the major anatomic limiting factor. Leaving vascular control for the end of the excision and perfusing them to maintain viability of the gut until a comfortable vascular anastomosis can be constructed, should solve the problem. Misdiagnosis proved to be a prominent source of error, causing delays and inappropriate therapy. The Cancer Registry of Puerto Rico has documented an incidence of carcinoma of the duodenum similar to that of the ampulla of Vater. This fact demands the same care in the conduct of diagnostic procedures of the distal duodenum as is customary in the visualization of the ampulla.