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

The Modulatory Role of Vitamin C in Boldenone Undecylenate Induced Testicular Oxidative Damage and Androgen Receptor Dysregulation in Adult Male Rats

Background: This study explored the effect of vitamin C (Vit-C) administration on the reproductive function of adult male Wistar rats injected with boldenone undecylenate (BOL). Methods: Rats were randomly assigned into control, vehicle control, Vit-C (120 mg/kg b.wt./day, orally), BOL (received 5 mg/kg b.wt./week, IM) and BOL+Vit-C-treated groups. After eight weeks, hormonal assay, semen evaluation, testicular enzymes, and antioxidants biomarkers were assessed. Besides, the histopathological and immunohistochemical investigations of the androgen receptor (AR) expression were performed. Results: The results revealed that serum testosterone, acid phosphatase, sorbitol dehydrogenase, sperm abnormalities, and testicular malondialdehyde were significantly incremented in the BOL-treated group. Testicular weight, sperm count, and sperm motility together with serum levels of luteinizing hormone, follicle-stimulating hormone, and estradiol, and testicular testosterone, catalase, superoxide dismutase, and reduced glutathione showed a significant decrease following BOL treatment. Besides, the AR immunoreactivity was significantly decreased in testicular tissues. Vit-C co-administration with BOL significantly relieved the BOL-induced sperm abnormalities, reduced sperm motility, testicular enzyme leakage, and oxidative damage. However, Vit-C could rescue neither BOL-induced hormonal disturbances nor AR down-regulation. Conclusions: The results provide further insight into the mechanisms of BOL-induced reproductive dysfunction and its partial recovery by Vit-C

Effect of Dietary Modulation of Selenium Form and Level on Performance, Tissue Retention, Quality of Frozen Stored Meat and Gene Expression of Antioxidant Status in Ross Broiler Chickens

This study compares between different selenium forms (sodium selenite; SeS, selenomethionine; Met-Se or nano-Se) and levels on growth performance, Se retention, antioxidative potential of fresh and frozen meat, and genes related to oxidative stress in Ross broilers. Birds (n = 450) were randomly divided into nine experimental groups with five replicates in each and were fed diets supplemented with 0.3, 0.45, and 0.6 mg Se/kg as (SeS, Met-Se), or nano-Se. For overall growth performance, dietary inclusion of Met-Se or nano-Se significantly increased (p < 0.05) body weight gain and improved the feed conversion ratio of Ross broiler chicks at the level of 0.45 and 0.6 mg/kg when compared with the group fed the same level of SeS. Se sources and levels significantly affected (p < 0.05) its concentrations in breast muscle, liver, and serum. Moreover, Se retention in muscle was higher (p < 0.05) after feeding of broiler chicks on a diet supplemented with Met-Se or nano-Se compared to the SeS group, especially at 0.6 mg/kg. Additionally, higher dietary levels from Met-Se or nano-Se significantly reduced oxidative changes in breast and thigh meat in the fresh state and after a four-week storage period and increased muscular pH after 24 h of slaughter. Also, broiler’s meat in the Met-Se and nano-Se groups showed cooking loss and lower drip compared to the SeS group (p < 0.05). In the liver, the mRNA expression levels of glutathione peroxidase, superoxide dismutase, and catalase were elevated by increasing dietary Se levels from Met-Se and nano-Se groups up to 0.6 mg/kg when compared with SeS. Therefore, dietary supplementation with 0.6 mg/kg Met-Se and nano-Se improved growth performance and were more efficiently retained than with SeS. Both sources of selenium (Met-Se and nano-Se) downregulated the oxidation processes of meat during the first four weeks of frozen storage, especially in thigh meat, compared with an inorganic source. Finally, dietary supplementation of Met-Se and nano-Se produced acceptable Se levels in chicken meat offered for consumers

The Effect of Dietary Replacement of Fish Meal with Whey Protein Concentrate on the Growth Performance, Fish Health, and Immune Status of Nile Tilapia Fingerlings, Oreochromis niloticus

The present study was conducted to assess the effect of replacing fish meal with whey protein concentrate (WPC) on the growth performance, histopathological condition of organs, economic efficiency, disease resistance to intraperitoneal inoculation of Aeromonas hydrophila, and the immune response of Oreochromis niloticus. The toxicity of WPC was tested by measuring the activity of caspase 3 as an indicator of cellular apoptosis. Oreochromis niloticus fingerlings with average initial weight 18.65 ± 0.05 gm/fish (n = 225) for a 10-week feeding trial. The fish were randomly allocated to five experimental groups, having five replacement percentages of fish meal with WPC: 0%, 13.8%, 27.7%, 41.6%, and 55.5% (WPC0, WPC13.8, WPC27.7, WPC41.6, and WPC55.5); zero percentage represented the control group. The results show that the fish fed WPC had the same growth performance as the WPC0. The total weight of bacterially challenged surviving fish increased linearly and quadratically (p ≤ 0.05) by increasing the replacement percentage of fish meal with WPC. The growth hormone, nitric oxide, IgM, complement 3, and lysozyme activity were seen to increase significantly in WPC27.7, especially after a bacterial challenge. The phagocytic percentage and phagocytic index increased significantly in WPC27.7, WPC41.6, and WPC55.5 groups. Histopathological examination of liver sections was badly affected by high replacement in WPC41.6–55.5. The activity of caspase 3 in the immunohistochemical stained sections of the intestine was increased significantly by increasing the inclusion level of WPC. Economically, the total return of the total surviving fish after the bacterial challenge was increased significantly by fish meal replacement with WPC. It could be concluded that WPC could replace the fish meal in Nile tilapia diets up to 27.7%, with improving the gut health, the total weight of survival fish, and immune status of fish challenged with A. hydrophila. High inclusion levels of WPC are not recommended in fish diets, since they negatively affected the intestinal and liver tissues and increased the level of cellular apoptosis, as indicated by the increased caspase 3 activity. Further researches are recommended to evaluate the effect of fish meal replacement with WPC on the histopathological examination of the kidney and to test the capacity of serum IgM to clot the bacteria used for the challenge

Potential use of cowpea protein hydrolysate as a dietary supplement in broiler chickens: effects on growth, intestinal morphology, muscle lipid profile, and immune status

In the current study, we tested the effects of dietary cowpea protein hydrolysate (CPH) on broilers’ growth, carcase traits, intestinal histomorphology, The fatty acid profile of breast muscle, blood biochemical parameters, and immune status. Three-day age male Ross-308 broilers (n = 300, average weight 86.72 g ± 0.20) were distributed into five groups and fed on five diets supplied with five levels of CPH at 0, 2, 4, 6, and 8 g kg−1 for 35 days. The results revealed that dietary CPH did not change (P  0.05) changes in response to dietary CPH. Moreover, the dietary CPH levels 4–8 g kg−1 upregulated the immunostaining of IgG in the spleen of these groups. These findings suggested that including CPH in broiler diets could be an effective candidate for modulating the chickens’ metabolic and immune status; however, it had no increased effect on broiler growth

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially