A proposed increase in retinal field-of-view may lead to spatial shifts in images

Visual information determines majority of our spatial behavior. The eye projects a 2-D image of the world on the retina. We demonstrate that when a monocular-like imaging system operates entirely with optically dense fluids, an increase in field-of-view (FOV) is observed compared to an experimental condition, where the ocular medium is optically neutral. Resulting spatial shifts in the retinal image towards the fovea complement the photoreceptor distribution pattern, incidentally revealing a new role for ocular fluids in the image space. Possible effects on the perceived egocentric object location are discussed.Comment: 13 pages, 2 figures, 1 tabl

Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter from Sorghum bicolor.

About 50% of the world's arable land is strongly acidic (pH ≤ 5). The low pH solubilizes root-toxic ionic aluminium (Al3+) species from clay minerals, driving the evolution of counteractive adaptations in cultivated crops. The food crop Sorghum bicolor upregulates the membrane-embedded transporter protein SbMATE in its roots. SbMATE mediates efflux of the anionic form of the organic acid, citrate, into the soil rhizosphere, chelating Al3+ ions and thereby imparting Al-resistance based on excluding Al+3 from the growing root tip. Here, we use electrophysiological, radiolabeled, and fluorescence-based transport assays in two heterologous expression systems to establish a broad substrate recognition profile of SbMATE, showing the proton and/or sodium-driven transport of 14C-citrate anion, as well as the organic monovalent cation, ethidium, but not its divalent analog, propidium. We further complement our transport assays by measuring substrate binding to detergent-purified SbMATE protein. Finally, we use the purified membrane protein as an antigen to discover native conformation-binding and transport function-altering nanobodies using an animal-free, mRNA/cDNA display technology. Our results demonstrate the utility of using Pichia pastoris as an efficient eukaryotic host to express large quantities of functional plant transporter proteins. The nanobody discovery approach is applicable to other non-immunogenic plant proteins

Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.publishedVersio

Adolescent transport and unintentional injuries: a systematic analysis using the Global Burden of Disease Study 2019

Background: Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10–24 years during the past three decades. Methods: Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10–14, 15–19, and 20–24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019. Findings: In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10–24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010–19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010–19. Interpretation: As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low–middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury. Funding: Bill & Melinda Gates Foundation

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12.2 million (95% UI 11.0-13.6) incident cases of stroke, 101 million (93.2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6.55 million (6.00-7.02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11.6% 10.8-12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% 5.1-6.2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70.0% (67.0-73.0), prevalent strokes increased by 85.0% (83.0-88.0), deaths from stroke increased by 43.0% (31.0-55.0), and DALYs due to stroke increased by 32.0% (22.0-42.0). During the same period, age-standardised rates of stroke incidence decreased by 17.0% (15.0-18.0), mortality decreased by 36.0% (31.0-42.0), prevalence decreased by 6.0% (5.0-7.0), and DALYs decreased by 36.0% (31.0-42.0). However, among people younger than 70 years, prevalence rates increased by 22.0% (21.0-24.0) and incidence rates increased by 15.0% (12.0-18.0). In 2019, the age-standardised stroke-related mortality rate was 3.6 (3.5-3.8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3.7 (3.5-3.9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62.4% of all incident strokes in 2019 (7.63 million 6.57-8.96]), while intracerebral haemorrhage constituted 27.9% (3.41 million 2.97-3.91]) and subarachnoid haemorrhage constituted 9.7% (1.18 million 1.01-1.39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79.6 million 67.7-90.8] DALYs or 55.5% 48.2-62.0] of total stroke DALYs), high body-mass index (34.9 million 22.3-48.6] DALYs or 24.3% 15.7-33.2]), high fasting plasma glucose (28.9 million 19.8-41.5] DALYs or 20.2% 13.8-29.1]), ambient particulate matter pollution (28.7 million 23.4-33.4] DALYs or 20.1% 16.6-23.0]), and smoking (25.3 million 22.6-28.2] DALYs or 17.6% 16.4-19.0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries

Global, regional, and national mortality among young people aged 10-24 years, 1950-2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Documentation of patterns and long-term trends in mortality in young people, which reflect huge changes in demographic and social determinants of adolescent health, enables identification of global investment priorities for this age group. We aimed to analyse data on the number of deaths, years of life lost, and mortality rates by sex and age group in people aged 10-24 years in 204 countries and territories from 1950 to 2019 by use of estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Methods We report trends in estimated total numbers of deaths and mortality rate per 100 000 population in young people aged 10-24 years by age group (10-14 years, 15-19 years, and 20-24 years) and sex in 204 countries and territories between 1950 and 2019 for all causes, and between 1980 and 2019 by cause of death. We analyse variation in outcomes by region, age group, and sex, and compare annual rate of change in mortality in young people aged 10-24 years with that in children aged 0-9 years from 1990 to 2019. We then analyse the association between mortality in people aged 10-24 years and socioeconomic development using the GBD Socio-demographic Index (SDI), a composite measure based on average national educational attainment in people older than 15 years, total fertility rate in people younger than 25 years, and income per capita. We assess the association between SDI and all-cause mortality in 2019, and analyse the ratio of observed to expected mortality by SDI using the most recent available data release (2017). Findings In 2019 there were 1.49 million deaths (95% uncertainty interval 1.39-1.59) worldwide in people aged 10-24 years, of which 61% occurred in males. 32.7% of all adolescent deaths were due to transport injuries, unintentional injuries, or interpersonal violence and conflict; 32.1% were due to communicable, nutritional, or maternal causes; 27.0% were due to non-communicable diseases; and 8.2% were due to self-harm. Since 1950, deaths in this age group decreased by 30.0% in females and 15.3% in males, and sex-based differences in mortality rate have widened in most regions of the world. Geographical variation has also increased, particularly in people aged 10-14 years. Since 1980, communicable and maternal causes of death have decreased sharply as a proportion of total deaths in most GBD super-regions, but remain some of the most common causes in sub-Saharan Africa and south Asia, where more than half of all adolescent deaths occur. Annual percentage decrease in all-cause mortality rate since 1990 in adolescents aged 15-19 years was 1.3% in males and 1.6% in females, almost half that of males aged 1-4 years (2.4%), and around a third less than in females aged 1-4 years (2.5%). The proportion of global deaths in people aged 0-24 years that occurred in people aged 10-24 years more than doubled between 1950 and 2019, from 9.5% to 21.6%. Interpretation Variation in adolescent mortality between countries and by sex is widening, driven by poor progress in reducing deaths in males and older adolescents. Improving global adolescent mortality will require action to address the specific vulnerabilities of this age group, which are being overlooked. Furthermore, indirect effects of the COVID-19 pandemic are likely to jeopardise efforts to improve health outcomes including mortality in young people aged 10-24 years. There is an urgent need to respond to the changing global burden of adolescent mortality, address inequities where they occur, and improve the availability and quality of primary mortality data in this age group. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd

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