Comparative Analysis of Agri-Food Systems for Extensive Livestock in the High Pyrenees and Creation of a Multicriterian Tool for Its Evaluation

The main objective of this study is to compare the different agri-food systems of extensive livestock (ecological and conventional) of big and small ruminants (cattle and sheep respectively) in high Pyrenees. This objective is formulated by looking at the general lack of knowledge of the population regarding the functionality of these systems, the changes of management that have been introduced in the recent years, especially in terms of commercialization, and the different capacity of response of extensive livestock systems to climate change and other socio-economic complementary changes. Attributes and indicators have been selected for the comparative evaluation of livestock systems, focusing on three political perspectives ecofeminism, adaptation to climate change and food sovereignty. The methodology adopted is mixed, including secondary databases and interviews for the analysis of extensive livestock agri-food systems and a series of participatory workshops with scientists and women livestock operators to select indicators that allow to highlight different critical points along the chain to compare agri-food systems. Four archetypes of each agri-food system studied were identified by following the product of meat from extensive livestock management of bovine and sheep. Although there are several differences between the organic and conventional beef and sheep meat systems, similarities have also been found. Sheep production, and in particular organic production, is the simplest, is the most traditional and shortest chain system. A set of 123 indicators have been identified by the dialogue between researchers and practitioners, grouped in 9 dimensions. When evaluating these systems, so far there have been many aspects that have not been valued or have been invisible, especially in the dimension of Dignified life and Social equity. There are also certain gaps of information, that should be filled in future research

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA in cancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

COVID-19; Mechanical ventilation; Ventilatory ratioCOVID-19; Respiració assistida; Relació ventilatòriaCOVID-19; Ventilación mecánica; Relación ventilatoriaBackground Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.Financial support was provided by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", and by the Centro de Investigación Biomedica En Red – Enfermedades Respiratorias (CIBERES). DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/”Investing in your future”

Embryological-origin-dependent differences in homeobox expression in adult aorta: role in regional phenotypic variability and regulation of NF-κB activity

OBJECTIVE: Different vascular beds show differing susceptibility to the development of atherosclerosis, but the molecular mechanisms underlying these differences are incompletely understood. This study aims to identify factors that contribute to the phenotypic heterogeneity of distinct regions of the adult vasculature. APPROACH AND RESULTS: High-throughput mRNA profiling in adult mice reveals higher expression of the homeobox paralogous genes 6 to 10 (Hox6-10) in the athero-resistant thoracic aorta (TA) than in the athero-susceptible aortic arch (AA). Higher homeobox gene expression also occurs in rat and porcine TA, and is maintained in primary smooth muscle cells isolated from TA (TA-SMCs) compared with cells from AA (AA-SMCs). This region-specific homeobox gene expression pattern is also observed in human embryonic stem cells differentiated into neuroectoderm-SMCs and paraxial mesoderm-SMCs, which give rise to AA-SMCs and TA-SMCs, respectively. We also find that, compared with AA and AA-SMCs, TA and TA-SMCs have lower activity of the proinflammatory and proatherogenic nuclear factor-κB (NF-κB) and lower expression of NF-κB target genes, at least in part attributable to HOXA9-dependent inhibition. Conversely, NF-κB inhibits HOXA9 promoter activity and mRNA expression in SMCs. CONCLUSION: Our findings support a model of Hox6-10-specified positional identity in the adult vasculature that is established by embryonic cues independently of environmental factors and is conserved in different mammalian species. Differential homeobox gene expression contributes to maintaining phenotypic differences between SMCs from athero-resistant and athero-susceptible regions, at least in part through feedback regulatory mechanisms involving inflammatory mediators, for example, reciprocal inhibition between HOXA9 and NF-κB.The authors’ laboratories Sources of Funding supported are by grants from the Ministerio de Economía y Competitividad (MINECO; SAF201016044), Instituto de Salud Carlos III (ISCIII; RD/06/0014/0021, RD12/0042/0028), the Belgian Society of Cardiology (Dr. Léon Dumont Prize 2010), the European Commission (Liphos-317916), the Wellcome Trust (WT078390MA), and the Cambridge Biomedical Research Center. C. Cheung was sponsored by the Agency for Science, Technology and Research (Singapore). J.M. GonzálezGranado and P. Fernández received salary support from the ISCIII (CP11/00145 and CD07/00021, respectively). The CNIC is supported by MINECO and Pro-CNIC Foundation.S

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.Instituto de Salud Carlos III de Madrid COV20/00110, ISCII

Higher frequency of comorbidities in fully vaccinated patients admitted to the ICU due to severe COVID-19: a prospective, multicentre, observational study

Severe COVID-19 disease requiring ICU admission is possible in the fully vaccinated population, especially in those with immunocompromised status and other comorbidities. Interventions to improve vaccine response might be necessary in this population.Peer ReviewedArticle signat per 23 autors/es: Anna Motos, Alexandre López-Gavín, Jordi Riera, Adrián Ceccato, Laia Fernández-Barat, Jesús F. Bermejo-Martin, Ricard Ferrer, David de Gonzalo-Calvo, Rosario Menéndez, Raquel Pérez-Arnal, Dario García-Gasulla, Alejandro Rodriguez, Oscar Peñuelas, José Ángel Lorente, Raquel Almansa, Albert Gabarrus, Judith Marin-Corral, Pilar Ricart, Ferran Roche-Campo, Susana Sancho Chinesta, Lorenzo Socias, Ferran Barbé, Antoni Torres on behalf of the CIBERESUCICOVID Project (COV20/00110, ISCIII).Postprint (published version

Lateral position during severe mono-lateral pneumonia: an experimental study

Patients with mono-lateral pneumonia and severe respiratory failure can be positioned in lateral decubitus, with the healthy lung dependent, to improve ventilation-perfusion coupling. Oxygenation response to this manoeuvre is heterogeneous and derecruitment of dependent lung has not been elucidated. Nine pigs (32.2 ± 1.2 kg) were sedated and mechanically ventilated. Mono-lateral right-sided pneumonia was induced with intrabronchial challenge of Pseudomonas aeruginosa. After 24 h, lungs were recruited and the animals were randomly positioned on right or left side. After 3 h of lateral positioning, the animals were placed supine; another recruitment manoeuvre was performed, and the effects of contralateral decubitus were assessed. Primary outcome was lung ultrasound score (LUS) of the dependent lung after 3-h lateral positioning. LUS of the left non-infected lung worsened while positioned in left-lateral position (from 1.33 ± 1.73 at baseline to 6.78 ± 4.49; p = 0.005). LUS of the right-infected lung improved when placed upward (9.22 ± 2.73 to 6.67 ± 3.24; p = 0.09), but worsened in right-lateral position (7.78 ± 2.86 to 13.33 ± 3.08; p < 0.001). PaO2/FiO2 improved in the left-lateral position (p = 0.005). In an animal model of right-lung pneumonia, left-lateral decubitus improved oxygenation, but collapsed the healthy lung. Right-lateral orientation further collapsed the diseased lung. Our data raise potential clinical concerns for the use of lateral position in mono-lateral pneumonia

