Approaches to control the COVID-19 pandemic

Tese de Mestrado, Biologia Humana e Ambiente, 2021, Universidade de Lisboa, Faculdade de CiênciasO coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2), é o agente patogénico responsável pela COVID-19 (do inglês coronavírus disease 2019), a pandemia que já causou mais de 250 milhões de infecções e 5 milhões de mortes em todo o mundo. O SARS-CoV-2 foi detectado e identificado pela primeira vez na cidade de Wuhan, na China, nos finais de 2019. Devido à sua rápida disseminação em vários países, a Organização Mundial de Saúde (OMS) declarou a COVID-19 como Emergência de Saúde Pública de Interesse Internacional (ESPII) e pandemia a 30 de Janeiro e 11 de Março de 2020, respetivamente. Esta dissertação de mestrado foi elaborada no âmbito de dois projetos que exploraram questões pertinentes e metodologias cruciais para o controlo da atual pandemia. O primeiro projecto teve como principal objectivo determinar a capacidade de anticorpos gerados em resposta à infecção pelo SARS CoV-2 em neutralizar as variantes do vírus. A evolução do novo coronavírus tem sido marcada pelo aparecimento de diversas ariantes, em diferentes países, alguns com rápida disseminação pelo mundo, o que provocou sérias preocupações no seio da comunidade científica internacional devido ao seu potencial de maior transmissibilidade, evasão ao sistema imunitário e severidade da doença relativamente ao vírus original. Como consequência, a OMS classificou quatro dessas variantes como variantes de preocupação (variants of concern - VOCs): Alfa, Beta, Gama e Delta, detectadas pela primeira vez no Reino Unido, África do Sul, Brasil e Índia, respectivamente. Estas variantes possuem e partilham várias mutações na proteína espícula (spike), a proteína responsável pela entrada do vírus nas células (através da ligação ao receptor celular, a enzima conversora da angiotensina 2, conhecida como ACE2) e reconhecimento por anticorpos, sendo por isso o principal alvo das vacinas contra a COVID-19. A monitorização das VOCs e das suas mutações, bem como a compreensão dos mecanismos que conferem ao vírus resistência à acção dos anticorpos neutralizantes gerados por infecção natural e pela vacinação é crucial para a gestão e controlo da pandemia. Neste sentido, foram feitos ensaios de neutralização in vitro, com soro de pacientes recuperados da COVID-19, de partículas pseudovirais que expressam a proteína spike contendo diferentes combinações das mutações mais prevalentes e reportadas nas VOCs Alfa, Beta e Gama, assim como da variante Kappa, que partilha a mesma linhagem com a variante Delta. Através desta análise pode observar-se que os pseudovírus contendo as mutações das variantes Beta e Gama diminuíram significativamente a capacidade dos anticorpos de neutralizarem a sua entrada nas células comparativamente aos pseudovírus da variante Alfa e da variante selvagem (wild type, WT), confirmando resultados descritos na literatura. Foram também confirmadas e identificadas duas mutações (E484K e S494P) no domínio de ligação da proteína spike ao receptor (receptor binding domain, RBD), capazes de reduzir a capacidade neutralizante dos anticorpos. Observou-se uma diminuição ainda mais acentuada da capacidade neutralizante quando estas mutações foram complementadas com as mutações K417N e N501Y, conhecidas por aumentar a afinidade ao receptor celular ACE2. Este efeito aditivo sugere a existência de interacções sinérgicas entre mutações, não só pela regulação da ligação de anticorpos, como também da capacidade de entrada do vírus. O ensaio de neutralização com pseudovírus descrito neste projecto é um ensaio de alto rendimento e adequado para experiências em contexto de Laboratórios de Biossegurança de Nível 2 (BSL-2), útil para a monitorização continuada da evolução das variantes do SARS-CoV-2, mas que também pode ser usado para o estudo de outros vírus altamente patogénicos num contexto envolvendo menos riscos biológicos. No segundo projecto avaliaram-se metodologias alternativas de diagnóstico da infecção pelo SARS-CoV-2, tendo como principal objectivo determinar a sensibilidade analítica da testagem molecular portranscrição reversa do RNA viral seguida de reacção em cadeia da polimerase quantitativa (Reverse Transcription – quantitative Polymerase Chain Reaction, RT-qPCR) do SARS-CoV-2, usando a saliva de uma população pediátrica. O método de diagnóstico padrão para a COVID-19 é a detecção do RNA viral por RT-qPCR em amostras do tracto respiratório superior. As zaragatoas oro e nasofaríngeas são as amostras biológicas de eleição para a detecção do SARS-CoV-2, no entanto a sua colheita é invasiva para crianças, envolvendo riscos acrescidos de biossegurança. A saliva tem sido apontada como uma amostra alternativa em vários estudos, e que poderá ter um grande potencial na testagem e monitorização de crianças, principalmente em contexto escolar. A campanha global de vacinação contra a COVID-19 é uma das estratégias mais promissoras para o controlo e erradicação da atual pandemia. No entanto as crianças abaixo dos 12 anos ainda não são um grupo elegível para a vacinação, o que suscita questões relativamente ao seu papel na transmissão do SARS-CoV-2 e das suas variantes. Apesar da maioria não apresentar sintomas clínicos da doença, são susceptíveis à infecção podendo transmitir o vírus para a comunidade. Neste sentido, metodologias de testagem que sejam facilmente implementadas e não invasivas são cruciais para identificar, conter e controlar os casos de infecção na população pediátrica. Para tal, validou-se o método de testagem molecular do SARS-CoV-2 usando a saliva de uma população adulta hospitalizada, simptomática para a COVID-19 e com amostras emparelhadas de zaragatoa nasofaríngea. Uma vez validado o método, este foi aplicado numa população pediátrica de 85 crianças com idade até 10 anos, tendo sido avaliados dois protocolos: com e sem extracção de RNA viral. Nos adultos, a sensibilidade do teste foi de 100%, tendo sido identificados eficientemente todos os casos de COVID-19, quer no protocolo com extracção, quer no protocolo sem extracção de RNA. Ainda na análise referente aos adultos, obteve-se uma exatidão do método de 98.0% para o protocolo com extracção e 97.9% para o protocolo sem extracção. Nas crianças, quando se comparam os resultados da saliva com os da zaragatoa nasofaríngea, obtiveram-se valores de sensibilidade, especificidade e exatidão de 84.8%, 100% e 91.8%, respectivamente, no protocolo em que se procedeu à extracção de RNA. Relativamente ao protocolo sem extracção de RNA, os mesmos parâmetros foram de 81.8%, 100% e 90.4%. Estes resultados indicam que o método é eficiente em diagnosticar casos de infecções activas do SARS-CoV-2 em crianças até 10 anos. O método revelou-se igualmente eficaz no protocolo em que não se procedeu à extracção de RNA, o que pode ser extremamente vantajoso em contextos com limitações de recursos. A aplicação deste método, bem como a complementaridade com outros testes como os testes de antigénio depende do contexto, recursos e situação epidemiológica de cada região/país. Neste sentido, a saliva surge como uma amostra promissora na monitorização da população e crianças em contexto escolar. Em suma, os dois projectos desenvolvidos nesta dissertação permitiram gerar conhecimento e desenvolver metodologias cruciais no contexto da pandemia da COVID-19. Por ainda ser um problema de saúde pública e ter ainda muitas questões em aberto, as abordagens deste trabalho são pertinentes para o futuro.The novel human coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic that, to date, resulted in ~250 million infections and over 5 million fatalities. Despite prevention measures and vaccination efforts, the virus remains a public health concern with many outstanding questions related to viral control, evolution, disease understanding and therapy development. We explored two approaches in this study for providing knowledge and tools to better respond to the pandemic. First, we engineered spike-pseudotyped particles to analyse how single and multiple mutations in the spike protein of the different SARS-CoV-2 variants of concern impaired the neutralizing potential of antibodies elicited by natural infection. Pseudoviruses with Alpha (UK) variant and WT spike were efficiently neutralized by convalescent sera antibodies, but those mimicking mutations in Beta (SA) and Gamma (Brazil) variants escaped neutralization significantly. We identified mutations (E484K and S494P) in the receptor-binding domain (RBD) of spike that reduced antibody neutralizing capacity and, when combined with mutations known to increase receptor binding (K417N and N501Y), exacerbated host immune escape. The second project involved using easier, cheaper, but sensitive diagnostic methods for detecting infected people to substitute nasopharyngeal (NP) swabs. We implemented an 98% accurate saliva molecular testing method in adults and asked whether the method was suitable for children up to 10 years old. In children, the sensitivity, specificity, and accuracy were, respectively, 84.8%, 100%, and 91.8% for a protocol with RNA extraction, and 81.8%, 100%, and 90.4% for a protocol without. Thus, saliva molecular testing is suitable to diagnose SARS-CoV-2 infected children up to 10-years-old, even bypassing RNA extraction. In summary, the two projects generated critical tools addressing scientific questions regarding immunity and diagnostic. As SARS-CoV-2 is still a public health challenge with many unanswered questions, the tools developed in this study are pertinent for the future

VIII Encuentro de Docentes e Investigadores en Historia del Diseño, la Arquitectura y la Ciudad

Acta de congresoLa conmemoración de los cien años de la Reforma Universitaria de 1918 se presentó como una ocasión propicia para debatir el rol de la historia, la teoría y la crítica en la formación y en la práctica profesional de diseñadores, arquitectos y urbanistas. En ese marco el VIII Encuentro de Docentes e Investigadores en Historia del Diseño, la Arquitectura y la Ciudad constituyó un espacio de intercambio y reflexión cuya realización ha sido posible gracias a la colaboración entre Facultades de Arquitectura, Urbanismo y Diseño de la Universidad Nacional y la Facultad de Arquitectura de la Universidad Católica de Córdoba, contando además con la activa participación de mayoría de las Facultades, Centros e Institutos de Historia de la Arquitectura del país y la región. Orientado en su convocatoria tanto a docentes como a estudiantes de Arquitectura y Diseño Industrial de todos los niveles de la FAUD-UNC promovió el debate de ideas a partir de experiencias concretas en instancias tales como mesas temáticas de carácter interdisciplinario, que adoptaron la modalidad de presentación de ponencias, entre otras actividades. En el ámbito de VIII Encuentro, desarrollado en la sede Ciudad Universitaria de Córdoba, se desplegaron numerosas posiciones sobre la enseñanza, la investigación y la formación en historia, teoría y crítica del diseño, la arquitectura y la ciudad; sumándose el aporte realizado a través de sus respectivas conferencias de Ana Clarisa Agüero, Bibiana Cicutti, Fernando Aliata y Alberto Petrina. El conjunto de ponencias que se publican en este Repositorio de la UNC son el resultado de dos intensas jornadas de exposiciones, cuyos contenidos han posibilitado actualizar viejos dilemas y promover nuevos debates. El evento recibió el apoyo de las autoridades de la FAUD-UNC, en especial de la Secretaría de Investigación y de la Biblioteca de nuestra casa, como así también de la Facultad de Arquitectura de la UCC; va para todos ellos un especial agradecimiento

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

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research

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

BackgroundRegular, 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.MethodsThe 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.FindingsThe 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.InterpretationLong-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