Toll-like receptor signaling pathways: Novel therapeutic targets for cerebrovascular disorders

Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen and glucose supply. TLRs have a critical role in the activation of inflammatory cascades following hypoxic-ischemic events and subsequently contribute to neuroprotective or det-rimental effects of CVD-induced neuroinflammation. The TLR signaling pathway and downstream cascades trigger immune responses via the production and release of various inflammatory media-tors. The present review describes the modulatory role of the TLR signaling pathway in the inflammatory responses developed following various CVDs and discusses the potential benefits of the modulation of different TLRs in the improvement of functional outcomes after brain ischemia. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Anemia prevalence in women of reproductive age in low- and middle-income countries between 2000 and 2018

Anemia is a globally widespread condition in women and is associated with reduced economic productivity and increased mortality worldwide. Here we map annual 2000–2018 geospatial estimates of anemia prevalence in women of reproductive age (15–49 years) across 82 low- and middle-income countries (LMICs), stratify anemia by severity and aggregate results to policy-relevant administrative and national levels. Additionally, we provide subnational disparity analyses to provide a comprehensive overview of anemia prevalence inequalities within these countries and predict progress toward the World Health Organization’s Global Nutrition Target (WHO GNT) to reduce anemia by half by 2030. Our results demonstrate widespread moderate improvements in overall anemia prevalence but identify only three LMICs with a high probability of achieving the WHO GNT by 2030 at a national scale, and no LMIC is expected to achieve the target in all their subnational administrative units. Our maps show where large within-country disparities occur, as well as areas likely to fall short of the WHO GNT, offering precision public health tools so that adequate resource allocation and subsequent interventions can be targeted to the most vulnerable populations.Peer reviewe

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

A framework for linked data fusion and quality assessment

The growth of semantic web technologies underpins the ever-increasing development of linked data and their applications. In recent years, the number of linked data sources has been raised from 12 to more than 2973 sets. The datasets are managed as decentralized sources, and their quality is a serious concern. The assessment of the quality of linked data is a key to adopting them in different fields because each data set has been developed by a different group, using various methods and tools. Moreover, crowd sourcing contributes as one of the main strategies in data collection. This contribution is seen in the tourism industry or E-commerce fields and deserves attention. The qualitative and quantitative diversity of such data is higher than those generated by official organizations and firms. In this paper, we first overview and evaluate the dimensions and measures for the quality assessment of data. Then, we present a novel framework as a solution for improving linked data quality evaluation and data fusion. Finally, we adopt several tools to assess the quality of data of some reputable data sources using the proposed framework

Mapping routine measles vaccination in low- and middle-income countries

The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)(1-4). Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)(5-8). Here we generated annual estimates of routine childhood MCV1 coverage at 5 x 5-km(2) pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children.Peer reviewe

Measuring the availability of human resources for health and its relationship to universal health coverage for 204 countries and territories from 1990 to 2019: A systematic analysis for the Global Burden of Disease Study 2019

Background Human resources for health (HRH) include a range of occupations that aim to promote or improve human health. The UN Sustainable Development Goals (SDGs) and the WHO Health Workforce 2030 strategy have drawn attention to the importance of HRH for achieving policy priorities such as universal health coverage (UHC). Although previous research has found substantial global disparities in HRH, the absence of comparable cross-national estimates of existing workforces has hindered efforts to quantify workforce requirements to meet health system goals. We aimed to use comparable and standardised data sources to estimate HRH densities globally, and to examine the relationship between a subset of HRH cadres and UHC effective coverage performance. Methods Through the International Labour Organization and Global Health Data Exchange databases, we identified 1404 country-years of data from labour force surveys and 69 country-years of census data, with detailed microdata on health-related employment. From the WHO National Health Workforce Accounts, we identified 2950 country-years of data. We mapped data from all occupational coding systems to the International Standard Classification of Occupations 1988 (ISCO-88), allowing for standardised estimation of densities for 16 categories of health workers across the full time series. Using data from 1990 to 2019 for 196 of 204 countries and territories, covering seven Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) super-regions and 21 regions, we applied spatiotemporal Gaussian process regression (ST-GPR) to model HRH densities from 1990 to 2019 for all countries and territories. We used stochastic frontier meta-regression to model the relationship between the UHC effective coverage index and densities for the four categories of health workers enumerated in SDG indicator 3.c.1 pertaining to HRH: physicians, nurses and midwives, dentistry personnel, and pharmaceutical personnel. We identified minimum workforce density thresholds required to meet a specified target of 80 out of 100 on the UHC effective coverage index, and quantified national shortages with respect to those minimum thresholds. Findings We estimated that, in 2019, the world had 104·0 million (95% uncertainty interval 83·5–128·0) health workers, including 12·8 million (9·7–16·6) physicians, 29·8 million (23·3–37·7) nurses and midwives, 4·6 million (3·6–6·0) dentistry personnel, and 5·2 million (4·0–6·7) pharmaceutical personnel. We calculated a global physician density of 16·7 (12·6–21·6) per 10 000 population, and a nurse and midwife density of 38·6 (30·1–48·8) per 10 000 population. We found the GBD super-regions of sub-Saharan Africa, south Asia, and north Africa and the Middle East had the lowest HRH densities. To reach 80 out of 100 on the UHC effective coverage index, we estimated that, per 10 000 population, at least 20·7 physicians, 70·6 nurses and midwives, 8·2 dentistry personnel, and 9·4 pharmaceutical personnel would be needed. In total, the 2019 national health workforces fell short of these minimum thresholds by 6·4 million physicians, 30·6 million nurses and midwives, 3·3 million dentistry personnel, and 2·9 million pharmaceutical personnel. Interpretation Considerable expansion of the world's health workforce is needed to achieve high levels of UHC effective coverage. The largest shortages are in low-income settings, highlighting the need for increased financing and coordination to train, employ, and retain human resources in the health sector. Actual HRH shortages might be larger than estimated because minimum thresholds for each cadre of health workers are benchmarked on health systems that most efficiently translate human resources into UHC attainment. Funding Bill & Melinda Gates Foundation

Global, regional, and national sex differences in the global burden of tuberculosis by HIV status, 1990–2019: results from the Global Burden of Disease Study 2019

Background: Tuberculosis is a major contributor to the global burden of disease, causing more than a million deaths annually. Given an emphasis on equity in access to diagnosis and treatment of tuberculosis in global health targets, evaluations of differences in tuberculosis burden by sex are crucial. We aimed to assess the levels and trends of the global burden of tuberculosis, with an emphasis on investigating differences in sex by HIV status for 204 countries and territories from 1990 to 2019. Methods: We used a Bayesian hierarchical Cause of Death Ensemble model (CODEm) platform to analyse 21 505 site-years of vital registration data, 705 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, and 680 site-years of mortality surveillance data to estimate mortality due to tuberculosis among HIV-negative individuals. We used a population attributable fraction approach to estimate mortality related to HIV and tuberculosis coinfection. A compartmental meta-regression tool (DisMod-MR 2.1) was then used to synthesise all available data sources, including prevalence surveys, annual case notifications, population-based tuberculin surveys, and tuberculosis cause-specific mortality, to produce estimates of incidence, prevalence, and mortality that were internally consistent. We further estimated the fraction of tuberculosis mortality that is attributable to independent effects of risk factors, including smoking, alcohol use, and diabetes, for HIV-negative individuals. For individuals with HIV and tuberculosis coinfection, we assessed mortality attributable to HIV risk factors including unsafe sex, intimate partner violence (only estimated among females), and injection drug use. We present 95% uncertainty intervals for all estimates. Findings: Globally, in 2019, among HIV-negative individuals, there were 1·18 million (95% uncertainty interval 1·08–1·29) deaths due to tuberculosis and 8·50 million (7·45–9·73) incident cases of tuberculosis. Among HIV-positive individuals, there were 217 000 (153 000–279 000) deaths due to tuberculosis and 1·15 million (1·01–1·32) incident cases in 2019. More deaths and incident cases occurred in males than in females among HIV-negative individuals globally in 2019, with 342 000 (234 000–425 000) more deaths and 1·01 million (0·82–1·23) more incident cases in males than in females. Among HIV-positive individuals, 6250 (1820–11 400) more deaths and 81 100 (63 300–100 000) more incident cases occurred among females than among males in 2019. Age-standardised mortality rates among HIV-negative males were more than two times greater in 105 countries and age-standardised incidence rates were more than 1·5 times greater in 74 countries than among HIV-negative females in 2019. The fraction of global tuberculosis deaths among HIV-negative individuals attributable to alcohol use, smoking, and diabetes was 4·27 (3·69–5·02), 6·17 (5·48–7·02), and 1·17 (1·07–1·28) times higher, respectively, among males than among females in 2019. Among individuals with HIV and tuberculosis coinfection, the fraction of mortality attributable to injection drug use was 2·23 (2·03–2·44) times greater among males than females, whereas the fraction due to unsafe sex was 1·06 (1·05–1·08) times greater among females than males. Interpretation: As countries refine national tuberculosis programmes and strategies to end the tuberculosis epidemic, the excess burden experienced by males is important. Interventions are needed to actively communicate, especially to men, the importance of early diagnosis and treatment. These interventions should occur in parallel with efforts to minimise excess HIV burden among women in the highest HIV burden countries that are contributing to excess HIV and tuberculosis coinfection burden for females. Placing a focus on tuberculosis burden among HIV-negative males and HIV and tuberculosis coinfection among females might help to diminish the overall burden of tuberculosis. This strategy will be crucial in reaching both equity and burden targets outlined by global health milestones. Funding: Bill & Melinda Gates Foundation. © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens