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Concentrated solar energy gives controlled high flux density with a wide wavelength spectrum by means of solar furnaces, which design allows to attain very high heating rates and very high temperatures up to 3500 K. Solar furnaces are specially suitable for transformation or synthesis process, these installations are devoted to research in the fields of material characterization and treatment as well as chemical processes. During 2001, several test campaigns have been carried out in the Solar Furnace at the Plataforma Solar de Almería in collaboration with different European research institutes, under the umbrella of the European Commission`s Improving Human Potential Programme. Thus different lines of work have been launched demonstrating the feasibility and potential use of solar furnaces for such R&D field.La energía solar concentrada permite proporcionar de forma controlada altas densidades de flujo energético con un amplio espectro de longitudes de onda mediante el uso de hornos solares, cuyo diseño permite alcanzar velocidades de calentamiento muy altas y temperaturas de hasta 3500ºC. Los hornos solares, por sus características, son especialmente adecuados para aplicaciones que conlleven la transformación o síntesis de materiales, siendo instalaciones dedicadas a la investigación en los campos de tratamiento y caracterización de materiales y procesos químicos. Durante el año 2001 en el Horno Solar de la Plataforma Solar de Almería se han realizado varias campañas de ensayos en colaboración con distintos centros de investigación europeos dentro del programa IHP de la Comisión Europea, abordándose diversas líneas de trabajo que han vuelto a demostrar la viabilidad y potencialidad del uso de los hornos solares para el tratamiento de materiales.

Objetivo: Estimar la probabilidad de supervivencia en España desde 1975 hasta 1995 según quintiles de renta per cápita. Métodos: En los años 1975, 1981, 1985, 1990 y 1995 se han ordenado las 50 provincias según su nivel de renta per cápita. En cada uno de los quintiles y en cada año se ha estimado la probabilidad de supervivencia hasta los 75 años de edad y la probabilidad de supervivencia entre diferentes tramos de edad en varones y mujeres. Estas probabilidades se han estimado en forma de porcentaje. Posteriormente, se ha calculado la diferencia entre las probabilidades de supervivencia en los quintiles con mayor renta y con menor renta per cápita. Resultados: La diferencia en la probabilidad de supervivencia hasta los 75 años aumentó de 1,3 en 1975 a 3,1 en 1995 en las mujeres, mientras que en los varones el aumento fue de 0,1 en 1975 a 3,7 en 1995. Conclusiones: En España, como en otros países desarrollados, durante los últimos años del siglo xx se produjo un aumento de las diferencias socioeconómicas relacionadas con la mortalidad prematura.

Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Water Distribution Networks (WDNs) are critical infrastructures that ensure a continuous supply of safe water to homes. In the face of challenges, like water scarcity, establishing resilient networks is imperative, especially in regions vulnerable to water crises. This study evaluates the resilience of network designs through graph theory, including its hydraulic feasibility using EPANET software, an aspect often overlooked. Novel mathematical algorithms, including Resilience by Design (RbD) and Resilience-strengthening (RS) algorithms, provide cost-effective and resilient network designs, even with budget constraints. A novel metric, Water Availability (WA), is introduced to offer a comprehensive measure of network resilience, thereby addressing ongoing discrepancies in resilience evaluation methods. Practical benefits are illustrated through a case study in which a resilient-by-design reclaimed water network is created, and an existing equivalent non-resilient network is improved. The resilient-by-design network demonstrates remarkably better results compared to the equivalent non-resilient design, including up to a 36 % reduction in the probability of service disruptions and a nearly 65 % decrease in the annual average unserved water due to service disruptions. These findings underscore the enormous advantages of a resilience-focused network design approach. When compared to the equivalent non-resilient design, the resilient-by-design network generated effectively safeguards up to a significant 91,700m 3 of water from the impacts of water disruption events over a 50-year operational period. In addition, the resilient-by-design WDN solution incurs a subtle decrease in overall costs compared to consuming tap water from the drinking WDN baseline over a 50-year operational period. These findings highlight the cost-effectiveness of the approach, even offering financial benefits. This paper builds on our previous research by expanding its scope to include resilience considerations, providing algorithms that can be easily adapted from reclaimed to drinking WDNs. Ultimately, we contribute to the enhancement of water resource management and infrastructure planning in ever-evolving urban