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

Does Alzheimer disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (II)

Introduction: In the ageing process there are some species of non-human primates which can show some of the defining characteristics of the Alzheimer's disease (AD) of man, both in neuropathological changes and cognitive-behavioural symptoms. The study of these species is of prime importance to understand AD and develop therapies to combat this neurodegenerative disease. Development: In this second part of the study, these AD features are discussed in the most important non-experimental AD models (Mouse Lemur—Microcebus murinus, Caribbean vervet—Chlorocebus aethiops, and the Rhesus and stump-tailed macaque—Macaca mulatta and M. arctoides) and experimental models (lesional, neurotoxic, pharmacological, immunological, etc.) non-human primates. In all these models cerebral amyloid neuropathology can occur in senility, although with different levels of incidence (100% in vervets; <30% in macaques). The differences between normal and pathological (Alzheimer's) senility in these species are difficult to establish due to the lack of cognitive-behavioural studies in the many groups analysed, as well as the controversy in the results of these studies when they were carried out. However, in some macaques, a correlation between a high degree of functional brain impairment and a large number of neuropathological changes (“possible AD”) has been found. Conclusions: In some non-human primates, such as the macaque, the existence of a possible continuum between “normal” ageing process, “normal” ageing with no deep neuropathological and cognitive-behavioural changes, and “pathological ageing” (or “Alzheimer type ageing”), may be considered. In other cases, such as the Caribbean vervet, neuropathological changes are constant and quite marked, but its impact on cognition and behaviour does not seem to be very important. This does assume the possible existence in the human senile physiological regression of a stable phase without dementia even if neuropathological changes appeared. Resumen: Introducción: Existen algunas especies de primates no humanos con algunas de las carac-terísticas definitorias de la enfermedad de Alzheimer (EA) del hombre, tanto en el aspecto neuropatológico como en el cognoscitivo-comportamental, y que son de importancia capital para entender y/o tratar esta enfermedad. Desarrollo: En esta segunda parte del estudio se analizan estas características durante el proceso de envejecimiento en los modelos de EA más importantes de primates no humanos no experimentales (lémur ratón—Microcebus murinus, cercopiteco verde—Chlorocebus aethiops—y los macacos Rhesus y de cola en tirabuzón—Macaca mulatta y M. arctioides) y experimentales (modelos lesionales, neurotóxicos, farmacológicos, inmunológicos, etc.). En todos estos modelos se puede presentar neuropatología amiloidea cerebral senil, aunque con diferente grado de incidencia (100% en cercopitecos; <30% en macacos). Las diferencias entre senilidad normal y patológica (Alzheimer) en estas especies son difíciles de establecer por la falta de estudios cognoscitivo-comportamentales en muchos grupos analizados, así como por la controversia existente en los resultados de estos estudios cuando se llevaron a cabo. Sin embargo, en algunos macacos se ha comprobado la correlación entre un alto grado de deterioro funcional cerebral y una gran cantidad de alteraciones neuropatológicas (posible «Alzheimer»). Conclusiones: En los macacos, se puede considerar la existencia de un posible «continuum» entre proceso de envejecimiento «normal», «normal con no profundas alteraciones neuropatoló-gicas y cognoscitivo-comportamentales», y «envejecimiento patológico» o «envejecimiento tipo Alzheimer». En otros casos, como el de los cercopitecos verdes, las alteraciones neuropatológi-cas son constantes y bastante marcadas, pero sus repercusiones cognoscitivo-comportamentales no parecen muy importantes. Ello hace suponer la posible existencia en la involución senil fisiológica de una fase estable sin demencia aun cuando existan alteraciones neuropatológicas. Keywords: Alzheimerĭs disease, Non-human primates, Alzheimer models, Ageing, Senility, Amyloid, Tau protein, Cognitive functions, Behaviour, Palabras clave: Enfermedad de Alzheimer, Modelos Alzheimer, Primates no humanos, Envejecimiento, Senilidad, Amiloide, Proteína tau, Alteraciones cognoscitivo, Comportamentale

