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Introducción. La tomografía corporal (TC) total en la evaluación de pacientes con trauma grave, puede ser una herramienta eficaz y segura para decidir entre un tratamiento quirúrgico y uno no quirúrgico, pero aún no son claras las implicaciones diagnósticas y los riesgos asociados con esta técnica. Métodos. Se incluyeron pacientes mayores de 15 años con trauma grave que fueron sometidos a TC total. Se evaluaron la seguridad, la efectividad y la eficiencia por medio de los parámetros de incidencia de nefropatía inducida por los medios de contraste, dosis total de radiación por paciente, proporción de casos en los que la TC total cambió el manejo, y el retraso en el diagnóstico. Resultados. Se incluyeron 263 pacientes, 83 % sufrieron trauma cerrado y 17 % sufrieron trauma penetrante. La gravedad de la lesión fue mayor en estos últimos y, sin embargo, el trauma cerrado con inestabilidad hemodinámica se presentó con mayores grados de choque. El 65 % de los pacientes recibió tratamiento selectivo no operatorio. Entre los subgrupos, no hubo diferencias significativas en el tiempo entre el ingreso a la sala de urgencias y la toma de la TC total (p=0,96) y, en la mayoría de los casos, el tiempo entre la práctica de la TC total y el diagnóstico de presencia o ausencia de heridas fue menor de 25 minutos. La mediana de radiación total estuvo por debajo de 20 mSv en todos los grupos. No hubo diferencias significativas en la mortalidad (p=0,17). Conclusión. La TC total es una herramienta segura y eficiente para decidir entre un tratamiento quirúrgico y uno no quirúrgico en los casos de trauma grave, independientemente del mecanismo de la lesión o la estabilidad hemodinámica al ingreso.

Càrrega feta de Scopus d'articles UAB 2019 (Gold, hybrid o Bronze) procedents de l'Observatori d'Accés Obert (càrrega maig 2020). Compte! Cal comprovar la versió permesa per l'editor en els bronze. This work was supported by grants BIO2012?40133 and SAF2016?80255-R from the Spanish Ministry of Economy and Competitivity (MINECO) and Pirepred (EFA086/15) from the Interreg program POCTEFA, supported by the European Regional Development Fund (ERDF) to X. dC.; FIS PI12/02585 and PI15/00355 to O. D.; PI13/01711 and PI16/01218 to S. G-E. from the Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds. S. B. and S. G-E. are supported by the Asociaci?n Espa?ola contra el C?ncer [AECC] and the Miguel Servet Progam [CP16/00034], respectively. The CAGI experiment coordination is supported by NIH U41 HG007346 and the CAGI conference by NIH R13 HG006650. BRCA1 and BRCA2 (BRCA1/2) germline variants disrupting the DNA protective role of these genes increase the risk of hereditary breast and ovarian cancers. Correct identification of these variants then becomes clinically relevant, because it may increase the survival rates of the carriers. Unfortunately, we are still unable to systematically predict the impact of BRCA1/2 variants. In this article, we present a family of in silico predictors that address this problem, using a gene-specific approach. For each protein, we have developed two tools, aimed at predicting the impact of a variant at two different levels: Functional and clinical. Testing their performance in different datasets shows that specific information compensates the small number of predictive features and the reduced training sets employed to develop our models. When applied to the variants of the BRCA1/2 (ENIGMA) challenge in the fifth Critical Assessment of Genome Interpretation (CAGI 5) we find that these methods, particularly those predicting the functional impact of variants, have a good performance, identifying the large compositional bias towards neutral variants in the CAGI sample. This performance is further improved when incorporating to our prediction protocol estimates of the impact on splicing of the target variant.

Noncompressible torso hemorrhage is one of the leading causes of preventable death worldwide. An efficient and appropriate evaluation of the trauma patient with ongoing hemorrhage is essential to avoid the development of the lethal diamond (hypothermia, coagulopathy, hypocalcemia, and acidosis). Currently, the initial management strategies include permissive hypotension, hemostatic resuscitation, and damage control surgery. However, recent advances in technology have opened the doors to a wide variety of endovascular techniques that achieve these goals with minimal morbidity and limited access. An example of such advances has been the introduction of the Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA), which has received great interest among trauma surgeons around the world due to its potential and versatility in areas such as trauma, gynecology & obstetrics and gastroenterology. This article aims to describe the experience earned in the use of REBOA in noncompressible torso hemorrhage patients. Our results show that REBOA can be used as a new component in the damage control resuscitation of the severely injured trauma patient. To this end, we propose two new deployment algorithms for hemodynamically unstable noncompressible torso hemorrhage patients: one for blunt and another for penetrating trauma. We acknowledge that REBOA has its limitations, which include a steep learning curve, its inherent cost and availability. Although to reach the best outcomes with this new technology, it must be used in the right way, by the right surgeon with the right training and to the right patient. Resumen La hemorragia no compresible del torso es una de las principales causas de muerte prevenibles alrededor del mundo. Una evaluación eficiente y apropiada del paciente traumatizado con hemorragia activa es la esencia para evitar el desarrollo del rombo de la muerte (hipotermia, coagulopatía, hipocalcemia y acidosis). Actualmente, las estrategias de manejo inicial incluyen hipotensión permisiva, resucitación hemostática y cirugía de control de daños. Sin embargo, los recientes avances tecnológicos han abierto las puertas a una amplia variedad de técnicas endovasculares que logran esos objetivos con una morbilidad mínima y un acceso limitado. Un ejemplo de estos avances ha sido la introducción del balón de resucitación de oclusión aortica; REBOA ( Resuscitative Endovascular Balloon Occlusion of the Aorta , por sus sigla en inglés ), el cual, ha tenido gran provecho entre los cirujanos de trauma alrededor del mundo debido a su potencial y versatilidad en áreas como trauma, ginecología y obstetricia, y gastroenterología. El objetivo de este artículo es describir la experiencia lograda en el uso del REBOA en pacientes con hemorragia no compresible del torso. Nuestros resultados muestran que el REBOA puede usarse como un nuevo actor en la resucitación de control de daños del paciente con trauma severo, para este fin, nosotros proponemos dos nuevos algoritmos para el manejo de pacientes hemodinámicamente inestables: uno para trauma cerrado y otro para trauma penetrante. Se reconoce que el REBOA tiene sus limitaciones, las cuales incluye un periodo de aprendizaje, su costo inherente y la disponibilidad. A pesar de esto, para lograr los mejores resultados con esta nueva tecnología, el REBOA debe ser usado en el momento correcto, por el cirujano correcto con el entrenamiento y el paciente correcto.

