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

Differential regulation of central vasopressin receptors in transgenic rats with low brain angiotensinogen

The consequences of permanent alteration to the brain renin-angiotensin system (RAS) on central vasopressinergic system was studied in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Levels of vasopressin (AVP) and V1a receptor mRNAs were measured by ribonuclease protection assay (RPA) and AVP by radioimmunoassay (RIA). AVP (100 pmol/50nl) was microinjected into the nucleus tractus solitarii (NTS) of urethane-anesthetized TGR(ASrAOGEN) and Sprague-Dawley (SD) rats and the mean arterial pressure (MAP) and heart rate (HR) baroreflex induced by phenylephrine were evaluated. AVP but not its mRNA levels were significantly lower in the hypothalamus and hypophysis of TGR(ASrAOGEN) rats. Brainstem V1a mRNA levels were significantly higher in TGR(ASrAOGEN) in comparison to SD rats (5.2±0.4% vs. 3.3±0.2% of β-actin mRNA, P<0.05). In contrast, the hypothalamic V1a mRNA levels in TGR(ASrAOGEN) were not different from those found in SD rats. AVP microinjections induced a greater decrease in MAP in TGR(ASrAOGEN) in comparison with SD rats (-19.9±5.2 vs. -7.5±0.7 mm Hg, P<0.01). The significantly higher baroreflex sensitivity observed in TGR compared to that of SD rats was normalized after AVP microinjection. The increased brainstem V1a mRNA levels and sensitivity to AVP in TGR(ASrAOGEN) rats indicates a functional upregulation of AVP receptors in the NTS. The fact that the hypothalamic V1a mRNA levels are not altered indicates that these receptors are differentially regulated in different brain regions. This study demonstrates that a permanent deficit in brain angiotensinogen synthesis can alter the functionality of central vasopressinergic system

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein

Activation of the angiotensin (Ang) converting enzyme 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system induces protective mechanisms in different diseases.  Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein.  The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain.  Plasma Ang-(1-7) levels, measured by radioimmunoassay were similar to control SD rats, however high Ang-(1-7) levels were found in the hypothalamus.  TG7371 showed lower baseline mean arterial pressure, assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma ANP and higher urinary sodium concentration.  Evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decreased total peripheral resistance.  TG7371 rats also presented increased cardiac and global sympathetic tone, increased plasma AVP levels and decreased free water clearance.  Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance.  This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower BP.  Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions

Multiplicação in vitro e aclimatação de Vernonia condensata Baker In vitro multiplication and acclimation of Vernonia condensata Baker

A espécie medicinal Vernonia condensata, vulgarmente conhecida por alumã, pertencente à família Asteraceae, possui propriedades analgésicas e de proteção gástrica. A crescente utilização dessa planta no Nordeste, pelas propriedades terapêuticas, justifica a necessidade de medidas que minimizem o impacto de sua exploração nas reservas naturais. O objetivo desse trabalho foi multiplicar in vitro plantas de alumã sob diferentes concentrações de BAP e aclimatá-las. Gemas axilares foram desinfestadas em solução de álcool etílico 70%, durante 2 minutos e em solução de hipoclorito de sódio (2% de cloro ativo) na concentração de 3:1, durante 15 minutos, seguido de três lavagens em água destilada estéril. Os tratamentos para multiplicação consistiram em doses de BAP (0,0; 1,0; 2,0; 3,0; 4,0 e 5,0 mg L-1) em meio MS semi-sólido. O delineamento experimental foi o inteiramente casualizado, com 5 repetições, contendo 10 gemas por repetição. Após 30 dias de cultivo observou-se maior taxa de explantes responsivos, 84% na concentração de 1,0 mg L-1 de BAP, com produção de 4,0 brotos/explante. Nos tratamentos 3,0; 4,0 e 5,0 mg L-1 ocorreu hiperhidricidade nas folhas. As microplantas de alumã provenientes da metodologia utilizada neste trabalho alcançaram 100% de sobrevivência na aclimatação.<br>The medicinal species Vernonia condensata, commonly known as "alumã", belongs to the family Asteraceae and has analgesic and gastric protective properties. The increasing use of this plant in the Northeast of Brazil due to its therapeutic properties justifies the need of measures to minimize the impact of its exploitation in natural reserves. The aim of this study was to multiply, in vitro, "alumã" plants under different BAP levels, acclimating them. Axillary buds were sterilized in 70% (v/v) alcohol solution for 2 minutes and in 75% sodium hypochlorite solution (2% active chlorine) at 3:1 concentration for 15 minutes, followed by three washings in sterile distilled water. Multiplication treatments consisted of different BAP levels (0.0; 1.0; 2.0; 3.0; 4.0 and 5.0 mg L-1) in semi-solid MS medium. The experimental design was completely randomized, with 5 replicates and 10 buds per replicate. After 30 days of cultivation, the highest rate of responsive explants was obtained: 84% at 1.0 mg L-1 BAP, producing 4.0 sprouts/explant. In the treatments 3.0, 4.0 and 5.0 mg L-1, there were vitrified leaves. The "alumã" microplants used in this study had 100% survival in acclimation