Impact of the parasitic helminth Schistosoma mansoni on host anti-viral vaccine responses: proof of concept from the anti-polio vaccine

Schistosomiasis is a devastating and neglected tropical disease caused by Schistosoma spp. parasites. The disease remains greatly neglected by global health control programmes thus classified as a top neglected tropical disease of humankind. One of the most common species of these parasites, Schistosoma mansoni, causes hepatosplenic schistosomiasis and distributes widely in sub-Saharan Africa. Schistosoma mansoni is physiologically debilitating and potentially deadly with a known potential as a master regulator of the host immune responses. However, the mechanistic bases and the scope of this immunoregulatory potential of S. mansoni still remain poorly understood. This study explored the influence of S. mansoni-driven schistosomiasis on vaccine-induced memory immunity in schoolchildren from a rural endemic area of Cameroon and in laboratory mice. As a proof of concept, a well-established anti-viral vaccination programme with wide global coverage, i.e., anti-polio vaccination, was evaluated for its sustainability in the face of schistosomiasis in human and mouse hosts. Our findings using the poliovirus specific enzyme-linked immunosorbent assay revealed a schistosomiasis-associated impairment of polio specific serologic antibody memory responses in previously vaccinated schoolchildren and mice, as judged by significantly reduced serum anti-polio IgG antibody levels. To explore our findings further, cellular evaluations were conducted using flow cytometry in mouse modes of vaccination and schistosomiasis. The reduction of anti-polio elicited antibody responses was paralleled by the general depletion, through reduced survival and increased cell death, of bone marrow plasma cells and plasma blasts in schistosomiasis-diseased mice. Notably, schistosomiasis reduced memory T cell responses as well in vaccinated hosts and considerably impaired the expression of survival markers on antibody-producing long term plasma cells in the bone marrow. When attempting to control the disease by administration of the sole commercially available drug for schistosomiasis control, praziquantel, the parasite-driven depletion of the plasma cell and memory T cell compartment was restored followed by a partial recovery of antibody-producing abilities in vaccinated hosts. Taken together, our findings unprecedentedly demonstrate how schistosomiasis might negatively influence the efficacy and potentially the effectiveness of anti-viral vaccine memory immunity. Additionally, we present findings on how strategic therapeutic interventions against schistosomiasis might positively influence vaccine-elicited anti-viral immunity in schistosomiasis-diseased hosts. Our results have robust implications for future more informed deployment of effective vaccination campaigns, beyond the sole consideration of coverage and encourage frequent mass drug administration of praziquantel in schistosomiasis-endemic areas to ensure the sustainability of vaccine elicited responses thus protection of the hosts against vaccine preventable diseases

The Practicality of the Use of Liquid Biopsy in Early Diagnosis and Treatment Monitoring of Oral Cancer in Resource-Limited Settings

An important driving force for precision and individualized medicine is the provision of tailor-made care for patients on an individual basis, in accordance with best evidence practice. Liquid biopsy(LB) has emerged as a critical tool for the early diagnosis of cancer and for treatment monitoring, but its clinical utility for oral squamous cell carcinoma (OSCC) requires more research and validation. Hence, in this review, we have discussed the current applications of LB and the practicality of its routine use in Africa; the potential advantages of LB over the conventional “gold-standard” of tissue biopsy; and finally, practical considerations were discussed in three parts: pre-analytic, analytic processing, and the statistical quality and postprocessing phases. Although it is imperative to establish clinically validated and standardized working guidelines for various aspects of LB sample collection, processing, and analysis for optimal and reliable use, manpower and technological infrastructures may also be an important factor to consider for the routine clinical application of LB for OSCC. LB is poised as a non-invasive precision tool for personalized oral cancer medicine, particularly for OSCC in Africa, when fully embraced. The promising application of different LB approaches using various downstream analyses such as released circulating tumor cells (CTCs), cell free DNA (cfDNA), microRNA (miRNA), messenger RNA (mRNA), and salivary exosomes were discussed. A better understanding of the diagnostic and therapeutic biomarkers of OSCC, using LB applications, would significantly reduce the cost, provide an opportunity for prompt detection and early treatment, and a method to adequately monitor the effectiveness of the therapy for OSCC, which typically presents with ominous prognosis

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

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

Investigating the use of standardized EuroFlow flow cytometry panels for the characterisation and diagnosis of Chronic lymphocytic leukaemia in the Tygerberg Academic Hospital, South Africa.

Thesis (MScMedSc)--Stellenbosch University, 2017ENGLISH ABSTRACT : Background: Flow cytometry (FC) immunophenotyping is crucial in the diagnosis and classification standardisation of haematological malignancies. FC techniques require standardisation to produce reliable and reproducible results which are important in inter-laboratory studies for laboratory methodology improvement. The aim of this study is to introduce standardised multicolour FC in the diagnosis of haematological malignancies using chronic lymphocytic leukaemia (CLL) as the proof of principle. In addition, we aim to document the incidence of CLL from the year 2011 to 2016 in the Tygerberg Academic Hospital (TAH) catchment area of Cape Town, South Africa (SA). Methods: Twenty CLL patients were recruited at TAH. Bio-specimens were prepared and analysed on the Beckman Coulter Navios flow cytometer using Euroflow™ standardised FC protocols and immunophenotypic panels with two tubes for detecting B-cell chronic lymphoproliferative disorders (B-CLPD). Tube 1 included CD20, CD4, CD45, CD8, lg-Kappa, CD56, lg-Lambda, CD5, CD19, TCRyσ, CD3 and CD38. Tube 2 included CD20, CD45, CD23, CD10, CD79b, CD19, CD200 and CD43. Combined, the two tubes identified CLL from other B-CLPD. The CLL immunophenotypic profiles were stored in a database using the compass tool of the Infinicyt™ FC software. In addition, the clinical records of patients diagnosed with CLL at TAH over a 6-year period from the year 2011 to 2016 were retrieved and analysed using descriptive statistics. Results: In comparison with the SA National Health Laboratory Service (NHLS) results at TAH, the Euroflow™ standardised multicolour FC panels and protocols are suitable for immunophenotyping CLL in this SA population. An immunophenotype database for 20 CLL diagnosed at TAH was constructed using the EuroFlow™ standardised multicolour FC panels. For the epidemiology part of the study, a total of 80 CLL patients were studied. There were slightly more females (51.2%) and the mean age at diagnosis was 67 years (37 to 95). Ninety one percent of the patients were aged 50 years and above. Males presented with the disease at a younger age (mean 63 years) than females (mean 70 years). CLL concurrent with HIV was not common (4%) and these patients were younger than 50 years. Twenty-one patients were tested for chromosomal aberrations trisomy 12 and deletion 11q, 24% and 33% were positive respectively. Deletion 13q was assessed in 25 patients and 16% were positive. Twenty patients were tested for deletion 17p and all were negative. Translocations t(8;14), t(11;14) and t (14;18) were negative in 1, 8 and 4 patients respective. Discussion: Accurate and consistent laboratory techniques and strict standardisation in FC enhances the confidence in inter-laboratory studies. Establishment of haematological malignancy immunophenotype databases would allow for faster differential diagnoses of new disease cases which is needed within our setting. Furthermore, these databases permit clear identification of atypical cases. Monitoring haematological malignancy trends is a crucial step in the management of the disease.AFRIKAANSE OPSOMMING : Agtergrond: Vloeisitometrie (FC) immunofenotipering is van kardinale belang in die diagnose en standaardisering van hematologiese kwaardaardighede/maligniteite. Die FC tegnieke vereis ten einde betroubare en herhaalbale resultate wat belangrik is in inter-laboratorium studies vir die verbetering van laboratorium metodiek. Die doel van hierdie studie was om gestandaardiseerde multi FC in die diagnose van hematologiese maligniteite te gebruik met chroniese limfositiese leukemie (CLL) as bewys van beginsel. Daarbenewens, streef ons daarna om die voorkoms van CLL te dokumenteer in die tydperk van 2011 tot 2016 in die Tygerberg Akademiese Hospitaal (TAH) opvanggebied van Kaapstad, Suid-Afrika (SA). Metodes: Twintig CLL pasiënte was gewerf by TAH. Bio-monsters is voorberei en ontleed op die Beckman Coulter Navios vloeisitometer met behulp van Euroflow™ gestandaardiseerde FC protokolle en immunofenotipe panele met twee buise, vir die opsporing van B-sel chroniese limfoproliferatiewe versteurings (B-CLPD). Buis 1 het CD20, CD4, CD45, CD8, LG-Kappa, CD56, LG-Lambda, CD5, CD19, TCRyσ, CD3 en CD38 bevat. Buis 2 het CD20, CD45, CD23, CD10, CD79b, CD19, CD200 and CD43 bevat. In kombinasie het die twee buise CLL van ander B-CLPD onderskei. Die CLL immunofenotipe profiele is gestoor in 'n databasis met behulp van die kompas instrument (“compas tool”) van die Infinicyt™ FC sagteware. Daarbenewens was die kliniese rekords van pasiënte gediagnoseer met CLL by TAH, oor 'n tydperk van 5 jaar vanaf die jaar 2011-2016, opgespoor en ontleed met behulp van beskrywende statistiek. Resultate: In vergelyking met die SA Nasionale Gesondheids Laboratoriumdienste (National Haleth Laboratory Services - NHLS) resultate by TAH, is die Euroflow™ gestandaardiseerde multi FC paneel en protokolle geskik vir die immunofenotipering van CLL in die SA bevolking. 'n Immunofenotipe databasis vir 20 CLL gevalle, gediagnoseer by TAH, is gebou met behulp van die EuroFlow™ gestandaardiseerde multi FC paneel. Vir die epidemiologiese deel van hierdie studie is 'n totaal van 80 CLL pasiënte bestudeer. Daar was effens meer vroue (51,2%) en die gemiddelde ouderdom by diagnose was 67 jaar (37-95). Een en negentig persent van die pasiënte was 50 jaar en ouer. Mans het die siekte vertoon op 'n vroeër ouderdom (gemiddeld 63 jaar) as vroue (gemiddeld 70 jaar). CLL tesame met MIV was nie algemeen nie (4%) en hierdie pasiënte was jonger as 50 jaar. Een en twintig pasiënte wat getoets was vir chromosoomafwyking, trisomie 12, en verwydering van 11q, was onderskeidelik 24% en 33% positief. Verwydering van 13q is getoets in 25 pasiënte en 16% was positief. Twintig pasiënte was getoets vir verwydering 17p en almal was negatief. Translokasies t (8; 14), t (11; 14) en t (14; 18) was negatief in 1, 8 en 4 pasiënte, onderskeidelik. Bespreking: Akkurate, konsekwente laboratoriumtegnieke en streng standaardisering in FC verhoog die vertroue in inter-laboratorium studies. Die vestiging van immunofenotipe databasisse vir hematologiese maligniteite sal lei tot vinniger differensiële diagnose van nuwe siekte gevalle wat nodig is in ons omgewing. Verder sal hierdie databasisse die duidelike identifisering van atipiese gevalle toelaat. Die monitering van hematologiese maligniteit tendense is 'n belangrike stap in die bestuur van die siektes. (4%) en hierdie pasiënte was jonger as 50 jaar. Een en twintig pasiënte wat getoets was vir chromosoomafwyking, trisomie 12, en verwydering van 11q, was onderskeidelik 24% en 33% positief. Verwydering van 13q is getoets in 25 pasiënte en 16% was positief. Twintig pasiënte was getoets vir verwydering 17p en almal was negatief. Translokasies t (8; 14), t (11; 14) en t (14; 18) was negatief in 1, 8 en 4 pasiënte, onderskeidelik. Bespreking: Akkurate, konsekwente laboratoriumtegnieke en streng standaardisering in FC verhoog die vertroue in inter-laboratorium studies. Die vestiging van immunofenotipe databasisse vir hematologiese maligniteite sal lei tot vinniger differensiële diagnose van nuwe siekte gevalle wat nodig is in ons omgewing. Verder sal hierdie databasisse die duidelike identifisering van atipiese gevalle toelaat. Die monitering van hematologiese maligniteit tendense is 'n belangrike stap in die bestuur van die siektes