ICU-acquired pneumonia is associated with poor health post-COVID-19 syndrome

Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients. Methods: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. Results: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19. Conclusions: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.Financial support was provided by the Instituto Carlos III de Madrid (COV20/00110, ISCIII) and by the Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES). DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/ “Investing in your future”Peer ReviewedArticle signat per 53 autors/es: Ignacio Martin-Loeches (1,2,3), Anna Motos (1,3), Rosario Menéndez (1,4), Albert Gabarrús (1,4), Jessica González (5,6), Laia Fernández-Barat (1,3), Adrián Ceccato (1,3), Raquel Pérez-Arnal (7), Dario García-Gasulla (7), Ricard Ferrer (1,8), Jordi Riera (1,8), José Ángel Lorente (1,9), Óscar Peñuelas (1,9), Jesús F. Bermejo-Martin (1,10,11), David de Gonzalo-Calvo (5,6), Alejandro Rodríguez (12), Ferran Barbé (5,6), Luciano Aguilera (13), Rosario Amaya-Villar (14), Carme Barberà (15), José Barberán (16), Aaron Blandino Ortiz (17), Elena Bustamante-Munguira (18), Jesús Caballero (19), Cristina Carbajales (20), Nieves Carbonell (21),Mercedes Catalán-González (22), Cristóbal Galbán (23), Víctor D. Gumucio-Sanguino (24), Maria del Carmen de la Torre (25), Emili Díaz (26), Elena Gallego (27), José Luis García Garmendia (28), José Garnacho-Montero (29), José M. Gómez (30), Ruth Noemí Jorge García (31), Ana Loza-Vázquez (32), Judith Marín-Corral (33), Amalia Martínez de la Gándara (34), Ignacio Martínez Varela (35), Juan Lopez Messa (36), Guillermo M. Albaiceta (37,38), Mariana Andrea Novo (39), Yhivian Peñasco (40), Pilar Ricart (41), Luis Urrelo-Cerrón (42), Angel Sánchez-Miralles (43), Susana Sancho Chinesta (44), Lorenzo Socias (45), Jordi Solé-Violan (1,46), Luis Tamayo Lomas (47), Pablo Vidal (48) and Antoni Torres (1,3)*, on behalf of CIBERESUCICOVID Project (COV20/00110 and ISCIII) // (1) CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain; (2) Pulmonary Department, Hospital Clinic, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain; (3) Department of Intensive Care Medicine, St. James’s Hospital, Multidisciplinary Intensive Care Research Organization (MICRO), James’s Street, D08 NHY1 Dublin, Ireland; (4) Pulmonary Department, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (5) Translational Research in Respiratory Medicine Group (TRRM), Lleida Biomedical Research Institute (IRBLleida), 25198 Lleida, Spain; (6) Pulmonary Department, Hospital Universitari Arnau de Vilanova and Santa Maria, 25198 Lleida, Spain; (7) Barcelona Supercomputing Centre (BSC), 08034 Barcelona, Spain; (8) Intensive Care Department, Vall d’Hebron Hospital Universitari, SODIR Research Group, Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (9) Hospital Universitario de Getafe, 28905 Madrid, Spain; (10) Hospital Universitario Río Hortega de Valladolid, 47012 Valladolid, Spain; (11) Instituto de Investigación Biomédica de Salamanca (IBSAL), Gerencia Regional de Salud de Castilla y León, 47007 Valladolid, Spain; (12) Critical Care Department, Hospital Joan XXIII, 43005 Tarragona, Spain; (13) Anestesia, Reanimación y Terapia del Dolor, Hospital Universitario de Basurto, 48013 Bilbao, Spain; (14) Intensive Care Clinical Unit, Hospital Universitario Virgen de Rocío, 41013 Sevilla, Spain; (15) Hospital Santa Maria, IRBLleida, 25198 Lleida, Spain; (16) Critical Care Department, Hospital Universitario HM Montepríncipe, Universidad San Pablo-CEU, 28660 Madrid, Spain; (17) Servicio de Medicina Intensiva, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (18) Department of Intensive Care Medicine, Hospital Clínico Universitario Valladolid, 47003 Valladolid, Spain; (19) Critical Care Department, Hospital Universitari Arnau de Vilanova, IRBLleida, 25198 Lleida, Spain; (20) Hospital Álvaro Cunqueiro, 36213 Vigo, Spain; (21) Intensive Care Unit, Hospital Clínico y Universitario de Valencia, 46010 Valencia, Spain; (22) Department of Intensive Care Medicine, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain, (23) Department of Medicine, CHUS, Complejo Hospitalario Universitario de Santiago, 15076 Santiago de Compostela, Spain; (24) Department of Intensive Care, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (25) Hospital de Mataró de Barcelona, 08301 Mataró, Spain; (26) Department of Medicine, Universitat Autònoma de Barcelona (UAB), Critical Care Department, Corpo-Ració Sanitària Parc Taulí, Sabadell, 08208 Barcelona, Spain; (27) Unidad de Cuidados Intensivos, Hospital San Pedro de Alcántara, 10003 Cáceres, Spain; (28) Intensive Care Unit, Hospital San Juan de Dios del Aljarafe, 41930 Sevilla, Spain; (29) Intensive Care Clinical Unit, Hospital Universitario Virgen Macarena, 41009 Seville, Spain; (30) Hospital General Universitario Gregorio Marañón, 28009 Madrid, Spain; (31) Intensive Care Department, Hospital Nuestra Señora de Gracia, 50009 Zaragoza, Spain; (32) Unidad de Medicina Intensiva, Hospital Universitario Virgen de Valme, 41014 Sevilla, Spain; (33) Critical Care Department, Hospital del Mar-IMIM, 08003 Barcelona, Spain; (34) Department of Intensive Medicine, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain; (35) Critical Care Department, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain; (36) Critical Care Department, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain; (37) Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33011 Oviedo, Spain; (38) Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Central de Asturias, 33011 Oviedo, Spain; (39) Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, 07120 Illes Balears, Spain; (40) Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; (41) Servei de Medicina Intensiva, Hospital Universitari Germans Trias, 08916 Badalona, Spain; (42) Hospital Verge de la Cinta, 08916 Tortosa, Spain; (43) Hospital de Sant Joan d’Alacant, 03550 Alacant, Spain; (44) Servicio de Medicina Intensiva, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain; (45) Intensive Care Unit, Hospital Son Llàtzer, Palma de Mallorca, 07198 Illes Balears, Spain; (46) Critical Care Department, Hospital Dr. Negrín., 35019 Las Palmas de GC, Spain; (47) Critical Care Department, Hospital Universitario Río Hortega de Valladolid, 47102 Valladolid, Spain; (48) Intensive Care Unit, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain.Postprint (published version

Assessment of in vivo versus in vitro biofilm formation of clinical methicillin-resistant Staphylococcus aureus isolates from endotracheal tubes

Our aim was to demonstrate that biofilm formation in a clinical strain of methicillin-resistant Staphylococcus aureus (MRSA) can be enhanced by environment exposure in an endotracheal tube (ETT) and to determine how it is affected by systemic treatment and atmospheric conditions. Second, we aimed to assess biofilm production dynamics after extubation. We prospectively analyzed 70 ETT samples obtained from pigs randomized to be untreated (controls, n = 20), or treated with vancomycin (n = 32) or linezolid (n = 18). A clinical MRSA strain (MRSA-in) was inoculated in pigs to create a pneumonia model, before treating with antibiotics. Tracheally intubated pigs with MRSA severe pneumonia, were mechanically ventilated for 69 ± 16 hours. All MRSA isolates retrieved from ETTs (ETT-MRSA) were tested for their in vitro biofilm production by microtiter plate assay. In vitro biofilm production of MRSA isolates was sequentially studied over the next 8 days post-extubation to assess biofilm capability dynamics over time. All experiments were performed under ambient air (O2) or ambient air supplemented with 5% CO2. We collected 52 ETT-MRSA isolates (placebo N = 19, linezolid N = 11, and vancomycin N = 22) that were clonally identical to the MRSA-in. Among the ETT-MRSA isolates, biofilm production more than doubled after extubation in 40% and 50% under 5% CO2 and O2, respectively. Systemic antibiotic treatment during intubation did not affect this outcome. Under both atmospheric conditions, biofilm production for MRSA-in was at least doubled for 9 ETT-MRSA isolates, and assessment of these showed that biofilm production decreased progressively over a 4-day period after extubation. In conclusion, a weak biofilm producer MRSA strain significantly enhances its biofilm production within an ETT, but it is influenced by the ETT environment rather than by the systemic treatment used during intubation or by the atmospheric conditions used for bacterial growth

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis

Background: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. Methods: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Results: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. Conclusions: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannula.Financial support was provided by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", and the Centro de Investigación Biomedica En Red – Enfermedades Respiratorias (CIBERES). DdGC has received financial support from the Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/”Investing in your future”.Peer ReviewedArticle signat per 70 autors/es: Jordi Riera*1,2; Enric Barbeta*2,3,4; Adrián Tormos5; Ricard Mellado-Artigas2,3; Adrián Ceccato6; Anna Motos4; Laia Fernández-Barat4; Ricard Ferrer1; Darío García-Gasulla5; Oscar Peñuelas7; José Ángel Lorente7; Rosario Menéndez8; Oriol Roca1,2; Andrea Palomeque4,9; Carlos Ferrando2,3; Jordi SoléViolán10; Mariana Novo11; María Victoria Boado12; Luis Tamayo13; Ángel Estella14, Cristóbal Galban15; Josep Trenado16; Arturo Huerta17; Ana Loza18; Luciano Aguilera19; José Luís García Garmendia20; Carme Barberà21; Víctor Gumucio22; Lorenzo Socias23; Nieves Franco24; Luis Jorge Valdivia25; Pablo Vidal26; Víctor Sagredo27; Ángela Leonor Ruiz-García28; Ignacio Martínez Varela29; Juan López30; Juan Carlos Pozo31; Maite Nieto32; José M Gómez33; Aaron Blandino34; Manuel Valledor35; Elena Bustamante-Munguira36; Ángel Sánchez-Miralles37; Yhivian Peñasco38; José Barberán39; Alejandro Ubeda40; Rosario Amaya-Villar41; María Cruz Martín42; Ruth Jorge43; Jesús Caballero44; Judith Marin45; José Manuel Añón46; Fernando Suárez Sipmann47; Guillermo Muñiz2,48;Álvaro Castellanos-Ortega49; Berta Adell-Serrano50; Mercedes Catalán51; Amalia Martínez de la Gándara52; Pilar Ricart53; Cristina Carbajales54; Alejandro Rodríguez55; Emili Díaz6; Mari C de la Torre56; Elena Gallego57; Luisa Cantón-Bulnes58; Nieves Carbonell59, Jessica González60, David de Gonzalo-Calvo60, Ferran Barbé60 and Antoni Torres2,4,9 on behalf of the CiberesUCICOVID Consortium. // 1. Critical Care Department, Hospital Universitari Vall d’Hebron; SODIR, Vall d’Hebron Institut de Recerca, Barcelona, Spain. 2. CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. 3.Surgical Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain. 4. Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. 5. Barcelona Supercomputing Center (BSC), Barcelona, Spain. 6. Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Sabadell, Spain. Universitat Autonoma de Barcelona (UAB), Spain. 7. Hospital Universitario de Getafe, Universidad Europea, Madrid, Spain. 8. Pneumology Department, Hospital Universitario y Politécnico La Fe/Instituto de Investigación Sanitaria (IIS) La Fe, 46026 Valencia, Spain; Pneumology Department, Hospital Universitario y Politécnico La Fe, Avda, Fernando Abril Martorell 106, 46026 Valencia, Spain. 9.Respiratory Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain. 10. Critical Care Department, Hospital Dr. Negrín Gran Canaria. Universidad Fernando Pessoa. Las Palmas, Gran Canaria, Spain. 11. Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, Illes Balears, Spain. 12. Hospital Universitario de Cruces, Barakaldo, Spain. 13. Critical Care Department, Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain. 14. Departamento Medicina Facultad Medicina Universidad de Cádiz. Hospital Universitario de Jerez, Jerez de la Frontera, Spain. 15. Department of Medicine, CHUS, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. 16. Servicio de Medicina Intensiva, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, Spain. 