Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. 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 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

On the lateral organisation of the thylakoid membrane

In this work the lateral heterogeneity of the thylakoid membrane was investigated by quantifying the amount of photosystem I (PSI), photosystem II (PSII) and some PSII complexes and PSII proteins in different domains of the thylakoid. Grana, grana core, grana margins and stroma lamellae + end fractions were obtained by sonication and separation in a non-detergent, aqueous polymer two-phase system. Y-100 was obtained by Yeda press and centrifugation. EPR spectroscopy was used to quantify PSI (P700+) and PSII (YD·) in the different fractions. These measurements showed a successively increasing amount of PSI from grana core, grana, grana margins and stroma lamellae + end membranes to Y-100. On the contrary the amount of PSII is decreased successively from grana core to Y-100. The ratio PSI/PSII increases from 0,25 in grana core to 13 in Y-100. For the entire thylakoid the PSI/PSII ratio is 1,13. Gel electrophoresis was performed to trace five PSII complexes (supercomplexes, dimers, monomers with CP43 and monomers without CP43, and core reaction centres) in the different fractions of the thylakoid. These were then quantified by western blotting. The supercomplexes are most common in grana core and the fragments of the complexes are most common in Y-100, in a gradient through the fractions. This gives strong support to the notion of a lateral transport of PSII centres from grana core to Y-100 and back again, in a repair process. Thirteen PSII proteins were also analysed and quantified in the different fractions. PsbS, PsbW, PsbZ were overrepresented in grana or grana core and absent or nearly absent in Y-100. It agrees with their assumed function of preserving and stabilising the fully developed PSII complexes in grana core. Using counter-current distribution, a diagram was obtained showing heterogeneity within all the sub-fractions according to their surface properties

Fragmentation and separation analysis of the photosynthetic membrane from spinach.

Membrane vesicles, originating from grana, grana core (appressed grana regions), grana margins and stroma lamellae/end membranes, were analysed by counter current distribution (CCD) using aqueous dextran-polyethylene glycol two-phase systems. Each vesicle population gave rise to distinct peaks in the CCD diagram representing different vesicle subpopulations. The grana vesicles and grana core vesicles each separated into 3 different subpopulations having different chlorophyll a/b ratios and PSI/PSII ratios. Two of the grana core subpopulations had a chlorophyll a/b ratio of 2.0 and PSI/PSII ratio of 0.10 and are among the most PSII enriched thylakoid vesicle preparation obtained so far by a non detergent method. The margin vesicles separated into 3 different populations, with about the same chlorophyll a/b ratios, but different fluorescence emission spectra. The stroma lamellae/end membrane vesicles separated into 4 subpopulations. Plastoglobules, connected to membrane vesicles, were highly enriched in 2 of these subpopulations and it is proposed that these 2 subpopulations originate from stroma lamellae while the 2 others originate from end membranes. Fragmentation and separation analysis shows that the margins of grana constitute a distinct domain of the thylakoid and also allows the estimation of the chlorophyll antenna sizes of PSI and PSII in different thylakoid domains

Aqueous polymer two-phase systems and their use in fragmentation and separation of biological membranes for the purpose of mapping the membrane structure.

When solutions of two different polymers are mixed, phase separation often occurs even at low concentrations of polymers. One polymer usually collects in one phase and the other polymer in the other phase. When water is used as solvent, two aqueous, immiscible, phases are obtained. The same holds for aqueous mixtures of a salt and a polymer. Such aqueous two-phase systems (ATPS) are very useful for separation of high-molecular-weight biomolecules such as proteins and nucleic acids and also for cells, cell organelles, and membrane vesicles. The phase systems can be made highly selective and they are also mild toward biomolecules and cell particles. In this review we describe how ATPS can be used for fragmentation and separation analyses of biological membranes and how this can be used for mapping of the photosynthetic membrane, the thylakoid, of green leaves

Aluminium Adjuvants : a Nanomaterial used as Adjuvants in Human Vaccines for Decades

