Utilidad de la ecografía pulmonar clínica en la bronquiolitis moderada-grave

La bronquiolitis aguda es un síndrome clínico muy frecuente en la infancia. Es una enfermedad inflamatoria de los bronquiolos, fundamentalmente causado por el virus respiratorio sincitial, que supone una gran carga asistencial anual tanto en atención primaria como hospitalaria. Sólo un pequeño porcentaje de los niños precisan ingreso en la Unidad de Cuidados Intensivos Pediátricos (UCIP), fundamentalmente los lactantes más pequeños, y aquellos con factores de riesgo, por insuficiencia respiratoria o complicaciones de la enfermedad. Las pausas de apnea y el fallo hipercápnico secundario a fatiga son las causas más frecuentes de necesidad de ingreso en UCIP, aunque la hipoxemia producida por la formación de atelectasias puede también requerir soporte respiratorio avanzado. La bronquiolitis aguda es una entidad de difícil manejo clínico, ya que suele comportarse con un patrón mixto de patología restrictiva con áreas de pérdida de aireación y cortocircuito intrapulmonar, y un patrón obstructivo de atrapamiento aéreo y sobredistensión. El diagnóstico es clínico, y su tratamiento se basa fundamentalmente en medidas de soporte. El soporte respiratorio no invasivo (oxigenoterapia de alto flujo y ventilación no invasiva con uno o dos niveles de presión) proporciona oxígeno húmedo y caliente, y mejora los flujos inspiratorio y espiratorio, consiguiendo disminuir el esfuerzo respiratorio, el colapso dinámico de la vía aérea, y una mejoría del intercambio gaseoso, en muchos casos evitando la necesidad de intubación y ventilación mecánica. La ecografía clínica o en el punto de atención, llevada a cabo por los profesionales directamente encargados del cuidado de los pacientes, ha supuesto un gran avance en la práctica clínica, permitiendo un estudio dinámico y dirigido, que aporta una información anatómica y/o fisiológica que integrar a los datos clínicos y de laboratorio, para la toma de decisiones terapéuticas y la monitorización de la respuesta. Su disponibilidad, inocuidad y la posibilidad de repetirla tantas veces como sea necesario, la han convertido en una herramienta indispensable en los Servicios de Cuidados Intensivos. El mayor potencial cancerígeno de la radiación ionizante en niños ha despertado el interés de esta disciplina en el campo de la Pediatría en los últimos años. La ecografía pulmonar clínica es una de las modalidades que más posibilidades ofrece. La técnica y la semiología son fáciles de aprender. La imágenes que se obtienen son una combinación de artefactos e imágenes reales, en función de la normal aireación del pulmón, o de la pérdida de la misma por ocupación parcial o total de líquido. Dado que los artefactos pueden clasificarse de acuerdo con la relación aire/líquido, es posible crear puntuaciones que reflejen inversamente el grado de aireación pulmonar. En adultos se han usado distintos scores de puntuación cuantitativos para valorar el grado de aireación pulmonar, que parecen ser sólo útiles en trastornos pulmonares restrictivos (síndrome de distrés respiratorio agudo, neumonías, etc.). En los últimos años se han ido publicando algunos estudios sobre la utilidad de la ecografía pulmonar clínica en las bronquiolitis agudas. Se ha descrito el patrón ecográfico de las mismas, la correlación con la gravedad clínica, y cierta capacidad predictiva de los hallazgos ecográficos con la necesidad y duración de hospitalización, oxigenoterapia y soporte respiratorio distinto del oxígeno convencional, aunque no hay estudios suficientes que incluyan pacientes graves en UCIP. Por lo tanto, no está comprobado que la mejoría de la función respiratoria que experimentan los niños con bronquiolitis agudas moderadas y graves sometidos a soporte respiratorio no invasivo en la UCIP sea debido a una mejoría de la aireación pulmonar, ni que patrones de mayor pérdida de aireación pulmonar supongan una mayor gravedad clínica. Por ello llevamos a cabo este estudio, para cuantificar la aireación pulmonar mediante ecografía, describir el patrón ecográfico al ingreso en UCIP de las bronquiolitis agudas moderadas y graves, analizar la asociación entre el score ecográfico de aireación pulmonar con la escala de gravedad clínica y con la evolución clínica, valorar la capacidad predictiva del score ecográfico de aireación pulmonar con la necesidad de ventilación mecánica, y estudiar la concordancia inter-observador en cuanto a los hallazgos ecográficos. 95 Llevamos a cabo un estudio prospectivo observacional en la UCIP del Hospital Universitario Ramón y Cajal, en tres periodos epidémicos de virus respiratorio sincitial. El estudio incluyó un total de 36 niños <2 años con diagnóstico de bronquiolitis aguda, que precisaron soporte respiratorio con oxigenoterapia de alto flujo o ventilación no invasiva, y en los que fue posible realizar dos exploraciones ecográficas. Se realizó una primera valoración clínica y ecográfica al ingreso en UCIP, y una segunda valoración tras 2-3 horas de haber iniciado el soporte respiratorio no invasivo. Se obtuvo un score de aireación pulmonar cuantitativo que poder comparar. No pudimos demostrar que la aireación pulmonar cuantificada mediante el score ecográfico de aireación pulmonar tuviera correlación alguna con la puntuación de la escala clínica de gravedad, pero si encontramos relación con la evolución clínica posterior en cuanto a duración del ingreso en UCIP y duración de hospitalización total. Los niños menores de 3 meses presentaron una mayor pérdida de aireación pulmonar reflejando un mayor componente de afectación restrictiva. El virus respiratorio sincitial aislado o en coinfección con otros virus respiratorios no condicionó diferentes patrones de aireación pulmonar. Tampoco encontramos capacidad predictiva del score ecográfico de aireación pulmonar al inicio del soporte respiratorio no invasivo con la necesidad ni duración de ventilación mecánica. Los hallazgos ecográficos de las bronquiolitis agudas son múltiples pero inespecíficos, por lo que la ecografía pulmonar clínica no puede utilizarse como una prueba