Resumen Introducción. La miastenia grave es una enfermedad autoinmunitaria con una prevalência mundial de 150 a 250 casos por 1'000.000 de habitantes. El tratamiento recomendado para la miastenia grave sin timoma es la timectomía total, la cual es la única alternativa de curación. Métodos. Se llevó a cabo un estudio descriptivo y retrospectivo de una serie de casos de pacientes adultos con miastenia grave sin timoma sometidos a timectomía, durante el periodo de 2010 a 2017. En el análisis estadístico descriptivo, se utilizaron frecuencias absolutas y porcentajes para las variables cualitativas y, para las variables cuantitativas, se utilizaron la mediana y el rango intercuartílico. Resultados. Veintiocho pacientes con miastenia grave sin timoma se sometieron a timectomía desde el año 2oio hasta el 2017. Se categorizaron según la clasificación del estado posterior a la intervención de la Myasthenia Gravis Foundation of America y se evidenció que 4 (14,3 %) pacientes presentaban remisión completa y el grado 3 de manifestaciones clínicas mínimas fue el más frecuente en 19 (67,9 %); 26 (92,9 %) tuvieron mejoría con respecto al cambio del estado clínico, en 2 (7,1 %) no se documentaron cambios y en ningún paciente hubo empeoramiento, exacerbación o muerte secundaria a la enfermedad. Conclusiones. A lo largo de siete años se practicó timectomía a 28 pacientes con diagnóstico de miastenia grave sin timoma, aproximadamente, en el 15 % de los pacientes hubo remisión completa, el grado 3 de manifestaciones mínimas fue el más frecuente y el 93 % presentó mejoría de su estatus clínico. Abstract Introduction: Myasthenia gravis is an autoimmune disease with a worldwide prevalence of 150 to 250 cases per 1,000,000 inhabitants. The recommended treatment for myasthenia gravis without thymoma is total thymectomy, which is the only cure alternative. Methods: A descriptive and retrospective study of a series of cases of adult patients with myasthenia gravis without thymoma undergoing thymectomy was conducted during the period from 2010 to 2017. In the descriptive statistical analysis, absolute frequencies and percentages were used for the qualitative variables, and for the quantitative variables the median and the interquartile range were used. Results: Twenty-eight patients with myasthenia gravis without thymoma underwent thymectomy from 2010 to 2017. They were categorized according to the Myasthenia Gravis Foundation of America post-intervention status classification, and it was found that four (14,3 %) patients had complete remission, and grade 3 of minimal clinical manifestations was the most frequent in 19 (67,9 %); 26 (92,9 %) had improvement with respect to the change of the clinical state, in two (7,1 %) no changes were documented and in no patient there was worsening, exacerbation or death secondary to the disease. Conclusion: Over seven years, 28 patients diagnosed with myasthenia gravis without thymoma underwent thymectomy. Approximately in 15 % of patients achieve complete remission, grade 3 of minimal manifestations was the most frequent and 93 % presented improvement in their clinical status.

The liver is the most commonly affected solid organ in cases of abdominal trauma. Management of penetrating liver trauma is a challenge for surgeons but with the introduction of the concept of damage control surgery accompanied by significant technological advancements in radiologic imaging and endovascular techniques, the focus on treatment has changed significantly. The use of immediately accessible computed tomography as an integral tool for trauma evaluations for the precise staging of liver trauma has significantly increased the incidence of conservative non-operative management in hemodynamically stable trauma victims with liver injuries. However, complex liver injuries accompanied by hemodynamic instability are still associated with high mortality rates due to ongoing hemorrhage. The aim of this article is to perform an extensive review of the literature and to propose a management algorithm for hemodynamically unstable patients with penetrating liver injury, via an expert consensus. It is important to establish a multidisciplinary approach towards the management of patients with penetrating liver trauma and hemodynamic instability. The appropriate triage of these patients, the early activation of an institutional massive transfusion protocol, and the early control of hemorrhage are essential landmarks in lowering the overall mortality of these severely injured patients. To fear is to fear the unknown, and with the management algorithm proposed in this manuscript, we aim to shed light on the unknown regarding the management of the patient with a severely injured liver. Resumen El hígado es el órgano solido más comúnmente lesionado en casos de trauma abdominal. El manejo del trauma penetrante hepático es un dilema para los cirujanos. Sin embargo, con la introducción del concepto de la cirugía de control de daños y los avances tecnológicos en imagenología y técnicas endovasculares han permitido que el enfoque del tratamiento cambie. La disponibilidad inmediata de la tomografía computarizada permite estadificar el grado de la lesión e incrementar la posibilidad de un manejo conservador en pacientes hemodinámicamente estables con trauma hepático. El trauma hepático severo que se asocia con inestabilidad hemodinámica tiene una alta mortalidad debido a la hemorragia activa. El objetivo de este artículo es proponer un algoritmo de manejo producto de un consenso de expertos acerca del abordaje de los pacientes hemodinámicamente inestables con trauma hepático penetrante. El manejo debe ser por parte de un equipo multidisciplinario que comienza desde la evaluación inicial de los pacientes, la activación temprana de protocolo de transfusión masiva y el control temprano de la hemorragia, siendo estos aspectos esenciales para disminuir la mortalidad. El miedo a lo desconocido es el dilema quirúrgico donde existen pocas opciones y es imperante decisiones rápidas y oportunas; por esta razón, se propone dar una luz de guía sobre lo desconocido respecto al manejo del paciente con trauma hepático severo.

