Complicaciones en pacientes en tratamiento con terapia anticoagulante oral dicumarínica en un servicio de urgencias hospitalario

Introducción: El número de pacientes en tratamiento anticoagulante oral (TAO) ha aumentado de manera importante en los últimos años. El estrecho margen terapéutico de estos fármacos y la descompensación del mismo debido a diferentes aspectos, como la toma de otros medicamentos o la alimentación, hace que el riesgo de sufrir complicaciones no sea para nada despreciable. Las complicaciones incluyen eventos tromboembólicas en pacientes que están por debajo de rango terapéutico, y hemorragias desde leves hasta graves como hemorragias intracraneales en pacientes en rango supraterapéutico. Este margen terapéutico se consigue mediante el control de dosis de fármaco de manera que se mantenga un nivel adecuado en sangre, el cual se mide mediante el denominado INR (International normalizad ratio). El rango de INR terapéutico varía según la indicación de anticoagulación del paciente. Objetivos: · Conocer cúantos pacientes en tratamiento con TAO acuden al año a urgencias de nuestro hospital. · Describir sus características sociodemográficas. · Conocer el motivo por el que acuden a urgencias. · Especificar cual es la indicación de TAO en estos pacientes. · Describir cual es el porcentaje de pacientes con TAO cuya dosis está en rango terapéutico. Y más concretamente, centrándonos en las posibles complicaciones de estos fármacos: · Conocer el porcentaje de complicaciones en de pacientes con TAO que acuden al servicio de Urgencias. · Explicar de qué tipo de complicaciones se trata. · Describir cuales son las complicaciones más frecuentes en los pacientes con TAO. · Establecer si existe o no relación entre la aparición de complicaciones y el nivel supra o infraterapéutico de INR. · Averiguar si se ha llevado a cabo alguna medida respecto al tratamiento con TAO tras sufrir algún tipo de complicación. Metodología: Para responder a las cuestiones planteadas en los objetivos de este estudio, realizamos un estudio descriptivo retrospectivo de los pacientes en tratamiento con anticoagulantes orales atendidos durante dos años consecutivos en el servicio de Urgencias del Hospital Lozano Blesa de Zaragoza, a los cuales se les solicitó por cualquier motivo un estudio de coagulación. La muestra incluye dos grandes grupos: el primero está formado por los pacientes atendidos desde el 1 diciembre 2010 hasta el 30 noviembre de 2011 y el segundo comprende los pacientes asistidos desde el 1 de diciembre de 2011 hasta el 30 de noviembre de 2012. Para realizar el muestreo de manera aleatoria, fueron recogidos a partir de los estudios de coagulación solicitados a los pacientes en tratamiento con TAO de cada primera semana de mes, un total de 39719. De éstos, fueron incluidos en la muestra los correspondientes a pacientes con TAO atendidos en urgencias durante la primera semana de cada mes, completando un total de 1077 pacientes. Diferentes aspectos de cada uno de estos pacientes fueron registrados en una ficha que se elaboró en la que se incluyeron una serie de variables necesarias para cumplir los objetivos de este estudio: edad, sexo, motivo de asistencia a urgencias, grado de prioridad (según triaje), fecha y hora de ingreso, fecha y hora de alta, indicación de TAO, valor de INR, administración de fármacos con probabilidad de interactuar con TAO, intervención sobre TAO, complicaciones de TAO: por exceso de coagulación (hemorragia leve, hemorragia moderada o hemorragia grave), por defecto de coagulación o ninguna; solicitud de TAC e informe del mismo, diagnóstico al alta, vuelta a urgencias en los 30 días posteriores, tiempo de estancia en urgencias, destino al alta y proporción de instrucciones al alta. Para el análisis de estas variables se ha creó una base de datos en el programa informático spss v15.0 y se han analizado en spss y stata. Resultados: La media de edad en los pacientes estudiados es de 78 años, IC 95% (77,41 – 78,60), siendo un 49,9% hombres y un 50,51% hombres. El motivo de ingreso en urgencias fue disnea (27,14%), signos o síntomas de sangrado (16,08%), signos o síntomas de trombosis (12,73%), caída o fractura (6,04%) y motivos relacionados con el TAO (3,44%) y otros 34,57%. El 75% de los pacientes obtuvieron una prioridad en el triaje de III o IV. Presentaron un rango terapéutico el 35,13% de los pacientes y fuera de los límites considerados terapéuticos para su indicación el 64,87%, siendo el 22,88% infraterapéutico y el 36,99% supraterapéutico. El destino al alta fue el 45,78% ingreso, domicilio 44,65, 9,38% sala de observación y éxitus, 0,19%. Reingresaron por el mismo motivo en los 30 días posteriores el 12,16% de los pacientes. Se realizó TAC al 7,34%. El TAO fue prescrito por fibrilación auricular en el 71,19%, por enfermedad tromboembólica venosa en el 8,64%, sustitución valvular protésica 8,74%, síndrome antifosfolípido 0,09%, facto V de Leiden 0,9%, hipertensión pulmonar 2,04%. Presentan complicaciones trombóticas el 4,92% de los pacientes y hemorrágicas el 27,11%. El tipo de complicación (trombótica o hemorrágica) está en la mayoría de los casos en relación con el nivel de anticoagulación. Sin embargo, éste no se relaciona con la gravedad de las complicaciones. Entre los pacientes estudiados, las complicaciones trombóticas se objetivan más frecuentemente en mujeres. Se proporcionan instrucciones al alta al 54,32% de los pacientes, preferiblemente a los que se encuentran fuera de rango terapéutico y a los que presentan complicaciones hemorrágicas. Se administran fármacos susceptibles de interaccionar con Acenocumarol al 36,47% de los pacientes, sobre todo corticoides y quinolonas. La intervención sobre TAO realizadas son: ajuste de dosis 25,81%, heparina 3,16, plasma fresco 0,46%, vitamina K 11,23%, factores de coagulación 0,84%. Conclusiones: en un elevado porcentaje de los pacientes con TAO que acuden a urgencias se objetiva un nivel de anticoagulación inadecuado. La mayoría de estos pacientes no presentan complicaciones, y en caso de presentarlas son de tipo hemorrágico leve. Los pacientes infracoagulados presentan más frecuentemente complicaciones trombóticas; los que tienen un nivel de coagulación supraterapéutico, presentan con mayor frecuencia complicaciones hemorrágicas. No se observa relación entre el nivel de anticoagulación y la gravedad de las complicaciones. Se administran frecuentemente fármacos que interactúan con esta terapia. En la mayoría de los casos no se proporcionan instrucciones al alta. Como profesionales sanitarios, debemos tener en cuenta estos puntos para mejorar la seguridad y la efectividad de este tipo de tratamiento

