Background Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. Methods GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. Findings The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6–47·0) in 1990 to 63·4 years (63·1–63·7) in 2023. For males, mean age increased from 45·4 years (45·1–45·7) to 61·2 years (60·7–61·6), and for females it increased from 48·5 years (48·1–48·8) to 65·9 years (65·5–66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9–81·0) and for males 74·8 years (74·8–74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5–38·4) for females and 35·6 years (35·2–35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. Interpretation We examined global mortality patterns over the past three decades, highlighting—with enhanced estimation methods—the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Funding Gates Foundation.

Background Antimicrobial resistance (AMR) is an urgent global crisis and one of the world's most complex challenges. Although there is increasing evidence of its impact on human mortality and morbidity, precise burden estimation has many challenges, and thus far has been elusive for the Eastern Mediterranean Region. Here, we present a comprehensive time-trend analysis of regional and country-level AMR burden estimates in the WHO Eastern Mediterranean Region (EMR), between 1990 and 2021, with forecasts up to 2050. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with AMR for 11 infectious syndromes, 22 bacterial pathogens, and 84 pathogen–drug combinations for the WHO EMR and each of its countries from 1990 to 2021. Data were obtained from mortality registries, surveillance systems, hospital records, systematic literature reviews, and other sources. We based our modelling approach on five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths and DALYs attributable to AMR (considering an alternative scenario where drug-resistant infections are replaced with susceptible infections), and deaths and DALYs associated with AMR (considering an alternative scenario where infections would not occur at all). Predictive statistical modelling was applied to generate estimates of AMR burden for each country. We also generated AMR burden forecasts up to 2050. We generated 95% uncertainty intervals (UIs) for the final estimates by taking the 2·5th and 97·5th percentiles across 500 draws through the multistage computational pipeline, and models were cross-validated for out-of-sample predictive validity. Findings We estimated 380 000 deaths (95% UI 332 000–426 000) associated with bacterial AMR and 92 800 deaths (78 300–111 000) attributable to bacterial AMR in the EMR in 2021. In the past 31 years, there was considerable variation in AMR mortality trends across countries of the region and different age groups. Between 1990 and 2021, associated deaths among children younger than 5 years decreased by 50·0% (38·2–62·0), while those among adults aged 70 and older rose by over 85·7% (95% UI 57·0–115·7). Six pathogens were identified as the primary generators of burden: Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter baumannii , and Pseudomonas aeruginosa . A substantial increase in the AMR burden due to S aureus was observed between 1990 (28 200 deaths [21 600–34 000]) and 2021 (49 500 deaths [43 100–56 200]); consequently, in 2021, methicillin-resistant S aureus was a leading pathogen–drug combination for most countries in the region for deaths and DALYs attributable to, and associated with AMR. Somalia had the highest age-standardised mortality rates in the region: for deaths attributable to and associated with AMR per 100 000 population in both 1990 and 2021; conversely, the country with the lowest burden in the EMR was Qatar. By 2050, the number of deaths attributable to AMR in region is forecasted to reach 187 000 (157 000–223 000) and deaths associated with AMR were projected to reach 752 000 (629 000–879 000). Interpretation Our study shows that bacterial AMR has been a serious public health threat in the EMR for more than 30 years, with a substantial fatal and non-fatal burden for priority bacterial pathogens and pathogen–drug combinations. The magnitude of this issue, future projects, and the inadequate response capacity in many countries underscore the need for more stringent regional leadership in this field. The insights gained from this study can direct targeted mitigation strategies for individual countries within the region, aiding in resource allocation and funding decisions, and emphasising the need for collaborative multisectoral endeavours among nations to address this issue. Funding Wellcome Trust, and the UK Department of Health and Social Care using aid funding managed by the Fleming Fund.