Pelvic fractures occur in up to 25% of all severely injured trauma patients and its mortality is markedly high despite advances in resuscitation and modernization of surgical techniques due to its inherent blood loss and associated extra-pelvic injuries. Pelvic ring volume increases significantly from fractures and/or ligament disruptions which precludes its inherent ability to self-tamponade resulting in accumulation of hemorrhage in the retroperitoneal space which inevitably leads to hemodynamic instability and the lethal diamond. Pelvic hemorrhage is mainly venous (80%) from the pre-sacral/pre-peritoneal plexus and the remaining 20% is of arterial origin (branches of the internal iliac artery). This reality can be altered via a sequential management approach that is tailored to the specific reality of the treating facility which involves a collaborative effort between orthopedic, trauma and intensive care surgeons. We propose two different management algorithms that specifically address the availability of qualified staff and existing infrastructure: one for the fully equipped trauma center and another for the very common limited resource center. Resumen Las fracturas de pelvis ocurren en más del 25% de los pacientes con trauma severo y su mortalidad es alta, a pesar de los avances en la resucitación hemodinámica y las técnicas quirúrgicas. Esta mortalidad se explica por la hemorragia inherente y las lesiones extra pélvicas asociadas, las fracturas o las disrupciones ligamentarias de la pelvis aumentan el volumen del espacio pélvico, y conlleva a que la hemorragia pélvica se acumule en el espacio retroperitoneal. En poco tiempo, esto conduce a la inestabilidad hemodinámica y el rombo de la muerte. La hemorragia pélvica es un 80% venosa proveniente de los plexos pre-sacro / pre-peritoneal. El restante 20% es arterial por sangrado de las ramas de la arteria iliaca interna. Esta realidad podría ser cambiada a través de un manejo secuencial enfocado según la disposición de recursos del centro de atención y de un trabajo colaborativo entre ortopedistas, cirujanos de trauma e intensivistas. Este articulo propone dos algoritmos de manejo que están enfocados según la disponibilidad de un equipo calificado e infraestructura existente: uno para un centro de trauma totalmente equipado, y el otro para un centro con recursos limitados.

Trauma is a complex pathology that requires an experienced multidisciplinary team with an inherent quick decision-making capacity, given that a few minutes could represent a matter of life or death. These management decisions not only need to be quick but also accurate to be able to prioritize and to efficiently control the injuries that may be causing impending hemodynamic collapse. In essence, this is the cornerstone of the concept of damage control trauma care. With current technological advances, physicians have at their disposition multiple diagnostic imaging tools that can aid in this prompt decision-making algorithm. This manuscript aims to perform a literature review on this subject and to share the experience on the use of whole body computed tomography as a potentially safe, effective and efficient diagnostic tool in cases of severely injured trauma patients regardless of their hemodynamic status. Our general recommendation is that, when feasible, perform a whole body computed tomography without interrupting ongoing hemostatic resuscitation in cases of severely injured trauma patients with or without signs of hemodynamic instability. The use of this technology will aid in the decision-making of the best surgical approach for these patients without incurring any delay in definitive management and/or increasing significantly their radiation exposure. Resumen El trauma es una compleja patología que requiere un equipo experimentado y multidisciplinario con una capacidad para la toma de decisiones Oportuna ya que en unos pocos minutos pueden representar la diferencia entre la vida y la muerte. Estas decisiones deben ser precisas para ser capaces de priorizar y controlar eficientemente las lesiones que puedan estar causando el compromiso hemodinámico. En esencia, este es el punto clave del concepto de control de daños en la atención del trauma. Con los nuevos avances tecnológicos, el equipo médico tiene a disposición múltiples herramientas imagenológicas de diagnóstico. Este artículo presenta una revisión de la literatura y descripción de la experiencia local con el uso de la tomografía corporal total como una herramienta diagnostica potencialmente segura, efectiva y eficiente en casos de pacientes con trauma severo sin importar su estado hemodinámico. La recomendación general, cuando sea posible, es que se debe realizar una tomografía corporal total sin interrumpir las maniobras de resucitación hemostática en casos de pacientes severamente traumatizados con o sin signos de inestabilidad hemodinámica. El uso de esta tecnología tiene como objetivo tomar decisiones pertinentes y definir el mejor abordaje quirúrgico para el paciente sin incurrir en tardanzas en el manejo definitivo o incrementar el tiempo de exposición a la radiación.

