TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis

BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB

Assessing performance of the Healthcare Access and Quality Index, overall and by select age groups, for 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019

Background: Health-care needs change throughout the life course. It is thus crucial to assess whether health systems provide access to quality health care for all ages. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we measured the Healthcare Access and Quality (HAQ) Index overall and for select age groups in 204 locations from 1990 to 2019. Methods: We distinguished the overall HAQ Index (ages 0–74 years) from scores for select age groups: the young (ages 0–14 years), working (ages 15–64 years), and post-working (ages 65–74 years) groups. For GBD 2019, HAQ Index construction methods were updated to use the arithmetic mean of scaled mortality-to-incidence ratios (MIRs) and risk-standardised death rates (RSDRs) for 32 causes of death that should not occur in the presence of timely, quality health care. Across locations and years, MIRs and RSDRs were scaled from 0 (worst) to 100 (best) separately, putting the HAQ Index on a different relative scale for each age group. We estimated absolute convergence for each group on the basis of whether the HAQ Index grew faster in absolute terms between 1990 and 2019 in countries with lower 1990 HAQ Index scores than countries with higher 1990 HAQ Index scores and by Socio-demographic Index (SDI) quintile. SDI is a summary metric of overall development. Findings: Between 1990 and 2019, the HAQ Index increased overall (by 19·6 points, 95% uncertainty interval 17·9–21·3), as well as among the young (22·5, 19·9–24·7), working (17·2, 15·2–19·1), and post-working (15·1, 13·2–17·0) age groups. Large differences in HAQ Index scores were present across SDI levels in 2019, with the overall index ranging from 30·7 (28·6–33·0) on average in low-SDI countries to 83·4 (82·4–84·3) on average in high-SDI countries. Similarly large ranges between low-SDI and high-SDI countries, respectively, were estimated in the HAQ Index for the young (40·4–89·0), working (33·8–82·8), and post-working (30·4–79·1) groups. Absolute convergence in HAQ Index was estimated in the young group only. In contrast, divergence was estimated among the working and post-working groups, driven by slow progress in low-SDI countries. Interpretation: Although major gaps remain across levels of social and economic development, convergence in the young group is an encouraging sign of reduced disparities in health-care access and quality. However, divergence in the working and post-working groups indicates that health-care access and quality is lagging at lower levels of social and economic development. To meet the needs of ageing populations, health systems need to improve health-care access and quality for working-age adults and older populations while continuing to realise gains among the young. Funding: Bill & Melinda Gates Foundation

Temporal patterns of cancer burden in Asia, 1990–2019: a systematic examination for the Global Burden of Disease 2019 study

BackgroundCancers represent a challenging public health threat in Asia. This study examines the temporal patterns of incidence, mortality, disability and risk factors of 29 cancers in Asia in the last three decades. MethodsThe age, sex and year-wise estimates of incidence, mortality, and disability-adjusted life years (DALYs) of 29 cancers for 49 Asian countries from 1990 through 2019 were generated as a part of the Global Burden of Disease, Injuries and Risk Factors 2019 study. Besides incidence, mortality and DALYs, we also examined the cancer burden measured in terms of DALYs and deaths attributable to risk factors, which had evidence of causation with different cancers. The development status of countries was measured using the socio-demographic index. Decomposition analysis was performed to gauge the change in cancer incidence between 1990 and 2019 due to population growth, aging and age-specific incidence rates. FindingsAll cancers combined claimed an estimated 5.6 million [95% uncertainty interval, 5.1–6.0 million] lives in Asia with 9.4 million [8.6–10.2 million] incident cases and 144.7 million [132.7–156.5 million] DALYs in 2019. The age-standardized incidence rate (ASIR) of all cancers combined in Asia was 197.6/100,000 [181.0–214.4] in 2019, varying from 99.2/100,000 [76.1–126.0] in Bangladesh to 330.5/100,000 [298.5–365.8] in Cyprus. The age-standardized mortality rate (ASMR) was 120.6/100,000 [110.1–130.7] in 2019, varying 4-folds across countries from 71.0/100,000 [59.9–83.5] in Kuwait to 284.2/100,000 [229.2–352.3] in Mongolia. The age-standardized DALYs rate was 2970.5/100,000 [2722.6–3206.5] in 2019, varying from 1578.0/100,000 [1341.2–1847.0] in Kuwait to 6574.4/100,000 [5141.7–8333.0] in Mongolia. Between 1990 and 2019, deaths due to 17 of the 29 cancers either doubled or more, and 20 of the 29 cancers underwent an increase of 150% or more in terms of new cases. Tracheal, bronchus, and lung cancer (both sexes), breast cancer (among females), colon and rectum cancer (both sexes), stomach cancer (both sexes) and prostate cancer (among males) were among top-5 cancers in most Asian countries in terms of ASIR and ASMR in 2019 and cancers of liver, stomach, hodgkin lymphoma and esophageal cancer posted the most significant decreases in age-standardized rates between 1990 and 2019. Among the modifiable risk factors, smoking, alcohol use, ambient particulate matter (PM) pollution and unsafe sex remained the dominant risk factors between 1990 and 2019. Cancer DALYs due to ambient PM pollution, high body mass index and fasting plasma glucose has increased most notably between 1990 and 2019. InterpretationWith growing incidence, cancer has become more significant public health threat in Asia, demanding urgent policy attention and guidance. Its heightened risk calls for increased cancer awareness, preventive measures, affordable early-stage detection, and cost-effective therapeutics in Asia. The current study can serve as a useful resource for policymakers and researchers in Asia for devising interventions for cancer management and control. FundingThe GBD study is funded by the Bill and Melinda Gates Foundation.This work is supported by: - University Grants Commission - Chandigarh University - National Science and Technology Council - grant no. [112-2410-H-003-031] - Bill and Melinda Gates Foundation - grant no. [OPP1152504] - Fundamental Research Funds for the Central Universities - grant no. [30923011101] - Social Science Foundation of Jiangsu Province - grant no. [21GLD008] - National Natural Science Foundation of China - grant no. [72204112

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

Durability studies on conventional concrete and slag-based geopolymer concrete in aggressive sulphate environment

As a potential substitute to conventional concrete, slag-based geopolymer concrete can be a promising material towards green and low carbon building approach. However, the lack of understanding of its performance subjected to sulphate environment can prohibit its use to some extent. This study examines the properties of conventional concrete exposed to a severe sulphate environment in comparison with slag-based geopolymer (SGPC). Plain cement concrete (PCC) also known as conventional concrete was cast using ordinary Portland Cement (OPC) as a binder. The durability of both types of concrete was examined by immersing test specimens in sulphate solutions (for varied salt concentrations of 2 and 4 g/l) for different curing ages up to a year. The performance of both types of concrete was studied for both mechanical and durability properties. Mechanical properties included compressive, tensile and flexural strengths (FS), while durability consisted of sorptivity, chloride diffusion, corrosion, EDS and SEM studies. The outcomes of this study revealed that the compressive (CS) and split tensile strengths (STS) of both OPC and SGPC decreased with the increase in magnesium sulphate salt concentrations and curing age. After being exposed to a 4% sulphate solution for 365 days, a decrease in the compressive strength was observed by 36.53% in SGPC and 55.97% in OPC, and a similar trend was found for the FS and STS. Rapid chloride permeability (RCPT) and sorptivity test results showed an increased diffusion with age and thus supported the findings of the compressive strength. Micro-structural properties were also studied, and observations showed that the formation of Sodium alumino-silicate hydrate (N–A–S–H) and Calcium alumino-silicate hydrate (C–A–S–H) was more obvious with the curing age in SGPC. At the same time, C–S–H gel formation decreased in conventional concrete with an increase in sulphate salt concentration. The cumulative effect of all these factors led to a much higher corrosion rate of rebars embedded in conventional concrete than in SGPC. Therefore, slag-based geopolymer concrete performed better than conventional concrete in an aggressive sulphate environment for all curing periods