Exploring the linkage between root system architecture and grain iron content in wheat (Triticum aestivum L.)

Iron (Fe) is a vital element that is equally important for plants, animals, and humans. High Fe concentrations in wheat grains have reliance on plant roots, the hidden half of the plant with a role in nutrient mining. Enhanced grain Fe content of wheat can positively mitigate Fe malnutrition in poor populations. In the present study, 100 wheat varieties were studied to identify the root architectural characteristics in relation to grain Fe concentration. Germinated seeds were transplanted in a rhizobox kept in a standard nutrient solution and were harvested 12 days after transplanting. Roots were scanned and the images were processed using smart root software. A total of 12 wheat varieties, which had a vigorous and weak root system architecture (RSA), in combination with higher and lower Fe grain concentrations, were selected using principal component analysis. The uptake and translocation of Fe from root to shoot were determined through a pot experiment conducted for the above-mentioned 12 wheat varieties, with or without Fe fertilizer applied as FeSO4 to the soil. The data obtained from the pot experiment revealed that Dharabi-11 with vigorous RSA exhibited the highest grain Fe concentration (57.20 mg kg−1), low phytate concentration (6.50 mg kg−1), and maximum 1,000 grain weight, whereas Ujala-16 with weaker RSA had the lowest grain Fe concentration (13.33 mg kg−1), highest phytate concentration (9.07 mg kg−1), and lowest 1,000 grain weight. There were also varieties showing higher grain Fe concentrations with weaker RSA and vice versa. Although it is indicated that vigorous RSA leads to high grain Fe concentration, it is not the sole factor in high grain Fe concentration. Nevertheless, the results demonstrate that large genetic diversity is available among indigenous wheat germplasm in terms of grain Fe concentration and RSA. This information may be utilized in the development of new varieties through conventional and marker-assisted breeding programs using RSA traits for Fe biofortification in wheat, leading to the mitigation of Fe malnutrition

Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females

Background Use of supplements to aid performance is common practice amongst recreationally active individuals, including those without a sufficient evidence base. This investigation sought to assess whether acute supplementation with 8 g of citrulline malate (CM) (1.11: 1 ratio) would improve anaerobic performance. Methods A randomised double blind placebo control trial was employed, using a counterbalanced design. We recruited recreationally active men and women to take part in an isokinetic chair protocol, based on German Volume Training (GVT) whereby participants attempted to perform 10 sets of 10 repetitions against a force representing 70% of their peak concentric force. Results The number of repetitions achieved over the course of the GVT was 94.0 ± 7.9 and 90.9 ± 13.9 for placebo and CM respectively. There was no significant difference between the placebo and CM treatment for number of repetitions (P = 0.33), isometric (P = 0.60), concentric (P = 0.38), or eccentric (P = 0.65) peak force following the GVT. Total muscle soreness was significantly higher in the CM compared to the placebo treatment following the GVT protocol over 72 h (P = 0.01); although this was not accompanied by a greater workload/number of repetitions in the CM group. Conclusions We conclude that an acute dose of CM does not significantly affect anaerobic performance using an isokinetic chair in recreational active participants. Practical implications include precaution in recommending CM supplementation. Coaches and athletes should be aware of the disparity between the chemical analyses of the products reviewed in the present investigation versus the manufacturers’ claims

A 3D individual-based model to investigate the spatially heterogeneous response of bacterial biofilms to antimicrobial agents

The response of bacterial biofilms to treatment with antimicrobial agents is often characterized by the emergence of recalcitrant cellular microcolonies. We present an individual-based model to investigate the biophysical mechanisms of the selective resistance that arises within the biofilm and leads to a spatially heterogeneous response upon treatment with antibiotics. The response occurs in 3 distinct phases. In the first phase, the subpopulation of metabolically active cells diminishes due to antibiotic-induced cell death. Subsequently, in the second phase, increased nutrient availability allows dormant cells in the lower layers of the biofilm to transform into metabolically active cells. In the third phase, survival of the biofilm is governed by the interplay between 2 contrasting factors: (1) rate of antibiotic-induced cell death and (2) rate of transformation of dormant cells into active ones. Metabolically active cells at the distal edge of the biofilm sacrifice themselves to protect the dormant cells in the interior by (1) reducing local antibiotic concentrations and (2) increasing nutrient availability. In the presence of quorum sensing, biofilms exhibit increased tolerance compared with the quorum sensing-negative strains. Extracellular polymeric substance (EPS) forms a protective layer at the top of the biofilm, thereby limiting antibiotic penetration. The surviving cells, in turn, produce EPS resulting in a feedback-like mechanism of resistance. Whereas resistance in QS- biofilms occurs because of transformation of dormant cells into metabolically active cells, this transformation is less pronounced in QS+ biofilms, and resistance is a consequence of the sequestration of the antibiotic by EPS

Saving and Empowering young lives in PAKistan (SEPAK): An Exploratory Cluster Randomized Controlled Trial (cRCT)

