Expression of Glucose Transporters in the Prelaminar Region of the Optic-Nerve Head of the Pig as Determined by Immunolabeling and Tissue Culture

Background: To develop the use of cultured tissue of the prelaminar optic nerve of the pig to explore possible alterations of the astrocyte-axon metabolic pathways in glaucoma, we map the distribution of the glucose transporters GLUT1 and GLUT3 in fresh and cultured tissue.Methods: We monitor cell survival in cultures of the prelaminar optic-nerve tissue, measuring necrosis and apoptosis markers biochemically as well as morphologically, and establish the presence of the glucose transporters GLUT1 and GLUT3. We map the distribution of these transporters with immunolabeling in histological sections of the optic nerve using confocal and electronic transmission microscopy.Results: We find that the main death type in prelaminar culture is apoptosis. Caspase 7 staining reveals an increment in apoptosis from day 1 to day 4 and a reduction from day 4 to day 8. Western blotting for GLUT1 shows stability with increased culture time. CLSM micrographs locate GLUT1 in the columnar astrocytes and in the area of axonal bundles. Anti-GLUT3 predominantly labels axonal bundles. TEM immunolabeling with colloidal gold displays a very specific distribution of GLUT-1 in the membranes of vascular endothelial cells and in periaxonal astrocyte expansions. The GLUT-3 isoform is observed with TEM only in axons in the axonal bundles.Conclusions: Tissue culture is suitable for apoptosis-induction experiments. The results suggest that glucose is transported to the axonal cleft intracytoplasmically and delivered to the cleft by GLUT1 transporters. As monocarboxylate transporters have been reported in the prelaminar region of the optic-nerve head, this area is likely to use both lactate and glucose as energy sources.This work was supported by a grant from the Consejería de Salud, Junta de Andalucia, Spain, Project PI-0655-2013

High dose chemotherapy and autologous stem cell transplantation in patients with peripheral T-cell lymphoma not achieving complete response after induction chemotherapy. The GEL-TAMO experience

Background and objectives: patients with aggressive non-Hodgkin's lymphomas (NHL) who do not obtain a complete response (CR) after induction chemotherapy have a poor prognosis. However, provided they are sensitive to the first regimen of chemotherapy, 25-40% of them with a B-cell phenotype may achieve long-term survival when treated with high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT). The aim of this study was to analyze the efficacy of this therapy in the corresponding patients with peripheral T-cell lymphoma (PTCL). Design and methods: we retrospectively evaluated the efficacy of ASCT in 35 patients with PTCL from the GEL-TAMO registry, who did not achieve a CR to standard induction chemotherapy regimens for aggressive NHL. Thirty-one patients underwent transplantation after achieving a partial response (PR) and 4 patients were non-responders. Results: following HDC/ASCT, 23 (66%) of the patients achieved a CR, 4 (11%) a PR and in 7 (20%) cases the transplant failed. One patient was not evaluated because of early toxic death. With a median follow-up of the survivors of 37.5 months, 18 patients (51%) are alive and 15 patients (43%) are free of disease. Transplant-related mortality rate at 100 days was 11% and at 5 years the probabilities of survival, freedom from progression and disease-free survival for complete responders were 37%, 36% and 55% respectively. Pre-transplant lactate-dehydrogenase level, age-adjusted International Prognostic Index (aa-IPI) and tumor score correlated with survival. Interpretation and conclusions: one third of the patients with PTCL who fail to achieve CR to the first chemotherapeutic regimen can be rescued with HDC/ASCT. Pre-transplant values of IPI and tumor score risk systems for aggressive lymphomas were useful to predict subsequent survival