¿Existe la enfermedad de Alzheimer en todos los primates? Afección de Alzheimer en primates no humanos y sus implicaciones fisiopatológicas (I)

Resumen: Introducción: En muchas publicaciones se considera que la enfermedad de Alzheimer (EA) es privativa de la especie humana, y que ninguna otra especie animal padece dicha enfermedad. Sin embargo, diversos estudios han mostrado que existen en algunas especies algunas de las características definitorias de la enfermedad en el hombre, tanto en el aspecto neuropatológico como en el cognoscitivo-comportamental. Desarrollo: En este trabajo se recogen los resultados mostrados en la bibliografía (PubMed) sobre alteraciones cerebrales en la senilidad en primates no humanos de diferente grado de evolución. Las alteraciones neuropatológicas relacionadas con la acumulación de amiloide o de proteína tau altamente fosforilada son muy raras fuera del orden primate, pero en todos los subórdenes, las familias, géneros y especies de primates que se han estudiado han mostrado que algunos individuos seniles presentan acumulaciones amiloideas en el cerebro. Incluso en algunas especies, la presencia de acumulaciones amiloideas en la senilidad es constante. Las alteraciones neuropatológicas relacionadas con la acumulación de proteína tau, siempre de muy escasa relevancia, se han detectado solo en algunas especies de primates no humanos, tanto poco evolucionados como muy evolucionados. En diferentes especies de primates no humanos, algunos tipos de alteraciones cognoscitivo-comportamentales están presentes en algunos individuos seniles con una mayor intensidad tanto frente a los individuos adultos normales como a otros individuos seniles de la especie. Se analiza además la importancia de la determinación de la longevidad de las especies en los diferentes hábitat (hábitat naturales, nuevos hábitat, semilibertad, cautiverio) para acreditar la condición de «senil» de los individuos en estudio. Conclusiones: Existen características morfohistoquímicas y cognoscitivo-comportamentales involutivas generales en los primates no humanos seniles similares a las observadas en el hombre anciano y otras características que pudieran ser indicio de un envejecimiento patológico «tipo Alzheimer». Abstract: Introduction: Many publications consider that Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the human disease, including both neuropathological changes and cognitive-behavioural symptoms. Development: In this work, the results published (PubMed) on senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. In fact, in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are more common in some senile individuals when compared with both normal adult individuals and other senile individuals of the species. The importance of determining the longevity of the species in different habitats (natural habitats, new habitats, semi-captivity, captivity) is stressed in these studies. Conclusions: Morphological, histochemical and cognitive-behavioural features similar to those observed in elderly humans are present in senile non-human primates. Moreover, other characteristics seen in non-human primates could be indicative of a pathological «Alzheimer type» ageing. Palabras clave: Enfermedad de Alzheimer, Primates no humanos, Envejecimiento, Senilidad, Amiloide, Proteína tau, Alteraciones cognoscitivo-comportamentales, Keywords: Alzheimer's disease, Non-human primates, Ageing, Senility, Amyloid, Tau protein, Cognitive functions behaviou

¿Existe la enfermedad de Alzheimer en todos los primates? Patología Alzheimer en primates no humanos y sus implicaciones fisiopatológicas (II)

Resumen: Introducción: Existen algunas especies de primates no humanos con algunas de las características definitorias de la enfermedad de Alzheimer (EA) del hombre, tanto en el aspecto neuropatológico como en el cognoscitivo-comportamental, y que son de importancia capital para entender y/o tratar esta enfermedad. Desarrollo: En esta segunda parte del estudio se analizan estas características durante el proceso de envejecimiento en los modelos de EA más importantes de primates no humanos no experimentales (lémur ratón —Microcebus murinus—, cercopiteco verde —Chlorocebus aethiops— y los macacos Rhesus y de cola en tirabuzón —Macaca mulatta y M. arctioides—) y experimentales (modelos lesionales, neurotóxicos, farmacológicos, inmunológicos, etc.). En todos estos modelos se puede presentar neuropatología amiloidea cerebral senil, aunque con diferente grado de incidencia (100% en cercopitecos; < 30% en macacos). Las diferencias entre senilidad normal y patológica (Alzheimer) en estas especies son difíciles de establecer por la falta de estudios cognoscitivo-comportamentales en muchos grupos analizados, así como por la controversia existente en los resultados de estos estudios cuando se llevaron a cabo. Sin embargo, en algunos macacos se ha comprobado la correlación entre un alto grado de deterioro funcional cerebral y una gran cantidad de alteraciones neuropatológicas (posible «Alzheimer»). Conclusiones: En los macacos, se puede considerar la existencia de un posible «continuum» entre proceso de envejecimiento «normal», «normal con no profundas alteraciones neuropatológicas y cognoscitivo-comportamentales», y «envejecimiento patológico» o «envejecimiento tipo Alzheimer». En otros casos, como el de los cercopitecos verdes, las alteraciones neuropatológicas son constantes y bastante marcadas, pero sus repercusiones cognoscitivo-comportamentales no parecen muy importantes. Ello hace suponer la posible existencia en la involución senil fisiológica de una fase estable sin demencia aun cuando existan alteraciones neuropatológicas. Abstract: Introduction: In the ageing process there are some species of non-human primates which can show some of the defining characteristics of the Alzheimer's disease (AD) of man, both in neuropathological changes and cognitive-behavioural symptoms. The study of these species is of prime importance to understand AD and develop therapies to combat this neurodegenerative disease. Development: In this second part of the study, these AD features are discussed in the most important non-experimental AD models (Mouse Lemur —Microcebus murinus, Caribbean vervet —Chlorocebus aethiops, and the Rhesus and stump-tailed macaque —Macaca mulatta and M. arctoides) and experimental models (lesional, neurotoxic, pharmacological, immunological, etc.) non-human primates. In all these models cerebral amyloid neuropathology can occur in senility, although with different levels of incidence (100% in vervets; < 30% in macaques). The differences between normal and pathological (Alzheimer's) senility in these species are difficult to establish due to the lack of cognitive-behavioural studies in the many groups analysed, as well as the controversy in the results of these studies when they were carried out. However, in some macaques, a correlation between a high degree of functional brain impairment and a large number of neuropathological changes (“possible AD”) has been found. Conclusions: In some non-human primates, such as the macaque, the existence of a possible continuum between “normal” ageing process, “normal” ageing with no deep neuropathological and cognitive-behavioural changes, and “pathological ageing” (or “Alzheimer type ageing”), may be considered. In other cases, such as the Caribbean vervet, neuropathological changes are constant and quite marked, but its impact on cognition and behaviour does not seem to be very important. This does assume the possible existence in the human senile physiological regression of a stable phase without dementia even if neuropathological changes appeared. Palabras clave: Enfermedad de Alzheimer, Modelos Alzheimer, Primates no humanos, Envejecimiento, Senilidad, Amiloide, Proteína tau, Alteraciones cognoscitivo, Comportamentales, Keywords: Alzheimeŕs Disease, Non-human primates, Alzheimer models, Ageing, Senility, Amyloid, Tau protein, Cognitive functions, Behaviou

Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I)