© 2021. Published by The Company of Biologists Ltd., Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays in mouse astrocytic cultures, we reveal a regulatory crosstalk between PHF8 and the Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain chromatin homeostasis and limit heterochromatin formation at synaptogenic genes. Our studies provide insights into the involvement of epigenetics in intellectual disability, This study was supported by grants from the Spanish Ministry of Economy (Ministerio de Economıa, Industria y Competitividad, Gobierno de España; BFU2015-69248-P and PGC2018-096082-B-I00 to M.A.M.-B.) and Ministerio de Ciencia e Innovación (PID2019-111217RB-I00 to X.C) and a Travelling Fellowship from Boehringer Ingelheim to S.I. Open access funding provided by Consejo Superior de Investigaciones Cientıficas. Deposited in PMC for immediate release.

Pancreatic trauma is a rare but potentially lethal injury because often it is associated with other abdominal organ or vascular injuries. Usually, it has a late clinical presentation which in turn complicates the management and overall prognosis. Due to the overall low prevalence of pancreatic injuries, there has been a significant lack of consensus among trauma surgeons worldwide on how to appropriately and efficiently diagnose and manage them. The accurate diagnosis of these injuries is difficult due to its anatomical location and the fact that signs of pancreatic damage are usually of delayed presentation. The current surgical trend has been moving towards organ preservation in order to avoid complications secondary to exocrine and endocrine function loss and/or potential implicit post-operative complications including leaks and fistulas. The aim of this paper is to propose a management algorithm of patients with pancreatic injuries via an expert consensus. Most pancreatic injuries can be managed with a combination of hemostatic maneuvers, pancreatic packing, parenchymal wound suturing and closed surgical drainage. Distal pancreatectomies with the inevitable loss of significant amounts of healthy pancreatic tissue must be avoided. General principles of damage control surgery must be applied when necessary followed by definitive surgical management when and only when appropriate physiological stabilization has been achieved. It is our experience that viable un-injured pancreatic tissue should be left alone when possible in all types of pancreatic injuries accompanied by adequate closed surgical drainage with the aim of preserving primary organ function and decreasing short and long term morbidity. Resumen El trauma pancreático es un tipo de trauma poco común potencialmente fatal que está asociado con lesiones de órganos abdominales o vasculares. Usualmente, los signos clínicos son tardíos aumentado el riesgo de complicaciones respecto al manejo y al pronóstico general. Debido a la baja prevalencia de la lesión del trauma, no existe consenso entre los cirujanos alrededor del mundo sobre cómo se debe diagnosticar y tratar adecuadamente este desafío quirúrgico. La precisión en el diagnóstico es difícil por la localización anatómica y las manifestaciones clínicas tardías. El abordaje quirúrgico ha ido cambiando de dirección hacia la preservación del órgano para evitar complicaciones secundarias asociada a la perdida de la función exocrina y endocrina, o de potenciales complicaciones postquirúrgicas incluyendo las dehiscencias y fistulas. El objetivo de este artículo es proponer un algoritmo de manejo del trauma pancreático a través de un consenso de expertos. Las lesiones del páncreas pueden ser manejadas con una combinación de maniobras hemostáticas, empaquetamiento pancreático, sutura de la herida y drenaje quirúrgico cerrado. La pancreatectomía distal con la perdida de tejido vital pancreático debe ser evitadas. Los principios generales de la cirugía de control de daños deben ser aplicados cuando sea necesario para un manejo quirúrgico definitivo cuando y solo cuando la estabilización fisiológica haya sido lograda. En nuestra experiencia, el tejido pancreático sano debe preservarse cuando el trauma se asocia de un manejo mediante un drenaje quirúrgico cerrado con el objetivo de preservar la función primaria del órgano y disminuir a corto y largo tiempo las morbilidades.

