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Abstract The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.

In May 1962 Pier Paolo Pasolini began recording some of his poems for the Rca Italiana record label. His participation, edited by Sergio Bardotti, begins the «Edizioni letterarie» series in which there will be collaborations with Giuseppe Ungaretti, Eugenio Montale or Salvatore Quasimodo. This project marks the turning point of the Rca in the studios of via Tiburtina and as regards contemporary Italian literature, it calls into question the possible benefits of recording the voice of poets on the written text. For Pasolini, it represents the opportunity to deal with his voice for the first time as an author-reader. But not only that, in the act of reading the tercets of the text chosen for the recording, the unpublished La Guinea, he reworks the poem by bringing this new multimedia medium closer to the modus operandi of Pasolini’s laboratory. From the following recording with Rca; the readings in the films for Rai and Rsi up to the debate held in Lecce in October 1975. In this essay we will retrace all the moments in which the poet reads his poems aloud.

Introduction: Breastfeeding appears to protect the onset of obesity in infants. The aim is to know whether breastfeeding duration is associated with the risk of obesity in infants and toddlers aged 12 and 24 months. Material and methods: Prospective longitudinal study in a cohort of children born in Spain between April 2017 and March 2018 (LAyDI study) in the paediatric primary care system conducted in the framework of the PAPenRed research network. Analysis of breastfeeding duration (group 1: fewer than 6 months; group: more than 6 months) and its association with anthropometric variables. Results: A total of 1495 patients attended the 12 months preventive child health visit and 1073 patients the 24 months visit. We found a statistically significant association between breastfeeding duration and weight-for-age, BMI-for-age and weight-for-length/height at 12 and 24 months; breastfeeding duration of less than 6 months was significantly associated with overweight and obesity (based on BMI-for-age and weight-for-length/height) at ages 12 and 24 months. Maternal pre-pregnancy BMI acted as a modifier on the association between breastfeeding duration and overweight and obesity (based on BMI-for-age). Conclusions: A breastfeeding duration of less than 6 months is associated with a higher percentage of overweight and obesity at ages 12 and 24 months, although maternal pre-pregnancy BMI modifies this relationship at 24 months. Resumen: Introducción: La lactancia materna parece proteger la aparición de la obesidad en los lactantes. El objetivo es conocer si la duración de la lactancia materna se relaciona con el riesgo de obesidad en lactantes de 12 y 24 meses de edad. Material y métodos: Estudio longitudinal prospectivo de una cohorte de nacidos en España entre abril de 2017 y marzo de 2018 (estudio LAyDI) en pediatría de atención primaria, dentro de la red de investigación PAPenRed. Análisis de duración de lactancia materna (Grupo 1: menos de 6 meses, Grupo: más de 6 meses) y su relación con parámetros somatométricos. Resultados: Acudieron a la visita de los 12 meses un total de 1495 pacientes, y a la de los 24 meses 1073 pacientes. Se observa una relación estadísticamente significativa entre la duración de la lactancia materna y el peso para la edad, el IMC para la edad y el peso para longitud/talla a los 12 y 24 meses, la duración de la lactancia materna menor de 6 meses se relaciona con el sobrepeso y obesidad (según los índices IMC para la edad y peso para la longitud/talla) de forma estadísticamente significativa a los 12 y 24 meses de edad. El IMC pregestacional materno es una variable modificadora de efecto sobre la relación entre la duración de la lactancia materna y el sobrepeso y obesidad (por IMC para la edad). Conclusiones: La duración menor de 6 meses de la lactancia materna se asocia a un mayor porcentaje de sobrepeso y obesidad a los 12 y 24 meses, aunque el IMC materno pregestacional modifica esta relación a los 24 meses.

IntroductionEnrolling children with cancer in early phase trials is crucial to access innovative treatments, contributing to advancing pediatric oncology research and providing tailored therapeutic options. Our objective is to analyze the impact of these trials on patient outcomes and safety, and to examine the evolution and feasibility of trials in pediatric cancer over the past decade.MethodsAll patients recruited in pediatric anticancer phase I/II clinical trials from January 2014 to December 2022 were included. Clinical records and trial protocols were analyzed.ResultsA total of 215 patients (median age 11.2 years, range 1–29.5) were included in 52 trials (258 inclusions). Patients with extracranial solid tumors (67%), central nervous system (CNS) tumors (24%), and leukemia (9%) were included. The most common investigational drugs were small molecules (28.3%) and antibodies (20.5%). Serious adverse events were experienced by 41% of patients, 4.4% discontinued treatment because of toxicity and two had toxic deaths. Median event-free survival was 3.7 months (95%CI: 2.8–4.5), longer in phase II trials than in phase I (2 vs. 6.3 months; p ≤ 0.001). Median overall survival was 12 months (95%CI: 9–15), higher in target-specific vs. non-target-specific trials (14 vs. 6 months; p ≤ 0.001).DiscussionA significant and increasing number of patients have been included in early clinical trials, suggesting that both oncologists and families consider it valuable to be referred to specialized Units to access new therapies. Moreover, our data suggests that participation in early clinical trials, although not without potential toxicities, might have a positive impact on individual outcomes.

Climate change is causing the alteration of atmospheric dynamics, leading to extreme precipitation events and floods. On the other hand, landscape modification and increased imperviousness due to urbanization exacerbate the impacts of flooding. In order to become more permeable, cities are increasingly embracing aquatic Nature-based Solutions which, using natural processes, allow for the mitigation of water-related hazards. One of these solutions is floodable parks, where pluvial runoff is conveyed for its temporal storage into, firstly, permanent retention ponds and, eventually, the partial or totality of their surface. Floodable parks are still a novel aquatic Nature-based Solution and have not yet been investigated. In this paper, a systematic review on current floodable parks was performed in order to study (1) the conditions needed for their implementation, (2) their design, and (3) the connection between design and ecosystem services. A subsequent systematic review was performed to understand (4) the processes occurring within the park. With the obtained information, a conceptual model of floodable parks was developed. The results indicate that both the vegetation surrounding the permanent pond of the floodable park and the biodiversity within the pond enhance the performance of this solution and allow potential water reuse. The implementation of floodable parks will therefore facilitate the transformation of urban areas to create sustainable, climate-resilient, and circular cities.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström’s macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Abstract MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients.

In sight of a growing urban population and intensified extreme weather events, cities must integrate in their urban planning elements to both reduce their impact (i.e., air and water pollution, degradation of habitats, loss of biodiversity) and increase their resilience to climate change. In contrast to engineering solutions, which normally not only fail to adequately address these issues but often also exacerbate them, Nature-based Solutions are an efficient strategy which can help cities become more sustainable. Aqua-Nature-based Solutions (aNBS) tackle water-related hazards by enhancing water regulation and mitigating flood and drought impacts. However, under a warming climate, aNBS are expected to often dry-out, changing biodiversity and the ecosystem services they support. The aim of this study is to compare the biodiversity of temporarily and permanently wet urban waterbodies which function as aNBS. We selected two pond complexes with different hydroperiod (i.e., different duration, amplitude and frequency of inundation) and studied the riparian vegetation and aquatic macroinvertebrate biodiversity. The Multimetric Macroinvertebrate Index of Flanders was used to determine the macroinvertebrate biodiversity and to assess water quality of the ponds. Using water stable isotopes and piezometers, the hydrological dynamics were studied in order to identify the water regulating ecosystem services these ponds deliver. The results showed that the selected pond complexes have a high plant biodiversity, particularly in temporary ponds. Water quality ranged from moderate to poor and macroinvertebrate biodiversity tended to be greater in permanent ponds. Plant and macroinvertebrate alien species were also found in the aNBS. Regarding water regulating ecosystem services, the pond complexes enhanced infiltration and groundwater recharge, providing resilience to both flooding and drought. Our findings corroborate previous studies on the need of diversifying urban ponds’ hydroperiod to support biodiversity. Thus, integrating well-designed aNBS into urban planning might be a way to make cities more resilient to water climate-related hazards while enhancing biodiversity.

Resumen: Objetivo: Conocer estadísticas reales sobre lactancia materna en España, así como factores socioculturales y perinatales que afectan a su inicio y mantenimiento. Diseño: Estudio prospectivo, multicéntrico, longitudinal, de ámbito nacional (estudio LAyDI). Sitio: Consulta de pediatras de atención primaria. Participantes: Cohorte de recién nacidos entre abril de 2017 y marzo de 2018 en España que se siguieron hasta los dos años en ocho visitas. Medidas principales: Se analizaron las tasas de los diferentes tipos de lactancia en cada visita y también se analizaron variables relacionadas con la gestación, el parto, el período neonatal, sociales, económicas y biológicas. Resultados: Muestra inicial de 1.946 (50,1% varones). El 90,7% decidieron iniciar lactancia materna al nacimiento. La cifra de lactancia materna exclusiva (LME) fue del 66,4% a los 15 días y del 35,2% a los 6 meses. Cualquier tipo de lactancia materna (lactancia materna total [LMT]) a los 6 meses fue del 61,7%. La supervivencia de LMT presentó una mediana de 6,0 meses (IC 95%: 6,0-6,1). Variables relacionadas con LME a los 15 días: hijos previos, nivel de educación de madre, ausencia de enfermedad durante el embarazo, no separación madre e hijo al nacer, no utilización de chupete, no existencia de problemas en pezones, y momento de decisión tipo lactancia. Variables relacionadas con mayor duración LMT son: la relación mayor de 5 años de los padres, no usar de chupete, colecho al mes de vida, decidir lactancia materna antes del embarazo, recibir información sobre lactancia durante el embarazo y utilizar apoyo de asociaciones. Conclusiones: El abandono temprano de la lactancia materna es un problema importante en las sociedades occidentales. Existen factores sobre los que se puede actuar para mejorar resultados. Abstract: Objective: To find out actual statistics on breastfeeding in Spain, as well as sociocultural and perinatal factors that affect its initiation and maintenance. Design: Prospective, multicentre, longitudinal, nationwide study (XXX study). Site: Primary care paediatricians’ office. Participants: Cohort of newborns born between April 2017 and March 2018 in Spain who were followed up to two years of age in 8 visits. Main measures: Rates of different types of breastfeeding were analysed at each visit and variables related to gestation, delivery, neonatal period, social, economic and biological variables were also analysed. Results: Initial sample of 1946 (50.1% male). 90.7% decided to initiate breastfeeding at birth. Exclusive breastfeeding (EBF) was 66.4% at 15 days and 35.2% at 6 months. Any type of breastfeeding (total breastfeeding [TBF]) at 6 months was 61.7%. Median survival from TBF was 6.0 months (95% CI: 6.0-6.1). Variables related to EBF at 15 days: previous children, mother's level of education, absence of illness during pregnancy, no separation of mother and child at birth, no dummy use, no nipple problems, and time of decision to breastfeed. Variables related to longer duration of TBF: relationship of parents older than 5 years, no dummy use, co-sleeping at one month of life, deciding to breastfeed before pregnancy, receiving information on breastfeeding during pregnancy and using support from associations. Conclusions: Early abandonment of breastfeeding is a major problem in Western societies. There are factors that can be worked on to improve outcomes.