Overview of recent TJ-II stellarator results

The main results obtained in the TJ-II stellarator in the last two years are reported. The most important topics investigated have been modelling and validation of impurity transport, validation of gyrokinetic simulations, turbulence characterisation, effect of magnetic configuration on transport, fuelling with pellet injection, fast particles and liquid metal plasma facing components. As regards impurity transport research, a number of working lines exploring several recently discovered effects have been developed: the effect of tangential drifts on stellarator neoclassical transport, the impurity flux driven by electric fields tangent to magnetic surfaces and attempts of experimental validation with Doppler reflectometry of the variation of the radial electric field on the flux surface. Concerning gyrokinetic simulations, two validation activities have been performed, the comparison with measurements of zonal flow relaxation in pellet-induced fast transients and the comparison with experimental poloidal variation of fluctuations amplitude. The impact of radial electric fields on turbulence spreading in the edge and scrape-off layer has been also experimentally characterized using a 2D Langmuir probe array. Another remarkable piece of work has been the investigation of the radial propagation of small temperature perturbations using transfer entropy. Research on the physics and modelling of plasma core fuelling with pellet and tracer-encapsulated solid-pellet injection has produced also relevant results. Neutral beam injection driven Alfvénic activity and its possible control by electron cyclotron current drive has been examined as well in TJ-II. Finally, recent results on alternative plasma facing components based on liquid metals are also presentedThis work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under Grant Agreement No. 633053. It has been partially funded by the Ministerio de Ciencia, Inovación y Universidades of Spain under projects ENE2013-48109-P, ENE2015-70142-P and FIS2017-88892-P. It has also received funds from the Spanish Government via mobility grant PRX17/00425. The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona S.C. It has been supported as well by The Science and Technology Center in Ukraine (STCU), Project P-507F

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Atlas de las praderas marinas de España

Knowledge of the distribution and extent of seagrass habitats is currently the basis of management and conservation policies of the coastal zones in most European countries. This basic information is being requested through European directives for the establishment of monitoring programmes and the implementation of specific actions to preserve the marine environment. In addition, this information is crucial for the quantification of the ecological importance usually attributed to seagrass habitats due to, for instance, their involvement in biogeochemical cycles, marine biodiversity and quality of coastal waters or global carbon budgets. The seagrass atlas of Spain represents a huge collective effort performed by 84 authors across 30 Spanish institutions largely involved in the scientific research, management and conservation of seagrass habitats during the last three decades. They have contributed to the availability of the most precise and realistic seagrass maps for each region of the Spanish coast which have been integrated in a GIS to obtain the distribution and area of each seagrass species. Most of this information has independently originated at a regional level by regional governments, universities and public research organisations, which explain the elevated heterogeneity in criteria, scales, methods and objectives of the available information. On this basis, seagrass habitats in Spain occupy a total surface of 1,541,63 km2, 89% of which is concentrated in the Mediterranean regions; the rest is present in sheltered estuarine areas of the Atlantic peninsular regions and in the open coastal waters of the Canary Islands, which represents 50% of the Atlantic meadows. Of this surface, 71.5% corresponds to Posidonia oceanica, 19.5% to Cymodocea nodosa, 3.1% to Zostera noltii (=Nanozostera noltii), 0.3% to Zostera marina and 1.2% to Halophila decipiens. Species distribution maps are presented (including Ruppia spp.), together with maps of the main impacts and pressures that has affected or threatened their conservation status, as well as the management tools established for their protection and conservation. Despite this considerable effort, and the fact that Spain has mapped wide shelf areas, the information available is still incomplete and with weak precision in many regions, which will require an investment of major effort in the near future to complete the whole picture and respond to demands of EU directives

Transferencia de investigaciones virológicas a sectores educativos y generales de la comunidad

