The Transcription Factor TCF21 is necessary for adoption of cell fates by Foxd1+ stromal progenitors during kidney development.

Normal kidney development requires coordinated interactions between multiple progenitor cell lineages. The Foxd1+ stromal progenitors are critical for normal nephrogenesis and their heterogeneity is increasingly appreciated. However, the molecular mechanisms and trajectories that drive the differentiation of Foxd1+ cells toward the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs) are poorly understood. Recent work has implicated Tcf21, a mesoderm-specific bHLH transcription factor critical for embryogenesis, in the development of the kidney stroma and perivascular cells. To investigate the role of Tcf21 in Foxd1+ cells, we performed single-cell RNA sequencing (scRNA-seq) on GFP+ cells from E14.5 Foxd1 Cre ;Rosa26 mTmG ;Tcf21 f/f kidneys ( Tcf21 -cKO) and Foxd1 Cre controls. Clustering of the entire dataset identified a large stromal population and a smaller representation of non-stromal lineages. Subclustering of stromal cells identified six populations associated with healthy kidney development: medullary/perivascular, proliferating, differentiating nephron, nephrogenic zone-associated, collecting duct-associated, and ureteric. Loss of Tcf21 resulted in a dramatic reduction in the medullary/perivascular, proliferating, nephrogenic zone-associated, and collecting duct-associated stromal subpopulations. Immunostaining confirmed that Tcf21 -cKO has a severe constriction of the medullary and collecting duct-associated stromal space. We identified and validated a cluster unique to Tcf21 -cKO kidneys exhibiting mosaic expression of genes from nephrogenic, proliferating, medullary, and perivascular stromal cells spanning across all pseudotime, suggesting cells halted in the midst of differentiation. These findings underscore a critical role for Tcf21 in the emergence of Foxd1+ derivatives, with loss of Tcf21 leading to a shift in stromal cell fates that results in abnormal kidney development. NEW & NOTEWORTHY: The mechanisms responsible for the emergence of renal stromal heterogeneity has been unknown. Using scRNA-seq on Foxd1+ enriched cells from E14.5 kidneys, we identified seven molecularly distinct stromal populations and their regional association. The data suggest that the transcription factor Tcf21 regulates the adoption of fates by Foxd1+ cells that is required to form the normal milieu of stromal derivatives for the development of a kidney of normal size and function.

Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State.

BACKGROUND: Renin-expressing cells are myoendocrine cells crucial for the maintenance of homeostasis. Renin is regulated by cAMP, p300 (histone acetyltransferase p300)/CBP (CREB-binding protein), and Brd4 (bromodomain-containing protein 4) proteins and associated pathways. However, the specific regulatory changes that occur following inhibition of these pathways are not clear. METHODS: We treated As4.1 cells (tumoral cells derived from mouse juxtaglomerular cells that constitutively express renin) with 3 inhibitors that target different factors required for renin transcription: H-89-dihydrochloride, PKA (protein kinase A) inhibitor; JQ1, Brd4 bromodomain inhibitor; and A-485, p300/CBP inhibitor. We performed assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA sequencing, cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation sequencing for H3K27ac (acetylation of lysine 27 of the histone H3 protein) and p300 binding on biological replicates of treated and control As4.1 cells. RESULTS: In response to each inhibitor, Ren1 expression was significantly reduced and reversible upon washout. Chromatin accessibility at the Ren1 locus did not markedly change but was globally reduced at distal elements. Inhibition of PKA led to significant reductions in H3K27ac and p300 binding specifically within the Ren1 super-enhancer region. Further, we identified enriched TF (transcription factor) motifs shared across each inhibitory treatment. Finally, we identified a set of 9 genes with putative roles across each of the 3 renin regulatory pathways and observed that each displayed differentially accessible chromatin, gene expression, H3K27ac, and p300 binding at their respective loci. CONCLUSIONS: Inhibition of renin expression in cells that constitutively synthesize and release renin is regulated by an epigenetic switch from an active to poised state associated with decreased cell-cell communication and an epithelial-mesenchymal transition. This work highlights and helps define the factors necessary for renin cells to alternate between myoendocrine and contractile phenotypes.

An efficient inducible model for the control of gene expression in renin cells.

Fate mapping and genetic manipulation of renin cells have relied on either noninducible Cre lines that can introduce the developmental effects of gene deletion or bacterial artificial chromosome transgene-based inducible models that may be prone to spurious and/or ectopic gene expression. To circumvent these problems, we generated an inducible mouse model in which CreERT2 is under the control of the endogenous Akr1b7 gene, an independent marker of renin cells that is expressed in a few extrarenal tissues. We confirmed the proper expression of Cre using Akr1b7CreERT2/+;R26RmTmG/+ mice in which Akr1b7+/renin+ cells become green fluorescent protein (GFP)+ upon tamoxifen administration. In embryos and neonates, GFP was found in juxtaglomerular cells, along the arterioles, and in the mesangium, and in adults, GFP was present mainly in juxtaglomerular cells. In mice treated with captopril and a low-salt diet to induce recruitment of renin cells, GFP extended along the afferent arterioles and in the mesangium. We generated Akr1b7CreERT2/+;Ren1cFl/-;R26RmTmG/+ mice to conditionally delete renin in adult mice and found a marked reduction in kidney renin mRNA and protein and mean arterial pressure in mutant animals. When subjected to a homeostatic threat, mutant mice were unable to recruit renin+ cells. Most importantly, these mice developed concentric vascular hypertrophy ruling out potential developmental effects on the vasculature due to the lack of renin. We conclude that Akr1b7CreERT2 mice constitute an excellent model for the fate mapping of renin cells and for the spatial and temporal control of gene expression in renin cells.NEW & NOTEWORTHY Fate mapping and genetic manipulation are important tools to study the identity of renin cells. Here, we report on a novel Cre mouse model, Akr1b7CreERT2, for the spatial and temporal regulation of gene expression in renin cells. Cre is properly expressed in renin cells during development and in the adult under basal conditions and under physiological stress. Moreover, renin can be efficiently deleted in the adult, leading to the development of concentric vascular hypertrophy.

Organised and non-organised activities contribute to overall physical activity levels in adolescents and young adults with Down syndrome: a cross-sectional study.

BACKGROUND: Participation in organised and non-organised physical activities among adolescents and young adults with Down syndrome is underexplored. This study aimed to examine differences between organised and non-organised physical activities among adolescents and young adults with Down syndrome. METHODS: Forty participants with Down syndrome (27 woman; mean age 21.4 ± 4.9 years) were recruited. Data on physical activity participation were collected by self- or proxy-reported questionnaires about attendance, involvement and type of physical activity. RESULTS: Adolescents and young adults with Down syndrome participated in more organised than non-organised activities (P < 0.05), more often (P < 0.05), but there was no difference in the total time spent participating in these activities overall. Participants spent more time in vigorous physical activity during organised activities (P < 0.05) and spent more time in light physical activity during non-organised physical activities (P < 0.05). Dancing (organised activity) and walking (non-organised activity) were the most reported activities. CONCLUSIONS: Participation in both organised and non-organised physical activities is important to increase overall physical activity levels of adolescents and young adults with Down syndrome. Future research exploring physical activity preferences may help guide the planning and adaption of community programmes for this group.

Pediatric asthma comorbidities: Global impact and unmet needs.

Real-world data on the range and impact of comorbid health conditions that affect pediatric asthma are scant, especially from developing countries. Lack of data hinders effective diagnosis, treatment, and overall management of these complex cases. We, hereby, describe the common pediatric asthma comorbid conditions in terms of evidence for association, potential mechanisms of impact on asthma control, and treatment benefit. Obesity, upper airway allergies, dysfunctional breathing, multiple sensitizations, depressive disorders, food allergy, and gastro-esophageal reflux are common associations with difficult-to-treat asthma. On the other hand, asthma symptoms and/or management may negatively impact the well-being of children through drug adverse effects, worsening of anaphylaxis symptoms, and disturbing mental health. Awareness of these ailments may be crucial for designing the optimum care for each asthmatic child individually and may ultimately improve the quality of life of patients and their families. A multidisciplinary team of physicians is required to identify and manage such comorbidities aiming to mitigate the over-use of asthma pharmacotherapy. Asthma research should target relevant real-world difficulties encountered at clinical practice and focus on interventions that would mitigate the impact of such comorbidities. Finally, policymakers and global healthcare organizations are urged to recognize pediatric asthma control as a healthcare priority and allocate resources for research and clinical interventions. In other words, global asthma control needs support by compassionate scientific partnership.

Proteomic diversification of spermatostyles among six species of whirligig beetles.

Seminal fluid protein composition is complex and commonly assumed to be rapidly divergent due to functional interactions with both sperm and the female reproductive tract (FRT), both of which evolve rapidly. In addition to sperm, seminal fluid may contain structures, such as mating plugs and spermatophores. Here, we investigate the evolutionary diversification of a lesser-known ejaculate structure: the spermatostyle, which has independently arisen in several families of beetles and true bugs. We characterized the spermatostyle proteome, in addition to spermatostyle and FRT morphology, in six species of whirligig beetles (family Gyrinidae). Spermatostyles were enriched for proteolytic enzymes, and assays confirmed they possess proteolytic activity. Sperm-leucylaminopeptidases (S-LAPs) were particularly abundant, and their localization to spermatostyles was confirmed by immunohistochemistry. Although there was evidence for functional conservation of spermatostyle proteomes across species, phylogenetic regressions suggest evolutionary covariation between protein composition and the morphology of both spermatostyles and FRTs. We postulate that S-LAPs (and other proteases) have evolved a novel structural role in spermatostyles and discuss spermatostyles as adaptations for delivering male-derived materials to females.

Worldwide diversity in mammalian life histories: Environmental realms and evolutionary adaptations.

Mammalian life history strategies can be characterised by a few axes of variation, conforming a space where species are positioned based on the life history strategies favoured in the environment they exploit. Yet, we still lack global descriptions of the diversity of realised mammalian life history and how this diversity is shaped by the environment. We used six life history traits to build a life history space covering worldwide mammalian adaptation, and we explored how environmental realms (land, air, water) influence mammalian life history strategies. We demonstrate that realms are tightly linked to distinct life history strategies. Aquatic and aerial species predominantly adhere to slower life history strategies, while terrestrial species exhibit faster life histories. Highly encephalised terrestrial species are a notable exception to these patterns. Furthermore, we show that different mode of life may play a significant role in expanding the set of strategies exploitable in the terrestrial realm. Additionally, species transitioning between terrestrial and aquatic realms, such as seals, exhibit intermediate life history strategies. Our results provide compelling evidence of the link between environmental realms and the life history diversity of mammals, highlighting the importance of differences in mode of life to expand life history diversity.

Tcf21 as a Founder Transcription Factor in Specifying Foxd1 Cells to the Juxtaglomerular Cell Lineage.

Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Foxd1+ stromal progenitors. However, the factors guiding these progenitors toward the renin-secreting cell fate are not fully understood. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Utilizing Foxd1 Cre/+ ;Tcf21 f/f and Ren1 dCre/+ ;Tcf21 f/f mouse models, we investigated the role of Tcf21 in the differentiation of Foxd1+ progenitor cells into juxtaglomerular (JG) cells. Immunostaining and in-situ hybridization demonstrated significantly fewer renin-positive areas and altered renal arterial morphology in Foxd1 Cre/+ ;Tcf21 f/f kidneys compared with controls, indicating Tcf21's necessity for renin cell emergence. However, Tcf21 inactivation in renin-expressing cells ( Ren1 dCre/+ ;Tcf21 f/f ) did not recapitulate this phenotype, suggesting Tcf21 is dispensable once renin cell identity is established. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on GFP+ cells (stromal lineage) from E12, E18, P5, and P30 Foxd1 Cre/+ ;Rosa26 mTmG control kidneys revealed that Tcf21 expression peaks at embryonic day 12, crucial for early JG cell specification. Subsequent analyses confirmed Tcf21's critical role in early kidney development, with expression declining as development progresses. Our results highlight the temporal and spatial dynamics of Tcf21, showing its importance in the early specification of Foxd1+ cells into JG cells. These findings provide new insights into the molecular mechanisms governing JG cell differentiation and underscore Tcf21's pivotal role in kidney development. The data suggest that Tcf21 expression in Foxd1+ progenitors is essential for the specification of renin-expressing JG cells, but once renin cell identity is assumed, Tcf21 becomes redundant. NEW & NOTEWORTHY: This manuscript provides novel insights into the role of Tcf21 in the differentiation of Foxd1+ cells into JG cells. Utilizing integrated scRNA-seq and scATAC-seq, the study reveals that Tcf21 expression is crucial during early embryonic stages, with its peak at embryonic day 12. The findings demonstrate that inactivation of Tcf21 leads to fewer renin-positive areas and altered renal arterial morphology, underscoring the importance of Tcf21 in the specification of renin-expressing JG cells and kidney development.

XEN® 45 en el manejo quirúrgico del glaucoma en fases tempranas: estudio nacional de consenso según metodología Delphi / XEN-45 in the management of Early Glaucoma Surgery: A National Delphi Consensus Study

Antecedentes y objetivo: Las recomendaciones sobre el manejo general del glaucoma y el uso de cirugías mínimamente-invasivas y microincisionales en fases tempranas son limitadas. El objetivo de este estudio fue establecer un consenso sobre el manejo del glaucoma, centrándose en el implante XEN 45 (AbbVie Inc., North Chicago, IL, EE. UU.). Métodos: Se utilizó un método Delphi. El comité científico dirigió el estudio, identificó el panel de expertos y participó en la elaboración del cuestionario. Se invitó a 51 expertos a completar, en una escala Likert de 9 puntos, un cuestionario de 89 ítems que cubría 3 bloques temáticos. Se realizaron 2 rondas Delphi. Se logró consenso si≥66,6% de los expertos llegaron a un acuerdo o desacuerdo. Resultados: Los panelistas acordaron 84 ítems relacionados con la calidad de vida, el algoritmo terapéutico y el perfil del paciente, y el manejo quirúrgico pre y postoperatorio. Los panelistas consideraron el implante XEN idóneo para tratar el glaucoma en diferentes etapas y para diferentes perfiles de pacientes: pacientes jóvenes/ancianos/con comorbilidades-significativas, glaucoma-miópico, pacientes con fracaso quirúrgico previo y con postoperatorio complejo. El implante XEN se consideró un paso terapéutico previo a la cirugía filtrante clásica y una posible primera opción quirúrgica en pacientes ancianos con comorbilidades y presión intraocular descontrolada. El implante XEN permite al paciente retomar sus actividades diarias más rápidamente que las cirugías filtrantes convencionales y reducir y/o eliminar los tratamientos tópicos. Conclusiones: Este consenso según la metodología Delphi proporcionó una serie de recomendaciones generales para el tratamiento del glaucoma, incluidas aquellas relacionadas con la calidad de vida del paciente, el algoritmo terapéutico y el perfil del paciente, y específicas con respecto al uso del implante XEN.(AU)

Background and objective: Recommendations on general glaucoma management and the use of early minimally invasive and microincisional surgeries are limited. This study aimed to establish consensus regarding glaucoma management, focusing on the XEN-45 gel stent implant. Methods: A Delphi consensus-driven process was used. The scientific committee led the study, identified the expert panel, and participated in elaborating the questionnaire. Fifty-one panelists were invited to complete, on a nine-point Likert scale, an 89-item questionnaire covering three topic blocks. Two Delphi rounds were performed. Consensus was achieved if ≥66.6% of panelists reached agreement or disagreement. Results: Panelists agreed on 84 items related to the patients’ quality of life, the therapeutic algorithm and patient profile, and surgical and pre- and post-operative management. Panelists agreed on the suitability of XEN stent implants to treat glaucoma at different stages and for different patient profiles: young patients, elderly or with significant comorbidities, and with myopic glaucoma, patients who failed previous surgeries, and with previous poor post-operative experience. XEN surgery was considered a therapeutic step prior to classic filtering surgery and a possible first surgical option in elderly patients with comorbidities and uncontrolled intraocular pressure. XEN surgery allows the patient to return to routine daily activities faster than conventional filtering surgeries and to reduce and/or eliminate topical treatments. Conclusions: This Delphi-driven consensus resulted in a series of general recommendations for glaucoma management, including those related to patient quality of life, therapeutic algorithm, and patient profile, and specific ones regarding the use of XEN stent gel surgery.(AU)

XEN-45 in the management of early glaucoma surgery: A national Delphi consensus study.

BACKGROUND AND OBJECTIVE: Recommendations on general glaucoma management and the use of early minimally invasive and microincisional surgeries are limited. This study aimed to establish consensus regarding glaucoma management, focusing on the XEN-45 gel stent implant. METHODS: A Delphi consensus-driven process was used. The scientific committee led the study, identified the expert panel, and participated in elaborating the questionnaire. Fifty-one panelists were invited to complete, on a nine-point Likert scale, an 89-item questionnaire covering three topic blocks. Two Delphi rounds were performed. Consensus was achieved if ≥66.6% of panelists reached agreement or disagreement. RESULTS: Panelists agreed on 84 items related to the patients' quality of life, the therapeutic algorithm and patient profile, and surgical and pre- and post-operative management. Panelists agreed on the suitability of XEN stent implants to treat glaucoma at different stages and for different patient profiles: young patients, elderly or with significant comorbidities, and with myopic glaucoma, patients who failed previous surgeries, and with previous poor post-operative experience. XEN surgery was considered a therapeutic step prior to classic filtering surgery and a possible first surgical option in elderly patients with comorbidities and uncontrolled intraocular pressure. XEN surgery allows the patient to return to routine daily activities faster than conventional filtering surgeries and to reduce and/or eliminate topical treatments. CONCLUSIONS: This Delphi-driven consensus resulted in a series of general recommendations for glaucoma management, including those related to patient quality of life, therapeutic algorithm, and patient profile, and specific ones regarding the use of XEN stent gel surgery.

Obstructive sleep apnea and periodic limb movement in children: is there really an association?

PURPOSE: Periodic limb movements (PLMs) can be found isolated or related to other sleep disorders, as Obstructive Sleep Apnea (OSA). Nevertheless, this association was described before the proposal for modification of the World Association of Sleep Medicine (WASM), which incorporated major changes modifying the definition of respiratory-related leg movements (RRLM) so that the relationship between OSA and PLM could be affected. METHODS: A total of 131 PSG were studied (children with ages from 5 to 12 years old), all referred because of a suspicion of sleep-disordered breathing (65 children were diagnosed of OSA, and 66 presented snoring but no sleep apnea). Leg movements were manually scored according to both 2006 and 2016 WASM/IRLSSG criteria. RESULTS: According to 2006 WASM rules, statistical differences were found, not only for PLM index (p 0.002), but all indexes. Nevertheless, according to new 2016 WASM rules, no statistical differences were found for PLM index (p 0.677), non-REM PLM index (p 0.299), REM PLM index (P 0.511) or PLM with arousal index (p 0.180), between OSA and non-OSA group. Positive correlation between PLM and RRLM have been found with both set of rules. The percentage of children with PLM>5/h is higher when using the prior PLM scoring criteria developed in 2006 (38.93%) versus the updated PLM scoring criteria (19.08%). CONCLUSION: The lack of association when using the new WASM/IRLSSG scoring rules together with the absence of a previous clear etiopathology explanation may suggest that the association between OSA and PLM might be indeed overestimated and that, perhaps, it really did not exist.

Toasted Vine Shoots as an Alternative Enological Tool. Impact on the Sensory Profile of Tempranillo Wines during Bottle Aging.

The use of toasted vine shoots (SEGs) as an enological tool is a new practice that seeks to improve wines by differentiating between them and encouraging sustainable wine production. The sensorial impact during bottle aging of wines treated with SEGs is a key factor to consider. This paper studies the influence of SEGs on Tempranillo wines treated with their own SEGs in two different doses (12 and 24 g/L) at two differences moments (during alcoholic fermentation and after malolactic fermentation) throughout 1 year of bottle aging. The results indicate that addition moment is the factor that most affects the evolution of sensorial descriptors. The greatest evolution in the wines was observed during the first 4 months, wherein improved integration of the notes related to addition of SEGs occurred. A reduction in the perception of dryness and bitterness was observed in the treated wines, therefore, SEGs could be considered accelerators to eliminate these initial sensations from wines.

Evolution in the Bottling of Cabernet Sauvignon Wines Macerated with Their Own Toasted Vine-Shoots.

This work studies, for the first time, the effect of the use of Cabernet Sauvignon vine-shoots as an enological additive (called "Shoot Enological Granule", SEG) in wines of the same variety. SEGs were added in two doses (12 and 24 g/L) at the end of malolactic fermentation, and after that, wines were bottled for six months. The phenolic and volatile composition and sensory profiles of wines were analyzed at bottling and after six months. The results showed a decrease in the total content of phenolic compounds with bottle time; however, stilbenes─specifically trans-resveratrol─were maintained at significant levels in SEG wines. In contrast, the total content of volatile compounds, mainly esters, increased with bottle aging. Finally, in terms of sensory profile, SEG wines showed a clear differentiation between the descriptors and the control, with more-integrated aromas after bottle time with more toasted, nutty vanilla notes, as well as silkier and less bitter tannins, compared to the control.

Comparative study of the doses of cytokinin in the quality of caigua (Cyclanthera pedata L.) in Peru.

Bioavailability of nutrients, the scarcity of synthetic fertilisers, and the rising cost of fuel have all contributed to an increase in production costs, which has in turn reduced crop productivity and led scientists to seek out new methods to ensure high-quality output. In this context, various cytokinins dosages were tested in Peru to see whether they affected the quality of caigua, in an effort to address these issues. To mitigate these problems, a pot experiment was carried out to check the effects of various doses of cytokinin in the quality of caigua in Peru. The experiment consisted of 5 treatments including (0, 50, 100, 150 and 200 mL of cytokinin) by using (Anthesis Plus per 200 L of water) as a source, each with three replicates and placed following a randomized complete block design (RCBD). Treatment with 100 mL of cytokinins foliar analysis resulted in a caigua length of 18.9 cm, an increase in diameter of 5.65 cm, and an improvement in pulp thickness of 7.60 millimeters. Physiological parameters of caigua plants taken after 45 days of sowing were considerably improved with the same treatment. Similarly, N, K and Zn concentration in leaf was higher in case of 100 mL of cytokinins foliar analysis. Therefore, policymakers must advise using the recommended quantity of cytokinins to bring about regime transition, and formers can gain by injecting 100 mL of cytokinins to boost production and the economy. It was concluded that the adequate dose of cytokinins is in treatment T3, which raised value of potassium concentration in leaves, this influenced optimal development, strengthening against environmental stress and therefore quality. For this reason, research was carried out on the comparative study of cytokinin doses in the quality of caigua in Peru; the objective was to determine the appropriate dose to obtain higher quality fruit. Likewise, it was underlined that the objective was to employ an ecological alternative of plant origin such as the usage of phytohormone that stimulates the growth of the plant and consequently the quality of the fruit. The obtained the results were served as a recommendation for farmers in the area.

Effectiveness and safety of oral anticoagulant therapy in a real-world cohort with atrial fibrillation: The SIESTA-A study protocol.

INTRODUCTION: Oral anticoagulants (OACs) are first-line drugs for stroke prevention in patients with atrial fibrillation (AF). The introduction of new lines of therapy with direct oral anticoagulants (DOACs) has led to a decreased use of vitamin K antagonists (VKAs). Comparative analyses of DOACs in clinical trials are scarce and the comparator has mostly been warfarin. Their impact on health outcomes in observational studies has not always been consistent. The aim of this study is to evaluate the effectiveness and safety of DOACs and VKAs in patients with AF using Real-World Data (RWD). METHODS AND ANALYSIS: Population-based retrospective cohort study using RWD from actual practice. Period: January 2012-December 2020. Inclusion criteria: patients with AF who had not taken OACs in the previous 12 months. Exclusion criteria: <40 years, with severe mitral stenosis, or valvular heart disease or aortic and/or mitral valve procedures. Data source: The Andalusian Population Health Database, Spain. Outcome measures: a) Effectiveness: ischaemic stroke, transient ischaemic attack, systemic and pulmonary embolism, and death; b) Safety: gastrointestinal and intracranial haemorrhaging; Independent variables: age, sex, comorbidities, medication and health resource use, CHA2DS2-VASC, HAS-BLED, and analytical tests. Statistical analysis: crude incidence analysis, survival models, Kaplan-Meier, Cox regression analysis adjusted for possible confounding and paired analysis by propensity score matching.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper.

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

Environmental vs psychosocial barriers to active commuting to university: which matters more?

OBJECTIVES: The aims of this study were (1) to examine the differences in the mode of commuting and barriers to active commuting to university between the sexes (men and women) and in different countries (Chile and Spain); and (2) to analyse the association between the mode of commuting and the perceived barriers for male and female university students in Chile and Spain. STUDY DESIGN: This cross-sectional study took place between April 2017 and May 2018 in Chile and Spain. METHODS: The study population included 2269 university students (53.0% women). The mode of commuting and barriers to active commuting to university were assessed by a self-reported questionnaire. Multinomial logistic regression analysis was used to examine the associations. RESULTS: In both sexes, public and private transport were the main modes of commuting used in Chile and Spain, respectively, followed by active commuting in all participants, except for female students in Spain. Women perceived more environmental and psychosocial barriers compared to men (Chile: P < 0.001; Spain: P = 0.006). Perceived environmental barriers showed higher significant differences between students in Chile and Spain (P < 0.05). Private commuters reported a larger proportion of psychosocial barriers compared to active commuters (Chile: men P = 0.001, women P < 0.001; Spain: men P < 0.001, women P = 0.036). CONCLUSIONS: The study findings suggest that the mode of commuting and the barriers to active commuting to university may be influenced by sex and country.

Renin Cells, From Vascular Development to Blood Pressure Sensing.

During embryonic and neonatal life, renin cells contribute to the assembly and branching of the intrarenal arterial tree. During kidney arteriolar development renin cells are widely distributed throughout the renal vasculature. As the arterioles mature, renin cells differentiate into smooth muscle cells, pericytes, and mesangial cells. In adult life, renin cells are confined to the tips of the renal arterioles, thus their name juxtaglomerular cells. Juxtaglomerular cells are sensors that release renin to control blood pressure and fluid-electrolyte homeostasis. Three major mechanisms control renin release: (1) ß-adrenergic stimulation, (2) macula densa signaling, and (3) the renin baroreceptor, whereby a decrease in arterial pressure leads to increased renin release whereas an increase in pressure results in decrease renin release. Cells from the renin lineage exhibit plasticity in response to hypotension or hypovolemia, whereas relentless, chronic stimulation induces concentric arterial and arteriolar hypertrophy, leading to focal renal ischemia. The renin cell baroreceptor is a nuclear mechanotransducer within the renin cell that transmits external forces to the chromatin to regulate Ren1 gene expression. In addition to mechanotransduction, the pressure sensor of the renin cell may enlist additional molecules and structures including soluble signals and membrane proteins such as gap junctions and ion channels. How these various components integrate their actions to deliver the exact amounts of renin to meet the organism needs is unknown. This review describes the nature and origins of renin cells, their role in kidney vascular development and arteriolar diseases, and the current understanding of the blood pressure sensing mechanism.