Organ-specific allergen challenges in airway allergy: Current utilities and future directions

Atopy has been long used as the screening method for airway allergy. Nevertheless, aeroallergens can trigger respiratory symptoms not only in atopic patients (atopic res piratory allergy, ARA), but also in non-atopic subjects (local respiratory allergy, LRA). Moreover, ARA and LRA can coexist in the same patient, and this clinical scenario has been called dual respiratory allergy (DRA). When the clinical history cannot determine the relevance of sensitizations in ARA patients, nasal, conjunctival or bronchial aller gen challenges (NAC, CAC, and BAC, respectively) should be conducted. Moreover, these tests are required to identify patients with LRA and DRA. The clarification of the allergic triggers of airway diseases has a profound impact on the management strategies the patients can be offered. Importantly, allergen immunotherapy (AIT) remains as the only disease-modifying intervention for ARA. Recent data indicate that AIT might have a similar effect on LRA patients. Nevertheless, AIT success relies largely on the correct phenotyping of allergic individuals, and NAC, CAC, and BAC are very helpful tools in this regard. In this review, we will summarize the main indications and methodology of CAC, NAC, and BAC. Importantly, the clinical implementation of these tests might translate into precision medicine approaches and better health outcomes for patients with airway allergy.Consejería de Salud, Junta de Andalucía, Grant/Award Number: P20_00405; Instituto de Salud Carlos III, Grant/Award Number: PI20/01715, RD21/0002/0008, CM21/00262, CM20/00160, JR22/00048 and JR19/00029. Funding for open access charge: Universidad de Málaga / CBUA

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

IMPORTANCE: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES: To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS:The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES:Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES: The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS: Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE: Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS

The amino terminal domain from Mrt4 protein can functionally replace the RNA binding domain of the ribosomal P0 protein

In Saccharomyces cerevisiae, the Mrt4 protein is a component of the ribosome assembly machinery that shares notable sequence homology to the P0 ribosomal stalk protein. Here, we show that these proteins can not bind simultaneously to ribosomes and moreover, a chimera containing the first 137 amino acids of Mrt4 and the last 190 amino acids from P0 can partially complement the absence of the ribosomal protein in a conditional P0 null mutant. This chimera is associated with ribosomes isolated from this strain when grown under restrictive conditions, although its binding is weaker than that of P0. These ribosomes contain less P1 and P2 proteins, the other ribosomal stalk components. Similarly, the interaction of the L12 protein, a stalk base component, is affected by the presence of the chimera. These results indicate that Mrt4 and P0 bind to the same site in the 25S rRNA. Indeed, molecular dynamics simulations using modelled Mrt4 and P0 complexes provide further evidence that both proteins bind similarly to rRNA, although their interaction with L12 displays notable differences. Together, these data support the participation of the Mrt4 protein in the assembly of the P0 protein into the ribosome and probably, that also of the L12 protein

Multicentre observational study on multisystem inflammatory syndrome related to COVID-19 in Argentina

Background: The impact of the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in low- and middle-income countries remains poorly understood. Our aim was to understand the characteristics and outcomes of PIMS-TS in Argentina. Methods: This observational, prospective, and retrospective multicenter study enrolled patients younger than 18 years-old manifesting PIMS-TS, Kawasaki disease (KD) or Kawasaki shock syndrome (KSS) between March 2020 and May 2021. Patients were followed-up until hospital discharge or death (one case). The primary outcome was pediatric intensive care unit (PICU) admission. Multiple logistic regression was used to identify variables predicting PICU admission. Results: Eighty-one percent, 82%, and 14% of the 176 enrolled patients fulfilled the suspect case criteria for PIMS-TS, KD, and KSS, respectively. Temporal association with SARS-CoV-2 was confirmed in 85% of the patients and 38% were admitted to the PICU. The more common clinical manifestations were fever, abdominal pain, rash, and conjunctival injection. Lymphopenia was more common among PICU-admitted patients (87% vs. 51%, p < 0.0001), who also showed a lower platelet count and higher plasmatic levels of inflammatory and cardiac markers. Mitral valve insufficiency, left ventricular wall motion alterations, pericardial effusion, and coronary artery alterations were observed in 30%, 30%, 19.8%, and 18.6% of the patients, respectively. Days to initiation of treatment, rash, lymphopenia, and low platelet count were significant independent contributions to PICU admission. Conclusion: Rates of severe outcomes of PIMS-TS in the present study agreed with those observed in high-income countries. Together with other published studies, this work helps clinicians to better understand this novel clinical entity.Fil: Vainstein, Eduardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Baleani, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Urrutia, Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Affranchino, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ackerman, Judith. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Cazalas, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Goldsman, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Sardella, Angela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Tolin, Ana Laura. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Goldaracena, Pablo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Fabi, Mariana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Cosentino, Mariana. Hospital Británico de Buenos Aires; ArgentinaFil: Magliola, Ricardo. Hospital Británico de Buenos Aires; ArgentinaFil: Roggiero, Gustavo. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Manso, Paula. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Triguy, Jésica. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Ballester, Celeste. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Cervetto, Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Vaccarello, María. Sanatorio de la Trinidad; ArgentinaFil: De Carli, Domingo Norberto. Clínica del Niño de Quilmes; ArgentinaFil: De Carli, Maria Estela. Clínica del Niño de Quilmes; ArgentinaFil: Ciotti, Ana Laura. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Sicurello, María Irene. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Rios Leiva, Cecilia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Villalba, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Hortas, María. Sanatorio de la Trinidad; ArgentinaFil: Peña, Sonia. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: González, Gabriela. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Grippo, M.. No especifíca;Fil: Vázquez, H.. No especifíca;Fil: Morós, C.. No especifíca;Fil: Di Santo, M.. No especifíca;Fil: Villa, A.. No especifíca;Fil: Lazota, P.. No especifíca;Fil: Foti, M.. No especifíca;Fil: Napoli, N.. No especifíca;Fil: Katsikas, M. M.. No especifíca;Fil: Tonello, L.. No especifíca;Fil: Peña, J.. No especifíca;Fil: Etcheverry, M.. No especifíca;Fil: Iglesias, D.. No especifíca;Fil: Alcalde, A. L.. No especifíca;Fil: Bruera, M.J.. No especifíca;Fil: Bruzzo, V.. No especifíca;Fil: Giordano, P.. No especifíca;Fil: Pena Acero, F.. No especifíca;Fil: Netri Pelandi, G.. No especifíca;Fil: Pastaro, D.. No especifíca;Fil: Bleiz, J.. No especifíca;Fil: Rodríguez, M. F.. No especifíca;Fil: Laghezza, L.. No especifíca;Fil: Molina, M. B.. No especifíca;Fil: Patynok, N.. No especifíca;Fil: Chatelain, M. S.. No especifíca;Fil: Aguilar, M. J.. No especifíca;Fil: Gamboa, J.. No especifíca;Fil: Cervan, M.. No especifíca;Fil: Ruggeri, A.. No especifíca;Fil: Marinelli, I.. No especifíca;Fil: Checcacci, E.. No especifíca;Fil: Meregalli, C.. No especifíca;Fil: Damksy Barbosa, J.. No especifíca;Fil: Fernie, L.. No especifíca;Fil: Fernández, M. J.. No especifíca;Fil: Saenz Tejeira, M.M.. No especifíca;Fil: Cereigido, C.. No especifíca;Fil: Nunell, A.. No especifíca;Fil: Villar, D.. No especifíca;Fil: Mansilla, A. D.. No especifíca;Fil: Darduin, M. D.. No especifíca

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Advanced therapy medicinal products for eye diseases: Goals and challenges

Producción CientíficaThe concept of advanced therapy medicinal products (ATMPs) encompasses novel kinds of medicines for human use that are based on genes, cells or tissues. These intend to offer not only regeneration, but complete functional recovery of diseased tissues and organs using different strategies. Gene therapy, cell therapy and tissue engineering are the main areas in which promising advanced therapies are emerging. The eye is a very complex organ whose main structures, the cornea and the retina, play a pivotal role in maintaining normal vision, as severe alterations in these tissues can lead to blindness. Ocular tissues are starting to benefit from ATMPs by fighting against the enormous complexity and devastating potential of many ocular diseases. However, developments arising from this field of work face important challenges related to vectors to deliver drugs and genetic material to target tissues, suitable biomaterials to prepare cell scaffolds and cell stemness, among others—not to mention the complicated legislation around ATMPs, the complexity in production and quality control and the absence of standardized protocols. The purpose of this Special Issue is to serve as an overview of the current progress in the application of cell and gene therapies, as well as tissue engineering to restore functionality in diseased ocular structures, and the challenges they deal with in order to get to patients.Ministerio de Economía y Competitividad e Instituto de Salud Carlos III - FEDER (FIS PI20/0317 e ICI21-00010)Junta de Andalucía - Consejería de Salud y Familias (PI-0086-2020)Junta de Andalucía - Consejería de Transformación Económica, Industria, Conocimiento y Universidades- FEDER (B-CTS-504-UGR20