Resumen: Introducción: El monitor NIPE (Newborn Infant Parasympathetic Evaluation) es una herramienta rápida, continua y objetiva de evaluación del disconfort neonatal. Los objetivos fueron describir los cambios del NIPE tras una extracción sanguínea y los factores implicados en su variación. Material y métodos: Estudio observacional analítico con recogida de datos prospectiva. Se incluyeron los recién nacidos ingresados en cuidados intensivos entre junio y diciembre de 2021 a quienes se les realizó extracción sanguínea. Se recogieron variables demográficas, las relacionadas con la realización del procedimiento, la puntuación NIPE, la frecuencia cardiaca previa y en los minutos 1, 2, 3, 4, 5, 10 y 15 posteriores. Resultados: Se incluyeron 86 registros de 49 pacientes. Durante los primeros cuatro minutos tras el procedimiento hubo un descenso significativo en la puntuación NIPE, siendo el descenso máximo de un 22,8% respecto al valor basal, produciéndose el nadir a los 2,79 minutos. El mayor descenso del NIPE ocurrió en pacientes prematuros, varones, con menor Apgar a los cinco minutos, en procedimientos ya realizados previamente, tras cesárea y en horario matutino. No hubo diferencias con la realización en canguro. La correlación entre NIPE y frecuencia cardíaca fue débil. Conclusiones: Tras un procedimiento doloroso, como una extracción sanguínea, el monitor NIPE mostró un descenso significativo los primeros cuatro minutos, agudizándose el descenso con la prematuridad, la reiteración de procedimientos o el nacimiento tras cesárea. El monitor NIPE puede ayudar a identificar eficazmente a aquellos neonatos que sufren dolor agudo tras un procedimiento, complementándose con las escalas de valoración clínica. Abstract: Introduction: The Newborn Infant Parasympathetic Evaluation (NIPE) index is an instrument that enables continuous, fast and objective assessment of neonatal discomfort. The aim of the study was to analyse changes in NIPE values after performance of blood draws and the factors involved in this variation. Material and methods: We conducted a prospective observational study. We included infants admitted to the neonatal intensive care unit between June and December 2021 who underwent blood draws. We recorded demographic data, aspects related to the procedure, the NIPE index and the heart rate at baseline and 1, 2, 3, 4, 5, 10 and 15 min after the procedure. Results: The study included 86 records for 49 patients. In the first 4 min after the procedure, there was a significant decrease in the NIPE index, with a maximum decrease of 22.8% relative to baseline and the nadir at 2.79 min. The decrease in NIPE values was greater in infants born preterm, male, with lower 5-min Apgar scores and following procedures that had been performed previously, after caesarean section or in the morning. There were no differences when the blood draw was obtained during kangaroo care. The correlation between the NIPE index and the heart rate was weak. Conclusions: After a painful procedure, such as a blood draw, the NIPE monitor showed a significant decrease in the first 4 min, which was more pronounced in preterm infants, in repeated procedures or after caesarean delivery. The NIPE index could help identify infants experiencing acute procedural pain, complementing clinical rating scales.

For the film Edipo re (1967), Pier Paolo Pasolini wrote four screenplays, which are now in the “Alessandro Bonsanti” Contemporary Archive at the Gabinetto G. P. Vieusseux in Florence. From the first script written in 1966 to the final one published in the volume edited by Garzanti, Pasolini made continuous modifications and corrections to the text in order to make it suitable for the film. A careful study of the four different scripts conserved in the Vieusseux allows us not only to examine Pasolini’s modus operandi as a scriptwriter, but also to observe the evolution between the different scripts. In fact, the final text is the combination of a technical script with a narrative text: these two typologies are combined, giving rise to a single hybrid text with original characteristics.

