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Stephanie Vairy,* Julia Lopes Garcia,* Pierre Teira, Henrique Bittencourt Division of Haematology and Oncology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada *These authors contributed equally to this work Abstract: Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsed/refractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractory/relapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies. Keywords: CTL019, tisagenlecleucel, B-cell acute lymphoblastic leukemia

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p

Sr. Editor: Las lesiones coronarias calcificadas siguen siendo un desafío clínico a la hora de realizar intervenciones, ya que se asociana índices más altos de complicaciones como infraexpansión y mala aposición del stent. Esto conlleva un mayor riesgo de revascularización de la lesión diana (RLD), trombosis del stent, infarto de miocardio (IM) y muerte1. Mientras que los stents farmacoactivos (SFA) de última generación y los dispositivos contemporáneos son más seguros y efectivos, sigue siendo necesario recurrir a técnicas de modificación de la placa ateroesclerótica para una adecuada expansión y aposición de dichos stents cuando fracasan las técnicas convencionales. Los balones de corte están diseñados para tratar lesiones complejas, como placas fibróticas y lesiones calcificadas2,3; no obstante, su uso puede haberse visto limitado por su peor perfil de cruce y poca evidencia que avale su perfil de eficacia y seguridad4. Además, la literatura publicada disponible se basa en estudios con diseños de no inferioridad y tamaños de muestra pequeños5 y no en análisis con la suficiente potencia estadística como para poder valorar la eficacia clínica de los balones de corte en pacientes con enfermedad coronaria (EC) de vaso nativo. En este sentido, se realizó una revisión sistemática y metanálisis para llevar a...

To the Editor, Calcified coronary lesions remain a procedural and clinical challenge associated with higher rates of procedural complications such as stent underexpansion and malapposition leading to an increased risk of target lesion revascularization (TLR), stent thrombosis, myocardial infarction (MI), and death.1 While newer drug-eluting stents and advanced devices are considered safer and more effective, there is still a need for atherosclerotic plaque modification techniques that allow for adequate stent expansion and apposition when traditional techniques fail. Cutting and scoring balloons have been designed to treat complex lesions such as fibrotic plaque and calcified lesions.2,3 However, their use may have been limited by problems of crossability and limited evidence supporting their efficacy and safety.4 In addition, the available published literature is based on studies with noninferiority designs and small sample sizes,5 which may not provide adequately powered analyses to evaluate the clinical efficacy of cutting and scoring balloons in patients with native-vessel coronary artery disease (CAD). Therefore, we performed a systematic review and meta-analysis to compare cutting and scoring balloons with conventional balloons (semi- and non-compliant balloons) in patients with native vessel CAD. This meta-analysis was conducted according to the PRISMA guidelines for the reporting of systematic reviews. Two reviewers independently identified...

ABSTRACT Introduction and objectives: Although drug-eluting stents are the main treatment in percutaneous coronary interventions (PCI), drug-coated balloons (DCB) represent an appealing alternative as they eliminate the risk of stent thrombosis and avoid leaving any metal structure in the vessel wall. However, limited evidence has been published to date on the vessel wall healing processes, plaque remodeling, plaque composition, and the impact on the coronary microcirculation after percutaneous coronary intervention with DCB (DCB-PCI). Methods: This is investigator-initiated, single-center, single-arm, open-label, pilot study of 30 patients with native vessel disease undergoing DCB-PCI. Intravascular ultrasound and angiography-derived index of microvascular resistance (IMRangio) will be performed before and immediately after PCI, and at 3 months of follow-up. Conclusions: The study aims to provide new evidence on the modification of atherosclerotic plaque in patients with de novo lesions undergoing PCI with DCB. This will be assessed by examining the change in the percentage of atheroma volume and late lumen enlargement using intravascular ultrasound and by evaluating changes in the microcirculation using IMRangio. Registered at Clinicaltrials.gov (NCT06080919). Keywords: Drug-coated balloon. Intravascular ultrasound. Angiography-derived index of microvascular resistance. RESUMEN Introducción y objetivos: Pese a que los stents farmacoactivos son el tratamiento principal en las angioplastias coronarias, los balones farmacoactivos representan una alternativa interesante dado...

RESUMEN Introducción y objetivos: Pese a que los stents farmacoactivos son el tratamiento principal en las angioplastias coronarias, los balones farmacoactivos representan una alternativa interesante dado que eliminan el riesgo de trombosis del stent sin dejar ningún tipo de estructura metálica en la pared del vaso. No obstante, la evidencia en cuanto a los procesos de cicatrización de la pared del vaso, el remodelado, los cambios en la composición de la placa ateroesclerótica y el impacto en la microcirculación coronaria tras el intervencionismo coronario percutáneo (ICP) con balón farmacoactivo aún no se ha esclarecido. Métodos: Estudio piloto abierto, de un solo grupo, iniciado por el investigador, de 30 pacientes con enfermedad de vaso nativo sometidos a ICP con balón farmacoactivo. Se realizará ecografía intravascular y se determinará el índice de resistencia microvascular derivado de la angiografía (angio-IRM) antes, inmediatamente después y a los 3 meses de seguimiento de la angioplastia. Conclusiones: Se aportará nueva evidencia sobre la modificación de la placa en pacientes con enfermedad de vaso nativo tratados con balón farmacoactivo, evaluando el cambio en el porcentaje del volumen de ateroma y el aumento luminal tardío, así como los cambios en la microcirculación mediante angio-IRM. Registrado en Clinicaltrials.gov (NCT06080919).

Measurements of dissolved organic carbon (DOC), nitrogen (DON), and phosphorus (DOP) concentrations are used to characterize the dissolved organic matter (DOM) pool and are important components of biogeochemical cycling in the coastal ocean. Here, we present the first edition of a global database (CoastDOM v1; available at https://doi.org/10.1594/PANGAEA.964012, Lønborg et al., 2023) compiling previously published and unpublished measurements of DOC, DON, and DOP in coastal waters. These data are complemented by hydrographic data such as temperature and salinity and, to the extent possible, other biogeochemical variables (e.g. chlorophyll a, inorganic nutrients) and the inorganic carbon system (e.g. dissolved inorganic carbon and total alkalinity). Overall, CoastDOM v1 includes observations of concentrations from all continents. However, most data were collected in the Northern Hemisphere, with a clear gap in DOM measurements from the Southern Hemisphere. The data included were collected from 1978 to 2022 and consist of 62 338 data points for DOC, 20 356 for DON, and 13 533 for DOP. The number of measurements decreases progressively in the sequence DOC > DON > DOP, reflecting both differences in the maturity of the analytical methods and the greater focus on carbon cycling by the aquatic science community. The global database shows that the average DOC concentration in coastal waters (average ± standard deviation (SD): 182±314 µmol C L−1; median: 103 µmol C L−1) is 13-fold higher than the average coastal DON concentration (13.6±30.4 µmol N L−1; median: 8.0 µmol N L−1), which is itself 39-fold higher than the average coastal DOP concentration (0.34±1.11 µmol P L−1; median: 0.18 µmol P L−1). This dataset will be useful for identifying global spatial and temporal patterns in DOM and will help facilitate the reuse of DOC, DON, and DOP data in studies aimed at better characterizing local biogeochemical processes; closing nutrient budgets; estimating carbon, nitrogen, and phosphorous pools; and establishing a baseline for modelling future changes in coastal waters.

Los Modelos Centrados en la Familia del ámbito de la Atención Temprana dan como resultado el empoderamiento familiar junto a una mayor competencia de los menores en las rutinas. El presente estudio de intervención de caso único se ha realizado bajo este modelo. Durante un año, se ha acompañado a la familia de un niño con síndrome de PACS1, un trastorno del neurodesarrollo de origen genético y muy baja prevalencia. Mediante la Escala PICCOLO de observación de las interacciones parentales con los/las niños/as, se analizaron grabaciones mensuales del padre jugando con su hijo. Tras establecer tres meses de evaluación de línea base, se realizaron devoluciones bimensuales por videoconferencia a la familia, basadas en sus preocupaciones y en aspectos concretos de cada uno de los 4 dominios de la escala, con el fin de facilitar su comprensión del desarrollo e interacciones con el menor. El padre se encontraba en la media poblacional de puntuaciones en estos cuatro dominios, y evolucionó positivamente y de forma constante en uno de los objetivos de intervención planteados (ítem 3 de la escala de enseñanza: “Repite o expande las palabras o los sonidos del niño”). Al finalizar, se valoró con la familia este modo de intervención destacando la utilidad del visionado de las grabaciones a posteriori y su sensación de competencia.

Para recabar datos lingüísticos se suelen usar textos fonéticamente (fonológicamente) equilibrados. Una búsqueda de este tipo de textos en español descubre pocos textos con estas características. El objetivo del presente trabajo es proponer un texto nuevo, El ratón Arturo, a partir de la adaptación de un texto original en inglés. La principal motivación para confeccionar un texto nuevo es que los que existen son demasiado cortos. Su lectura es inferior a los 2 minutos, lo que dificulta calcular medidas estadísticamente fiables para un análisis vocal. La ventaja de usar este texto frente a los existentes en español es que es más largo, supera los dos minutos, presenta un menor número de repeticiones de palabras, está compuesto por palabras frecuentes y oraciones sencillas. A pesar de la longitud mayor, no es un texto difícil de leer o de procesar porque su complejidad es similar a la de los textos anteriores. Además, puede servir para recoger datos de población adulta e infantil. Cumple con los dos requisitos de este tipo de textos: presenta al menos una ocurrencia de cada uno de los fonemas del español y estos se encuentran distribuidos según la frecuencia de uso de esta lengua. Además, se han recogido ejemplos de los grupos consonánticos y las codas más frecuentes. Asimismo, se ha confeccionado con palabras simples y derivadas, con acento contrastivo, con oraciones con presencia/ausencia de consonantes nasales y con oraciones con diversas modalidades oracionales. Las características específicas con las que se ha construido permiten que pueda ser utilizado tanto en la investigación fonética como para evaluar problemas motores del habla y de la función vocal, como disartrias y apraxias.

Objectives: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). Methods: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. Results: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P

Objective. The aim of this study was to evaluate the behavior and performance of steers in two different housing areas (10 vs. 100 m2/animal) and two feeding models (daily supply vs. self-feeding) during the fattening period. Materials and methods: Forty-eight Hereford steers with initial live weight (LW): 214,0 kg were housed under four treatments: 100DS (100 m2/animal and daily supply), 100SF (100 m2/animal and self-feeding), 10DS (10 m2/animal and daily supply), 10SF (10 m2/animal and self-feeding) until reaching a final LW of 370 – 390 kg. Behavior was recorded by observation. Dry matter intake (DMI) and average daily gain (ADG) were recorded to estimate feed conversion ratio (FCR). Back fat thickness (BFT) and Longissimus muscle area (LMA) were measured. Steers were sent to a commercial abattoir to evaluate carcass yield. Results: The frequency of rest and walking was higher in steers in the largest housing area. Self-feeding contributed to the intake distribution during the day. No differences were detected in DMI, ADG and FCR. However, the confined animals (10DS and 10SF) produced more BFT and less LMA. In addition, they had less carcass yield at slaughter. Conclusions: Therefore, a larger housing area and the self-feeding model could contribute to express steers’ natural behavior and improve their performance. KEYWORDS: animal welfare, cattle, feedlot, housing area, feeding (Source: MESH)

Coastal upwelling areas are extraordinarily productive environments where prokaryotic communities, the principal remineralizers of dissolved organic matter (DOM), rapidly respond to phytoplankton bloom and decay dynamics. Nevertheless, the extent of variability of key microbial functions in such dynamic waters remains largely unconstrained. Our metatranscriptomics analyses of 162 marker genes encoding ecologically relevant prokaryotic functions showed distinct spatial-temporal patterns in the NW Iberian Peninsula upwelling area. Short-term (daily) changes in specific bacterial functions associated with changes in biotic and abiotic factors were superimposed on seasonal variability. Taxonomic and functional specialization of prokaryotic communities, based mostly on different resource acquisition strategies, was observed. Our results uncovered the potential influence of prokaryotic functioning on phytoplankton bloom composition and development (e.g., Cellvibrionales and Flavobacteriales increased relative gene expression related to vitamin B12 and siderophore metabolisms during Chaetoceros and Dinophyceae summer blooms). Notably, bacterial adjustments to C- or N-limitation and DMSP availability during summer phytoplankton blooms and different spatial-temporal patterns of variability in the expression of genes with different phosphate affinity indicated a complex role of resource availability in structuring bacterial communities in this upwelling system. Also, a crucial role of Cellvibrionales in the degradation of DOM (carbohydrate metabolism, TCA cycle, proteorhodopsin, ammonium, and phosphate uptake genes) during the summer phytoplankton bloom was found. Overall, this dataset revealed an intertwined mosaic of microbial interactions and nutrient utilization patterns along a spatial-temporal gradient that needs to be considered if we aim to understand the biogeochemical processes in some of the most productive ecosystems in the world´s oceans.

Objective. The aim of this study was to evaluate the behavior and performance of steers in two different housing areas (10 vs. 100 m2/animal) and two feeding models (daily supply vs. self-feeding) during the fattening period. Materials and methods: Forty-eight Hereford steers with initial live weight (LW): 214,0 kg were housed under four treatments: 100DS (100 m2/animal and daily supply), 100SF (100 m2/animal and self-feeding), 10DS (10 m2/animal and daily supply), 10SF (10 m2/animal and self-feeding) until reaching a final LW of 370 – 390 kg. Behavior was recorded by observation. Dry matter intake (DMI) and average daily gain (ADG) were recorded to estimate feed conversion ratio (FCR). Back fat thickness (BFT) and Longissimus muscle area (LMA) were measured. Steers were sent to a commercial abattoir to evaluate carcass yield. Results: The frequency of rest and walking was higher in steers in the largest housing area. Self-feeding contributed to the intake distribution during the day. No differences were detected in DMI, ADG and FCR. However, the confined animals (10DS and 10SF) produced more BFT and less LMA. In addition, they had less carcass yield at slaughter. Conclusions: Therefore, a larger housing area and the self-feeding model could contribute to express steers’ natural behavior and improve their performance.

ObjectivesThis study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA.MethodsWe present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient’s disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience.ResultsTwo patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2–7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT.ConclusionWe report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk–benefit ratio of this procedure.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

Las vacas de refugo son un subproducto de la actividad de cría. Debido a su baja condición corporal y palatabilidad de la carne, poseen un menor precio y frecuentemente son destinadas a elaboración de conservas. Se ha visto que los taninos podrían ser una estrategia nutricional alternativa a algunos moduladores ruminales, que mejorarían el perfil de aminoácidos de la carne. Además, la maduración de esta carne resaltaría sus características organolépticas, aportándole un mayor valor de mercado. El objetivo de este trabajo fue evaluar el efecto del agregado de taninos condensados en la suplementación de una dieta de terminación de vacas de refugo basada en pasturas naturales, sobre el perfil de aminoácidos, calidad sensorial y estabilidad oxidativa de la carne madurada. Los resultados obtenidos muestran que la adición de taninos podría utilizarse en esta categoría, mejorando la terneza, sin comprometer otras características de calidad ni el contenido de aminoácidos esenciales.

Summary: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is recommended in revascularization guidelines for intermediate lesions. However, recent studies comparing FFR-guided PCI with non-physiology-guided revascularization have reported conflicting results. PubMed and Embase were searched for studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, coronary artery bypass grafting). Data were pooled by meta-analysis using random-effects model. 26 studies enrolling 78,897 patients were included. FFR-guided PCI as compared to non-physiology-guided coronary revascularization had lower risk of all-cause mortality (odds ratio [OR] 0.79 95% confidence interval [CI] 0.64–0.99, I2 = 53%) and myocardial infarction (MI) (OR 0.74 95% CI 0.59–0.93, I2 = 44.7%). However, no differences between groups were found in terms of major adverse cardiac events (MACEs) (OR 0.86 95% CI 0.72–1.03, I2 = 72.3%) and repeat revascularization (OR 1 95% CI 0.82–1.20, I2 = 43.2%). Among patients with coronary artery disease (CAD), FFR-guided PCI as compared to non-physiology-guided revascularization was associated with a lower risk of all-cause mortality and MI.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

IntroductionInflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.MethodsWe collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.ResultsForty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT.ConclusionsIn this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

Los hoyos ocasionados por la caída de árboles son uno de los edaforrasgos más comunes en los suelos. Su origen puede ser tanto natural, la muerte y caída de un árbol, como antropogénico, relacionado con la tala del bosque. Este tipo de estructuras se han encontrado en varios yacimientos del Noroeste ibérico en las últimas décadas, pero han sido entendidas como fondos de cabaña. Además, la investigación reciente no ha tenido en cuenta las incoherencias entre sus dataciones de C14 y los eventos que supuestamente fechan. El objetivo de este trabajo es abordar los errores basados en una interpretación equivocada de los hoyos provocados por la caída de árboles y en una metodología inadecuada en la recuperación de los restos arqueobotánicos utilizados en la datación radiocarbónica. Reexaminar estos rasgos arqueológicos puede arrojar luz sobre las evidencias de deforestación y empujarnos a reconsiderar las teorías sobre la construcción de los espacios domésticos en el Noroeste ibérico.

BackgroundThe survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non–central nervous system tumors.MethodsT-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST).ResultsFifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to

Las oraciones de relativo ambiguas con doble antecedente nominal han sido ampliamente estudiadas en español por cuestionar la presencia de principios universales en el procesamiento sintáctico. La investigación actual apunta a la posibilidad de una contribución temprana de la información prosódica en la desambiguación de este tipo de oraciones en tareas de producción y comprensión oral. En este trabajo, presentamos dos experimentos de comprensión de oraciones de relativo localmente ambiguas con doble antecedente nominal en español, con tareas en las que se manipularon varios correlatos acústicos de la prosodia, de suerte que esta fuera congruente o incongruente con la estructura sintáctica, al objeto de comprobar su influencia en las preferencias de adjunción de la cláusula de relativo y en los tiempos de respuesta de los participantes en dichas tareas. Asimismo, se manipularon en distintos subexperimentos los rasgos prosódicos frecuenciales (F0) y temporales (distribución de pausas) de los enunciados, a fin de comprobar la contribución de cada uno de ellos al rendimiento de los participantes. Los resultados indican un uso efectivo de la información prosódica por los oyentes en un momento relativamente temprano del procesamiento. En concreto, una prosodia congruente con la sintaxis facilita, en términos generales, las respuestas de los participantes en tareas de comprensión, si bien se han observado diferencias en el efecto de la prosodia según el tipo de adjunción requerido. Finalmente, la contribución de las claves prosódicas frecuenciales y temporales resultó ser bastante similar, con tan solo algunas diferencias puntuales.

El bienestar de los animales es un concepto que debe abordarse en todas las etapas de la vida de los bovinos. Su preservación no solo está integrada por aspectos éticos, sino también por la posibilidad de mejorar los niveles de producción y la calidad de la carne. Es importante que todos los sujetos que intervienen en la crianza, traslado y faena de los bovinos para producción de alimentos entiendan la importancia del cuidado de los animales. Para ello, es necesario conocer los mecanismos por los cuales las condiciones brindadas afectan las características sensoriales y nutritivas de la carne. Ello se debe a que la composición de la carne comienza a definirse en la etapa de producción primaria. Los sistemas de producción intensiva que se orientan a maximizar la producción deben garantizar el bienestar animal. En este sentido, es responsabilidad del hombre encargado de los animales garantizar alimento, agua y condiciones ambientales adecuadas. El confort de los animales, la alimentación y la genética contribuyen a la obtención de una res bien conformada. Mientras que los eventos de estrés agudo y crónico repercuten negativamente sobre las características y la conservación de los productos cárnicos. El objetivo de la presente revisión es abordar los efectos del bienestar animal sobre la producción y calidad de la carne. Además, se presenta un modelo de engorde intensivo desarrollado por el Instituto Nacional de Tecnología Agropecuaria (INTA) donde se consideran las condiciones de manejo y alimentación para contribuir al bienestar animal.

En esta reseña de A Structuralist Theory of Economics de Adolfo García de la Sienra se discuten las aportaciones de este libro de metodología de la economía.

En esta reseña de A Structuralist Theory of Economics de Adolfo García de la Sienra se discuten las aportaciones de este libro de metodología de la economía.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

Abstract Microbial heterotrophic activity is a major process regulating the flux of dissolved organic matter (DOM) in the ocean, while the characteristics of this DOM strongly influence its microbial utilization and fate in the ocean. In order to broaden the vertical resolution of leucine-to-carbon conversion factors (CFs), needed for converting substrate incorporation into biomass production by heterotrophic bacteria, 20 dilution experiments were performed in the North Atlantic Ocean. We found a depth-stratification in empirical CFs values from epipelagic to bathypelagic waters (4.00 ± 1.09 to 0.10 ± 0.00 kg C mol Leu−1). Our results demonstrated that the customarily used theoretical CF of 1.55 kg C mol Leu−1 in oceanic samples can lead to an underestimation of prokaryotic heterotrophic production in epi- and mesopelagic waters, while it can overestimate it in the bathypelagic ocean. Pearson correlations showed that CFs were related not only to hydrographic variables such as temperature, but also to specific phylogenetic groups and DOM quality and quantity indices. Furthermore, a multiple linear regression model predicting CFs from relatively simple hydrographic and optical spectroscopic measurements was attempted. Taken together, our results suggest that differences in CFs throughout the water column are significantly connected to DOM, and also reflect differences linked to specific prokaryotic groups.

Coastal ecosystems deteriorate globally due to human-induced stress factors, like nutrient loading and pollution. Bacteria are critical to marine ecosystems, e.g., by regulating nutrient cycles, synthesizing vitamins, or degrading pollutants, thereby providing essential ecosystem services ultimately affecting economic activities. Yet, until now bacteria are overlooked both as mediators and indicators of ecosystem health, mainly due to methodological limitations in assessing bacterial ecosystem functions. However, these limitations are largely overcome by the advances in molecular biology and bioinformatics methods for characterizing the genetics that underlie functional traits of key bacterial populations – “key” in providing important ecosystem services, being abundant, or by possessing high metabolic rates. It is therefore timely to analyze and define the functional responses of bacteria to human-induced effects on coastal ecosystem health. We posit that categorizing the responses of key marine bacterial populations to changes in environmental conditions through modern microbial oceanography methods will allow establishing the nascent field of genetic counselling for our coastal waters. This requires systematic field studies of linkages between functional traits of key bacterial populations and their ecosystem functions in coastal seas, complemented with systematic experimental analyses of the responses to different stressors. Research and training in environmental management along with dissemination of results and dialogue with societal actors are equally important to ensure the role of bacteria is understood as fundamentally important for coastal ecosystems. Using the responses of microorganisms as a tool to develop genetic counselling for coastal ecosystems can ultimately allow for integrating bacteria as indicators of environmental change.