environments., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection., Methods: Prospective, multicenter, noninferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus, negative for a bacterial pathogen, and had a favourable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with an uneventful resolution, whereas the secondary endpoints were days of fever, days of hospitalization, requirement of antimicrobial treatment readministration, sepsis, paediatric intensive care unit admission, and death., Results: A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a respiratory virus as a unique identified microorganism, of which 139 had a favourable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p < 0.001), with similar frequency of uneventful resolution 66/70 (94%) and 66/69 (96%); relative risk, 1.01; (95% CI, 0.93 to 1.09), absolute risk difference 0.01; (95% CI, -0.05 to 0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, paediatric intensive care unit admission, or death were reported., Discussion: We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral respiratory tract infection based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aims to describe resting state networks (RSN) in patients with disorders of consciousness (DOC)s after acute severe traumatic brain injury (TBI)., Methods: Adult patients with TBI with a GCS score <8 who remained in a coma, minimally conscious state (MCS), or unresponsive wakefulness syndrome (UWS), between 2017 and 2020 were included. Blood-oxygen-level dependent imaging was performed to compare their RSN with 10 healthy volunteers., Results: Of a total of 293 patients evaluated, only 13 patients were included according to inclusion criteria: 7 in coma (54%), 2 in MCS (15%), and 4 (31%) had an UWS. RSN analysis showed that the default mode network (DMN) was present and symmetric in 6 patients (46%), absent in 1 (8%), and asymmetric in 6 (46%). The executive control network (ECN) was present in all patients but was asymmetric in 3 (23%). The right ECN was absent in 2 patients (15%) and the left ECN in 1 (7%). The medial visual network was present in 11 (85%) patients. Finally, the cerebellar network was symmetric in 8 patients (62%), asymmetric in 1 (8%), and absent in 4 (30%)., Conclusions: A substantial impairment in activation of RSN is demonstrated in patients with DOC after severe TBI in comparison with healthy subjects. Three patterns of activation were found: normal/complete activation, 2) asymmetric activation or partially absent, and 3) absent activation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell-based clinical trials., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Protein kinase D (PKD) family members play controversial roles in prostate cancer (PC). Thus, PKD1 is nearly absent in advanced tumours, where PKD2 and PKD3 are upregulated. Additionally, consequences of activation of these kinases on PC progression remain largely unclear. Here, we first investigated PKD function on PC cell motility, analysing the underlying molecular mechanisms. We find a striking decrease of Snail levels after PKD inhibition followed by cell migration and invasion impairment, demonstrating an unprecedented role of PKD activity on the regulation of this key transcription factor in PC progression. Specifically, we show that PKD2 activity mediates the effects of MEK/ERK pathway on Snail expression, establishing a joint function of ERK/PKD2/Snail cascade in PC cell invasion regulation. These results led us to address the clinical relevance of the correlation between PKD2 and ERK activities with Snail abundance in samples from PC patients at different stages, analysing its impact on tumour prognosis and patients´ survival. Importantly, this is the first study defining a direct correlation between active PKD2 and Snail levels, further linked to ERK activity. We also evidence that PKD2 activity is associated with important poor prognostic factors. Thus, PC patients with the expression pattern: active PKD2 high /active ERK high /Snail high exhibit increased invasiveness and metastasis, and decreased survival. Our findings provide new insights for understanding the molecular mechanisms involved in PC progression, pinpointing the combination of active PKD2 and Snail levels, with the additional measurement of active ERK, as a confident biomarker to predict clinical outcome of patients with advanced PC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Head and neck cancer is a major health problem worldwide, with most cases arising in the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, accounting for over 90% of all cases. Compared to other types of cancer, OSCC, has the worse prognosis, with a 5-year survival rate of 50%. Additionally, OSCC is characterized by a high rate of resistance to chemotherapy treatment, which may be partly explained by the presence of cancer stem cells (CSC) subpopulation. CSC can adapt to harmful environmental condition and are highly resistant to both chemotherapy and radiotherapy treatments, thus contributing to tumor relapse. The aim of this review is to highlight the role of mitochondria in oral CSC as a potential target for oral cancer