Introduction: Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive–behavioural symptoms. Development: In this work, the results, published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive–behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies. Conclusions: Morphological and histochemical and cognitive–behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological “Alzheimer type” ageing. Resumen: Introducción: En muchas publicaciones se considera que la Enfermedad de Alzheimer (EA) es privativa de la especie humana, y que ninguna otra especie animal padece dicha enfermedad. Sin embargo, diversos estudios han mostrado que existen en algunas especies algunas de las características definitorias de la enfermedad en el hombre, tanto en el aspecto neuropatológico como en el cognoscitivo-comportamental. Desarrollo: En este trabajo se recogen los resultados mostrados en la bibliografía (PubMed) sobre alteraciones cerebrales en la senilidad en primates no humanos de diferente grado de evolución. Las alteraciones neuropatológicas relacionadas con la acumulación de amiloide o de proteína tau altamente fosforilada son muy raras fuera del orden primate, pero en todos los subórdenes, las familias, géneros y especies de primates que se han estudiado han mostrado que algunos individuos seniles presentan acumulaciones amiloideas en el cerebro. Incluso en algunas especies la presencia de acumulaciones amiloideas en la senilidad es constante. Las alteraciones neuropatológicas relacionadas con la acumulación de proteína tau, siempre de muy escasa relevancia, se han detectado solo en algunas especies de primates no humanos, tanto poco evolucionados como muy evolucionados. En diferentes especies de primates no humanos, algunos tipos de alteraciones cognoscitivo-comportamentales están presentes en algunos individuos seniles con una mayor intensidad tanto frente a los individuos adultos normales como a otros individuos seniles de la especie. Se analiza además la importancia de la determinación de la longevidad de las especies en los diferentes habitats (habitats naturales, nuevos habitats, semilibertad, cautiverio) para acreditar la condición de “senil” de los individuos en estudio. Conclusiones: Existen características morfohistoquímicas y cognoscitivo-comportamentales involutivas generales en los primates no humanos seniles similares a las observadas en el hombre anciano, y otras características que pudieran ser indicio de un envejecimiento patológico “tipo Alzheimer”. Keywords: Alzheimer's disease, Non-human primates, Ageing, Senility, Amyloid, Tau protein, Cognitive functions behaviour, Palabras clave: Enfermedad de Alzheimer, Primates no humanos, Envejecimiento, Senilidad, Amiloide, Proteína tau, Alteraciones cognoscitivo-comportamentale

Conocimiento etnoecólogico de los hongos entre los indígenas Uitoto, Muinane y Andoke de la Amazonía Colombiana Conhecimento etnoecológico de fungos entre os indígenas Uitoto, Muinane e Andoke da Amazônia Colombiana

El presente texto es el resultado de un compartir de conocimientos acerca de los hongos y sus relaciones ecológicas con animales y plantas, con las etnias Uitoto, Andoke y Muinane que habitan la región del medio Caquetá. Gran parte de la información ecológica encontrada está contenida en la tradición oral de estas etnias, y refleja la capacidad integradora y descriptiva que tienen los indígenas sobre el medio natural circundante. En la zona de estudio la madera es un sustrato muy abundante debido principalmente al tipo de agricultura que tienen los indígenas, y por tanto se desarrollan una gran cantidad de especies de hongos lignícolas. Muinanes, Uitotos y Andokes conocen algunas de las especies vegetales que sirven de sustrato para los hongos, sobretodo aquellas utilizadas en la alimentación tales como Lentinula raphanica y Lentinus scleropus, entre otros. El conocimiento ecológico que tienen estos indígenas sobre los hongos, incluye además datos acerca de cucarrones (Coleoptera) y larvas (Diptera), mamíferos como venados (Mazama americana y M. gouazoubira) y ardillas (Microsciurus flaviventer) y tortugas que incluyen los hongos en su dieta, así como sobre especies de hongos que parasitan plantas e insectos.<br>O presente texto é o resultado de um intercâmbio de conhecimentos sobre os fungos e as suas relações ecológicas com animais e plantas, com as etnias Uitoto, Andoke e Muinane que habitam a região do Medio Caquetá. Grande parte da informação ecológica encontrada está contida na tradição oral destas etnias e reflete a capacidade integradora e descritiva que os indígenas possuem sobre o meio natural que os circunda. Na zona de estudo a madeira é um substrato abundante devido principalmente ao tipo de agricultura que os indígenas têm, portanto uma grande quantidade de espécies de fungos lignícolas se desenvolve perto dessas tribos. Os Muinanes, Uitotos e Andokes conhecem algumas das espécies vegetais que servem de subtstrato para os fungos, principalmente daquelas que eles utilizam na alimentação, como Lentinula raphanica e Lentinus scleropus, entre outros. O conhecimento ecológico que estes indígenas possuem sobre fungos inclui ainda dados de besouros (Coleoptera) e larvas (Diptera), mamíferos, como veados (Mazama americana e M. gouazoubira) e esquilos (Microsciurus flaviventer), e tartarugas que incluem fungos nas suas dietas, assim como sobre espécies de fungos que parasitam plantas e insetos