Abstract Biological nitrogen fixation (BNF) is the reduction of N2 into NH3 in a group of prokaryotes by an extremely O2-sensitive protein complex called nitrogenase. Transfer of the BNF pathway directly into plants, rather than by association with microorganisms, could generate crops that are less dependent on synthetic nitrogen fertilizers and increase agricultural productivity and sustainability. In the laboratory, nitrogenase activity is commonly determined by measuring ethylene produced from the nitrogenase-dependent reduction of acetylene (ARA) using a gas chromatograph. The ARA is not well suited for analysis of large sample sets nor easily adapted to automated robotic determination of nitrogenase activities. Here, we show that a reduced sulfonated viologen derivative (S2Vred) assay can replace the ARA for simultaneous analysis of isolated nitrogenase proteins using a microplate reader. We used the S2Vred to screen a library of NifH nitrogenase components targeted to mitochondria in yeast. Two NifH proteins presented properties of great interest for engineering of nitrogen fixation in plants, namely NifM independency, to reduce the number of genes to be transferred to the eukaryotic host; and O2 resistance, to expand the half-life of NifH iron-sulfur cluster in a eukaryotic cell. This study established that NifH from Dehalococcoides ethenogenes did not require NifM for solubility, [Fe-S] cluster occupancy or functionality, and that NifH from Geobacter sulfurreducens was more resistant to O2 exposure than the other NifH proteins tested. It demonstrates that nitrogenase components with specific biochemical properties such as a wider range of O2 tolerance exist in Nature, and that their identification should be an area of focus for the engineering of nitrogen-fixing crops.

Background: Corticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology. Methods: Retrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a Spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease. Results: The study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/m2, and all doses were administered in a period during which the disease was in remission. The depletion of lymphocytes B (CD19, 0%) were confirmed after the first dose of Rituximab except for one, with a lymphocyte count of 1%. The period of depletion lasts 10,3 months (median; range 6,5–16 months), and only one of the patients registered a relapse of the disease in this period. A reduction of relapses suffered by patients has been shown after the treatment began (3,6 relapses/year in the previous year to the start of the treatment versus 0,1 relapses/year during the first year post-rituximab). The relapse-free survival in the first year reached 83,3% in patients who suffered more than one relapse (75% of patients), and without a relapse after the treatment began in 2 cases. One or more drugs could be removed in 87,5% of patients after the first cycle of rituximab. After the rituximab treatment, we reached a 96,5% decrease in the corticosteroids doses administered (28,5 mg/m2/day during the 3 months pre-treatment versus 1 mg/m2/day in the last 3 months of patient monitoring). Not a significant observed adverse effect attributed to the drug after the post-rituximab monitoring period (median 46,5 months, range 5–97 months). Conclusion: The favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms. Resumen: Introducción: La corticoterapia continúa siendo la piedra angular en el tratamiento del síndrome nefrótico. El manejo de los pacientes que desarrollan dependencia a esteroides es complejo, implicando distintas pautas de fármacos inmunosupresores. El rituximab, anticuerpo monoclonal anti-CD20, parece tener efectos beneficiosos en pacientes con síndrome nefrótico córtico-dependiente de difícil manejo clínico, si bien aún no está bien definido su papel en esta entidad. Con el fin de aportar información útil sobre el papel del rituximab en esta patología, presentamos nuestra experiencia personal en pacientes pediátricos tratados con este fármaco en los últimos años. Materiales y métodos: Estudio retrospectivo en pacientes con síndrome nefrótico idiopático cortico-dependiente controlados en la Sección de Nefrología Pediátrica de un hospital terciario español y que habían recibido, al menos, un ciclo de tratamiento con rituximab durante cualquier momento de la evolución de la enfermedad. Resultados: Se incluyeron en el estudio 8 pacientes. Todos habían recibido terapia inmunosupresora previamente. El rituximab se administró por vía intravenosa a una dosis de 375 mg/m2, y todas las dosis se administraron en situación de remisión de la enfermedad. Se confirmó la depleción completa de linfocitos B (CD19, 0%) tras la primera dosis de rituximab en todos excepto en uno, en el que el recuento fue del 1%. El período de depleción fue de 10,3 meses (mediana; rango 6,5–16 meses), y solamente en uno de los pacientes se registró una recaída de la enfermedad durante este período. Tras el inicio del tratamiento, se observó una reducción del número de recaídas (3,6 recaídas/año en el año previo al inicio del tratamiento versus 0,1 recaídas/año durante el primer año post-rituximab). La supervivencia libre de recaída en el primer año fue del 83,3% en los pacientes con más de una recaída (75% de los pacientes), sin existir recaídas tras el inicio del tratamiento en 2 pacientes. En un 87,5% de los pacientes se pudieron retirar uno o más fármacos tras el primer ciclo de rituximab. Tras el tratamiento con rituximab, se consiguió una reducción del 96,5% de las dosis de corticoides administrados (28,5 mg/m2/día en los 3 meses pre-tratamiento versus 1 mg/m2/día en los 3 últimos meses de seguimiento en los pacientes tratados). Tras el periodo de seguimiento post-rituximab (mediana 46,5 meses, rango 5–97 meses), no se observaron efectos adversos significativos atribuibles al fármaco. Conclusiones: Los resultados favorables reportados tras el tratamiento con rituximab en nuestros pacientes parecen confirmar la eficacia del fármaco en el síndrome nefrótico córtico-dependiente y lo hacen considerar como una opción terapéutica válida en casos de difícil manejo clínico en la edad pediátrica. Aun así, parece recomendable diseñar estudios apropiados que traten de aclarar, entre otros, el régimen óptimo de tratamiento (dosis, intervalo y número de ciclos), repercusión clínica y potenciales efectos adversos a largo plazo.

El síndrome de obesidad hipoventilación (SOH) se define como la coexistencia de obesidad (índice de masa corporal ≥ 30 kg/mg²), alteraciones respiratorias durante el sueño e hipoventilación alveolar crónica que acarrea hipercapnia diurna (pCO2 ≥ 45 mmHg), cuando otras causas de hipoventilación han sido excluidas. Los pilares de tratamiento para el SOH son la pérdida de peso y la presión positiva en la vía aérea (PAP) durante el sueño. El manejo de estos pacientes ha de ser multidisciplinario, con modificación de hábitos de vida, intensificación de la actividad física y estrategias de intervención farmacológica o quirúrgica para la pérdida de peso, individualizando las terapias según cada paciente y sus comorbilidades. El modo de inicio de la PAP dependerá de la coexistencia de apnea obstructiva del sueño (AOS), considerando que aproximadamente el 90% de los pacientes con SOH presentan concomitantemente AOS, aunque de estos el 73% se considera AOS grave. En aquellos pacientes con SOH y AOS grave en situación de estabilidad clínica se inclinará por inicio con presión positiva continua en la vía aérea. Por otra parte, en aquellos pacientes sin AOS grave o durante una hospitalización, se recomienda iniciar directamente ventilación mecánica no invasiva. El seguimiento del paciente debe contemplar los cambios de estrategia necesarios para intentar un control óptimo del peso y el cumplimiento de la PAP.

Abstract Background COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p

Immunoglobulin (Ig) rearrangement and translocation information are usually obtained by targeted sequencing of the respective loci. Here, the authors present the IgCaller algorithm, which extracts Ig heavy and light chain genetic properties from short-read whole-genome sequencing results to provide a feasible alternative to direct sequencing.

More than twenty years after the last mining operations were completed in the Hiendelaencina Mining District, it is necessary to carry out a geochemical characterisation of the tailings stored in two contiguous mine ponds. Both have significant amounts of quartz, siderite, barite and muscovite and show significant contents of As, Ba, Pb, Sb and Zn. The tailings show alkaline pH and low electrical conductivity values, which support the visual observation that rules out acid drainage into the environment. The comparison of the National Topographic Map of 1954 with LiDAR data from 2014 has allowed estimating the volume of abandoned waste. Based on the volume of slurry and its average density, the total tonnage of pollutants has been estimated at 279 ± 9 t stored in Pond North and 466 ± 11 t stored in Pond South. Although these are significant quantities that pose a risk to the environment and nearby populations, they are lower than those present in other Spanish districts, such as the Iberian Pyrite Belt or Cartagena-La Unión. The combined use of LiDAR data, aerial imagery and geochemical methods has proven to be very useful for the estimation of the volume of pollutants stored in mine ponds.

Background: Unplanned extubations are safety events relatively frequent in the neonatal intensive care units (NICU). This study aimed to describe the frequency and characteristics of unplanned extubations in a NICU. Methods: We conducted a retrospective observational study of unplanned extubations in the NICU of a tertiary regional referral hospital. We reviewed medical records for data collection and performed the statistical analysis, comparing the cases of unplanned extubations with those in which it did not occur among all the cases that received intubation and invasive neonatal mechanical ventilation. Results: A total of 958 newborns were admitted to the NICU, of which 174 required assistance with invasive mechanical ventilation (18.1%) and 28 experienced unplanned extubations (16.1%): 25 patients with one episode, one with two episodes, and two with three episodes. The rate was 2.93 unplanned extubations for every 100 days of invasive mechanical ventilation in 5 years, with a significant decrease in the last three years (p = 0.0158). We found a statistically significant correlation between a weight < 1500 g and unplanned extubation in the multivariate analysis, although sedation appears to affect its interaction. Conclusions: Unplanned extubations are a relatively frequent problem, although with a tendency to decrease in recent years. The weight of the patients at birth and sedation during ventilation are important factors in this safety problem.

The Hiendelaencina district in Spain was the most important silver producer in Europe during 1844–1925. At the end of the 20th century, with mines having closed, some waste rock dumps were reprocessed, and the sludge from the flotation process was stored in two tailings ponds. When this activity ceased, the residues began to be eroded and disperse. In this study, the state of degradation of both deposits was evaluated using historical mapping and light detection and ranging (LiDAR) data, incorporated into a Geographic Information System. In the aerial images (1946–2018), mine tailings and their main erosive and sedimentary forms were mapped. Geoforms linked to hydrological (channels, gullies, alluvial cones), wind (eolian mantles), hydric–gravitational (colluvium) and anthropic (motorbike tracks) processes which move sludge into the surrounding areas were identified. A net loss of 8849 m3 of sludge, a release of 10.3 t of potentially polluting substances and a high erosion rate of 346 t/ha*year were calculated based on LiDAR data from 2009 and 2014. The ponds show a current high degree of erosion that could increase due to both human activity and the growing frequency of drought and torrential rain periods if stabilization measures are not undertaken.

Background: Neonatal sepsis is a condition with high mortality and morbidity that contributes to high rates of antibiotic therapy at birth. In addition, very low birth weight newborns (VLBWN) are particularly vulnerable. Interleukin 6 (IL-6) seems to be an early and effective marker that could help a better selection of patients to be treated. This study aimed to evaluate the use of antibiotics in the first 72 hours of life in VLBW infants before and after using IL-6 as an infection marker. Also, we wanted to analyze the differences in morbidity and mortality during admission and other factors associated with the decision to start antibiotic treatment. Methods: We conducted a cohort retrospective study. We included VLBWN born in our hospital or admitted before 72 hours of life in two two-year periods (2007-2008 and 2011-2012). Results: Antibiotics use during the first 72 hours of life was analyzed as the primary variable, which was reduced by 20% on the second period (p = 0.002). Regarding the analysis of secondary variables, we found no significant differences in mortality during hospital admission and the incidence of nosocomial sepsis, enterocolitis, or invasive fungal infection. The multivariate analysis indicated extreme prematurity and the study group as the most strongly related factors to the start of antibiotic therapy. Conclusions: IL-6 was a useful marker of infection to reduce the use of antibiotic therapy in VLBW infants without increasing mortality.

X-linked hypophosphatemia (XLH) causes significant burden in pediatric patients in spite of maintained treatment with phosphate supplements and vitamin D derivatives. Administration of burosumab has shown promising results in clinical trial but studies assessing its effect in the everyday practice are missing. With this aim, we analyzed the response to one-year treatment with burosumab, injected subcutaneously at 0.8 mg/kg every 2 weeks, in five children (three females) aged from 6 to 16 years, with genetically confirmed XLH. Patients were being treated with phosphate and vitamin D analogs until the beginning of burosumab treatment. In all children, burosumab administration led to normalization of serum phosphate in association with marked increase of tubular reabsorption of phosphate and reduction of elevated serum alkaline phosphatase levels. Baseline height of patients, from −3.56 to −0.46 SD, increased in the three prepubertal children (+0.84, +0.89, and +0.16 SD) during burosumab treatment. Growth improvement was associated with reduction in body mass index (−1.75, −1.47, and −0.17 SD, respectively), suggesting a salutary effect of burosumab on physical activity and body composition. Burosumab was well-tolerated, mild local pain at the injection site and transient and mild headache following the initial doses of burosumab being the only reported undesirable side effects. No patient exhibited hyperphosphatemia, progression of nephrocalcinosis, worsening of metabolic control or developed hyperparathyroidism. Mild elevation of serum PTH present at the beginning of treatment in one patient 4 was not modified by burosumab administration. These results indicate that in the clinical setting, beyond the strict conditions and follow-up of clinical trials, burosumab treatment for 1 year exerts positive effects in pediatric patients with XLH without major adverse events.

Abstract Early recognition of sepsis is a key factor to improve survival to this disease in surgical patients, since it allows prompt control of the infectious source. Combining pro-inflammatory and immunosupression biomarkers could represent a good strategy to improve sepsis detection. Here we evaluated the combination of procalcitonin (PCT) with gene expression levels of HLA-DRA to detect sepsis in a cohort of 154 surgical patients (101 with sepsis and 53 with no infection). HLA-DRA expression was quantified using droplet digital PCR, a next-generation PCR technology. Area under the receiver operating curve analysis (AUROC) showed that the PCT/HLA-DRA ratio outperformed PCT to detect sepsis (AUROC [CI95%], p): PCT: 0.80 [0.73–0.88],

Summary: The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11cΔVhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11cΔVhl mice do not reverse pulmonary alveolar proteinosis when transplanted into Csf2rb−/− mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their intact oxygen-sensing capacity. : Izquierdo et al. show that the absence of VHL in lung alveolar macrophages prevents their terminal maturation. VHL-deficient alveolar macrophages induce HIF-target gene expression and are partially desensitized to oxygen. Moreover, they have a decreased self-renewal and surfactant clearance capacity, suggesting that oxygen sensing contributes to alveolar macrophage functional maturation. Keywords: alveolar macrophage, oxygen, VHL, HIF, self-renewal, differentiation, surfactant, lung, glycolysis, lipid metabolism

Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.

