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.S

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.We thank S. Bartlett for English language editing; V Labrador for advice on confocal imaging and immunofluorescent experiments; the CNIC Facilities of histology, microscopy, and advanced imaging; and AI Torralbo for excellent technical support and advice. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), the CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO and CNIC are Severo Ochoa Centers of Excellence (grants CEX2021-001154-S and CEX2020-001041-S, respectively) funded by MICIN/AEI/10.13039/ 501100011033. The project leading to these results has received funding from “La Caixa” Banking Foundation under project codes HR18-00068 (to MRC and JMR); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-BI00 (MICIU/AEI/FEDER, UE) to JMR, and grants PID2020-115217RB-100 and PID2021-122388OB-100 to MRC and JMR, respectively, funded by MCIN/AEI/ 10.13039/501100011033; Instituto de Salud Carlos III (CIBER-CV CB16/11/ 00264 and CB16/11/00479; and grants PI17/00381 to GT-T and PI21/00084 (co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) to JFN); Fundacio La Marato TV3 (20151330 to JMR); Instituto de Investigación Sanitaria Marqués de Valdecilla (IDIVAL) (INNVAL 21/24) to JFN; The Marfan Foundation USA Faculty grant 2017 MRF/1701 (to JMR); Fundación MERCKFundación Española de Enfermedades Raras 2022 and V-Ayudas “Muevete por ́ los que no pueden 2021” (to JO); and Spanish Ministerio de Ciencia e Innovación contracts FPI (BES-2016-077649) to MJR-R; Sara Borrell (CD18/ 00028) and Juan de la Cierva (IJC2020-044581-I) to MT; Ramón y Cajal (RYC2021-033343-I) to JO; and FPU (20/04814) to IA-R.S

Hypoxia-induced stabilization of HIF2A promotes cardiomyocyte proliferation by attenuating DNA damage.

INTRODUCTION Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure. AIM We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia. METHODS AND RESULTS We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence. CONCLUSION Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration.Ali SR was supported by 5T32HL125247–03 and K08HL153788. Sadek HA was supported by NIH R01 HL137415–02, NIH R01 HL147276–01, NIH R01 HL149137–01, NIH 1P01HL160476–01A1, NIH R35 HL166563–01 and Leducq Transatlantic Network of Excellence. Nguyen NUN was supported by grants from the American Heart Association (856552, 19POST34450039).S

Los virus dejan huellas inmunes imborrables en nuestro cuerpo

Artículo de divulgación publicado en The Conversation España el día 19/03/2024.Incluso años después de que la infección por un virus se haya resuelto, existen una serie de respuestas del sistema inmune que pueden volverlo más débil (inmunosupresión) o más reactivo de lo normal.N

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.Acknowledgments: We would like to thank the cell Sorting Service of the nUcleUS platform (University of Salamanca, Salamanca, Spain) for technical assistance. Funding: Financial support for this work was obtained from the Spanish Ministry of Science and innovation Mcin/Aei/10.13039/501100011033 (PiD2020- 115444GB- i00 to P.r.- n., PiD2019- 108160rB- i00 to P.M., Ple2021- 0075 to c.B., and PiD2020- 117323rB- 100 and PDc2021- 121711- 100 to l.Á.-V.), partially supported by the european regional Development Fund (erDF); the carlos iii health institute (iSciii) (Pi20/01030 to B.B., Pi19/00132 to l.S., Pi21- 01834 to P.P., Pi20/00822 to c.B., and DTS20/00089 to l.Á.-V.), partially supported by the erDF; the iSciii- ricorS within the next Generation eU program (plan de recuperación, Transformación y resilencia) (rD21/0017/0030 to B.B. and J.M.- l. and rD21/0017/0029 to P.M.); the iSciii- ciBeronc program (cB16/12/00400 to A.o.), the criS cancer Foundation (FcriS- 2021- 001 to J.M.- l. and FcriS- 2021- 0090 to l.Á.-V.), the Spanish Association Against cancer (Aecc) (PrYGn234975Mene to P.M., PrYGn211192BUen to c.B., and ProYe19084AlVA and PrYGn234844AlVA to l.Á.-V.); the Accelerator Award- cancer research UK/Airc/Aecc- incAr (GeAcc18001orF to A.o.), the Fundación “la caixa” (lcF/Pr/hr19/52160011 to P.M. and hr21- 00761 project il7r_lungcan to l.Á.-V.), the european research council (erc) (erc- Poc- 957466 to P.M.) and erc under the eU’s horizon Program (grant agreement 101100665 to P.M.), the Fundación de investigación Biomédica 12 de octubre (programa investiga 2022- 0082) to l.Á.-V.; the Fundación ramón Areces to P.P. l.D.-A. was supported by a rio hortega fellowship from the carlos iii health institute (cM20/00004). A.F. was supported by a postdoctoral fellowship from the Spanish Ministry of Science and innovation (FJc2021- 046789- i). A. Mayado was supported by the ciBeronc (PrF- 2869). A.P.- P. was supported by a grant from the Government of castilla y león (orden eDU/556/2019; Valladolid, Spain). M.G.- r. was supported by an industrial PhD ellowship from the comunidad de Madrid (inD2022/BMD- 23732). o.A.- S. was supported by a PhD fellowship from the complutense University of Madrid. c.D.-A. was supported by a PhD fellowship from the Spanish Ministry of Science and innovation (Pre2018- 083445). l.r.- P. was supported by a PhD fellowship from the immunology chair, Universidad Francisco de Vitoria/Merck. o.h. was supported by an industrial PhD fellowship from the comunidad de Madrid (inD2020/BMD- 17668). A.V. is supported by research institute hospital 12 de octubre (imas12). A.G.- o. is supported by hiGeA 2019/0123 Aie project to J.M.- l.S