Optokinetic stimulation rehabilitation in preventing seasickness

SummaryObjectivesSeasickness occurs when traveling on a boat: symptoms such as vomiting are very disturbing and may be responsible for discontinuing travel or occupation and can become life-threatening. The failure of classical treatment to prevent seasickness has motivated this retrospective study exploring optokinetic stimulation in reducing these symptoms.Patients and methodsExperimental training of 75 sailors with optokinetic stimulation attempted to reduce seasickness manifestations and determine the factors that could predict accommodation problems.ResultsEighty percent of the trained subjects were able to return on board. No predictive factors such as sex, occupation, degree of illness, number of treatment sessions, time to follow-up, and age were found to influence training efficacy.ConclusionOptokinetic stimulation appears to be promising in the treatment of seasickness. Nevertheless, statistically significant results have yet to demonstrate its efficacy

Metabolic challenges and key players in serpentinite-hosted microbial ecosystems

Serpentinite-hosted systems are amongst the most challenging environments for life on Earth. Serpentinization, a geochemical alteration of exposed ultramafic rock, produces hydrothermal fluids enriched in abiotically derived hydrogen (H2), methane (CH4), and small organic molecules. The hyperalkaline pH of these fluids poses a great challenge for metabolic energy and nutrient acquisition, curbing the cellular membrane potential and limiting electron acceptor, carbon, and phosphorous availability. Nevertheless, serpentinization supports the growth of diverse microbial communities whose metabolic make-up might shed light on the beginning of life on Earth and potentially elsewhere. Here, we outline current hypotheses on metabolic energy production, carbon fixation, and nutrient acquisition in serpentinizing environments. A taxonomic survey is performed for each important metabolic function, highlighting potential key players such as H2 and CH4 cycling Serpentinimonas, Hydrogenophaga, Methanobacteriales, Methanosarcinales, and novel candidate phyla. Methodological biases of the available data and future approaches are discussed

Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor

Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.The OncoImmunology group is funded by the Spanish Association against Cancer (AECC) [grant number PROYE16001ESCO]; Instituto de Salud Carlos III (ISCIII)-FEDER project grants [grant numbers FIS PI17/02119, FIS PI20/00010, COV20/00000, TRANSPOCART ICI19/00069]; a Biomedicine Project grant from the Department of Health of the Government of Navarre [grant number BMED 050-2019]; strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Project Horizon 2020 Improved Vaccination for Older Adults (ISOLDA; ID: 848166); Crescendo Biologics Ltd. supported the OncoImmunology group for the development and testing of PD-1 and LAG-3 bispecifics

Two novel conjugative plasmids from a single strain of Sulfolobus

Two conjugative plasmids (CPs) were isolated and characterized from the same 'Sulfolobus islandicus' strain, SOG2/4, The plasmids were separated from each other and transferred into Sulfolobus soltataricus. One has a high copy number and is not stable (pSOG1) whereas the other has a low copy number and is stably maintained (pSOG2). Plasmid pSOG2 is the first Sulfolobus CP found to have these characteristics. The genomes of both pSOG plasmids have been sequenced and were compared to each other and the available Sulfolobus CPs. Interestingly, apart from a very well-conserved core, 70% of the pSOG 1 and pSOG2 genomes is largely different and composed of a mixture of genes that often resemble counterparts in previously described Sulfolobus CPs. However, about 20% of the predicted genes do not have known homologues, not even in other CPs. Unlike pSOG1, pSOG2 does not contain a gene for the highly conserved PIrA protein nor for obvious homologues of partitioning proteins. Unlike pNOB8 and pKEF9, both pSOG plasmids lack the so-called clustered regularly interspaced short palindrome repeats (CRISPRs). The sites of recombination between the two genomes can be explained by the presence of recombination motifs previously identified in other Sulfolobus CPs. Like other Sulfolobus CPs, the pSOG plasmids possess a gene encoding an integrase of the tyrosine recombinase family. This integrase probably mediates plasmid site-specific integration into the host chromosome at the highly conserved tRNA(Glu) loci

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.This work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) to JF-I. and ES), the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2020-000028 to ES), the Instituto de Salud Carlos III (ISCIII)-FEDER project grants (Ref. FIS PI17/02119, FIS PI20/00010; COV20-00237 to DE), the Department of Health of the Government of Navarre (Ref: BMED 050-2019 to DE) and the European Project Horizon 2020 (ref: ID: 848166; Improved vaccination for older adults-ISOLDA to DE)

Clinical landscape of LAG-3-targeted therapy

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.The OncoImmunology group is funded by the Spanish Association against Cancer ( AECC ) [grant number PROYE16001ESCO ]; Instituto de Salud Carlos III (ISCIII)-FEDER project grants [grant numbers FIS PI17/02119, FIS PI20/00010, COV20/00000, TRANSPOCART ICI19/00069]; a Biomedicine Project grant from the Department of Health of the Government of Navarre [grant number BMED 050-2019 ]; strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Project Horizon 2020 Improved Vaccination for Older Adults (ISOLDA; ID: 848166); Crescendo Biologics Ltd. supported the OncoImmunology group for the development and testing of PD-1 and LAG-3 bispecifics

Two novel families of plasmids from hyperthermophilic archaea encoding new families of replication proteins

Thermococcales (phylum Euryarchaeota) are model organisms for physiological and molecular studies of hyperthermophiles. Here we describe three new plasmids from Thermococcales that could provide new tools and model systems for genetic and molecular studies in Archaea. The plasmids pTN2 from Thermococcus nautilus sp. 30-1 and pP12-1 from Pyrococcus sp. 12-1 belong to the same family. They have similar size (∼12 kb) and share six genes, including homologues of genes encoded by the virus PAV1 from Pyrococcus abyssi. The plasmid pT26-2 from Thermococcus sp. 26-2 (21.5 kb), that corresponds to another plasmid family, encodes many proteins having homologues in virus-like elements integrated in several genomes of Thermococcales and Methanococcales. Our analyses confirm that viruses and plasmids are evolutionary related and co-evolve with their hosts. Whereas all plasmids previously isolated from Thermococcales replicate by the rolling circle mechanism, the three plasmids described here probably replicate by the theta mechanism. The plasmids pTN2 and pP12-1 encode a putative helicase of the SFI superfamily and a new family of DNA polymerase, whose activity was demonstrated in vitro, whereas pT26-2 encodes a putative new type of helicase. This strengthens the idea that plasmids and viruses are a reservoir of novel protein families involved in DNA replication