treatment. For this purpose, we reviewed some fundamental aspects of the most validated protein markers of stemness, autophagy, the mitochondrial function and energy metabolism in oral CSC. Moreover, a discussion will be made on why energy metabolism, especially oxidative phosphorylation in CSC, may offer such a diverse source of original pharmacological target for new drugs. Finally, we will describe some drugs able to disturb mitochondrial function, with emphasis on those aimed to interrupt the electron transport chain function, as novel therapeutic strategies in multidrug-resistant oral CSC. The reutilization of old drugs approved for clinical use as new antineoplastics, in cancer treatment, is also matter of revision., Competing Interests: Declaration of competing interest We declare there are not any conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Studies focused on identifying the viral species of Flavivirus in vectors are scarce in Latin America and particularly in Colombia. Therefore, the frequency of infection of the Flavivirus genus and its feeding preferences were identified in the mosquito species circulating in the municipality of Puerto Carreño-Vichada, located in the Eastern Plains of Colombia. This was done by sequencing the viral NS5 and vertebrate 12S rRNA genes, respectively, using Oxford Nanopore Technologies (ONT). A total of 1,159 mosquitoes were captured, with the most abundant species being Aedes serratus at 73.6% (n = 853). All the mosquitoes were processed in 230 pools (2-6 individuals) and 51 individuals, where 37.01% (n = 104) were found to be infected with Flavivirus. In these samples, infection by arboviruses of epidemiological importance, such as dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV), was ruled out by PCR. However, through sequencing, infection by different insect-specific viruses (ISFVs) and a medically important virus, West Nile virus (WNV), were identified in a mosquito of the Culex browni species. Additionally, the feeding patterns showed that most species present a generalist behavior. Given the above, conducting entomovirological surveillance studies is crucial, especially in areas of low anthropogenic intervention, due to the high probability that potentially pathogenic viruses could generate spillover events under deforestation scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Herbicide pollution poses a worldwide threat to plants and freshwater ecosystems. However, the understanding of how organisms develop tolerance to these chemicals and the associated trade-off expenses are largely unknown. This study aims to investigate the physiological and transcriptional mechanisms underlying the acclimation of the green microalgal model species Raphidocelis subcapitata (Selenastraceae) towards the herbicide diflufenican, and the fitness costs associated with tolerance development. Algae were exposed for 12 weeks (corresponding to 100 generations) to diflufenican at the two environmental concentrations 10 and 310 ng/L. The monitoring of growth, pigment composition, and photosynthetic performance throughout the experiment revealed an initial dose-dependent stress phase (week 1) with an EC 50 of 397 ng/L, followed by a time-dependent recovery phase during weeks 2 to 4. After week 4, R. subcapitata was acclimated to diflufenican exposure with a similar growth rate, content of carotenoids, and photosynthetic performance as the unexposed control algae. This acclimation state of the algae was explored in terms of tolerance acquisition, changes in the fatty acids composition, diflufenican removal rate, cell size, and changes in mRNA gene expression profile, revealing potential fitness costs associated with acclimation, such as up-regulation of genes related to cell division, structure, morphology, and reduction of cell size. Overall, this study demonstrates that R. subcapitata can quickly acclimate to environmental but toxic levels of diflufenican; however, the acclimation is associated with trade-off expenses that result in smaller cell size., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Neurofeedback (NF) is a paradigm that allows users to self-modulate patterns of brain activity. It is implemented with a closed-loop brain-computer interface (BCI) system that analyzes the user's brain activity in real-time and provides continuous feedback. This paradigm is of great interest due to its potential as a non-pharmacological and non-invasive alternative to treat non-degenerative brain disorders. Nevertheless, currently available NF frameworks have several limitations, such as the lack of a wide variety of real-time analysis metrics or overly simple training scenarios that may negatively affect user performance. To overcome these limitations, this work proposes ITACA: a novel open-source framework for the design, implementation and evaluation of NF training paradigms., Methods: ITACA is designed to be easy-to-use, flexible and attractive. Specifically, ITACA includes three different gamified training scenarios with a choice of five brain activity metrics as real-time feedback. Among them, novel metrics based on functional connectivity and network theory stand out. It is complemented with five different computerized versions of widespread cognitive assessment tests. To validate the proposed framework, a computational efficiency analysis and an NF training protocol focused on frontal-medial theta modulation were conducted., Results: Efficiency analysis proved that all implemented metrics allow an optimal feedback update rate for conducting NF sessions. Furthermore, conducted NF protocol yielded results that support the use of ITACA in NF research studies., Conclusions: ITACA implements a wide variety of features for designing, conducting and evaluating NF studies with the goal of helping researchers expand the current state-of-the-art in NF training., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Hornero reports financial support was provided by Spain Ministry of Science and Innovation. Diego Marcos-Martínez reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Sergio Pérez-Velasco reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Víctor Martínez–Cagigal reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Eduardo Santamaría-Vázquez reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Víctor Rodríguez-González reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Roberto Hornero reports administrative support was provided by Biomedical Research Network Centre of Bioengineering Biomaterials and Nanomedicine. Eduardo Santamaría-Vázquez reports financial support was provided by Junta de Castilla y León Consejería de Educación. Sergio Pérez-Velasco reports financial support was provided by Junta de Castilla y León Consejería de Educación. Diego Marcos-Martínez reports financial support was provided by Junta de Castilla y León Consejería de Educación. Víctor Rodríguez-González reports financial support was provided by Universidad de Valladolid., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In patients with non-small cell lung cancer (NSCLC), the presence of abnormal hiliar lymph nodes (clinical N1; cN1), central tumor location and/or tumor size (diameter >3 cm) increases the risk of occult mediastinal metastasis (OMM). This study investigates prospectively the diagnostic value of an integral mediastinal staging (IMS) strategy that combines EndoBronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) and Video-Assisted Mediastinoscopy (VAM) in patients with NSCLC at risk of OMM., Methods: Patients with NSCLC and radiologically normal mediastinum assessed non-invasively by positron emission tomography and computed tomography of the chest (PET-CT), and OMM risk factors (cN1, central tumor and/or >3 cm) underwent EBUS-TBNA followed by VAM if the former was negative. Those with negative IMS underwent resection surgery of the tumor., Results: EBUS-TBNA identified OMM in 2 out of the 49 patients evaluated (4%) and VAM in 1 of the 47 patients with negative EBUS (2%). Two patients with a negative IMS had OMM at surgery. Overall, the prevalence of OMM was 10%. EBUS-TBNA has a sensitivity of 40%, a negative predictive value (NPV) of 93.6%, and negative likelihood ratio of 0.60 (95%CI:0.30-1.16). The risk of not diagnosing OMM after EBUS was 6% and after IMS was 4.4%., Conclusion: Integral mediastinal staging in patients with NSCLC and clinical risk factors for OMM, does not seem to provide added diagnostic value to that of EBUS-TBNA, except perhaps in patients with cN1 disease who deserve further research., Competing Interests: Declaration of competing interest NR reports having received research grant suport from Pfizer and personal fees from Roche, MSD, Takeda, Amgen, Bayer and Pfizer, outside the submitted work. CML, RMD, MB, RMM, DS, MS, IV, DM, AF, LM, CA have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The high transmissibility rate of the Severe Acute Respiratory Syndrome Coronavirus 2 facilitated an exponential growth in the number of infections, posing a tremendous threat to healthcare systems across the world. The use of Non-oil 95% efficiency (N95) respirators demonstrated to reduce the risk of virus transmission. The escalated demand in N95 respirators during 2020 generated a massive shortage worldwide which resulted in serious implications, one being an increase in healthcare providers' costs. In response, various optimization strategies were implemented. This study aimed to assess the implementation of a safe and effective re-use policy for high-efficiency filtering facepiece respirators (FFRs) in a high-complexity university hospital in 2020. Associated costs were estimated through a descriptive accounting analysis of resources saved. Acceptability, appropriateness, and feasibility rates were 80.5%, 78.8%, and 83.6%, respectively. With an implementation cost of approximately 10,000 USD, there was a 56.1% reduction in FFRs consumption, compared with a non-policy scenario, with savings exceeding 500,000 USD in 2020. In a pandemic scenario where it is vital to spare resources, a FFRs rational use policy demonstrated to be a highly cost-efficient alternative in order to save resources without increasing contagion risk among healthcare workers., Competing Interests: None declared., (© 2022 The Author(s).)

Introduction: The ingestion of magnetic objects can cause complications in children, and there are no epidemiological or clinical data on the subject in Spain., Objectives: To determine the incidence, epidemiological characteristics and management of magnet ingestion in paediatric emergency departments in Spain., Material and Methods: Prospective observational multicentre study conducted over a 3-year period. The study universe consisted of patients aged less than 14 years., Results: The incidence was 4.8 cases per 100 000 emergency care episodes. Of the 72 patients included (mean age, 7.2 years), 54% were male. Seven percent had neuropsychiatric disorders. Sixty-one percent of the magnets were spherical and 69% came from toys. The size was variable, most frequently between 5 and 10 mm (50%), and ranging from 3 to 30 mm. Eighty-six percent of patients were asymptomatic. The most frequent symptom was abdominal pain. Eighty-three percent of the patients sought medical care within 6 h of ingestion and 92% within 24 h. Thirty-one percent of the cases were of multiple ingestion. Endoscopy was required for extraction in 15% of cases, a proportion that rose to 36% in the group of cases of multiple ingestion. None of the patients required surgery. We did not observe any gastrointestinal complications of magnet ingestion., Conclusions: The ingestion of multiple magnets is less frequent than single magnet ingestion, and we did not observe any complications despite the lower frequency of procedures compared to other studies., (Copyright © 2022 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Actual unawareness about paediatric resident's residency program factual clinical reasoning precludes professional retraining directed to solve deficiencies. Script Concordance Test (SCT) evaluates clinical reasoning due to its orientation to usual clinical practice but surprisingly it has not been used in Spain for Paediatric Primary Care clinical reasoning evaluation so far. Due to this we consider it to be of relevance to design a Paediatric Primary Care SCT which meets validity, reliability and accessibility criteria described on bibliography., Methods: Development, validation and application of an SCT questionnaire for clinical reasoning analysis in Paediatric Primary Care applied on a population of paediatric residents and which includes demographic and employment data in order to study possible relationship between them and achieved scores., Results: Our SCT was approved by an experts committee. It met reliability and accessibility criteria and it allowed distinguishing experts from paediatric internal residents. No statistically significant differences were found concerning age, gender, type and duration of the training received in Primary Care, and the completion of a course on that training., Conclusions: We developed a SCT that was approved by a Paediatric experts committee, it met reliability and accessibility criteria and it allowed distinguishing clinical reasoning from experts and paediatric internal residents. Except second year residency program, we didn't objectified relevant differences in residency program year, age, gender, duration and realization of Paediatric Primary Care rotation, and training course realization., (Copyright © 2021 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

The integrated use of multi-isotopic ( 87 Sr/ 86 Sr, δ 13 C-DIC, δ 2 H-H 2 O, δ 18 O-H 2 O) and hydrochemical data was applied in the highly anthropized Guadalhorce river basin, southern Spain, to improve the knowledge about water contamination sources and processes and to achieve improved water resource management. The results obtained highlight the importance of the use of isotopes as tracers of pollutants. DIC, δ 2 H-H 2 O, δ 18 O-H 2 O and δ 13 C-DIC allowed differentiating two water recharge end members: direct rainwater, infiltrated into the upper and lower detritic aquifers of the sub-basins, and the Guadalhorce dam system, which act as a source in some groundwater and surface waters of the lower sub-basin. 87 Sr/ 86 Sr data supported the existing conclusions in relation to pollution sources in the study area. The Triassic basement (evaporites) of the carbonate and detritic aquifers of the basin generally controls the natural 87 Sr/ 86 Sr composition in waters of the upper sub-basin. Only one groundwater sample reflects the influence of a human organic source (sewage) in its composition. On the other hand, mixing of human inorganic (fertilizers and detergents) strontium sources is required to explain the 87 Sr/ 86 Sr contents of the lower sub-basin waters. Discriminating the use of domestic detergents as another anthropogenic source of strontium and sulphate in waters is a novel finding in this research. The conclusions reached can be extrapolated to other anthropized basins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: In the treatment of patients with acute bronchiolitis there is great variability in clinical practice. Treatments whose efficacy has not been demonstrated are frequently used despite the recommendations contained in the Clinical Practice Guidelines., Material and Methods: A quality improvement strategy is implemented in the care of patients with acute bronchiolitis in the Emergency Department, which is maintained for five years and is periodically updated to be increasingly restrictive regarding the use of bronchodilators. To evaluate the impact of the intervention, a retrospective study of the rates of prescription of bronchodilators in children diagnosed with acute bronchiolitis in the month of December of four epidemic periods (2012, 2014, 2016 and 2018) was carried out., Results: 1767 children are included. There were no differences regarding age, respiratory rate, oxygen saturation or the estimated severity in each of the study seasons. The use of salbutamol in the Emergency Department decreased from 51.2% (95% CI: 46.6-55.8%) in 2012 to 7.8% (95% CI: 5.7%-10.5%) in 2018 (P < .001) and epinephrine prescription rates fell from 12.9% (95% CI: 10.1%-16.3%) to 0.2% (95% CI: 0-1.1%) (P < .001). At the same time, there was a decrease in the median time of attendance in the Emergency Department and in the admission rate without changing the readmission rate in 72 h., Conclusions: The systematic and continuous deployment over time of actions aimed at reducing the use of salbutamol and epinephrine in the treatment of bronchiolitis, prior to the epidemic period, seems an effective strategy to reduce the use of bronchodilators in the Emergency Department., (Copyright © 2021 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Hypercoagulability related to SARS-CoV-2 infection is one of the main extrapulmonary complications of COVID-19. We present three cases of intrabdominal thrombotic complications related to the state of hypercoagulability of COVID-19 and its tomographic features. Hypercoagulability state should be taking into account in the interpretation of radiological images in all infected patients with COVID-19., (© 2021 Published by Elsevier Inc. on behalf of University of Washington.)

PKCε is highly expressed in mast cells and plays a fundamental role in the antigen-triggered activation of the allergic reaction. Although its regulation by diacylglycerols has been described, its regulation by acidic phospholipids and how this regulation leads to the control of downstream vesicle secretion is barely known. Here, we used structural and evolutionary studies to find the molecular mechanism that explains the selectivity of the C1B domain of PKCε by Phosphatidic Acid (PA). This resided in a collection of Arg residues that form a specific rim on the outer surface of the C1B domain, around the diacylglycerol binding cleft. In RBL-2H3 cells, this basic rim allowed the kinase to respond specifically to phosphatidic acid signals that induced its translocation to the plasma membrane and subsequent activation. Further experiments in cells that overexpress PKCε and a mutant of the PA binding site, showed that PA-dependent PKCε activation increased vesicle degranulation in RBL-2H3 cells, and this correlated with increased SNAP23 phosphorylation. Over-expression of PKCε in these cells also induced an increase in the number of docked vesicles containing SNAP23, when stimulated with PA. This accumulation could be attributed to the stabilizing effect of phosphorylation on the formation of the SNARE complex, which ultimately led to increased release of content in the presence of Ca 2+ during the fusion process. Therefore, these findings reinforce the importance of PA signaling in the activation of PKCε, which could be an important target to inhibit the exacerbated responses of these cells in the allergic reaction., (Copyright © 2021. Published by Elsevier B.V.)

Cement removal during hip or knee arthroplasty revision surgery is technically demanding and prone to severe complications such as periprosthetic fractures, incomplete cement removal, or perforations. Several alternative techniques have been developed to enable complete, accurate, and safe removal of cement from bone, including osteotomies and cortical windows, endoscopic instruments, ultrasound devices, lithotripsy, and laser-assisted removal. We describe a cement-on-cement technique with a sterile, single-use tool for cement removal. The cement is removed piece by piece using a specifically designed device, without osteotomies or cortical windows., (© 2021 The Authors.)

Introduction: In the treatment of patients with acute bronchiolitis there is great variability in clinical practice. Treatments whose efficacy has not been demonstrated are frequently used despite the recommendations contained in the Clinical Practice Guidelines., Material and Methods: A quality improvement strategy is implemented in the care of patients with acute bronchiolitis in the Emergency Department, which is maintained for five years and is periodically updated to be increasingly restrictive regarding the use of bronchodilators. To evaluate the impact of the intervention, a retrospective study of the rates of prescription of bronchodilators in children diagnosed with acute bronchiolitis in the month of December of four epidemic periods (2012, 2014, 2016 and 2018) was carried out., Results: 1767 children are included. There were no differences regarding age, respiratory rate, oxygen saturation or the estimated severity in each of the study seasons. The use of salbutamol in the Emergency Department decreased from 51.2% (95% CI: 46.6%-55.8%) in 2012 to 7.8% (95% CI: 5.7%-10.5%) in 2018 (P<.001) and epinephrine prescription rates fell from 12.9% (95% CI: 10.1%-16.3%) to 0.2% (95% CI: 0-1.1%) (P<.001). At the same time, there was a decrease in the median time of attendance in the Emergency Department and in the admission rate without changing the readmission rate in 72h., Conclusions: The systematic and continuous deployment over time of actions aimed at reducing the use of salbutamol and epinephrine in the treatment of bronchiolitis, prior to the epidemic period, seems an effective strategy to reduce the use of bronchodilators in the Emergency Department., (Copyright © 2021 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation., Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets., Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database., Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC., Competing Interests: Disclosure SDP has declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen and Eisai. SG is an inventor on patents related to CAR-T cell therapy, filed by the University of Pennsylvania and licensed to Novartis or Tmunity; she receives research funding from Gilead and Roche and personal honoraria from Roche, Gilead, Celgene and Bristol-Myers Squibb. AP has declared an immediate family member being employed by Novartis; personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo; travel, accommodations and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb and patent PCT/EP2016/080056. All other authors have declared no conflicts of interest. Data sharing The original databases are all freely available online. Databases obtained after processing the originals, as described in the ‘Methods’ section, and containing raw data for the study analyses are available from the corresponding authors upon reasonable request. The R codes used for this study are available from the corresponding authors upon reasonable request. No original codes have been specifically developed for this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lung cancer in young patients is an uncommon and understudied entity that harbors distinctive epidemiological, clinic-demographic, and genomic features. We carried out a systematic review of genomic profiling in young patients with lung cancer from 2010 to 2020 in the main electronic databases and selected 23 manuscripts. Lung cancer in young patients occurs more frequently in women with adenocarcinoma histology and at more advanced stages. Some studies report higher oncogenic genomic alteration in this population, with higher anaplastic lymphoma kinase rearrangements, a distinct profile of epidermal growth factor receptor mutations, and other novel genomic alterations. Although still uncommon, the implementation of next-generation sequencing (NGS) has shed some light on germline genomic alterations associated with lung cancer in young patients. Although outcomes when compared with the older population are conflicting, the overall prognosis is still poor in this subset of patients and efforts to find targetable genomic alterations should be made to improve survival., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ischemia-reperfusion (I/R) injury, an inevitable result of kidney transplantation, triggers early inflammatory events that affect graft viability. Evidence from human transplantation and preclinical models of I/R suggests that a female hormonal environment positively influences the ability to recover from ischemic injury. However, the mechanisms behind these effects remain mostly unexplored. Here, we studied the influence of sex on pro-inflammatory mediators involved in the pathophysiology of acute I/R injury in male, female, and female ovariectomized (OVX) Wistar rats that underwent unilateral renal ischemia for 45 min, followed by 24 h of reperfusion. We found improved renal function, reduced cytokine expression, and decreased infiltration of myeloperoxidase-positive cells in females after I/R, when compared to their male and female OVX counterparts. Remarkably, citrullination of histone H3 was exacerbated in serum and renal tubules of females after I/R. In contrast, we observed lower levels of citrullinated histone H3 in male and female OVX rats in response to I/R, mostly in neutrophil extracellular traps. Our results demonstrate that female sex promotes renal I/R tolerance by attenuating pro-inflammatory mediators involved in I/R-induced damage., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The role of regulatory T cells (Tregs) on protective immunity in fungal infections, is controversial. Sporotrichosis is an emerging and worldwide-distributed subcutaneous mycosis caused by various related thermodimorphic fungi of the genus Sporothrix. Previously, we showed an elevated percent of Tregs around 21 days post-infection (dpi) in C57BL/6 mice infected with either Sporothrix schenckii or Sporothrix brasiliensis, but the effect of these cells in the ongoing infection was not evaluated. Here, we aim to characterize the role of Foxp3+ Tregs in a subcutaneous S. schenckii infection model. The flow cytometric analyses showed that S. schenckii infection elicited an expansion of a splenic CD4+Foxp3+ population, including a subset of Helios low + after ex vivo stimulation with S. schenckii-heat killed yeast. Depletion of Tregs in DEREG mice revealed a reduction of fungal burden in the skin and systemically in liver and kidneys, associated with enhanced Th1 and Th17 responses. Altogether, our results reveal for the first time that Tregs depletion in ongoing S. schenckii infection improves the protective antifungal immunity and these data suggest that Tregs modulation could be explored as a potential therapeutic strategy in sporotrichosis., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: The purpose of this study was to analyze the risk of aortic events (death, dissection, or aortic rupture) associated with Marfan syndrome and decide on the optimal timing for preventive surgery on the aortic root., Methods: From January 2004 to June 2015, 397 patients from Marfan Units were studied by echocardiographic and computed tomography and magnetic resonance imaging of aorta and periodic annual monitoring. Mean follow-up was 5.6 ± 2.7 years. The annual incidence of aortic events was assessed according to aortic diameters for the optimal time for prophylactic surgery to be decided on., Results: Mean age at the first visit was 28.4 ± 14.5 years, with mean sinuses of Valsalva diameter of 37.1 ± 6.6 mm., Eleven aortic events occurred during follow-up: seven deaths and four acute aortic dissections. Mean annual risk of an aortic event was 0.5% (risk of death 0.32% and risk of aortic dissection 0.18%). The increase in aortic diameters was associated with increased risk of 0.2% per year (95% confidence interval [CI], 0.03 to 0.5) with diameters less than 40 mm, 0.3% per year (95% CI, 0.1 to 1.4) between 40 and 44 mm, 1.3% per year (95% CI, 0.3 to 4.6) between 45 and 49 mm, and 5.2% per year (95% CI, 0.4 to 12.4) with diameters 50 mm or greater. Fifty-six patients underwent elective surgery with no inhospital mortality. Overall survival at 3, 5, and 10 years was 99% ± 5%, 98.6% ± 6%, and 95.5% ± 2.5%, respectively., Conclusions: The incidence of aortic events in patients with Marfan syndrome followed at specific units is low, although the risk increases with aortic diameters of 45 mm or greater. These results support current indications, but we consider it reasonable at experienced centers (elective root aortic surgery mortality less than 1%) to indicate an early surgery when the aortic root exceeds 45 mm., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Despite the improvement in the prognosis of acute coronary syndrome (ACS), substantial morbidity and mortality remain. We aimed to evaluate the effect of obstructive sleep apnoea (OSA) and its treatment with continuous positive airway pressure (CPAP) on the clinical evolution of patients with ACS., Methods: We designed a multicentre, open-label, parallel-group, randomised controlled trial of patients with ACS at 15 hospitals in Spain. Eligible non-sleepy patients were men and women aged 18 years and older, admitted to hospital for documented symptoms of ACS. All patients underwent respiratory polygraphy during the first 24-72 h after admission. OSA patients were randomly assigned (1:1) to CPAP treatment plus usual care (CPAP group) or usual care alone (UC group) by a computerised system available 24 h a day. A group of patients with ACS but without OSA was also included as a reference group. Because of the nature of the intervention, the trial intervention could not be masked to either investigators or patients. Patients were monitored and followed for a minimum of 1 year. Patients were examined at the time of inclusion; after 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months; and every 12 months thereafter, if applicable, during the follow-up period. The primary endpoint was the prevalence of a composite of cardiovascular events (cardiovascular death or non-fatal events [Acute myocardial infarction, non-fatal stroke, hospital admission for heart failure, and new hospitalisations for unstable angina or transient ischaemic attack]) in patients followed up for a minimum of 1 year. The primary analysis was done according to the intention-to-treat principle. This study is registered with Clinicaltrials.gov, NCT01335087 and is now closed., Findings: Between April 25, 2011, and Feb 2, 2018, a total of 2834 patients with ACS had respiratory polygraphy, of whom 2551 (90·01%) were recruited. 1264 (49·55%) patients had OSA and were randomly assigned to the CPAP group (n=633) or the UC group (n=631). 1287 (50·45%) patients did not have OSA, of whom 603 (46·85%) were randomly assigned to the reference group. Patients were followed up for a median of 3·35 years (IQR 1·50-5·31). The prevalence of cardiovascular events was similar in the CPAP and UC groups (98 events [16%] vs 108 events [17%]; hazard ratio [HR] 0·89 [95% CI 0·68-1·17]; p=0·40) during follow-up. Mean time of adherence to CPAP treatment was 2·78 h/night (SD 2·73). The prevalence of cardiovascular events was similar between patients in the reference group (90 [15%] events) and those in the UC group (102 (17%) events) during follow-up (1·01 [0·76-1·35]; p=0·93). The prevalence of cardiovascular events seem not to be related to CPAP compliance or OSA severity. 464 (74%) of 629 patients in the CPAP group had 1538 serious adverse events and 406 (65%) of 626 patients in the UC group had 1764 serious adverse events., Interpretation: Among non-sleepy patients with ACS, the presence of OSA was not associated with an increased prevalence of cardiovascular events and treatment with CPAP did not significantly reduce this prevalence., Funding: ResMed (Australia), Fondo de Investigación Sanitaria (Fondo Europeo de Desarrollo Regional), the Spanish Respiratory Society, the Catalonian Cardiology Society, Esteve-Teijin, Oxigen Salud, and ALLER., (Copyright © 2020 Elsevier Ltd. All rights reserved.)