Damage Control Resuscitation (DCR) seeks to combat metabolic decompensation of the severely injured trauma patient by battling on three major fronts: Permissive Hypotension, Hemostatic Resuscitation, and Damage Control Surgery (DCS). The aim of this article is to perform a review of the history of DCR/DCS and to propose a new paradigm that has emerged from the recent advancements in endovascular technology: The Resuscitative Balloon Occlusion of the Aorta (REBOA). Thanks to the advances in technology, a bridge has been created between Pre-hospital Management and the Control of Bleeding described in Stage I of DCS which is the inclusion and placement of a REBOA. We have been able to show that REBOA is not only a tool that aids in the control of hemorrhage, it is also a vital tool in the hemodynamic resuscitation of a severely injured blunt and/or penetrating trauma patient. That is why we propose a new paradigm "The Fourth Pillar": Permissive Hypotension, Hemostatic Resuscitation, Damage Control Surgery and REBOA.La resucitación en control de daños busca combatir la descompensación metabólica del paciente severamente traumatizado mediante tres ejes: la hipotensión permisiva, la resucitación hemostática y la cirugía de control de daños. El objetivo de este artículo es hacer una revisión de la historia de la resucitación en control de daños y la cirugía de control de daños proponiendo un nuevo paradigma basado en los recientes avances de la tecnología endovascular. Un puente ha sido creado entre el manejo prehospitalario y el control del sangrado, descrito antes de la etapa I de la cirugía de control de daños, que es la inclusión y colocación de un REBOA. Esta es una herramienta adicional en el control de la hemorragia y de soporte en la resucitación hemodinámica de los pacientes con trauma severo de tipo cerrado y/o penetrante. Por lo que se propone un nuevo paradigma “El cuarto pilar”: Hipotensión permisiva, resucitación hemostática, cirugía de control de daños y REBOA.

The objective of this study was to evaluate the implementation of a new single-pass whole-body computed tomography Protocol in the management of patients with severe trauma.This was a descriptive evaluation of polytrauma patients who underwent whole-body computed tomography. Patients were divided into three groups: 1. Blunt trauma hemodynamically stable 2. Blunt trauma hemodynamically unstable and 3. Penetrating trauma. Demographics, whole-body computed tomography parameters and outcome variables were evaluated.Were included 263 patients. Median injury severity score was 22 (IQR: 16-22). Time between arrival to the emergency department and completing the whole-body computed tomography was under 30 minutes in most patients [Group 1: 28 minutes (IQR: 14-55), Group 2: 29 minutes (IQR: 16-57), and Group 3: 31 minutes (IQR: 13-50;This new single-pass whole-body computed tomography protocol was safe, effective and efficient to decide whether the patient with severe trauma requires a surgical intervention independently of the mechanism of injury or the hemodynamic stability of the patient. Its use could also potentially reduce the rate of unnecessary surgical interventions of patients with severe trauma including those with penetrating trauma.El objetivo de este estudio fue evaluar la implementación de un nuevo protocolo de tomografía computarizada corporal total para el manejo de pacientes con trauma severo.Este estudio es una evaluación descriptiva de pacientes que recibieron tomografía computarizada corporal total. Los pacientes fueron divididos en 3 grupos: 1. Trauma cerrado hemodinámicamente estables, 2. Trauma cerrado hemodinámicamente inestables y 3. Trauma penetrante. Se evaluaron las características demográficas, parámetros relacionados con la técnica y los desenlaces de los pacientes.Se incluyeron 263 pacientes. La mediana del puntaje de severidad de la lesión fue 22 (RIQ: 16-22). El tiempo entre el ingreso a urgencias y completar la tomografía corporal total fue menor a 30 minutos en la mayoría de pacientes [Grupo 1: 28 minutos (RIQ: 14-55), Grupo 2: 29 minutos (RIQ: 16-57), y Grupo 3: 31 minutos (RIQ: 13-50;Este nuevo protocolo de tomografía corporal total de un solo pase fue seguro, efectivo y eficiente para definir si los pacientes con trauma severo requieren o no una intervención quirúrgica. Su uso podría reducir la tasa de intervenciones quirúrgicas innecesarias en estos pacientes incluyendo los que se presentan con trauma penetrante.

[Background] Strict guidelines delimit the use of computational information in the clinical setting, due to the still moderate accuracy of in silico tools. These guidelines indicate that several tools should always be used and that full coincidence between them is required if we want to consider their results as supporting evidence in medical decision processes. Application of this simple rule certainly decreases the error rate of in silico pathogenicity assignments. However, when predictors disagree this rule results in the rejection of potentially valuable information for a number of variants. In this work, we focus on these variants of the protein sequence and develop specific predictors to help improve the success rate of their annotation., [Results] We have used a set of 59,442 protein sequence variants (15,723 pathological and 43,719 neutral) from 228 proteins to identify those cases for which pathogenicity predictors disagree. We have repeated this process for all the possible combinations of five known methods (SIFT, PolyPhen-2, PON-P2, CADD and MutationTaster2). For each resulting subset we have trained a specific pathogenicity predictor. We find that these specific predictors are able to discriminate between neutral and pathogenic variants, with a success rate different from random. They tend to outperform the constitutive methods but this trend decreases as the performance of the constitutive predictor improves (e.g. with PON-P2 and PolyPhen-2). We also find that specific methods outperform standard consensus methods (Condel and CAROL)., [Conclusion] Focusing development efforts on the case of variants for which known methods disagree we may obtain pathogenicity predictors with improved performances. Although we have not yet reached the success rate that allows the use of this computational evidence in a clinical setting, the simplicity of the approach indicates that more advanced methods may reach this goal in a close future., This work has been supported by the spanish Ministerio de Economía y Competitividad (BIO2012–40133; SAF2016–80255-R). It has also been supported, and the publication costs have been defrayed, by the European Regional Development Fund (ERDF), through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014–2020), research grant PIREPRED (EFA086/15).

The secondary metabolism of bacteria, fungi and plants yields a vast number of bioactive substances. The constantly increasing amount of published genomic data provides the opportunity for an efficient identification of gene clusters by genome mining. Conversely, for many natural products with resolved structures, the encoding gene clusters have not been identified yet. Even though genome mining tools have become significantly more efficient in the identification of biosynthetic gene clusters, structural elucidation of the actual secondary metabolite is still challenging, especially due to as yet unpredictable post-modifications. Here, we introduce SeMPI, a web server providing a prediction and identification pipeline for natural products synthesized by polyketide synthases of type I modular. In order to limit the possible structures of PKS products and to include putative tailoring reactions, a structural comparison with annotated natural products was introduced. Furthermore, a benchmark was designed based on 40 gene clusters with annotated PKS products. The web server of the pipeline (SeMPI) is freely available at: http://www.pharmaceutical-bioinformatics.de/sempi.