Immunoinformatics Studies and Design of a Potential Multi-Epitope Peptide Vaccine to Combat the Fatal Visceral Leishmaniasis

Leishmaniasis is a neglected tropical disease caused by parasitic intracellular protozoa of the genus Leishmania. The visceral form of this disease caused by Leishmania donovani continues to constitute a major public health crisis, especially in countries of endemicity. In some cases, it is asymptomatic and comes with acute and chronic clinical outcomes such as weight loss, pancytopenia, hepatosplenomegaly, and death if left untreated. Over the years, the treatment of VL has relied solely on chemotherapeutic agents, but unfortunately, these drugs are now faced with challenges. Despite all efforts, no successful vaccine has been approved for VL. This could be as a result of limited knowledge/understanding of the immune mechanisms necessary to regulate parasite growth. Using a computational approach, this study explored the prospect of harnessing the properties of a disulfide isomerase protein of L. donovani amastigotses to develop a multi-epitope subunit vaccine candidate against the parasite. We designed a 248-amino acid multi-epitope vaccine with a predicted antigenicity probability of 0.897372. Analyses of immunogenicity, allergenicity, and multiple physiochemical parameters indicated that the constructed vaccine candidate was stable, non-allergenic, and immunogenic, making it compatible with humans and hence, a potentially viable and safe vaccine candidate against Leishmania spp. Parasites

Global, regional, and national incidence of six major immune-mediated inflammatory diseases: findings from the global burden of disease study 2019Research in context

Summary: Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38)

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

BackgroundEstimates 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.Methods22 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.FindingsGlobal 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.InterpretationGlobal 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 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