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

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified. (c) 2012 Elsevier B.V. All rights reserved

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant α-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease