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We assemble a dataset which enhances existing Central America and Mexico data for the NGASubduction (NGA-Sub) project, including now additional earthquake ground motions and site parameters from Mexico. This data has been used to provide regional customization of NGA-Sub global Ground Motion Models (GMMs) for application in Mexico, paying particular attention to the site response of Mexico City (CDMX). The expanded database for Mexico incorporates smaller magnitude earthquakes (M < 6) and three significant events (M 7.2-8.3) that occurred in 2017 and 2018. These latter events are particularly important, because they are well recorded over a broad distance range and apply for hazard-critical conditions. Our focus here is on presenting the observed site response in CDMX, which we model based on the time-averaged shear wavevelocity in the upper 30 meters (VS30) and the Peak Ground Acceleration at a reference rock site (PGAr). Theempirical model we propose is different from previous work in several ways. First, it is properly centered withrespect to GMMs. Second, it is referenced to VS30 = 760 m/s, which is significantly firmer than the reference sitepreviously used in practice, taken from a location on the UNAM campus with VS30 ~ 300 m/s. Third, we identifysite amplification as nonlinear, whereas linear response has been assumed in prior models. The extent of thisnonlinearity is characterized using an established seismic zonation for CDMX, being more pronounced in softersites (Zone III) compared to stiffer ones (Zone I). This nonlinear effect is prominent at short periods and disappears at long periods. The advantages of the provided model include a unified framework for both withinand outside CDMX (contrasting current practices) and the integration of applicable features from global modelswith necessary local customization.

Amphibian survival is imperiled by increasing anthropogenic disturbance and insufficient conservation efforts. Spatial prioritization is an essential tool that allows for optimization of scarce conservation resources and the identification of protected area networks that will maintain their effectiveness in the future. This study focuses on amphibians in the Sierra Madre del Sur, a Mexican biogeographic province with high amphibian species richness and endemism. We aim to (i) assess the performance of the current protected area network and (ii) identify potential expansion areas of the current network, considering their persistence in time. Using occurrence data of 107 species, we estimated distributions with species distribution models and buffers. Species were weighted according to their national and international conservation status, and future land‐use change scenarios were incorporated to identify priority areas using Zonation software. Results revealed poor performance of the current protected areas network for amphibian conservation, failing to cover any of the top 2% of amphibian priority areas. Many protected areas fall outside the top 30% priority, indicating inadequate location of protected areas for amphibian conservation. However, minimal network expansions could significantly enhance protection for high‐risk species, particularly for the Plethodontidae family. Our study highlights the potential of systematic conservation planning in improving efficient amphibian conservation, even with minimal expansions of key areas. Finally, our findings provide important insights into amphibian conservation in a region with high levels of endemism that has often been neglected in terms of biodiversity conservation efforts. [ABSTRACT FROM AUTHOR]