La Banya spit, located at the south of the River Ebro Delta, is a sandy formation, developed by annexation of bars forming successive beach ridges, which are oriented and modeled by the eastern and southern waves. The initial ridges run parallel to the coastline, and above them small dunes developed, the crests of which are oriented by dominant winds, forming foredune ridges and barchans. This study attempted to test a number of techniques in order to understand the dune dynamic on this coastal spit between 2004 and 2012: LiDAR data were used to reconstruct changes to the surface and volume of the barchan dunes and foredunes; ground-penetrating radar was applied to obtain an image of their internal structure, which would help to understand their recent evolution. GPS data taken on the field, together with application of GIS techniques, made possible the combination of results and their comparison. The results showed a different trend between the barchan dunes and the foredunes. While the barchan dunes increased in area and volume between 2004 and 2012, the foredunes lost thickness. This was also reflected in the radargrams: the barchan dunes showed reflectors related to the growth of the foresets while those associated with foredunes presented truncations associated with storm events. However, the global balance of dune occupation for the period 2004–2012 was positive.

Networks of picture processors is a massively distributed and parallel computational model inspired by the evolutionary cellular processes, which offers efficient solutions for NP-complete problems. This bio-inspired model computes two-dimensional strings (pictures) using simple rewriting rules (evolutionary operations). The functioning of this model mimics a community of cells (pictures) that are evolving according to these bio-operations via a selection process that filters valid surviving cells. In this paper, we propose an extension of this model that empowers it with a flexible method that selects the processed pictures based on a quantitative evaluation of its content. In order to show the versatility of this extension, we introduce a solver for a cryptographic proof-of-work based on the hardness of finding a solution to a set of random quadratic equations over the finite field F2. This problem is demonstrated to be NP-hard, even with quadratic polynomials over the field F2, when the number of equations and the number of variables are of roughly the same size. The proposed solution runs in O(n2) computational steps for any size (n,m) of the input pictures. In this context, this paper opens up a wide field of research that looks for theoretical and practical solutions of cryptographic problems via software/hardware implementations based on bio-inspired computational models.

This study presents the results of the geoenvironmental characterization of La Matildes riverbed, affected by mine tailings in the Cartagena–La Unión district, Murcia (southeast Spain). Soils and riverbeds in this area are highly polluted. Two Electrical Resistivity Imaging (ERI) profiles were carried out to obtain information about the thickness of the deposits and their internal structure. For the mine tailings deposits of La Murla, a tributary of the El Miedo riverbed, the geophysical method imaged two different units: the upper one characterized by low resistivity values and 5–8 m thickness, correlated with the mine tailings deposits; and the lower more resistive unit corresponding to the Paleozoic metasediments bedrock. The ERI profile transverse to the Las Matildes dry riverbed revealed the existence of three different units. The uppermost one has the lowest resistivity values and corresponds to the tailings deposits discharged to the riverbeds. An intermediate unit, with intermediate resistivity values, corresponds to the riverbed sediments before the mining operations. The lower unit is more resistive and corresponds to the bedrock. Significant amounts of pyrite, sphalerite, and galena were found both in tailings and riverbed sediments. The geochemical composition of borehole samples from the riverbed materials shows significantly high contents of As, Cd, Cu, Fe, Pb, and Zn being released to the environment. Mining works have modified the natural landscape near La Unión town. Surface extraction in three open-pit mines have changed the summits of Sierra de Cartagena–La Unión. Rock and metallurgical wastes have altered the drainage pattern and buried the headwaters of ephemeral channels. The environmental hazards require remediation to minimize the environmental impact on the Mar Menor coastal lagoon, one of the most touristic areas in SE Spain.

Objetivo: Conocer las explicaciones sobre prácticas sexuales de riesgo, la percepción del virus de la inmunodeficiencia humana (VIH) y propuestas de intervención para prevenir infecciones por VIH en un grupo de hombres que tienen sexo con hombres. Métodos: Estudio cualitativo con una muestra de 13 hombres que tenían sexo con hombres, participantes de una cohorte de VIH seronegativos contactados en saunas gay de Barcelona. Se realizaron entrevistas en profundidad semiestructuradas y un posterior análisis de contenido temático. Resultados: Las prácticas sexuales de riesgo se atribuyeron a una masculinidad asociada a una alta necesidad sexual, a determinados lugares de intercambio sexual (como saunas, fiestas privadas y clubs), al consumo de drogas y al deseo de experimentar con el riesgo y la propia sexualidad. La infección por VIH se percibía como una enfermedad normalizada, aunque contraerla se asociaba a vergüenza y culpa. Entre las propuestas de intervención se encontraban: concienciar sobre lo que significa vivir con el VIH, generar más alarma social, incorporar las nuevas tecnologías en la prevención y aumentar las acciones en lugares de encuentro gay. Conclusiones: El concepto de la masculinidad desempeña un papel fundamental en las prácticas sexuales entre los hombres que tienen sexo con hombres. Se sugiere innovar en los programas preventivos e incorporar la percepción de riesgo y la infección por el VIH desde una perspectiva de género.

