Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global, regional, and national progress towards Sustainable Development Goal 3.2 for neonatal and child health: all-cause and cause-specific mortality findings from the Global Burden of Disease Study 2019

Background Sustainable Development Goal 3.2 has targeted elimination of preventable child mortality, reduction of neonatal death to less than 12 per 1000 livebirths, and reduction of death of children younger than 5 years to less than 25 per 1000 livebirths, for each country by 2030. To understand current rates, recent trends, and potential trajectories of child mortality for the next decade, we present the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 findings for all-cause mortality and cause-specific mortality in children younger than 5 years of age, with multiple scenarios for child mortality in 2030 that include the consideration of potential effects of COVID-19, and a novel framework for quantifying optimal child survival. Methods We completed all-cause mortality and cause-specific mortality analyses from 204 countries and territories for detailed age groups separately, with aggregated mortality probabilities per 1000 livebirths computed for neonatal mortality rate (NMR) and under-5 mortality rate (USMR). Scenarios for 2030 represent different potential trajectories, notably including potential effects of the COVID-19 pandemic and the potential impact of improvements preferentially targeting neonatal survival. Optimal child survival metrics were developed by age, sex, and cause of death across all GBD location-years. The first metric is a global optimum and is based on the lowest observed mortality, and the second is a survival potential frontier that is based on stochastic frontier analysis of observed mortality and Healthcare Access and Quality Index. Findings Global U5MR decreased from 71.2 deaths per 1000 livebirths (95% uncertainty interval WI] 68.3-74-0) in 2000 to 37.1 (33.2-41.7) in 2019 while global NMR correspondingly declined more slowly from 28.0 deaths per 1000 live births (26.8-29-5) in 2000 to 17.9 (16.3-19-8) in 2019. In 2019,136 (67%) of 204 countries had a USMR at or below the SDG 3.2 threshold and 133 (65%) had an NMR at or below the SDG 3.2 threshold, and the reference scenario suggests that by 2030,154 (75%) of all countries could meet the U5MR targets, and 139 (68%) could meet the NMR targets. Deaths of children younger than 5 years totalled 9.65 million (95% UI 9.05-10.30) in 2000 and 5.05 million (4.27-6.02) in 2019, with the neonatal fraction of these deaths increasing from 39% (3.76 million 95% UI 3.53-4.021) in 2000 to 48% (2.42 million; 2.06-2.86) in 2019. NMR and U5MR were generally higher in males than in females, although there was no statistically significant difference at the global level. Neonatal disorders remained the leading cause of death in children younger than 5 years in 2019, followed by lower respiratory infections, diarrhoeal diseases, congenital birth defects, and malaria. The global optimum analysis suggests NMR could be reduced to as low as 0.80 (95% UI 0.71-0.86) deaths per 1000 livebirths and U5MR to 1.44 (95% UI 1-27-1.58) deaths per 1000 livebirths, and in 2019, there were as many as 1.87 million (95% UI 1-35-2.58; 37% 95% UI 32-43]) of 5.05 million more deaths of children younger than 5 years than the survival potential frontier. Interpretation Global child mortality declined by almost half between 2000 and 2019, but progress remains slower in neonates and 65 (32%) of 204 countries, mostly in sub-Saharan Africa and south Asia, are not on track to meet either SDG 3.2 target by 2030. Focused improvements in perinatal and newborn care, continued and expanded delivery of essential interventions such as vaccination and infection prevention, an enhanced focus on equity, continued focus on poverty reduction and education, and investment in strengthening health systems across the development spectrum have the potential to substantially improve USMR. Given the widespread effects of COVID-19, considerable effort will be required to maintain and accelerate progress. 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

Barrier Strengthening And Anti-Inflammatory Effect Of Cucurbit Fruits On Intestinal Epithelial Cells In-Vitro

Background: Acute and chronic infections and inflammations in the gut are highly prevalent in tropical and subtropical countries. Therapeutic measures like Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) often manifest toxic effects. Objective: Some herbal agents (cucurbit fruits) were investigated in-vitro for gut-barrier reinforcement and anti-inflammatory action. Methods: Zonula Occludens (ZO-1), mucin (MUC-2), cyclooxygenases (COX-1 and COX-2) expressions were estimated through ELISA kits. Nitric oxide (NO) was estimated through Griess reaction and adhesion of Lactobacillus rhamnosus (Lrh) to epithelial cells was evaluated microscopically. Results: TNF-α (10 ng/mL) induced inflammatory reaction in epithelial cells (HT-29 and Caco-2) by decreasing ZO-1 proteins. Cells pretreated with cucurbits, when challenged by TNF-α, countered the reduction of ZO-1 proteins, but pretreatment with indomethacin (NSAID) decreased the expression of ZO-1 further. Addition of Lrh to HT-29 cultures, enhanced mucin (MUC-2) production. Cucurbits alone did not enhance MUC-2 production in HT-29 cells but the addition of cucurbits to the combination of Lrh + HT-29 cells significantly increased MUC-2 production and adhesion of Lrh to epithelial cells. TNF-α and LPS treatment to Caco-2 cells increased COX-2 and NO production, but pretreatment with either cucurbits or indomethacin rendered their decrease. Pretreatment with indomethacin decreased COX-1 production in Caco-2 cells but pretreatment with cucurbits yielded enhanced COX-1 expression. Conclusion: This study revealed the potential of cucurbits as non-toxic anti-inflammatory and barrier strengthening agents against gut ailments

Radioprotective potential of Lagenaria siceraria extract against radiation induced gastrointestinal injury

The cucurbits (prebiotics) were investigated as novel agents for radio-modification against gastro-intestinal injury. The cell-cycle fractions and DNA damage were monitored in HCT-15 cells. A cucurbit extract was added to culture medium 2 h before irradiation (6 Gy) and was substituted by fresh medium 4 h post-irradiation. The whole extract of the fruits of Lagenaria siceraria (Ls), Luffa cylindrica (Lc) or Cucurbita pepo (Cp) extract enhanced G2 fractions (42 %, 34 % and 37 % respectively) as compared to control (20 %) and irradiated control (31 %). With cucurbits, the comet tail length remained shorter (Ls - 28 µm; Lc - 34.2 µm; Cp -36.75 µm) than irradiated control (41.75 µm). For in vivo studies, Ls extract (2mg/kg body wt.) was administered orally to mice 2 h before and 4 and 24 h after whole body irradiation (10 Gy). Ls treatment restored the GSH contents to 48.8 µmol/gm as compared to control (27.6 µmol/gm) and irradiated control (19.6 µmol/gm). Irradiation reduced the villi height from 379 to 350 µm and width from 54 to 27 µm. Ls administration countered the radiation effects (length - 366 and width - 30 µm respectively) and improved the villi morphology and tight junction integrity. This study reveals the therapeutic potential of cucurbits against radiation induced gastro-intestinal injury.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

An <em>in vitro</em> evaluation of <em>Tribulus terrestris</em> L. fruit extract for exploring therapeutic potential against certain gut ailments

430-436The enteric pathogens and oxidative stress are known to generate intestinal inflammation, chronic gut ailments and oncogenesis. Modulation of the gut microbial peak populations through herbal agents, offers a promising therapeutic modality. Tribulus terrestris Linn. (Tt), a widely documented medicinal herb in Ayurveda, was investigated for antioxidant, anti-inflammatory and antimicrobial activities in vitro. Fruit extract of Tt and quercetin, evaluated for free radical scavenging by DPPH method, revealed IC50 values as 98.83 and 24.77 µg/mL, respectively. Anti-inflammatory attributes of Tt fruit extract and indomethacin, a known anti-inflammatory drug, rendered IC50 values as 10.8 and 12.9 µg/mL against protein denaturation. MTT assay on HCT-15 cells revealed a decrease in viability from 78 to 22% against 30 and 70 µg/mL of Tt fruit extract, respectively. Zone of inhibition against E. coli increased from 0.19 to 9.82 cm2 at 200 and 1000 µg/mL of Tt, respectively. The fruit extract of Tt enhanced the growth of probiotic Lactobacillus rhamnosus (L.rh) by 19, 44 and 50 % over the control at 100, 150 and 200 µg/mL, respectively. This study indicated the potential of Tribulus terrestris fruit extract against inflammatory, oxidative and microbe generated pathogenic ailments in the digestive system

Evaluation of response in patients of metastatic castration resistant prostate cancer undergoing systemic radiotherapy with lutetium177-prostate-specific membrane antigen: A comparison between response evaluation criteria in solid tumors, positron-emission tomography response criteria in solid tumors, European organization for research and treatment of cancer, and MDA criteria assessed by gallium 68-prostate-specific membrane antigen positron-emission tomography-computed tomography

Introduction: We evaluated various morphological and molecular response criteria in metastatic castration-resistant prostate cancer (PCa) patient undergoing peptide receptor radioligand therapy (PRLT) with Lutetium177-prostate-specific membrane antigen (PSMA) by using Gallium 68-PSMA positron-emission tomography-computed tomography (Ga68-PSMA PET-CT). Methods: A total of 46 pre- and 8–12 weeks' post-PRLT Ga68-PSMA PET-CT studies were reanalyzed (23 comparisons). Prostate-specific antigen drop of ≥50% and ≥25% increase was considered as partial response (PR) and progressive disease (PD), respectively, for biochemical response (BR) while change in-between was considered as stable disease (SD). Response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson (MDA) criteria for morphological response while PET response criteria in solid tumors 1.0 (PERCIST 1.0) and European organization for research and treatment of cancer (EORTC) criteria for molecular response were used. Kappa coefficient was derived to see the level of agreement. Results: The proportion of PD, PR, and SD by BR and RECIST criteria was 9 (39.13%), 3 (13.04%), and 11 (47.83%) and 5 (21.74%), 2 (8.70%), and 16 (69.57%), respectively. The proportion of PD, PR, and SD was same by PERCIST and EORTC criteria and which were 8 (34.78%), 5 (21.74%), and 10 (43.48%). The proportion of PD, PR, and SD by MDA criteria was 1 (4.35%), 1 (4.35%), and 21 (91.30%), respectively. Poor agreement between BR and both morphological criteria while a statistically significant agreement with both molecular criteria seen. Conclusion: We concluded that molecular criteria performed better than morphological criteria in response assessment by Ga68-PSMA PET-CT in metastatic castration resistant PCa patients undergoing PRLT

Compositional and structural analysis of RF magnetron sputtered La3+-modified PZT thin films

In the present work, we report the preparation of lanthanum-modified lead zirconate titanate (PLZT) thin films in pure perovskite phase by RF magnetron sputtering. For this purpose, a 3-in. diameter target of PLZT (8/60/40) was prepared by conventional solid-state reaction route. The chemical composition of PLZT target was determined using gravimetric analysis followed by UV–vis and flame atomic absorption spectrometry. Various deposition parameters such as target-to-substrate spacing, deposition temperature, post-deposition annealing temperature and time have been optimized to obtain PLZT films in pure perovskite phase. The films prepared in pure argon at 100 W RF power without external substrate heating exhibited pure perovskite phase after rapid thermal annealing (RTA) as confirmed by X-ray diffraction (XRD). Compositional analysis of the PLZT film was performed by secondary ion mass spectroscopy (SIMS) using PLZT target as standard sample. Depth profile of the film shows very good stoichiometric uniformity of all elements of PLZT