Introduction: Blood eosinophil counts (BEC) have been related to the severity of bronchiectasis and its response to inhaled corticosteroids. However, only the baseline BEC has been used to assess this relationship and it is known that BEC could change over time. The objective of this study is to analyse the association of persistent eosinophilia or eosinopenia with outcomes in bronchiectasis., Methods: Multicentre, prospective and observational study from 43 centres in Spain derived from the Spanish Bronchiectasis Registry (RIBRON). Asthma and anti-eosinophil treatments were excluded. Patients with at least two yearly BEC measures (including the baseline measure) were included. Persistent eosinophilia (at least 300cells/μL) or persistent eosinopenia (less than 100cells/μL) were defined as the persistence in the same eosinophil group after three yearly measures (being the baseline the first measure)., Results: Five hundred two patients with at least three BEC measures were included; 24.5% and 16.6% presented baseline eosinophilia or eosinopenia, respectively. Of these, 57.7% and 56.6% presented persistent eosinophilia and eosinopenia, respectively. Patients with persistent eosinophilia presented greater severity and a higher number/greater severity of exacerbations than those with non-persistent eosinophilia and those with persistent or non-persistent eosinopenia. Finally, patients with non-persistent eosinopenia presented more severity and a higher number/greater severity of exacerbations than those with non-persistent eosinophilia., Conclusion: When only the baseline BEC was taken into account, patients with eosinopenia presented greater severity than those with eosinophilia. However, patients with persistent eosinophilia presented greater severity than those with persistent eosinopenia. Monitoring the BEC seems to be important in bronchiectasis., (Copyright © 2025 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The healthcare sector contributes significantly to global greenhouse emissions, with inhalers being major contributors., Objective: To develop a framework for reducing the environmental footprint of inhalers in Spain by implementing greener prescription practices., Methods: A multidisciplinary working group was formed, including hospital pharmacists, pulmonologists, and environmental experts. We created a comprehensive database on the environmental impact of inhalers marketed in Spain, incorporating product specifications and environmental data from the Spanish Agency of Medicines and Medical Devices and pharmaceutical companies. We developed a decision-making algorithm integrating clinical and environmental criteria and performed scenario projections to estimate potential benefits of transitioning from pressurised metered-dose inhalers (pMDIs) to dry powder inhalers (DPIs) and other eco-friendly alternatives. Scenarios included global and individual projections, as well as comparisons between sustainable prescriptions and waste-management strategies., Results: The national database revealed significant variability in the carbon footprint across inhaler types, with pMDIs showing the highest emissions. A shift of 10% from pMDIs to DPIs could reduce CO 2 emissions by approximately 40 000 tonnes/year, and a 50% shift by up to 200 000 tonnes. The decision-making algorithm effectively combined clinical and environmental considerations, facilitating the selection of more sustainable inhalers., Conclusion: The study highlights the importance of incorporating environmental criteria into inhaler prescribing choices to reduce healthcare's carbon footprint. Transitioning from pMDIs to DPIs when clinically indicated offers considerable environmental benefits without compromising patient health. The developed decision-making algorithm provides a practical tool for healthcare professionals, balancing clinical efficacy with sustainability. Future research should refine these practices and explore their application in other medical devices., Competing Interests: Competing interests: AC-L has received, in the past 3 years, fees for talks at meetings sponsored by AstraZeneca, Zambón, Boehringer Ingelheim, Chiesi, SANOFI, GSK, MSD, Novartis, Orion Pharma and Sanofi; has received travel and attendance expenses for conferences from Gebro, GSK, Novartis, AstraZeneca and Sanofi; and has received funds/grants for research projects from several state agencies, non-profit foundations, and MSD, AstraZeneca and GSK. BZ-Y has received, in the past 3 years, travel/attendance expenses and fees for talks sponsored by GSK, Boehringer Ingelheim and Galapagos Biopharma. DDlR has received, in the past 3 years, travel/attendance expenses, fees for talks and has participated in advisory boards sponsored by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Menarini, Praxis, TEVA, Zambon. NG has received, in the past 3 years, travel/attendance expenses, fees for talks and has participated in advisory boards sponsored by GSK, Janssen, Sanofi, Merck, Astra Zeneca, Pfizer and PharmaMar. The other authors have nothing to disclose., (© European Association of Hospital Pharmacists 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Sex differences exist in kidney physiology and disease which are underpinned by the biological actions of the sex hormones estrogen, progesterone and testosterone. In this review, we present an up-to-date discussion of the hormonal and molecular signalling pathways implicated in sex differences in kidney health and disease., Summary: Estrogen and progesterone have protective effects on renal blood flow, glomerular filtration rate and nephron ion and water reabsorptive processes, whereas testosterone tends to compromise these functions. The biological effects of estrogen appear to be the most important in reinforcing kidney function and protecting against kidney diseases in females. The actions of estrogen are myriad but all tend to bolster kidney physiology to maintain a steady-state and adaptable extracellular fluid volume (ECFV) and blood pressure. Estrogen safeguards ECFV homeostasis by stimulating renal epithelial sodium channel (ENaC) and water channel (AQP2) expression and transport function. Renal maintenance of ECFV within narrow physiological limits is a first-line of defense against hypertension and lowers the risk of cardiovascular disease in women. The estrogenic and XX chromosome basis for a female advantage are evident in a wide range of kidney diseases including acute kidney injury, chronic kidney disease, end-stage kidney disease, diabetic kidney disease, and polycystic kidney disease. The molecular mechanisms involve estrogen regulation of nephron ion and water transport, genetic immunogenic responses, activation of the protective arm of the renin angiotensin-aldosterone system and XX chromosome reinforcement of immune responses. Kidney disease can also predispose patients to cancer and women are protected in renal cancer with lower incidence, morbidity, and mortality than age-matched men with the disease., Key Messages: This review underscores the importance of incorporating sex-specific considerations into clinical practice and basic research to bridge the gap in understanding and addressing biological sex disparities in kidney disease and renal cancer., (© 2024 S. Karger AG, Basel.)

A species' diet is highly dependent on the availability of food resources in space and time, as well as on intrinsic factors such as sex or age. Accurate assessments of variations in the diet composition of bird populations across spatial scales, seasons and demographic groups are essential not only for understanding the basic ecology of species, but also for the conservation of endangered ones. However, our current knowledge about how birds' diet change according to spatio-temporal variations or intrinsic factors is very limited. Here, we used a multi-marker metabarcoding approach to characterize the diet of a declining shrub-steppe passerine, the Dupont's Lark (Chersophilus duponti), throughout a large part of its global distribution range. We also investigated spatial, phenological and sexual variations in its diet. Using markers from two genomic regions (18S and COI), we analyzed fecal samples from 303 adult Dupont's larks from Morocco and Spain during the breeding and non-breeding seasons. Overall, arthropods from the orders Coleoptera, Lepidoptera, Julida and Orthoptera were the main prey consumed by Dupont's Larks. We found that Dupont's Lark diet varied spatially, as well as temporally, reflecting dietary plasticity in response to changes in prey availability across landscapes and the species' phenological periods. High dietary overlap and no differences between sexes were observed, suggesting similar foraging behavior and nutritional requirements in both sexes. This is the first study providing detailed information on Dupont's Lark food ecology over much of its distribution, which is fundamental for the management and conservation of this declining steppe species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zurdo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are members of the steroid receptor subfamily of nuclear receptors. Their main function is to act as ligand-activated transcription factors, transducing the effects of corticosteroid hormones (aldosterone and glucocorticoids) by modulating gene expression. Corticosteroid signaling is essential for homeostasis and adaptation to different forms of stress. GR responds to glucocorticoids by regulating genes involved in development, metabolism, immunomodulation and brain function. MR is best known for mediating the effects of aldosterone, a key hormone controlling electrolyte and water homeostasis. In addition to aldosterone, MR binds glucocorticoids (cortisol and corticosterone) with equally high affinity. This ligand promiscuity has important repercussions to understand MR function, as well as glucocorticoid signaling. MR and GR share significant sequence and structural similarities, regulate overlapping sets of genes and are able to interact forming heteromeric complexes. However, the precise role of these heteromers in regulating corticosteroid-regulated transcriptional outcomes remains an open question. In this review, we examine the evidence supporting MR-GR heteromerization, the molecular determinants of complex formation and their possible role in differential regulation of transcription in different cellular contexts and ligand availability., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids., Competing Interests: Competing interests statement:The authors declare no competing interest.

Dispersal of individuals and gene flow are crucial aspects to maintain genetic diversity and viability of populations, especially in the case of threatened species. Landscape composition and structure may facilitate or limit individual movement within and among populations. We used a landscape genetics approach to assess the connectivity patterns of the threatened Dupont's lark ( Chersophilus duponti subsp. duponti ), considering their genetic patterns and the landscape features associated with its gene flow in Spain. We analysed the genetic relatedness based on 11 species-specific polymorphic microsatellites on 416 Dupont's lark individuals sampled across peninsular Spain between 2017 and 2019, covering most of the European distribution of the species. To assess the relationship between the landscape composition and the species gene flow, we estimated genetic distance at the individual level ( Dps ). Next, we built a set of environmental surfaces from two time periods (years 1990 and 2018), based on factors such as land use and topography, influencing individuals' movement. We then obtained resistance surfaces from an optimization process on landscape variables. Landscape genetics analyses were done for single and composite surface models for each year separately. Our findings from both time points show that scatter or mosaic-structured vegetation composed by low agricultural and tree cover and high presence of sclerophyllous shrubs favoured Dupont's lark dispersal, while dense and continuous tree cover, as well as areas of intensive agriculture, were limiting factors. Our results suggest the importance of steppe habitat patches for the species' establishment and dispersal. In addition, our results provide key information to develop conservation measures, including conserving and restoring steppe habitats as scattered and/or mosaic-structured vegetation that could warrant the connectivity and persistence of Dupont's lark populations., Competing Interests: The authors have no relevant financial or non‐financial interests to disclose., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate-size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

This paper describes a data collection experiment and the resulting dataset based on Bluetooth beacon messages collected in an indoor museum. The goal of this dataset is to study algorithms and techniques for proximity detection between people and points of interest (POI). To this purpose, we release the data we collected during 32 museum's visits, in which we vary the adopted smartphones and the visiting paths. The smartphone is used to collect Bluetooth beacons emitted by Bluetooth tags positioned nearby each POI. The visiting layout defines the order of visit of 10 artworks. The combination of different smartphones, the visiting paths and features of the indoor museum allow experiencing with realistic environmental conditions. The dataset comprises RSS (Received Signal Strength) values, timestamp and artwork identifiers, as long as a detailed ground truth, reporting the starting and ending time of each artwork's visit. The dataset is addressed to researchers and industrial players interested in further investigating how to automatically detect the location or the proximity between people and specific points of interest, by exploiting commercial technologies available with smartphone. The dataset is designed to speed up the prototyping process, by releasing an accurate ground truth annotation and details concerning the adopted hardware., Competing Interests: 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., (© 2024 Published by Elsevier Inc.)

Background and Objectives: In patients with COVID-19, high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP) are widely applied as initial treatments for moderate-to-severe acute hypoxemic respiratory failure. The aim of the study was to assess which respiratory supports improve 28-day mortality and to identify a predictive index of treatment response. Materials and Methods: This is a single-center retrospective observational study including 159 consecutive adult patients with COVID-19 and moderate-to-severe hypoxemic acute respiratory failure. Results: A total of 159 patients (82 in the CPAP group and 77 in the HFNC group) were included in the study. Mortality within 28 days was significantly lower with HFNC compared to CPAP (16.8% vs. 50%), while ICU admission and tracheal intubation within 28 days were significantly higher with CPAP compared to HFNC treatment (32% vs. 13%). We identified an index for survival in HFNC by including three variables easily available at admission (LDH, age, and respiratory rate) and the PaO 2 /FiO 2 ratio at 48 h. The index showed high discrimination for survival with an AUC of 0.88, a negative predictive value of 86%, and a positive predictive value of 95%. Conclusions: Treatment with HFNC appears to be associated with greater survival and fewer ICU admission than CPAP. LDH, respiratory rate, age, and PaO 2 /FiO 2 at 48 h were independently associated with survival and an index based on these variables allows for the prediction of treatment success and the assessment of patient allocation to the appropriate intensity of care after 48 h. Further research is warranted to determine effects on other outcomes and to assess the performance of the index in larger cohorts., Competing Interests: The authors declare no conflicts of interest.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K + and Na + homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K + excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na + channel β and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-β-hydroxysteroid-dehydrogenase 2 (11βHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process. NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.

Background: Although a proven relationship exists between the blood eosinophil count (BEC) and the severity of both asthma and COPD, its relationship with bronchiectasis has not been well established. The objective of this study was to analyze the relationship between BEC and the number and severity of exacerbations, and patients' responses to inhaled corticosteroid (IC) treatment in bronchiectasis RESEARCH QUESTION: Does an association exist among BEC, the number of exacerbations and severity of bronchiectasis, and IC treatment?, Study Design and Methods: This was a multicenter (43 centers) prospective observational study derived from the Spanish Bronchiectasis Registry. Patients with proven bronchiectasis and a known BEC were included, whereas those with asthma or antieosinophilic treatments were excluded. Patients were divided into four groups according to the BEC at the time of inclusion in the study in a steady-state situation: (1) eosinopenic bronchiectasis (< 50 eosinophils/μL), (2) low number of eosinophils (51-100/μL), (3) normal number of eosinophils (101-300/μL), and (4) eosinophilic bronchiectasis (> 300 eosinophils/μL)., Results: Nine hundred twenty-eight patients finally were included: 123 patients (13.3%) with < 50 eosinophils/μL (eosinopenic group), 164 patients (17.7%) with 50-100 eosinophils/μL, 488 patients (52.6%) with 101-300 eosinophils/μL, and 153 patients (16.5%) with > 300 eosinophils/μL (eosinophilic group). BEC showed a significant U-shaped relationship with severity, exacerbations, lung function, microbiologic profile, and IC treatment (these being higher in the eosinopenic group compared with the eosinophilic group). IC treatment significantly decreased the number and severity of exacerbations only in the group of bronchiectasis patients with > 300 eosinophils/μL., Interpretation: A significant U-shaped relationship was found between BEC and severity and exacerbations in bronchiectasis that was more pronounced in the eosinopenic group. IC treatment decreased the number and severity of exacerbations only in the eosinophilic group., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, patients may show lung sequelae on radiology and functional impairment at the 1-year follow-up. We aimed to describe the persistence of symptoms, radiological alterations, or reduced diffusing capacity of the lung for carbon monoxide (D LCO ) at 1-year follow-up in patients from the Spanish Registry RECOVID., Methods: RECOVID collected symptom and radiological and functional lung tests data on hospitalized patients with coronavirus disease 2019 during the acute phase and at the 6- and 12-month follow-up visits., Results: Of the 2500 enrolled survivors (90% admitted to the ward), 1874 had follow-up visits for up to a year. Of these, 42% continued to present with symptoms, 27% had radiological sequelae and 31% had reduced D LCO . Independently associated factors included female sex, asthma and the requirement for invasive or non-invasive mechanical ventilation. Complete radiological resolution was 72.2% at 12 months; associated factors with incomplete recovery were age, male sex, oxygen or respiratory support, corticosteroids and an initial SpO 2 /FiO 2 <450 or CURB-65 ≥2. Reduced D LCO was observed in 31% of patients at 12 months; associated factors were older age, female sex, smoking habit, SpO 2 /FiO 2 <450 and CURB-65 ≥2 and the requirement of respiratory support.At 12 months, a proportion of the asymptomatic patients showed reduced D LCO (9.5%), radiological findings (25%) or both (11%)., Conclusions: The factors associated with symptom persistence, incomplete radiological resolution and D LCO <80% differed according to age, sex, comorbidities and respiratory support. The burden of symptoms, reduced D LCO and incomplete radiological resolution were considerable in patients with SARS-CoV-2 pneumonia at the 1-year follow-up after hospitalisation., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR co-expression on MR genome-wide chromatin binding and transcriptional responses to aldosterone and glucocorticoids, both physiological ligands of this receptor. Our data show that GR co-expression alters MR genome-wide binding to consensus DNA sequences in a locus- and ligand-specific way. MR binding to consensus DNA sequences is affected by GR. Transcriptional responses of MR in the absence of GR are weak and show poor correlation with chromatin binding. In contrast, co-expression of GR potentiates MR-mediated transcription, particularly in response to aldosterone. Finally, single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that co-expression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids., Competing Interests: Competing Interest Statement: The authors have nothing to disclose.

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.

Introduction: Bronchiectasis is a very heterogeneous disease. This heterogeneity has several consequences: severity cannot be measured by a single variable, so multidimensional scores have been developed to capture it more broadly. Some groups of patients with similar clinical characteristics or prognoses (clinical phenotypes), and even similar inflammatory profiles (endotypes), have been identified, and these have been shown to require a more specific treatment., Areas Covered: We comment on this 'stratified' model of medicine as an intermediate step toward the application of the usual concepts on which precision medicine is based (such as cellular, molecular or genetic biomarkers, treatable traits and individual clinical fingerprinting), whereby each subject presents certain specific characteristics and receives individualized treatment., Expert Opinion: True precision or personalized medicine is based on concepts that have not yet been fully achieved in bronchiectasis, although some authors are already beginning to adapt them to this disease in terms of pulmonary and extrapulmonary etiologies, clinical fingerprinting (specific to each individual), cellular biomarkers such as neutrophils and eosinophils (in peripheral blood) and molecular biomarkers such as neutrophil elastase. In therapeutic terms, the future is promising, and some molecules with significant antibiotic and anti-inflammatory properties are being developed.

Bronchiectasis is a complex and heterogeneous disease. Its pathophysiology is poorly understood, but chronic bronchial infection plays an important role in its natural history, and is associated with poor quality of life, more exacerbations and increased mortality. Pseudomonas aeruginosa, Haemophilus influenzae and Staphylococcus aureus are the most common bacteria related to chronic bronchial infection. Non-tuberculous mycobacteria, fungi and respiratory viruses are also present during clinical stability, and may increase the risk of acute exacerbation. Chronic inflammation is present in bronchiectasis, especially neutrophilic inflammation. However, macrophages and eosinophils also play a key role in the disease. Finally, airway epithelium has innate mechanisms such as mucociliary clearance and antibacterial molecules like mucins and antimicrobial peptides that protect the airways from pathogens. This review addresses how the persistence of microorganisms in the airways and the imbalance of the immune system contribute to the development of chronic bronchial infection in bronchiectasis., (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators.

Acoustic signals are important markers to monitor physiological and pathological conditions, e.g., heart and respiratory sounds. The employment of traditional devices, such as stethoscopes, has been progressively superseded by new miniaturized devices, usually identified as microelectromechanical systems (MEMS). These tools are able to better detect the vibrational content of acoustic signals in order to provide a more reliable description of their features (e.g., amplitude, frequency bandwidth). Starting from the description of the structure and working principles of MEMS, we provide a review of their emerging applications in the healthcare field, discussing the advantages and limitations of each framework. Finally, we deliver a discussion on the lessons learned from the literature, and the open questions and challenges in the field that the scientific community must address in the near future.

Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The objective of this study was to assess whether the peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with different outcomes of severity in bronchiectasis. A total of 1369 patients with bronchiectasis from the Spanish Registry of Bronchiectasis were included. To compare groups, the sample was divided into increasing quartiles of NLR ratio. Correlations between quantitative variables were established using Pearson's P test. A simple linear regression (with the value of exacerbations as a quantitative variable) was used to determine the independent relationship between the number and severity of exacerbations and the NLR ratio. The area under the curve (AUC)-ROC was used to determine the predictive capacity of the NLR for severe bronchiectasis, according to the different multidimensional scores. Mean age: 69 (15) years (66.3% of women). The mean NLR was 2.92 (2.03). A higher NLR was associated with more severe bronchiectasis (with an especially significant discriminative power for severe forms) according to the commonly used scores (FACED, E-FACED and BSI), as well as with poorer quality of life (SGRQ), more comorbidities (Charlson index), infection by pathogenic microorganisms, and greater application of treatment. Furthermore, the NLR correlated better with severity scores than other parameters of systemic inflammation. Finally, it was an independent predictor of the incident number and severity of exacerbations. In conclusion, the NLR is an inexpensive and easy-to-measure marker of systemic inflammation for determining severity and predicting exacerbations (especially the most severe) in patients with bronchiectasis.

Introduction: Regardless corticosteroids are recommended for the treatment of organizing pneumonia there is limited evidence supporting this practice. Thus, we performed a systematic review of the literature on systemic corticosteroid treatment for organizing pneumonia., Methods: A search was implemented in the PubMed database (Medline) for articles published in the last 20 years. Those studies with incomplete or insufficient data and case reports were excluded. We collected data including: demographics, clinical data, diagnostic procedures, aetiology, treatment regimen (drug, posology, duration, response) and evolution., Results: A total of 135 publications were selected and finally 13 studies with 849 patients were included in the review: 12 retrospective observational studies and a single prospective observational study. Most of the patients were started on treatment with systemic corticosteroids - a total of 627 (30-100% depending on the series), but there was a great heterogeneity regarding drug, doses and duration. On those that started treatment, 226 (36%) presented a relapse of the disease during follow-up. Only one study provided information regarding treatment side-effects., Conclusion: The findings of this systematic review show the low quality data supporting the use of corticosteroids for the treatment of organizing pneumonia. This highlights a need to undertake appropriately designed studies to investigate which is the most appropriate treatment regimen that trades off benefits and risks of prolonged corticosteroid administration., (© 2022 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Endothelial mechanics control vascular reactivity and are regulated by the mineralocorticoid receptor (MR) and its downstream target, the epithelial Na + channel (ENaC). Endothelial dysfunction is a hallmark of chronic kidney disease (CKD), but its mechanisms are poorly understood. We hypothesized that CKD disrupts endothelial mechanics in an MR/ENaC-dependent process., Methods: Primary human endothelial cells were cultured with uremic serum derived from children with stage 3-5 (predialysis) CKD or adult hemodialysis (HD) patients or healthy controls. The height and stiffness of the endothelial glycocalyx (eGC) and cortex were monitored by atomic force microscopy (AFM) using an ultrasensitive mechanical nanosensor., Results: In a stage-dependent manner, sera from children with CKD induced a significant increase in eGC and cortex stiffness and an incremental reduction of the eGC height. AFM measurements were significantly associated with individual pulse wave velocity and serum concentrations of gut-derived uremic toxins. Serum from HD patients increased MR expression and mechanical stiffness of the endothelial cortex, an effect reversed by MR and ENaC antagonists, decreased eNOS expression and NO bioavailability, and augmented monocyte adhesion., Conclusion: These data indicate progressive structural damage of the endothelial surface with diminishing kidney function and identify the MR as a mediator of CKD-induced endothelial dysfunction.

Background: There are sex differences in the pathophysiology of aortic valve (AV) calcification in patients with aortic stenosis, although the molecular and cellular mechanisms have not been elucidated. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via the mineralocorticoid receptor (MR). We investigated the influence of sex in the role of Aldo/MR pathway in AV alterations in patients with aortic stenosis., Methods and Results: MR was expressed by primary aortic VICs and in AVs from patients with aortic stenosis. MR expression positively correlated with VIC activation markers in AVs from both sexes. However, MR expression was positively associated with molecules involved in AV calcification only in AV from men. Aldo enhanced VIC activation markers in cells from men and women. Interestingly, Aldo increased the expression of calcification markers only in VICs isolated from men. In female VICs, Aldo enhanced fibrotic molecules. MR antagonism (spironolactone) blocked all the above effects. Cytokine arrays showed ICAM (intercellular adhesion molecule)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 (intercellular adhesion molecule-1) and osteopontin. Only in female VICs, estradiol treatment blocked Aldo-induced VICs activation, inflammation, and fibrosis., Conclusions: These findings demonstrate that the Aldo/MR pathway could play a role in early stages of aortic stenosis by promoting VICs activation, fibrosis, and ulterior calcification. Importantly, Aldo/MR pathway is involved in fibrosis in women and in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV alterations.

The objective of the study was to analyze the factors associated with chronic bronchial infection (CBI) due to methicillin-susceptible Staphylococcus aureus (SA) and assess the clinical impact on severity, exacerbations, hospitalizations, and loss of lung function compared to patients with no isolation of PPMs in a large longitudinal series of patients from the Spanish bronchiectasis registry (RIBRON). Material and methods: A prospective, longitudinal, multicenter study was conducted with patients included in the RIBRON registry between January 2015 and October 2020. The inclusion criteria were an age of 18 years or older and an initial diagnosis of bronchiectasis. Patients recorded in the registry had a situation of clinical stability in the absence of an exacerbation in the four weeks before their inclusion. All patients were encouraged to provide a sputum sample at each visit for microbiological culture. Annual pulmonary function tests were performed according to the national spirometry guidelines. Results: A total of 426 patients were ultimately included in the study: 77 patients (18%) with CBI due to SA and 349 (82%) who did not present any isolation of PPMs in sputum. The mean age was 66.9 years (16.2), and patients 297 (69.7%) were female, with an average BMI of 25.1 (4.7) kg/m2 and an average Charlson index of 1.74 (1.33). The mean baseline value of FEV1 2 L was 0.76, with a mean FEV1% of 78.8% (23.1). One hundred and seventy-two patients (40.4%) had airflow obstruction with FEV1/FVC < 0.7. The mean predictive FACED score was 1.62 (1.41), with a mean value of 2.62 (2.07) for the EFACED score and 7.3 (4.5) for the BSI score. Patients with CBI caused by SA were younger (p < 0.0001), and they had a lower BMI (p = 0.024) and more exacerbations in the previous year (p = 0.019), as well as in the first, second, and third years of follow-up (p = 0.020, p = 0.001, and p = 0.018, respectively). As regards lung function, patients with CBI due to SA had lower levels of FEV1% at the time of inclusion in the registry (p = 0.021), and they presented more frequently with bronchial obstruction (p = 0.042). A lower age (OR: 0.97; 95% CI: 0.94−0.99; p < 0.001), lower FEV1 value% (OR: 0.98; 95% CI: 0.97−0.99; p = 0.035), higher number of affected lobes (OR: 1.53; 95% CI: 1.2−1.95; p < 0.001), and the presence of two or more exacerbations in the previous year (OR: 2.33; 95% CI: 1.15−4.69; p = 0.018) were observed as independent factors associated with CBI due to SA. The reduction in FEv1% in all patients included in the study was −0.31%/year (95% CI: −0.7; −0.07) (p = 0.110). When the reduction in FEv1% is analyzed in the group of patients with CBI due to SA and the group without pathogens, we observed that the reduction in FEV1% was −1.19% (95% CI: −2.09, −0.69) (p < 0.001) in the first group and −0.02% (95% CI: −0.07, −0.01) (p = 0.918) in the second group. According to a linear regression model (mixed effects) applied to determine which factors were associated with a more pronounced reduction in FEv1% in the overall group (including those with CBI due to SA and those with no PPM isolation), age (p = 0.0019), use of inhaled corticosteroids (p = 0.004), presence of CBI due to SA (p = 0.007), female gender (p < 0.001), and the initial value of FEV1 (p < 0.001) were significantly related. Conclusions: Patients with non-CF bronchiectasis with CBI due to SA were younger, with lower FEV1% values, more significant extension of bronchiectasis, and a higher number of exacerbations of mild to moderate symptoms than those with no PPM isolation in respiratory secretions. The reduction in FEV1% was −1.19% (95% CI: −2.09, −0.69) (p < 0.001) in patients with CBI caused by SA.

During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

We sought to investigate differential phenotypic characteristics according to neutrophil counts, using a biostatistics approach in a large-cohort study from the Spanish Online Bronchiectasis Registry (RIBRON). The 1034 patients who met the inclusion criteria were clustered into two groups on the basis of their blood neutrophil levels. Using the Mann-Whitney U test to explore potential differences according to FACED and EFACED scores between the two groups, a neutrophil count of 4990 cells/µL yielded the most balanced cluster sizes: (1) above-threshold ( n = 337) and (2) below-threshold ( n = 697) groups. Patients above the threshold showed significantly worse lung function parameters and nutritional status, while systemic inflammation levels were higher than in the below-threshold patients. In the latter group, the proportions of patients with mild disease were greater, while a more severe disease was present in the above-threshold patients. According to the blood neutrophil counts using biostatistics analyses, two distinct clinical phenotypes of stable patients with non-CF bronchiectasis were defined. Patients falling into the above-threshold cluster were more severe. Severity was characterized by a significantly impaired lung function parameters and nutritional status, and greater systemic inflammation. Phenotypic profiles of bronchiectasis patients are well defined as a result of the cluster analysis of combined systemic and respiratory variables.

Autologous hematopoietic stem cells transplantation (AHSCT) has been employed as treatment for severe systemic sclerosis (SSc) with high risk of organ failure. In the last 25 years overall survival and treatment-related mortality have improved, in accordance with a better patient selection and mobilization and conditioning protocols. This review analyzes the evidence from the last 5 years for AHSCT-treated SSc patients, considering in particular the outcomes related to interstitial lung disease. There are increasing data supporting the use of AHSCT in selected patients with rapidly progressive SSc. However, some unmet needs remain, such as an accurate patient selection, pre-transplantation analysis to identify subclinical conditions precluding the transplantation, and the alternatives for post-transplant ILD recurrence.