Situación Epidemiológica de los casos de Viruela del Mono en España. Datos extraídos de SiViES el 03/06/2024.

A fecha de esta actualización se han notificado un total de 8.030 casos confirmados de infección por mpox desde el inicio del brote en abril de 2022, procedentes de 17 Comunidades Autónomas.N

Presentación Acción Estratégica en Salud 2024

El ISCIII ha presentado la Acción Estratética en Salud (AES) 2024 con una jornada informativa celebrada en Toledo. La AES 2024 parte con más de 138 millones y espera movilizar a lo largo del año casi 285 para impulsar la I+D+I en salud. Como cada año, la AES concede ayudas, en proceso de concurrencia competitiva, para contratos y proyectos de investigación biomédica y sanitaria. En el acto han estado presentes Marina Pollán (directora del ISCIII), Carmen Encinas (directora general de Ordenación, Planificación e Inspección Sanitaria y Farmacia de la Consejería de Sanidad de Castilla-La Mancha), Pilar Gayoso (subdirectora de Evaluación y Fomento de la Investigación del ISCIII), Daniel Ruiz Iruela (subdirector de Programas Internacionales de Investigación y Relaciones Institucionales), Sagrario de la Azuela Gómez (directora de la Fundación del Hospital Nacional de Parapléjicos y directora gerente del Hospital Universitario de Toledo), Alberto Jara Sánchez (director gerente del Servicio de Salud de Castilla-La Mancha) y Alino José Martínez Marcos (vicerrector de Ciencias de la Salud de la Universidad de Castilla-La Mancha). Este año 2024 la AES consolidará su evaluación y adhesión a los principios de la Declaración de San Francisco (DORA), reafirmando el análisis cualitativo del impacto social de la ciencia en la evaluación de los proyectos financiados con fondos públicos. Las líneas de investigación en la AES 2024 consolidan y amplían las orientadas a la protección de la salud y el impacto social de políticas sanitarias a diversas áreas estratégicas: Quimioprevención del cáncer en personas sanas, Efectos terapéuticos a largo plazo en largos supervivientes de cáncer, Calidad de vida en enfermedades crónicas, en especial las ligadas a fragilidad y vulnerabilidad social, Impacto del consumo de alcohol y otros tóxicos en la salud, Desarrollo y aplicación de herramientas conductuales y biológicas con aplicación en medicina de precisión y salud pública, Nuevos sistemas de vigilancia epidemiológica con análisis de interoperabilidad y coste-efectividad, Economía de la salud y farmacoeconomía y Análisis de viabilidad de cribados poblacionales en patologías altamente letales y/o de elevada incidencia.​N

Analytical data as a predictor of duration of hospital admission in human parechovirus infections

This study was partially funded under two Health Care Facility Strategic Action (AESI: Acción Estratégica de Salud Intramural) projects that included the study of the analysed samples (PI15CIII/00020 and PI18CIII/00017). Spain.S

Vigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 167. Semana 04/2024 (del 22 de enero al 28 de enero del 2024)

Las infecciones respiratorias agudas continúan disminuyendo, tanto en Atención Primaria como en hospitales. También se observa un descenso en la positividad a gripe, SARSCoV-2 y VRS en los casos de IRAs y de IRAG en todos los ámbitos de la atención sanitaria. En la semana 04/2024, se mantiene el descenso de la actividad gripal en España y en todas las CCAA. La hospitalización por COVID-19 y por infección por VRS consolida su descenso en todos los grupos de edad.N

Vigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 179. Semana 16/2024 (del 15 al 21 de abril del 2024).

Informe elaborado por el Grupo de Vigilancia de la Gripe. Red Nacional de Vigilancia Epidemiológica. Servicio de Vigilancia Epidemiológica. Centro Nacional de Epidemiología.La positividad de casos de IRAs se situó por debajo del 10% desde la semana 01/2024 para VRS, desde la semana 03/2024 para SARS-CoV-2 y desde la semana 07/2024 para gripe. La variante de SARS-CoV-2 identificada en mayor proporción en los casos centinela de IRAs e IRAG en Atención Primaria y hospitales es la BA.2.86 (58% y 56%) desde la semana 03/2024. La infección por VRS sigue decreciendo o permanece estable en todos los ámbitos. Las estimaciones MoMo de excesos semanales de mortalidad por todas las causas muestran que la mortalidad está a niveles esperados, después de un periodo de elevada mortalidad observada.N