La educación es la única y verdadera herramienta válida, por excelencia, para lograr cambios positivos en la historia, en la política, en la salud o en cualquiera otro aspecto importante de la vida de los hombres. Entonces, deberíamos insistir en mejorar la calidad educativa de los ciudadanos y alumnos de todos los niveles, mejorando necesariamente la actualización de los saberes de los funcionarios, profesionales y docentes para que se inscriba en el discurso cotidiano. El desconocer, no prepararse, nos lleva a crisis sociales que inevitablemente incrementan flagelos como la pobreza, la pérdida de biodiversidad, las guerras, las epidemias, entre otros. Así, desde donde se produce y construye el conocimiento científico, la Universidad Nacional de Córdoba, Facultad de Ciencias Médicas y específicamente el Instituto de Virología "Dr. José María Vanella" también se promueve el objetivo de extensión comunitaria, brindando este proyecto a docentes, alumnos y comunidad en general de la provincia de Córdoba como servicio educativo y actualización. Las temáticas son variadas, los talleres convocan a la Divulgación científica y tecnológica de infecciones virales de importancia sanitaria su conocimiento, prevención y difusión, no solo para el sector educativo sino también para la comunidad en general. Las actividades son talleres, conferencias, laboratorios, jornadas de un día hasta dos semanas. Las metodologías aplicadas son charlas dialogadas, vídeos, dinámica de grupos, Hay evaluaciones de seguimiento a través de comentarios, relatos, encuestas. Todas las actividades de extensión del InViV cuentan con la aprobación de la Facultad Ciencias Médicas a través de las Res. Decanales anuales.Fil: Balangero, Marcos. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gil, Pedro Ignacio: Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gil, Pedro Ignacio: Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Frutos: María Cecilia: Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Frutos: María Cecilia: Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Díaz, Luis Adrián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ré, Viviana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Farias, Adrián Alejandro. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Spinsanti, Lorena. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Venezuela, Raúl Fernando. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Kiguen, Ana Ximena. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Konigheim, Brenda. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil:Masachessi, Gisela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Barril, Patricia Angélica. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Varella"; Argentina.Fil: Barril, Patricia Angelica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Castro, Gonzalo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Batallán, Pedro Gonzalo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Batallán, Pedro Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Quaglia, Agustín.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Tauro, Laura Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Tauro, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Flores, Fernando Sebastián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Flores, Fernando Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Beranek, Mauricio. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Beranek, Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Maturano, Eduardo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Rodríguez, Pamela Elizabeth. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Cámara, Jorge Augusto. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil, Albrieu Llinás, Guillermo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil, Albrieu Llinás, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Adamo, María Pilar. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ghietto, Lucía María. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ghietto, Lucía María. Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Pedranti, Mauro Sebastián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Giordano, Miguel Oscar. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Martínez, Laura Cecilia.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Isa, Maria Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ascheri, Stella Maris. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paredes, Norma Gladys. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Contigiani, Marta Silvia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Benítez, Marta. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Theiler, Gerardo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Augello, Marysol. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Fosatti, L. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; ArgentinaFil:Moreno, F. Colegio San Martín; Argentina.Fil:Marín, M. Colegio Nuestra Señora del Sagrado Corazón; Argentina.Fil: Carreras, G. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Navarro, A. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Fuentes, M. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Santiago, T. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Cámara, Alicia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paglini, María Gabriela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Cuffini, Cecilia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gallego, Sandra Verónica.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Aguilar, Javier. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paván, Jorge. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Nates, Silvia Viviana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Enfermedades Infecciosa

Atlas de las praderas marinas de España

Knowledge of the distribution and extent of seagrass habitats is currently the basis of management and conservation policies of the coastal zones in most European countries. This basic information is being requested through European directives for the establishment of monitoring programmes and the implementation of specific actions to preserve the marine environment. In addition, this information is crucial for the quantification of the ecological importance usually attributed to seagrass habitats due to, for instance, their involvement in biogeochemical cycles, marine biodiversity and quality of coastal waters or global carbon budgets. The seagrass atlas of Spain represents a huge collective effort performed by 84 authors across 30 Spanish institutions largely involved in the scientific research, management and conservation of seagrass habitats during the last three decades. They have contributed to the availability of the most precise and realistic seagrass maps for each region of the Spanish coast which have been integrated in a GIS to obtain the distribution and area of each seagrass species. Most of this information has independently originated at a regional level by regional governments, universities and public research organisations, which explain the elevated heterogeneity in criteria, scales, methods and objectives of the available information. On this basis, seagrass habitats in Spain occupy a total surface of 1,541,63 km2, 89% of which is concentrated in the Mediterranean regions; the rest is present in sheltered estuarine areas of the Atlantic peninsular regions and in the open coastal waters of the Canary Islands, which represents 50% of the Atlantic meadows. Of this surface, 71.5% corresponds to Posidonia oceanica, 19.5% to Cymodocea nodosa, 3.1% to Zostera noltii (=Nanozostera noltii), 0.3% to Zostera marina and 1.2% to Halophila decipiens. Species distribution maps are presented (including Ruppia spp.), together with maps of the main impacts and pressures that has affected or threatened their conservation status, as well as the management tools established for their protection and conservation. Despite this considerable effort, and the fact that Spain has mapped wide shelf areas, the information available is still incomplete and with weak precision in many regions, which will require an investment of major effort in the near future to complete the whole picture and respond to demands of EU directives.Versión del edito

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation