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Background: We aimed to describe changes in characteristics and treatment strategies of hospitalised patients with COVID-19 and detail the mortality trend over time., Methods: Observational cohort study of all consecutive patients admitted ≥ 48 h to Hospital Clinic of Barcelona for COVID-19 (1 March-30 September 2020)., Findings: A total of 1645 consecutive patients with COVID-19 were assessed over a 7-month period. Overall mortality (≤30 days) was 9.7% (159 patients), 7.7% in patients hospitalised in regular wards and 16.7 % in patients requiring ICU admission. Overall mortality decreased from 11.6% in the first month to 1.4% in the last month, reflecting a progressive, significant downward trend ( p for trend <0.001). Patients' age changed over time, peaking in June. Most changes in the use of antivirals and anti-inflammatory treatments were documented. Age (OR 1.1, CI 1.1-1.12), chronic heart disease, (OR 1.7, CI 1.1-2.9), D-dimer>700 ng/mL (OR 2.3, CI 1.3-4.1), ferritin>489 ng/mL (OR 1.9; CI 1.5-3.2), C-RP>7 mg/dL (OR 2.6; CI 1.5-4.6), and shorter duration from symptom onset to hospital admission (OR 1.11; CI 1.04-1.17) were factors associated with 30-day mortality at hospital admission. Conversely, hospital admission in the last months (OR 0.80; CI 0.65-0.98) was significantly associated with lower mortality., Interpretation: In-hospital mortality has decreased in patients with COVID-19 over the last, few months, even though main patient characteristics remain similar. Several changes made when managing patients may explain this decreasing trend. Our study provides current data on mortality of patients hospitalised with COVID-19 that might be useful in establishing quality of standard of care., Funding: EIT Health, European Union´s Horizon 2020 Research and Innovation Programme), EDRD. PPA [CM18/00132], NGP [FI19/00133], and CGV [FIS PI18/01061], have received grants from Ministerio de Sanidad y Consumo, ISCIII., Competing Interests: This research is part of an activity that has received funding from EIT Health. EIT Health is supported by the European Institute of Innovation and Technology (EIT), a body of the European Union that receives support from the European Union´s Horizon 2020 Research and Innovation Programme. This study has been co-funded by the European Regional Development Fund (EDRD). All authors report grants from EIT Health and the European Regional Development Fund (for themselves or their institution), during the conduct of the study. PPA [CM18/00132], NGP [FI19/00133], and CGV [FIS PI18/01061] have received research grants from the Ministerio de Sanidad y Consumo and Instituto de Salud Carlos III. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CGV has received honoraria for talks on behalf of Gilead Science, MSD, Novartis, Pfizer, Janssen, and Lilly, as well as a grant from Gilead Science and MSD. PPA has received honoraria for talks on behalf of Gilead Science and MSD. JM has received honoraria for talks on behalf of Merck Sharp and Dohme, Pfizer, Novartis, and Angellini. AS has received honoraria for talks on behalf of Merck Sharp and Dohme, Pfizer, Novartis, and Angellini, as well as grant support from Pfizer. Other authors do not declare conflict of interest outside the submitted work. Hospital Clinic of Barcelona COVID-19 Researchers: Infectious Diseases’ Research Group: Albiach L, Agüero D, Ambrosioni J, Blanco JL, De la Mora L, González-Cordón A, Inciarte A, Jordan C, Laguno M, Leal L, Lopera C, Macaya I, Mallolas J, Martínez E, Martínez M, Miró JM, Moreno A, Rojas J, Solá M, Torres B, Torres M, and all the staff members. Medical Intensive Care Unit: Adrian Téllez, Sara Fernández, and all the staff members. Department of International Health: Daniel Camprubi Ferrer, Maria Teresa de Alba, Marc Fernandez, Elisabet Ferrer, Berta Grau, Helena Marti, Magdalena Muelas, Maria Jesus Pinazo, Natalia Rodríguez, Montserrat Roldan, Carme Subira, Isabel Vera, Nana Williams, Jose Muñoz, and all the staff members. Department of Internal Medicine: Aldea A, Camafort M, Calvo J, Capdevila A, Cardellach F, Carbonell I, Coloma E, Foncillas A, Estruch R, Feliu M, Fernández-Solá J, Fuertes I, Gabara C, Grafia I, Ladino A, López-Alfaro R, López-Soto A, Masanés F, Matas A, Navarro M, Marco-Hernández J, Miguel L, Milisenda J, Moreno P, Naval J, Nicolás D, Oberoi H, Padrosa J, Prieto-González S, Pellicé M, Ribot J, Rodríguez-Núnez O, Sacanella E, Seguí F, Sierra C, Tomé A, Ugarte A, Ventosa H, Zamora-Martínez C, and all the staff members. Department of Microbiology: M. Almela, M. Alvarez, J. Bosch, C. Casals, J. Costa, G. Cuesta, M. Fernandez, B. Fidalgo, J. Gonzàlez, J.C. Hurtado, F. Marco, M.A. Marcos, M. Martínez, M. Mosquera, S. Narvaez, C. Pitart, E. Rubio, A. Vergara, M.E.Valls, J. Vila, Y. Zboromyrska and all the staff members. Department of Farmacy: E. López, D. Soy, M. Tuset and all the staff members. Data sharing statement: All data will be available under request after manuscript acceptance., (© 2021 Published by Elsevier Ltd.)

The relationship between morphine tolerance and pituitary-adrenocortical activity was examined. In rats made tolerant to morphine by implantation of morphine-containing pellets, there was a significant reduction in plasma levels of beta-endorphin-like immunoreactivity (beta-END-LI), whereas no significant changes in cortisol levels were seen. Naloxone treatment induced an increase in plasma beta-END-LI and cortisol levels in morphine-tolerant animals. Additionally, acute morphine administration induced an increase in plasma levels of beta-END-LI and cortisol, an effect which was prevented by naloxone. These results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine and with a decreased release of these peptides in tolerant rats, and suggest that opioid peptides play an important role in the regulation of pituitary-adrenocortical function.