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

The usage of next-generation sequencing with biomedical/clinical purposes has fuelled the demand for tools that assess the functional impact of sequence variants. For single amino acid variants, general methods (GM), based on biophysics/evolutionary principles and trained by pooling variants from many proteins, are already available. Until now, their accuracy range (∼80%) has limited their usage in clinical applications. In parallel, a series of studies indicate that protein-specific predictors (PSP), using only information from the protein of interest, could frequently surpass the performance of GM. However, two reasons suggest that this may not always be the case: the existence of a performance threshold affecting both GM and PSP, and the effect of training data scarcity. Here, we characterize the relationship between the two approaches deriving 82 PSP and comparing them with several GM (PolyPhen-2, SIFT, PON-P2, MutationTaster2, CADD). We find a complementary relationship between PSP and GM, with no approach always outperforming the other. However, the relationship varies between two limiting situations, for example, PSP are frequently outperformed by PON-P2, the best GM; however, the opposite happens when we compare PSP and SIFT. Finally, we explore how the observed complementarity could lead to increased success rates in pathogenicity prediction.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.

Morbidly adherent placenta (MAP), which includes accreta, increta, and percreta, is a condition characterized by the invasion of the uterine wall by placental tissue. The condition is associated with higher odds of massive post-partum hemorrhage. Several interventions have been developed to improve hemorrhage-related outcomes in these patients; however, there is no evidence to prefer any intervention over another. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an endovascular intervention that may be useful and effective to reduce hemorrhage and transfusions in MAP patients. The objective of this narrative review is to summarize the evidence for REBOA in patients with MAP. We posit that acute care surgeons can perform REBOA for patients with MAP.

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.

Background Attention Deficit Hyperactivity Disorders (ADHD) is a neurodevelopmental disorder characterized by impairment in sustaining attention and inability to control impulses and modulate activity level. The aetiology of ADHD is complex, involving genetic and environmental factors, with an estimated heritability of 70–80%. Nevertheless, inconsistencies in the results of the genetic studies on ADHD may be explained, in part, by epigenetic mechanisms such as microRNAs (miRNAs) which play important roles in the control of gene expression by pairing to target mRNAs. Under the hypothesis that alterations in the processing or target binding of miRNAs may result in differential mRNA expression profiles predisposing to ADHD, we performed mRNA and miRNA expression profiling in Peripheral Blood Mononuclear Cells (PBMCs) of 103 persistent ADHD individuals and 115 controls. Methods miRNA and mRNA expression profiling in PBMCs of 103 ADHD patients and 115 controls were assessed by high-throughput deep sequencing (HiSeq. 2000, Illumina) and the Human Gene 1,1 ST microarray (Affymetrix), respectively. The analyses of differential expression for miRNA and mRNA were carried out separately applying Linear Model Fit using the Limma R package. ROC curves were used to evaluate the accuracy of the differentially expressed miRNAs in discriminating patients with ADHD from controls in an independent sample of 46 cases and 46 controls. In order to build miRNA-mRNA interaction networks that may be relevant to ADHD, including positive and negative relationships, we integrated the expression data of miRNAs and mRNAs differentially expressed in ADHD (adjusted p-values Results After quality control, normalization and background correction, a total of 573 miRNAs and 19,784 transcripts were included in the analysis. We identified a total of 79 miRNAs and 1,592 transcripts differentially expressed in ADHD when compared to controls. Of them, miR-191-5p and miR-23a-5p showed values of AUC > 0.70 in the test sample; they were selected for the subsequent correlation analysis. Evidence for 126 miRNA-mRNA pairs was found (p Discussion In conclusion, our findings provide for the first time tentative evidence for the contribution of miR-23a-5p - OCIAD2 correlated network to ADHD etiology through a comprehensive differentially expression analysis of miRNA and mRNA in PMBCs.

Colobran, Roger et al., The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population., This study was funded by Instituto de Salud Carlos III, grant PI14/00405, cofinanced by the European Regional Development Fund (ERDF), and by MINECO grant CGL2013-44351-P.