17. Pulmonary and Critical Care Division; Emergency Department, Clínica Sagrada Família, Barcelona, Spain. 18. Hospital Virgen de Valme, Sevilla, Spain. 19. Hospital de Basurto, Bilbao, Spain. 20. Intensive Care Unit, Hospital San Juan de Dios del Aljarafe, Bormujos, Sevilla, Spain. 21. Hospital Santa Maria; IRBLleida, Lleida, Spain. 22. Department of Intensive Care. Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 23. Intensive Care Unit, Hospital Son Llàtzer, Palma de Mallorca, Illes Balears, Spain. 24. Hospital Universitario de Móstoles, Madrid, Spain. 25. Hospital Universitario de León, León, Spain. 26. Complexo Hospitalario Universitario de Ourense, Ourense, Spain. 27. Hospital Universitario de Salamanca, Salamanca, Spain. 28. Servicio de Microbiología Clínica, Hospital Universitario Príncipe de Asturias – Departamento de Biomedicina y Biotecnología, Universidad de Alcalá de Henares, Madrid, Spain. 29. Critical Care Department, Hospital Universitario Lucus Augusti, Lugo, Spain. 30. Complejo Asistencial Universitario de Palencia, Palencia, Spain. 31. UGC-Medicina Intensiva, Hospital Universitario Reina Sofia, Instituto Maimonides IMIBIC, Córdoba, Spain. 32. Hospital Universitario de Segovia, Segovia, Spain. 33. Hospital General Universitario Gregorio Marañón, Madrid, Spain. 34. Servicio de Medicina Intensiva, Hospital Universitario Ramón y Cajal, Madrid, Spain. 35. Hospital Universitario "San Agustín", Avilés, Spain. 36. Department of Intensive Care Medicine, Hospital Clínico Universitario Valladolid, Valladolid, Spain. 37. Servicio de Medicina Intensiva. Hospital Universitario Sant Joan d´Alacant, Alicante, Spain. 38. Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, Santander, Spain. 39. Hospital Universitario HM Montepríncipe, Universidad San Pablo-CEU, Madrid, Spain. 40. Servicio de Medicina Intensiva, Hospital Punta de Europa, Algeciras, Spain. 41. Intensive Care Clinical Unit, Hospital Universitario Virgen de Rocío, Sevilla, Spain. 42. Hospital Universitario Torrejón- Universidad Francisco de Vitoria, Madrid, Spain. 43. Intensive Care Department, Hospital Nuestra Señora de Gracia, Zaragoza, Spain. 44. Critical Care Department, Hospital Universitari Arnau de Vilanova; IRBLleida, Lleida, Spain. 45. Critical Care Department, Hospital del Mar-IMIM, Barcelona, Spain. 46. Hospital Universitario la Paz, Madrid, Spain. 47. Intensive Care Unit, Hospital Universitario La Princesa, Madrid, Spain. 48. Departamento de Biología Funcional. Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo; Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Central de Asturias, Oviedo, Spain. 49. Hospital Universitario y Politécnico la Fe, Valencia, Spain. 50. Hospital de Tortosa Verge de la Cinta, Tortosa, Tarragona, Spain. 51. Department of Intensive Care Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain. 52. Hospital Universitario Infanta Leonor, Madrid, Spain. 53. Servei de Medicina Intensiva, Hospital Universitari Germans Trias, Badalona, Spain. 54. Intensive Care Unit, Hospital Álvaro Cunqueiro, Vigo, Spain. 55. Hospital Universitari Joan XXIII de Tarragona, Tarragona, Spain. 56. Hospital de Mataró de Barcelona, Spain. 57. Unidad de Cuidados Intensivos, Hospital Universitario San Pedro de Alcántara, Cáceres, Spain. 58. Unidad de Cuidados Intensivos, Hospital Virgen Macarena, Sevilla, Spain. 59. Intensive Care Unit, Hospital Clínico y Universitario de Valencia, Valencia, Spain. 60. Translational Research in Respiratory Medicine, Respiratory Department, Hospital Universitari Aranu de Vilanova and Santa Maria, IRBLleida, Lleida, Spain.Postprint (published version