Background: Evidence from clinical practice on the effects of switching from emtricitabine/tenofovir disoproxil fumarate (F/TDF) to emtricitabine/tenofovir alafenamide (F/TAF)-based triple-therapy (TT) regimens on renal parameters is limited. Objective: This retrospective analysis evaluated the effects on renal function of switching from F/TDF to F/TAF-based TT regimens with no change in third agent among people living with HIV (PLWH). Methods: Data were from a multicenter Spanish PLWH cohort. Patients with a baseline estimated glomerular filtration rate (eGFR-EPI) measurement, ≥1 follow-up measurement, ≥30 days treatment with F/TAF, and who switched from F/TDF to F/TAF with no change in third agent were included. Multivariate mixed linear models were used to evaluate change from baseline over time in eGFR-EPI. eGFR-EPI changes before and after switch were analyzed in a matched patient subgroup. Results: Overall, 340 patients were included. Mean (95% CI) eGFR-EPI in patients with baseline eGFR-EPI

La investigación lingüística se ha beneficiado del desarrollo de las tecnologías y, a su vez, ha contribuido al mismo de manera significativa. El valor interdisciplinar de la Lingüística y sus diferentes ramas requieren nuevos materiales, herramientas y métodos, cuyo acceso y manejo ha facilitado la tecnología. Dentro de ella, se distinguen las tecnologías que permiten un mayor entendimiento del sistema lingüístico de los productos tecnológicos que lo utilizan para su funcionamiento. Se presenta a continuación un panorama general de recursos digitales que podrían contribuir en las diferentes etapas de una investigación lingüística, desde la revisión bibliográfica hasta la publicación final de resultados.

BackgroundWe compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America.MethodsWe included cohort data of human immunodeficiency virus (HIV)-positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs).ResultsWe included 208140 patients from 57 countries. Over a period of 1066572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals [CI], 2.73-7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34-3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09-6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/µL with those whose counts were

La utilización de mascarillas en la crisis sanitaria por el COVID-19 está generando numerosos interrogantes. Entre otros, el efecto que tiene en la percepción de habla en personas sordas con implante coclear. Con el fin de averiguarlo se realizó un estudio experimental sobre la discriminación de pares mínimos en español. Para ello, se controló la presencia y ausencia de mascarilla, así como el apoyo de la lectura labiofacial. Los resultados confirman la interferencia de las mascarillas en la percepción, especialmente en las personas con implante coclear, pero no así los beneficios de la multimodalidad.

Marine microorganisms are involved in a variety of biogeochemical cycles and live in diverse ecological communities where they interact with each other and with other organisms to guarantee ecosystem functions. The present study focused on a shallow marine environment located in Ría de Vigo (NW, Spain), where sediment and size-fractionated plankton samples were collected from 2016 to 2018. DNA metabarcoding was used to describe the eukaryote and prokaryote composition and diversity in sediments and plankton and to depict possible associations among the most frequent and abundant organisms by co-occurrence network analysis. High eukaryote and prokaryote diversity indices were obtained in all compartments. Significant differences among eukaryote and prokaryote communities were found between sediment and plankton samples, with a high percentage of exclusive operational taxonomic units (OTUs) associated with each compartment, especially from sediment. Despite these differences, shared taxa between water and sediment were also obtained, suggesting a relatively meaningful exchange of organisms between both environmental compartments. Significant co-occurrences were mainly obtained between prokaryotes (41%), followed by eukaryotes–prokaryotes (32%) and between eukaryotes (27%). The abundant and strong positive correlations between organisms, including representatives from the sediment and the water column, suggested an essential role of biotic interactions as community-structuring factors in shallow waters where beneficial associations likely prevail. This study provides a novel approach for the detailed description of the eukaryote and prokaryote diversity and co-occurrence patterns in a shallow marine area, including both the sediment and different water-size fractions. The high diversity obtained and the detection of predominantly coexisting interactions among organisms from sediment and the overlying water column suggest a movement of species between both habitats and therefore confirm the importance of integratively studying shallow marine ecosystems.