IntroductionSuicide is a leading cause of death among young people and most deaths by suicide occur in low and middle-income countries. School is the best place where we can identify and respond to youth suicide risk. School-based interventions for suicide prevention in young people have been successful across US, Europe and Australia, but require adaptations to be acceptable and feasible in Pakistan.ObjectivesTo develop and test culturally adapted preventative interventions for suicidal behaviours among pupils in secondary schools in Pakistan. The qualitative component aimed at exploring the views of students, parents, teachers and general practitioners on cultural adaptation, experience of participation, areas of improvement and suggestions for scale-up of the school-based suicide prevention program (SEPAK).MethodsA clustered randomised controlled trial. The four culturally modified interventions 1) Linking Education and Awareness of Depression and Suicide Awareness (LEADS) Training for pupils (students=260) 2) the Question, Persuade, and Refer (QPR) for teachers (students=203) 3) QPR for parents (students=445); 4) Screening by Professionals (Profscreen) (students=260) were compared against control intervention (educational posters) (students=227). Structured questionnaires were administered at baseline and 1-month post-intervention to assess suicidal behaviours, psychological well-being and quality of life. A total of 8 focus groups (FGs) were conducted at pre and post intervention stage with each stakeholders.ResultsPatient and public involvement and Engagement (PPIE) was strongly embedded in the project to ensure meaningful benefits for participants. A total of 40 schools were recruited from 8 cities across Pakistan. A total of 243 students attended LEADS intervention, 92 teachers and 304 parents completed QPR training, and 9 general practitioners were trained in ProfScreen. The retention rate at follow-up was 99% that shows feasibility of delivering intervention package in Pakistan. All participants marked SEPAK as effective in identifying risk of and preventing self-harm and suicide in young people and in improving pathways to treatment. Interventions were perceived as helpful in improving knowledge about mental health, impact of mental health difficulties on functioning, reducing stigma, equipping stakeholders to identify and signpost at-risk people. Improvement in clinical and teaching practice as well as understanding others behaviors were also reported.ConclusionsThis study suggest feasibility of integrating a suicide prevention program in existing educational system and highlights positive role of creating awareness about suicide in youth, introduction of school-based mental health programs, parental counseling and strengthening of the health system by training general practitioners in early identification of suicide risk and promoting suicide prevention strategiesDisclosure of InterestNone Declared</jats:sec

Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial

Background: Worldwide, more than half a billion women of reproductive age are anaemic. Each year, about 70 000 women who give birth die from postpartum haemorrhage. Almost all deaths are in low-income or middle-income countries. We examined the association between anaemia and the risk of postpartum haemorrhage. Methods: We did a prospective cohort analysis of data from the World Maternal Antifibrinolytic-2 (WOMAN-2) trial. This trial enrols women with moderate or severe anaemia giving birth vaginally in hospitals in Pakistan, Nigeria, Tanzania, and Zambia. Hospitals in each country where anaemia in pregnancy is common were identified from a network established during previous obstetric trials. Women who were younger than 18 years without permission provided by a guardian, had a known tranexamic acid allergy, or developed postpartum haemorrhage before the umbilical cord was cut or clamped were excluded from the study. Prebirth haemoglobin, the exposure, was measured after hospital arrival and just before giving birth. Postpartum haemorrhage, the outcome, was defined in three ways: (1) clinical postpartum haemorrhage (estimated blood loss ≥500 mL or any blood loss sufficient to compromise haemodynamic stability); (2) WHO-defined postpartum haemorrhage (estimated blood loss of at least 500 mL); and (3) calculated postpartum haemorrhage (calculated estimated blood loss of ≥1000 mL). Calculated postpartum haemorrhage was estimated from the peripartum change in haemoglobin concentration and bodyweight. We used multivariable logistic regression to examine the association between haemoglobin and postpartum haemorrhage, adjusting for confounding factors. Findings: Of the 10 620 women recruited to the WOMAN-2 trial between Aug 24, 2019, and Nov 1, 2022, 10 561 (99·4%) had complete outcome data. 8751 (82·9%) of 10 561 women were recruited from hospitals in Pakistan, 837 (7·9%) from hospitals in Nigeria, 525 (5·0%) from hospitals in Tanzania, and 448 (4·2%) from hospitals in Zambia. The mean age was 27·1 years (SD 5·5) and mean prebirth haemoglobin was 80·7 g/L (11·8). Mean estimated blood loss was 301 mL (SD 183) for the 8791 (83·2%) women with moderate anaemia and 340 mL (288) for the 1770 (16·8%) women with severe anaemia. 742 (7·0%) women had clinical postpartum haemorrhage. The risk of clinical postpartum haemorrhage was 6·2% in women with moderate anaemia and 11·2% in women with severe anaemia. A 10 g/L reduction in prebirth haemoglobin increased the odds of clinical postpartum haemorrhage (adjusted odds ratio [aOR] 1·29 [95% CI 1·21–1·38]), WHO-defined postpartum haemorrhage (aOR 1·25 [1·16–1·36]), and calculated postpartum haemorrhage (aOR 1·23 [1·14–1·32]). 14 women died and 68 either died or had a near miss. Severe anaemia was associated with seven times higher odds of death or near miss (OR 7·25 [95% CI 4·45–11·80]) than was moderate anaemia. Interpretation: Anaemia is strongly associated with postpartum haemorrhage and the risk of death or near miss. Attention should be given to the prevention and treatment of anaemia in women of reproductive age. Funding: The WOMAN-2 trial is funded by Wellcome and the Bill & Melinda Gates Foundation

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

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

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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill &amp; Melinda Gates Foundation

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