A Sample Preparation Procedure for Isobaric Labeling-Based Single-Cell Proteomics.

Mass spectrometry-based proteomics has traditionally been limited by the amount of input material for analysis. Single-cell proteomics has emerged as a challenging discipline due to the ultra-high sensitivity required. Isobaric labeling-based multiplex strategies with a carrier proteome offer an approach to overcome the sensitivity limitations. Following this as the basic strategy, we show here the general workflow for preparing cells for single-cell mass spectrometry-based proteomics. This protocol can also be applied to manually isolated cells when large cells, such as cardiomyocytes, are difficult to isolate properly with conventional fluorescence-activated cell sorting (FACS) sorter methods.

Differential requirement for RecFOR pathway components in Thermus thermophilus.

Recombinational repair is an important mechanism that allows DNA replication to overcome damaged templates, so the DNA is duplicated timely and correctly. The RecFOR pathway is one of the common ways to load RecA, while the RuvABC complex operates in the resolution of DNA intermediates. We have generated deletions of recO, recR and ruvB genes in Thermus thermophilus, while a recF null mutant could not be obtained. The recO deletion was in all cases accompanied by spontaneous loss of function mutations in addA or addB genes, which encode a helicase-exonuclease also key for recombination. The mutants were moderately affected in viability and chromosome segregation. When we generated these mutations in a Δppol/addAB strain, we observed that the transformation efficiency was maintained at the typical level of Δppol/addAB, which is 100-fold higher than that of the wild type. Most mutants showed increased filamentation phenotypes, especially ruvB, which also had DNA repair defects. These results suggest that in T. thermophilus (i) the components of the RecFOR pathway have differential roles, (ii) there is an epistatic relationship of the AddAB complex over the RecFOR pathway and (iii) that neither of the two pathways or their combination is strictly required for viability although they are necessary for normal DNA repair and chromosome segregation.

Incidence and time trends of childhood hematological neoplasms: a 36-year population-based study in the southern European context, 1983-2018.

Background: Hematological neoplasms (HNs) are the first and most common childhood cancers globally. Currently, there is a lack of updated population-based data on the incidence of these cancers in the Spanish pediatric population. This study aimed to describe the incidence and incidence trends of HNs in children (0-14 years) in Spain using data from the Spanish Network of Cancer Registries and to compare the results with other southern European countries. Methods: Data were extracted from 15 Spanish population-based cancer registries between 1983 and 2018. Cases were coded according to the International Classification of Diseases for Oncology, third edition, first revision, and grouped according to the International Classification of Childhood Cancer, third edition. Crude rates (CRs), age-specific rates, and age-standardized incidence rates using the 2013 European population (ASRE) were calculated and expressed as cases per 1,000,000 child-years. Incidence trends and annual percentage changes (APCs) were estimated. Results: A total of 4,747 HNs were recorded (59.5% boys). Age distribution [n (%)] was as follows: <1 year, 266 (5.6%); 1-4 years, 1,726 (36.4%); 5-9 years, 1,442 (30.4%); and 10-14 years, 1,313 (27.6%). Leukemias were the most common group, with a CR and an ASRE of 44.0 (95%CI: 42.5; 45.5) and 44.1 (95%CI: 42.6; 45.7), respectively. The CR and ASRE of lymphomas were 20.1 (95%CI: 19.1; 21.1) and 20.0 (95%CI: 19.0; 21.1), respectively. The comparable incidence rates between our results and those of other southern European countries were similar for lymphomas, while some differences were observed for leukemias. From 1988 to 2016, the trend in leukemia incidence was stable for both sexes, with an APC of 0.0 (95%CI: -0.5; 0.7), whereas a constant overall increase was observed for lymphoma in both sexes, with an APC of 1.0 (95%CI: 0.4; 1.6). Conclusion: Leukemias are the most common HNs in children, and their incidence has remained stable since 1988, whereas the incidence of lymphomas has increased every year. Lymphoma incidence is like that of other southern European countries, while leukemia incidence is similar only to that of southwestern European countries. Collaborative cancer registry projects allow for assessing epidemiological indicators for cancers such as HNs, which helps health authorities and clinicians provide more knowledge about these malignancies.

Cardiomyocyte-Specific Wt1 Is Involved in Cardiac Metabolism and Response to Damage.

The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.

Internationalizing the business school: A comparative analysis of English-medium and Spanish-medium instruction impact on student performance.

Business degrees have been pioneers in adopting the internationalization of Higher Education Institutions with the option of English as Medium of Instruction (EMI). Research has grown about the EMI versus non-EMI lecturers and students' performance measured through perception, motivation, discursive analysis or satisfaction measures. However, results have not been conclusive in the scarce number of papers comparing quantitative course grades of EMI versus non-EMI students. The aim of this research paper is to prove that there is no difference in attaining learning objectives among students within a Business Administration Degree in Spain regardless the language of instruction. The present observational study considers all enrolled freshman throughout a horizon of six consecutive years allowing more reliable results not affected by the specificities of courses or years. All 212 students in the EMI track were matched to non-EMI track counterparts taking into account all available covariates. Results not only show that there is no difference in the attained learning objectives between the two tracks, but also that EMI students' grades are in fact better than their non-EMI counterparts, which might help to remove the believe many still have on the lower academic attainment of those following an EMI track.

Lóbulo hepático de Riedel, una falsa hepatomegalia / Riedel's lobe, a false impression of hepatomegaly

La hepatomegalia es un signo clínico relativamente frecuente en la exploración del paciente pediátrico. Esta puede ser la manifestación de una hepatopatía o de un trastorno sistémico con afectación hepática. Una variante de la normalidad del lóbulo hepático derecho es el llamado lóbulo de Riedel, que en ocasiones puede interpretarse como una hepatomegalia. Estas personas están asintomáticas y no presentan signos clínicos ni analíticos de hepatopatía. Se presenta el caso de un niño de 4 años en el que se encuentra, de forma casual, una hepatomegalia radiológica (AU)

Hepatomegaly is a relatively frequent clinical sign in the examination of the pediatric patient. This may be due to a hepatic disease or a generalized disease with hepatic involvement. A variant of the normal right hepatic lobe is the called Riedel´s lobe, which can sometimes be interpreted as hepatomegaly. These patients are asymptomatic and have no clinical or laboratory signs of the liver disease. We present the case of a 4-year-old boy in whom a radiological hepatomegaly was found by chance. (AU)

Incidence and survival of lymphoid neoplasms in Spain, 2002-2013: A population-based study from the Spanish Network of Cancer Registries (REDECAN).

Introduction: The aim of this study was to describe incidence, incidence trends and survival patterns of lymphoid neoplasms (LNs) and its subtypes in Spain in the period 2002-2013 using data from the Spanish Network of Cancer Registries (REDECAN). Materials and Methods: Data were extracted from 13 Spanish population-based cancer registries. LNs incident cases were codified using the International Classification of Diseases for Oncology, third edition (ICD-O-3) and grouped according to the WHO 2008 classification. Age-standardized incidence rates to the 2013 European standard population (ASIRe) were obtained. Poisson regression models were used to analyze trends in incidence rates and estimate the annual percentage change (APC) for each subtype. The number of cases in Spain for 2023 was estimated by applying the estimated age-specific rates for the year 2023 to the 2023 Spanish population. Observed survival (OS) was estimated by the Kaplan-Meier method and net survival (NS) by the Pohar-Perme method. Sex- and age-specific estimates of 5-year NS were calculated, as well as its changes according to two periods of diagnosis (2002-2007 and 2008-2013). Results: LNs accounted for 69% (n=39,156) of all hematological malignancies (n=56,751) diagnosed during the period of study. Median age at diagnosis was 67 years (interquartile range (IQR) = 52-77). The overall ASIRe was 34.23 (95% confidence interval (CI): 33.89, 34.57) and showed a marked male predominance in almost all subtypes (global sex ratio = 1.45). During the study period, incidence trends of LNs remained stable (APC: 0.3; 95% CI: -0.1, 0.6), nevertheless some subtypes showed statistically significant variations, such as LNs NOS category (APC: -5.6; 95% CI: -6.8, -4.3). Around 17,926 new cases of LNs will be diagnosed in 2023 in Spain. Survival rates differed considerably across age-groups, while they were similar between men and women. Five- year NS was 62.81% (95% CI: 62.1, 63.52) for all LNs, and varied widely across LNs subtypes, ranging from 39.21% to 90.25%. NS for all LNs improved from the first period of diagnosis to the second one, being 61.57% (95% CI: 60.56, 62.61) in 2002-2007 and 64.17% (95% CI: 63.29, 65.07) in 2008-2013. Conclusions: This study presents the first complete and extensive population-based analysis of LNs incidence and survival in Spain. These population-based data provide relevant information to better understand the epidemiology of LNs in Southern Europe and it features some useful points for public health authorities and clinicians. However, additional improvements regarding the registration of these hematological neoplasms can be implemented.

Accounting Earnings and Economic Growth, Trends, and Challenges: A Bibliometric Approach.

In recent years, studies have been conducted to quantify the relationship between microeconomic and macroeconomic development. Macroeconomics is the orientation of microeconomic development. Existing research hopes to quantify the relationship between macroeconomics and micro-firms, rather than just focusing on economic indicators. And some empirical studies try to use the relationship between them to discuss its usefulness for micro-firm decision-making. This article focuses on applying and developing aggregate earnings in connecting microenterprise earnings and macroeconomic development. To achieve this goal, this research did a comprehensive bibliometric analysis on macro-accounting on the two most influential databases, namely, Web of Science and Scopus. It used the information visualization software VOSviewer to draw knowledge maps to sort research lines. We also analyzed the research hotspots of macro-accounting in recent years according to the year scale and combined it with the neural network PSO-LSTM model to predict their future development. It turns out that the research on aggregate earnings related to economic growth has become a research hotspot in recent years. Scopus research and development potential is better than Web of Science in this field.

Lack of Clinical Relevance of Bilastine-Food Interaction in Healthy Volunteers: A Wheal and Flare Study.

INTRODUCTION: The aim of this study was to compare the pharmacodynamic activity of bilastine administered under fasting and fed conditions in healthy volunteers. METHODS: In this randomized, open-label, two-period, crossover study involving 24 healthy subjects, once-daily oral bilastine 20 mg was administered for 4 days under fasting and fed conditions, with a 7-day washout period. Bilastine plasma concentrations were measured for 24 h after the first and fourth doses in each period. Pharmacodynamic activity was assessed by wheal and flare surface inhibition and subjective assessment of itching, after intradermal injection of histamine 5 µg. RESULTS: When administered under fed versus fasting conditions, exposure to bilastine 20 mg decreased (mean maximum plasma concentration and area under the curve from time 0 to 24 h decreased by 34.27% and 32.72% [day 1], respectively, and 33.08% and 28.87% [day 4]). Despite this, the antihistaminic effect of bilastine 20 mg was not altered by food. On day 1, as assessed by wheal and flare surface inhibition, the maximum effect and duration of action of bilastine did not differ to a significant extent between fasting and fed conditions, with only a short 30-min delay in the onset of wheal inhibition. At steady state (day 4), bilastine's pharmacodynamic effects were not significantly affected under fasting or fed conditions. CONCLUSION: The pharmacokinetic interaction of bilastine with food does not imply a significant reduction of its peripheral antihistaminic efficacy. Despite a slight delay in onset of action on the first treatment day, the global clinical efficacy of bilastine is not affected by coadministration with food.

Regenerative potential of epicardium-derived extracellular vesicles mediated by conserved miRNA transfer.

AIMS: After a myocardial infarction, the adult human heart lacks sufficient regenerative capacity to restore lost tissue, leading to heart failure progression. Finding novel ways to reprogram adult cardiomyocytes into a regenerative state is a major therapeutic goal. The epicardium, the outermost layer of the heart, contributes cardiovascular cell types to the forming heart and is a source of trophic signals to promote heart muscle growth during embryonic development. The epicardium is also essential for heart regeneration in zebrafish and neonatal mice and can be reactivated after injury in adult hearts to improve outcome. A recently identified mechanism of cell-cell communication and signalling is that mediated by extracellular vesicles (EVs). Here, we aimed to investigate epicardial signalling via EV release in response to cardiac injury and as a means to optimize cardiac repair and regeneration. METHODS AND RESULTS: We isolated epicardial EVs from mouse and human sources and targeted the cardiomyocyte population. Epicardial EVs enhanced proliferation in H9C2 cells and in primary neonatal murine cardiomyocytes in vitro and promoted cell cycle re-entry when injected into the injured area of infarcted neonatal hearts. These EVs also enhanced regeneration in cryoinjured engineered human myocardium (EHM) as a novel model of human myocardial injury. Deep RNA-sequencing of epicardial EV cargo revealed conserved microRNAs (miRs) between human and mouse epicardial-derived exosomes, and the effects on cell cycle re-entry were recapitulated by administration of cargo miR-30a, miR-100, miR-27a, and miR-30e to human stem cell-derived cardiomyocytes and cryoinjured EHM constructs. CONCLUSION: Here, we describe the first characterization of epicardial EV secretion, which can signal to promote proliferation of cardiomyocytes in infarcted mouse hearts and in a human model of myocardial injury, resulting in enhanced contractile function. Analysis of exosome cargo in mouse and human identified conserved pro-regenerative miRs, which in combination recapitulated the therapeutic effects of promoting cardiomyocyte proliferation.

Delving into the Determinants of Default Risk in Savings Groups: Empirical Evidence from Ecuador.

Financial inclusion has been broadly recognized as critical in alleviating poverty and achieving inclusive economic growth. The capability of borrowers to repay their microcredit loans is a critical concern and is the first risk of Microfinance institutions sustainability. Exploring the determinants of credit risk is an issue of substantial importance in microfinance. The purpose of this research was to identify the savings group members' characteristics that have impact on default risk. We have used a multivariate regression model to identify the factors that affect default behaviour among microcredit borrowers from savings groups. We have analysed a sample of more than different 400 Savings Groups and 7251 active users of the "Saving and Learning" program in Ecuador. Empirical results demonstrated that factors such as seniority, accumulated savings and the number of members in the savings groups are determinant variables of default risk. The significant positive sign on variable "Gender" is consistent with the previous authors that indicate that the probability of having problems in loan repayment is higher for males than for females. The generalizability of our findings should, of course, be interpreted with caution, as they may be idiosyncratic of the sample, period or region. To contrast and contextualize these results, we had in-depth discussions with the Savinco managers and their field agent in Ecuador. There are many contributions. For practitioners, relevant factors that can affect savings groups default rates have been identified. For academics, the rich information provided by the Savinco mobile App could be a starting point for further quantitative research.

Il est largement reconnu que l'inclusion financière est essentielle pour réduire la pauvreté et parvenir à une croissance économique inclusive. La capacité des emprunteurs à rembourser leurs prêts de microcrédit est une préoccupation essentielle et constitue le premier risque pour la pérennité des institutions de microfinance. L'étude des déterminants du risque de crédit est une question d'une importance capitale en microfinance. Le but de cette étude est d'identifier les caractéristiques des membres de groupes d'épargne qui ont un impact sur le risque de défaut de paiement. Nous avons utilisé un modèle de régression multivariée pour identifier les facteurs qui affectent le comportement de défaut de paiement parmi les emprunteurs de microcrédit au sein de groupes d'épargne. Nous avons analysé un échantillon de plus de 400 groupes d'épargne différents et 7 251 utilisateurs actifs du programme « Épargne et apprentissage ¼ en Équateur. Les résultats empiriques ont démontré que des facteurs tels que l'ancienneté, l'épargne accumulée et le nombre de membres dans les groupes d'épargne sont des variables déterminantes du risque de défaut de paiement. Sur la variable « Genre ¼, le signe positif significatif est cohérent avec les études précédentes qui indiquent que la probabilité d'avoir des problèmes de remboursement de prêt est plus élevée chez les hommes que chez les femmes. Bien entendu, le caractère généralisable de nos résultats doit être interprété avec prudence, car ces résultats peuvent être uniques à l'échantillon, à la période ou à la région. Pour contraster et contextualiser ces résultats, nous avons eu des discussions approfondies avec les gestionnaires de Savinco et leur agent de terrain en Équateur. Les contributions sont nombreuses. Pour les praticiens, ont été identifiés les facteurs pertinents pouvant affecter le taux de défaut de paiement des groupes d'épargne. Pour les universitaires, les riches informations fournies par l'application mobile Savinco pourraient être un point de départ pour d'autres études quantitatives.

Bilastine 10 and 20 mg in paediatric and adult patients: an updated practical approach to treatment decisions.

BACKGROUND: Bilastine, a non-sedating H1-antihistamine, is indicated to treat the symptoms of allergic disorders (e.g. rhinoconjunctivitis and urticaria) in adults and adolescents and, more recently, in children. Following its marketing approval, many questions regarding the ideal use of bilastine in various clinical practice situations have been received by the Medical Information Department (MID) of Faes Farma Spain. This article is an update of a previous review, with a focus on recent clinical information on the use of bilastine in paediatric and other populations. METHODS: Results of recent clinical studies in paediatric and other populations as well as questions received and responses provided by the Faes Farma MID. RESULTS: The information regarding the use of bilastine in paediatric patients is the most relevant aspect of this updated review. The stepwise approval of the paediatric formulations in various countries started with the European Medicines Agency approval in 2017 in accordance with a 2009 Paediatric Investigation Plan, followed by approval in other countries. The queries that are most commonly received by the Faes Farma MID include the potential for drug interactions involving bilastine and other frequently used drugs, and the use of bilastine in special populations or to treat specific symptoms related to allergic conditions. As the concomitant use of many medications is not permitted during clinical trials, the advice provided regarding the concomitant use of other medications with bilastine considers the pharmacological properties of both the drug in question and bilastine, as well as expert opinion. Likewise, advice regarding the use of bilastine in special populations (e.g. patients with renal impairment, obesity, lactose intolerance, and elderly or pregnant individuals) or to treat specific symptoms (e.g. treatment-resistant urticaria, pruritus or BASCULE syndrome) considers the best evidence from a variety of sources, including clinical studies, real-world experience, guideline recommendations and expert opinion. CONCLUSION: This updated review provides current data regarding the best use of bilastine in specific situations and patients and identifies areas in which further knowledge is required. Although decisions regarding the use of bilastine may be aided by expert opinion that relies on knowledge of the underlying science, additional research and evidence are required to answer certain queries regarding the use of bilastine.

Application of a dual mechanistic approach to support bilastine dose selection for older adults.

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials.

Adecuación de la seguridad del metamizol y agranulocitosis / Adequacy of the safety of metamizole and agranulocytosis

Objetivo: Analizar si la nota informativa de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), de 30 de octubre del 2018, sobre agranulocitosis y metamizol contiene la información precisa y necesaria para proteger a los pacientes de la aparición de esta reacción adversa (RA) y si la documentación oficial de los medicamentos con metamizol para médicos, farmacéuticos y población general está adaptada a las directrices de la AEMPS para disminuir el riesgo. Emplazamiento y participantes: Nota informativa, búsqueda bibliográfica, información sobre los medicamentos con metamizol comercializados en España en la Agencia Europea del Medicamento, fichas técnicas, prospectos, base de datos de información sanitaria Bot PLUS y Catálogo de Especialidades Farmacéuticas. Notificación de 4casos de agranulocitosis por metamizol posteriores a la fecha de la nota informativa. Intervenciones y mediciones principales: Comparación de los puntos clave de la nota informativa y de los documentos oficiales sobre metamizol con la bibliografía. Descripción de 4casos de agranulocitosis por metamizol y aplicación del algoritmo de causalidad y gravedad. Resultados: La nota informativa presenta ausencias y dudas respecto a la bibliografía y al uso de metamizol en la práctica asistencial. Los documentos oficiales presentan faltas de actualización, indicaciones no aprobadas y dosis superiores a las recomendadas. La nota informativa no ha frenado la presentación de casos de agranulocitosis por metamizol. Conclusiones: La nota informativa de la AEMPS es mejorable y es necesario actualizar los documentos oficiales de información sobre el metamizol para profesionales sanitarios y pacientes para disminuir el riesgo de agranulocitosis.(AU)

Objective: To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk. Setting and participants: Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued. Main interventions and measurements: Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm. Results: The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole. Conclusions: The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.(AU)

[Adequacy of the safety of metamizole and agranulocytosis]. / Adecuación de la seguridad del metamizol y agranulocitosis.

OBJECTIVE: To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk. SETTING AND PARTICIPANTS: Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued. MAIN INTERVENTIONS AND MEASUREMENTS: Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm. RESULTS: The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole. CONCLUSIONS: The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.

Virtual meeting, real and sound science: report of the 17th Meeting of the Spanish Society for Developmental Biology (SEBD-2020).

The Spanish Society for Developmental Biology (SEBD) organized its 17th meeting in November 2020 (herein referred to as SEBD2020). This meeting, originally programmed to take place in the city of Bilbao, was forced onto an online format due to the SARS-CoV2, COVID-19 pandemic. Although, we missed the live personal interactions and missed out on the Bilbao social scene, we were able to meet online to present our work and discuss our latest results. An overview of the activities that took place around the meeting, the different scientific sessions and the speakers involved are presented here. The pros and cons of virtual meetings are discussed.

Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart.

Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria.

Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and Cmax values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC0-24 and Cmax were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo.Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar.What is Known:• Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day).• An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years.What is New:• As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years.• Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo.

Efficacy and safety of bilastine in reducing pruritus in patients with chronic spontaneous urticaria and other skin diseases: an exploratory study.

Purpose: To evaluate the efficacy/safety of bilastine in pruritus relief in patients with chronic spontaneous urticaria (CSU) or other pruritic skin diseases.Methods: In this multicenter, open-label, exploratory study (EudraCT No.: 2016-001505-17), 115 adults with CSU (n = 34), eczema/dermatitis (n = 30), prurigo (n = 25) or cutaneous pruritus (n = 26), received bilastine 20 mg once daily for 8 weeks, or in non-responder patients (<30% improvement in pruritus score at week 2), 40 mg/day from week 2.Results: The mean change in weekly pruritus severity score from baseline to week 8 (primary endpoint) was reduced with bilastine (overall and by disease group); overall, percentage and absolute reductions were 71.16% and 1.63 points, respectively (p < .001). Updosed non-responders (n = 31) had improved weekly pruritus severity scores from baseline to week 8; percentage and absolute reductions were 49.08% and 1.13 points, respectively (p < .001). Bilastine improved the Dermatology Life Quality Index at weeks 4 and 8 (p < .001) in all disease groups, and the 7-day Urticaria Activity Score in CSU patients (p < .001). Bilastine was well tolerated.Conclusions: Bilastine relieved pruritus associated with urticaria and other skin diseases, with a very good safety profile.

Bioequivalence Evaluation of Three Pediatric Oral Formulations of Bilastine in Healthy Subjects: Results from a Randomized, Open Label, Crossover Study.

BACKGROUND AND OBJECTIVE: Bilastine is a non-sedating H1 antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this trial was to assess the bioequivalence of three novel pediatric oral formulations of bilastine. METHODS: An open label, randomized, four-treatment-period, four-sequence, crossover, single-center study was conducted in 23 healthy volunteers. Each subject received four single doses of bilastine under fasting conditions: a 10-mg orodispersible tablet (DT1), a 10-mg oral solution (SOL), a 10-mg orodispersible tablet without water (DT2dry), and a 10-mg orodispersible tablet with water (DT2water, reference formulation). Blood samples were collected during 72 h with a washout period of at least 7 days. Bilastine maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between 0 to t time (AUC0-t) were calculated to assess bioequivalence. Tolerability was evaluated throughout the study. RESULTS: The three oral pediatric formulations tested were bioequivalent to the reference formulation as determined by the ratio test/reference of the geometric mean and their 90% confidence intervals (between 0.80 and 1.25) for the Cmax, AUC0-t and AUC0-∞. Bilastine was well tolerated when administered indistinctly as an orodispersible tablet or as an oral solution. CONCLUSION: The three oral pediatric formulations tested were found to be bioequivalent to the reference formulation. All formulations were well tolerated. TRIAL REGISTRATION: Spanish Clinical Studies Registry (REEC) number 2014-000786-41.