Las fundaciones son una de las manifestaciones de la Economía Social. Tradicionalmente, estas entidades han sido promovidas desde entornos familiares dando lugar a fundaciones de origen familiar. Dentro de la Comunidad Autónoma de Aragón constituyen un 24% del total de fundaciones activas. En estas entidades se concentran dos tipos de recursos humanos; trabajadores y voluntarios. El objetivo de este trabajo es estudiar la relación existente entre ambos dentro de este tipo de fundación, así como la influencia de las principales características económico-financieras de la misma sobre esta relación. Para ello, se ha tomado como punto de partida una muestra compuesta por 117 fundaciones activas en dicha Comunidad Autónoma. A través de un análisis de regresión y bajo un enfoque multigrupo se ha dado respuesta al objetivo de trabajo. Los resultados obtenidos muestran en términos generales una relación de complementariedad entre ambos recursos humanos. Además, se observa como las fundaciones más grandes, con fuerte liquidez, poco endeudadas, con dependencia de subvenciones públicas, bajos niveles de eficiencia económica y dedicadas a actividades religiosas intensifican la relación de complementariedad entre trabajadores y voluntarios

En este trabajo presentamos un diseño de investigación enmarcado en la epistemología feminista. Nos proponemos estudiar los impactos del desempleo masculino en la repartición de tareas domésticas y de cuidados, en un barrio de la ciudad de Barcelona. Entendiendo la complejidad que este tipo de diseños de investigación tiene, hemos realizado un marco teórico que nos permite entender lo mejor posible todos los elementos que tenemos que conocer para llevar a cabo esta investigación. ¿El desempleo —involuntario— masculino hace que ellos se involucren más en el ámbito doméstico? ¿Las crisis económicas obligan a cambiar los roles de género, basados en el binomio breadwinner/caregiver? Desde diversas investigaciones, utilizadas como soporte para este diseño, se da cuenta de que las negociaciones en el ámbito del hogar muchas veces exceden el monto del ingreso económico.

An estimated 30% of HIV cases in the European Union are not aware of their serological status. This study aimed to assess the effectiveness of a pilot HIV partner notification program.HIV cases diagnosed between January 2012 and June 2013 at two healthcare settings in Barcelona were invited to participate in a prospective survey. We identified process and outcome measures to evaluate this partner notification program, including the number of partners identified per interviewed index case, the proportion of partners tested for HIV as a result of the partner notification, and the proportion of new HIV diagnoses among their sex or needle-sharing partners.Of the 125 index cases contacted, 108 (86.4%) agreed to provide information about partners. A total of 199 sexual partners were identified (1.8 partners per interviewed index case). HIV outcome was already known for 58 partners (70.7% were known to be HIV-positive), 141 partners were tested as result of partner notification, and 26 were newly diagnosed with HIV. The case-finding effectiveness of the program was 18.4%.This pilot program provides evidence of the effectiveness of a partner notification program implemented in healthcare settings. This active partner notification program was feasible, acceptable to the user, and identified a high proportion of HIV-infected patients previously unaware of their status.

En este articulo se pretende verijicar la posibilidad de utilización de la termografía infrarrojn como técnica de inspección del estado de los edificios rurales. Se reúnen los resultados obtenidos en varios trabajos de campo. Mediante esta técnica se puede analizar: localización de materiales y elementos ocultos, localización de diferentes materiales en fachada, presencia de grietas, localización de estructuras, localización de zonas húmedas y puntos de pérdidas de calot Esta técnica permite inspeccionar un alto número de edificios en un breve período de tiempo, proporcionando resultados válidos. Los resultados muestran que en función del tipo de edijicio las inspecciones se deben realizar en diferentes momeritos del dia: por la noche en los edificios con muros de catga y al amanecer en edificios con estructuras internas.

Abstract Background Diagnosis of dementia with Lewy bodies (DLB) is challenging, especially in the earlier stages of the disease, owing to the clinical overlap with other neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). We aimed to identify the transcranial sonography (TCS) parameters that can help us to detect early DLB patients. Methods In this cross-sectional study, we prospectively recruited newly diagnosed DLB patients with less than 3 years from the onset of cognitive symptoms. For comparison purposes, we also included AD and PD patients, with a disease duration of less than 3 years, and a control group. TCS was performed to assess the substantia nigra (SN) echogenicity, the width of the third ventricle, and the frontal horns of the lateral ventricles. Subsequently, TCS images were analyzed with the medical image viewer Horos in order to quantify the intensity of the echogenicity of the SN. Univariate analysis and a logistic regression model were used to identify which variables can predict the diagnosis of DLB. Results One hundred and seven participants were included (23 DLB, 26 AD, 27 PD and 31 controls). The median age of DLB patients was 75(72–77) years, with a disease duration of 2 years. DLB and PD patients showed higher SN hyperechogenicity rates (72.73% and 81.82%, respectively) and a greater area of the SN compared to AD patients and controls (p