independiente para el diagnóstico, debiendo se considerada como una extensión de la evaluación clínica. La concordancia inter-observador fue buena, mejor para los patrones extremos que para los patrones intermedios de pérdida de aireación.Acute bronchiolitis is a very common lung infection in young children and infants. It is an acute inflammatory injury of the bronchioles caused by a viral infection, usually the respiratory syncytial virus, and represents a large annual health care burden in both outpatient and inpatient settings. Only a small proportion of children require admission to the Pediatric Intensive Care Unit, particularly young infants and those with risk factors, due to respiratory failure or disease´s complications. Apnea and hypercapnic respiratory failure due to muscular fatigue are the most frequent reasons for admission to PICU, although hypoxemia caused by development of atelectasis may also require advanced respiratory support. Acute bronchiolitis usually presents with a mixed pattern of restrictive disease with areas of loss of aeration and intrapulmonary shunt, and an obstructive pattern of air trapping and overdistention, being a challenge its clinical management. Diagnosis of acute bronchiolitis is based on typical history and results of a physical examination, and its treatment is focused on supportive care. Non-invasive respiratory support (high-flow oxygen therapy and non-invasive ventilation with continuous positive airway pressure or two pressure levels) provides heated and humidified oxygen and improves inspiratory and expiratory flows, reducing respiratory effort, dynamic airway collapse, and improving gas exchange, in many cases avoiding the need for intubation and mechanical ventilation. Point-of-care ultrasound, ultrasound imaging acquired and interpreted by a treating clinician at the bedside of the patient, has emerged as an advance in clinical practice, allowing a dynamic study, which provides anatomical and/or physiological information to be integrated with clinical and laboratory data, for therapeutic decision-making and monitoring response, increasing the diagnostic accuracy of the traditional bedside assessment. Its bedside availability, safety and the possibility of repeating it as many times as necessary, make point of care ultrasound an emerging valuable and essential tool in Intensive Care Units. The concern that children are at a greater risk than adults to develop cancer after being exposed to radiation, has increase the interest of this discipline in the field of Pediatrics in recent years. Clinical lung ultrasound offers a valuable tool for the management of respiratory diseases. The technique and semiology are easy to learn. Lung ultrasound is based on interpretation of artifacts along with true images, depending on the normal aeration of the lung or its partial or complete loss. Since artifacts can be classified according to the air/fluid ratio, it is possible to create scores that inversely reflect the degree of lung aeration. In adults, different quantitative scores have been used to assess the degree of pulmonary aeration, which seems to be only useful in restrictive pulmonary disorders (acute respiratory distress syndrome, pneumonia, etc.). In recent years, some studies have been published on the usefulness of clinical lung ultrasound in acute bronchiolitis. The ultrasound pattern and its correlation with clinical severity, and a certain predictive capacity of ultrasound findings for the need and length of hospitalization, oxygen therapy, and respiratory support other than conventional oxygen have been described, but there are lack of studies including critical patients in PICU. Therefore, it has not been proven yet that the improvement in the respiratory function experienced by children with moderate and severe acute bronchiolitis undergoing noninvasive respiratory support in PICU is due to an improvement in pulmonary aeration, and neither that patterns of greater loss of pulmonary aeration lead to greater clinical severity. For this reason, we carried out this study, to quantify pulmonary aeration by ultrasound, describe the ultrasound pattern on admission to the PICU of moderate and severe acute bronchiolitis, analyze the association between the ultrasound pulmonary aeration score with the clinical severity score and with the clinical progression, to assess the predictive capacity of the ultrasound lung aeration score with the need for mechanical ventilation, and to study the inter-observer agreement regarding the ultrasound findings. We conducted a prospective observational study in the PICU of Ramón y Cajal University Hospital, in three epidemic seasons of respiratory syncytial virus. The study included a 98 total of 36 children <2 years old with clinical diagnosis of acute bronchiolitis, who needed respiratory support with high flow oxygen therapy or noninvasive ventilation, and in whom it was possible to perform two ultrasound examinations. A first clinical and ultrasound evaluation was performed on admission to the PICU, and a second evaluation 2-3 hours after starting noninvasive respiratory support. A quantitative pulmonary aeration score was obtained. We failed to demonstrate that the pulmonary aeration quantified by the ultrasound pulmonary aeration score had any correlation with the clinical severity, but we did find a correlation with the clinical progression in terms of length of PICU stay and length of hospital admission. Children younger than 3 months showed a greater loss of pulmonary aeration, showing a greater component of restrictive affectation. Respiratory syncytial virus infection, in single infection or in coinfection with other respiratory viruses did not determine different pulmonary aeration patterns. The ultrasound findings of acute bronchiolitis are multiple but non-specific, so clinical lung ultrasound cannot be used as an independent test for diagnosis, and should be considered as an extension of clinical evaluation. Inter-observer agreement was good, better for extreme patterns than for intermediate aeration loss patterns

Experiencia con la prótesis de pericardio bovino Carpentier-Edwards® en posición pulmonar en pacientes con cardiopatías congénitas

Introducción. El número de pacientes con cardiopatías complejas corregidas en la infancia que necesitan una sustitución valvular pulmonar para restaurar la competencia o solucionar la estenosis del tracto de salida de ventrículo derecho ha aumentado en los últimos años. El injerto ideal continúa siendo motivo de controversia. En el servicio de cirugía cardiovascular del Hospital Ramón y Cajal de España, se comenzó a utilizar prótesis de pericardio bovina de Carpentier-Edwards® siendo el objetivo de este estudio su evaluación a corto y medio plazo. Materiales y Métodos. Entre enero de 2004 y mayo de 2010 fueron intervenidos 42 pacientes para sustitución valvular pulmonar mediante prótesis de pericardio bovino. El estudio fue ambispectivo con prospección durante los dos últimos años. Resultados. La mediana de la edad fue de 20,96 años (amplitud intercuartil 10,5 años). El número medio de cirugías previas fue de 1,9±0,9 siendo el tiempo medio entre la última cirugía y la implantación de la prótesis de 17,2±7 años. Las indicaciones quirúrgicas fueron: disfunción del ventrículo derecho (45%), su dilatación progresiva (38%), arritmias ventriculares (14%) y síncopes (3%). La mortalidad precoz de causa cardiológica fue de dos pacientes. El tiempo medio de seguimiento fue de 2,1±1,4 años (rango entre 0,1 y 6,3 años) estando el 94,3% de ellos en clase funcional I de la New York Heart Association. El gradiente Doppler pico transprotésico por ecocardiografía fue de 18,5±17 mm Hg. No se observaron cambios degenerativos ni ningún tipo de deterioro estructural de la prótesis. Conclusiones. La prótesis de pericardio bovino en posición pulmonar presenta excelentes resultados a corto y medio plazo. Sin embargo, es necesario un seguimiento mayor para confirmar lo resultados iniciales respecto a su durabilidad y hemodinamia a largo plazo. Palabras Clave: Cardiopatías congénitas. Prótesis valvulares cardíacas. Tetralogía de Fallot. Válvula pulmonar. &nbsp;&nbsp; Experience with Carpentier Edwards® bovine pericardium prosthesis in pulmonary position in patients with congenital heart diseases.Introduction. In recent years the number of patients with complex congenital heart disease previously corrected in infancy who need a pulmonary valve replacement has increased dramatically. The ideal substitute remains a source of dispute. Nowadays, in the unit of cardiovascular surgery of the Hospital Ramon y Cajal in Spain, its being implanting in this position the bovine pericardium Carpentier-Edwards® prosthesis. The aim of the study its short and medium-term assessment. Material and methods. Between January 2004 and May of 2010, 42 patients have been operated for pulmonary valve replacement with pericardium prosthesis. The study was ambispective, being prospective in its last two years. Results. The median age of the patients was 20.96 years (interquartile 10.5 years). The mean number of surgeries prior to the pulmonary valve replacement was 1.9±0.9, being the mean time between the “corrective” surgery and the prosthetic implantation 17.2±7 years. The main indications for this surgery were: right ventricle dysfunction (45%), progressive dilation of the same ventricle (38%), ventricular arrhythmias (14%) and syncopes (3%). Two patients died in the immediate postoperative due to cardiological causes. The mean follow-up time has been 2.1±1.4 years (0.1-6.3). The 94.3 % of the surviving patients are in functional class I, according to the New York Health Association. The peak Doppler transprosthetic gradient determined by echocardiography was 18.5±17 mm Hg. In the echocardiograpic follow-up there have been neither degenerative changes nor any type of structural deterioration of the prosthesis. Conclusions. The bovine pericardium prosthesis in pulmonary position presents excellent results in the short and medium-term. However, it is necessary a longer follow-up to confirm our initial results regarding its durability and long-term haemodynamics. Keywords: Congenital abnormalities. Heart valve prosthesis. Tetralogy of Fallot. Pulmonary valve. Valve prosthesis implantation

Model for predicting early and late-onset postoperative pulmonary complications in perioperative patients receiving neuromuscular blockade: a secondary analysis

Pulmonary complications continue to be the most common adverse event after surgery. The main objective was to carry out two independent predictive models, both for early pulmonary complications in the Post-Anesthesia Care Unit and late-onset pulmonary complications after 30 postoperative days. The secondary objective was to determine whether presenting early complications subsequently causes patients to have other late-onset events. This is a secondary analysis of a cohort study. 714 patients were divided into four groups depending on the neuromuscular blocking agent, and spontaneous or pharmacological reversal. Incidence of late-onset complications if we have not previously had any early complications was 4.96%. If the patient has previously had early complications the incidence of late-onset complications was 22.02%. If airway obstruction occurs, the risk of atelectasis increased from 6.88 to 22.58% (p = 0.002). If hypoxemia occurs, the incidence increased from 5.82 to 21.79% (p < 0.001). Based on our predictive models, we conclude that diabetes mellitus and preoperative anemia are two risk factors for early and late-onset postoperative pulmonary complications, respectively. Hypoxemia and airway obstruction in Post-Anesthesia Care Unit increased four times the risk of the development of pneumonia and atelectasis at 30 postoperative days

Validation of a survival benefit estimator tool in a cohort of European kidney transplant recipients

Producción CientíficaPre-transplant prognostic scores help to optimize donor/recipient allocation and to minimize organ discard rates. Since most of these scores come from the US, direct application in non-US populations is not advisable. The Survival Benefit Estimator (SBE), built upon the Estimated Post-Transplant Survival (EPTS) and the Kidney Donor Profile Index (KDPI), has not been externally validated. We aimed to examine SBE in a cohort of Spanish kidney transplant recipients. We designed a retrospective cohortbased study of deceased-donor kidney transplants carried out in two different Spanish hospitals. Unadjusted and adjusted Cox models were applied for patient survival. Predictive models were compared using Harrell’s C statistics. SBE, EPTS and KDPI were independently associated with patient survival (p ≤ 0.01 in all models). Model discrimination measured with Harrell’s C statistics ranged from 0.57 (KDPI) to 0.69 (SBE) and 0.71 (EPTS). After adjustment, SBE presented similar calibration and discrimination power to that of EPTS. SBE tended to underestimate actual survival, mainly among high EPTS recipients/high KDPI donors. SBE performed acceptably well at discriminating posttransplant survival in a cohort of Spanish deceased-donor kidney transplant recipients, although its use as the main allocation guide, especially for high KDPI donors or high EPTS recipients requires further testing.Rio Hortega contract (ISCIII-11453)Fondo de Investigaciones Sanitarias - Fondo Europeo de Desarrollo Regional (project PI16/0617)Redinren (project RD16/0009/001

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006

Laparoscopic surgery in 3D improves results and surgeon convenience in sleeve gastrectomy for morbid obesity

Purpose Advanced laparoscopic procedures are still challenging. One critical issue is the lack of stereoscopic vision. The aim of this surgical study is to evaluate whether 3D vision offers any advantages for surgical performance over 2D vision during sleeve gastrectomy for morbid obesity using a laparoscopic system that allows changing between 2D and 3D optics. Methods A total of 78 patients were analyzed, with 37 in the 2D group and 41 in the 3D group. Performance time, hospital stay, complications, and early outcomes were collected. To assess the quality of the 2D and 3D techniques, visual analog scales from 0 to 10 were designed, and image quality, depth of field, precision in performing tasks, and general ergonomics were measured. Results According to the vision system used, the mean duration of surgery was 85 ± 16.8 min for patients operated on with the 2D system and 69 ± 16.9 min for those operated on with the 3D system. There were no significant differences between the overall percentages of complications according to the type of vision used. However, postoperative complications were more severe in the 2D laparoscopy group. The average length of stay was shorter for patients in the 3D group. Regarding the differences perceived by the surgeon, the depth of field and the precision of tasks were better in the 3D vision group. Conclusion The 3D system provided greater depth perception and precision in more complex tasks, enabling safer surgery. This led to a reduction in the operative time and hospital stay. Moreover, the severity of complications was less

Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless legs syndrome in the Spanish caucasian population

Varios trabajos recientes sugieren un posible papel de la deficiencia de vitamina D en la etiología o el síndrome de las piernas inquietas (RLS). Hemos analizado la posible relación de 2 polimorfismos de un solo nucleótido (SNP) en el receptor de la vitamina D3 (GEN VDR) con el riesgo de SPI. Hemos estudiado la variante alélica genotipo y frecuencias de VDR rs2228570 y rs731236 VDR SNPs en 205 RLS pacientes y 445 controles sanos mediante un ensayo TaqMan. Las frecuencias de los rs731236AAgenotype y la variante alélica rs731236un SPI fue significativamente inferior en los pacientes que en los controles (P<0,005 y 0,01, respectivamente). El síndrome de las piernas inquietas pacientes portadoras de la variante alélica rs731236G había una edad temprana en el inicio, y los portadores del genotipo GG731236rs tuvieron mayor severidad de RLS, aunque estos datos desaparecieron después de los análisis multivariados. Ninguno de los SNPs estudiados estaba relacionada con la positividad de la historia familiar de SPI. Estos resultados sugieren una modesta, pero significativa asociación entre rs731236 VDR SNP y el riesgo de síndrome de piernas inquietas.Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS. We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay. The frequencies of the rs731236AAgenotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P<0.005 and<0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS. These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.• Instituto de Salud Carlos III, Madrid, Fondo de Investigación Sanitaria: Ayudas PI12/00241, PI12/00324, y RETICS RD12/0013/0002 • Junta de Extremadura: GR15026 y PRIS10016 • Ministerio de Ciencia e Innovación: Ayudas SAF2006-10126 (2006–2009) y SAF2010-22329-C02-01 (2011-2013) • Parciamente financiado con Fondos FEDERpeerReviewe

Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless legs syndrome in the Spanish caucasian population

Varios trabajos recientes sugieren un posible papel de la deficiencia de vitamina D en la etiología o el síndrome de las piernas inquietas (RLS). Hemos analizado la posible relación de 2 polimorfismos de un solo nucleótido (SNP) en el receptor de la vitamina D3 (GEN VDR) con el riesgo de SPI. Hemos estudiado la variante alélica genotipo y frecuencias de VDR rs2228570 y rs731236 VDR SNPs en 205 RLS pacientes y 445 controles sanos mediante un ensayo TaqMan. Las frecuencias de los rs731236AAgenotype y la variante alélica rs731236un SPI fue significativamente inferior en los pacientes que en los controles (P<0,005 y 0,01, respectivamente). El síndrome de las piernas inquietas pacientes portadoras de la variante alélica rs731236G había una edad temprana en el inicio, y los portadores del genotipo GG731236rs tuvieron mayor severidad de RLS, aunque estos datos desaparecieron después de los análisis multivariados. Ninguno de los SNPs estudiados estaba relacionada con la positividad de la historia familiar de SPI. Estos resultados sugieren una modesta, pero significativa asociación entre rs731236 VDR SNP y el riesgo de síndrome de piernas inquietas.Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS. We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay. The frequencies of the rs731236AAgenotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P<0.005 and<0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS. These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.• Instituto de Salud Carlos III, Madrid, Fondo de Investigación Sanitaria: Ayudas PI12/00241, PI12/00324, y RETICS RD12/0013/0002 • Junta de Extremadura: GR15026 y PRIS10016 • Ministerio de Ciencia e Innovación: Ayudas SAF2006-10126 (2006–2009) y SAF2010-22329-C02-01 (2011-2013) • Parciamente financiado con Fondos FEDERpeerReviewe

Heme oxygenase-1 and 2 common genetic variants and risk for restless legs syndrome

Varios neurotransmisores, neuropatológicos, neuroimagen, y los datos experimentales, sugieren que la deficiencia de hierro juega un papel importante en la fisiopatología del síndrome de piernas inquietas (RLS). HMOX (Hemeoxygenases) es un importante mecanismo de defensa contra el estrés oxidativo, principalmente a través de la degradación del hemo a biliverdin, libre de hierro, y monóxido de carbono. Hemos analizado si los genes HMOX1 y HMOX2 están relacionados con el riesgo de desarrollar el síndrome de piernas inquietas. Se analizó la distribución de genotipos y las frecuencias alélicas de los HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363 y rs1051308 HMOX2 SNPs, así como la presencia de variaciones de número de copia (CNVs) de estos genes en 205 sujetos RLS y 445 controles sanos. Las frecuencias de rs2071746 genotipo TT y R2071746T variante alélica fueron significativamente inferiores en los pacientes de SPI que en controles, aunque los otros 3 SNPs estudiados RLS no difirió entre pacientes y controles. Ninguno de los polimorfismos estudiados influyeron en el inicio de la enfermedad, la gravedad de la RLS, historia familiar de SPI, la ferritina sérica, o respuesta a agonistas dopaminérgicos, clonazepam o GABAergic drogas. El presente estudio sugiere una débil asociación entre el polimorfismo rs2071746 HMOX1 y el riesgo de desarrollar el SPI en la población española.Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Hemeoxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls. The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs. The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population.• Instituto de Salud Carlos III, Fondo de Investigación Sanitaria: Ayudas PI12/00241, PI12/00324 y RETICS RD12/0013/0002 • Junta de Extremadura: Ayuda GR10068 GR10068 y PRIS10016 (Fundesalud,Mérida, Spain) • Ministerio de Ciencia e Innovación: Ayudas SAF2006-10126 (2006–2009) y SAF2010-22329-C02-01 (2011–2013) • Parcialmente financiado Fondos FEDER – Fondo Europeo de Desarrollo RegionalpeerReviewe

TRAF3 alterations are frequent in del-3′IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3′IGH (del-3′IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3′IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3′IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3′IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3′IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3′IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.Funding information: Universidad de Salamanca; Fundación Española de Hematología y Hemoterapia (FEHH); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Grant/Award Number: CB16/12/00233; Red Temática de Investigación Cooperativa en Cáncer (RTICC); “Fundación Memoria Don Samuel Solórzano Barruso”: FS/33–2020, Grant/Award Number: RD12/0036/0069; “Gerencia Regional de Salud, SACYL”:, Grant/Award Numbers: GRS2385/A/21, GRS2140/A/20; Consejería de Educación, Junta de Castilla y León, Grant/Award Number: SA118P20; European Regional Development Fund and Instituto de Salud Carlos III, Grant/Award Numbers: CD19/00222, FI19/00191; Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI21/00983, PI18/0150