Background: Aluminium salts have been used for decades in vaccines as adjuvants to facilitate the adaptive immune response against co-administered antigens. Two types of aluminium adjuvant are mostly used, aluminium oxyhydroxide and aluminium hydroxyphosphate. Both types of aluminium adjuvant consist of nanoparticles that form loose, micrometre sized aggregates at circumneutral pH.Aluminium adjuvants constitute a well-documented example of administration of nanomaterials to humanswith infrequent side effects and a safety record generally regarded as excellent. However, despite its prolonged use in human and veterinary medicine, the mechanisms behind the enhanced response and the immune stimulatory effect are still by and large unknown.Methods: The present paper reviews existing ideas regarding the immunostimulatory effects of aluminium adjuvants, with a focus on the induction of an inflammatory response by cellular stress. Reviewed information was obtained from peer-reviewed scientific papers published in 1988 to date with one exception, a paper published 1931.Results: Cellular stress causes extra cellular signalling of danger associated molecular patterns (DAMPs) and upon phagocytosis of aluminium adjuvants the cells need to manage the ingested particles.Conclusion: A persistent intracellular accumulation of aluminium adjuvants will be a solid depository of sparingly soluble aluminium salts maintaining a constant concentration of Al3+ ions in the cytoplasm and this will affect multiple biochemical processes. The cell will be under constant stress and DAMP signalling will occur and we would like to suggest the maintenance of a constant concentration Al3+ ions in the cytoplasm as a general underlying feature of the immune stimulation properties of aluminium adjuvants

Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant

Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance in the development of new, safer, and efficient vaccines. To further our knowledge of the mode of action of aluminum-based adjuvants, the prospect of metabolic reprogramming of macrophages upon phagocytosis of aluminum-based adjuvants was investigated. Macrophages were differentiated and polarized in vitro from human peripheral monocytes and incubated with the aluminum-based adjuvant Alhydrogel((R)). Polarization was verified by the expression of CD markers and cytokine production. In order to recognize adjuvant-derived reprogramming, macrophages were incubated with Alhydrogel((R)) or particles of polystyrene as control, and the cellular lactate content was analyzed using a bioluminescent assay. Quiescent M0 macrophages, as well as alternatively activated M2 macrophages, exhibited increased glycolytic metabolism upon exposure to aluminum-based adjuvants, indicating a metabolic reprogramming of the cells. Phagocytosis of aluminous adjuvants could result in an intracellular depot of aluminum ions, which may induce or support a metabolic reprogramming of the macrophages. The resulting increase in inflammatory macrophages could thus prove to be an important factor in the immune-stimulating properties of aluminum-based adjuvants

Tracing Aluminium-based Adjuvants : Their Interactions with Immune Competent Cells and their Effect on Mitochondrial Activity

Background: Studies revealing the immune stimulatory properties of aluminium-based adjuvants (ABAs) have been impaired by the absence of simple and reliable methods of tracing the adjuvants and their effect on biochemical processes upon endocytosis. Objective: To verify that labelling of ABAs with lumogallion doesn’t affect the physicochemical properties of the adjuvant; tracing cellular interaction with aluminium adjuvants; explore their effect on metabolic activity upon endocytosis. Methods: Physicochemical characterization by Z-potential and size distribution of ABAs labelled with lumogallion. Cellular interactions with ABAs by flow cytometry and confocal microscopy. Metabolic activity explored by measuring transformation of tetrazolium into formazan. Results: No or minor change of zeta potential and average particle size of lumogallion labelled aluminium oxyhydroxide, AlO(OH) and aluminium hydroxyphosphate, Al(OH)x(PO4 )y. Both phagocytosing and non-phagocytosing leukocytes became associated with ABAs at concentrations expected after in vivo administration of a vaccine. The ABAs were relatively toxic, affecting both lymphocytes and monocytes, and Al(OH)x(PO4 )y was more toxic than AlO(OH). Endocytosed aluminium adjuvant particles were not secreted from the cells and remained intracellular throughout several cell divisions. The presence of ABAs increased the mitochondrial activity of the monocytic cell line THP-1 and peripheral monocytes, as based on the transformation of tetrazolium into formazan. Conclusion: Lumogallion labelled ABAs is a valuable tool tracing interactions between ABAs and cells. Labelled ABAs can be traced intracellularly and ABAs are likely to remain intracellular for a long period of time. Intracellular ABAs increase the mitochondrial activity and the presence of intracellular Al ions is suggested to cause an increased mitochondrial activity. Keywords: Aluminium based adjuvant, Lumogallion, Mitochondrial activity, MTT assay, Phagocytosis, ABAS, Zeolites

Tracing Aluminium-based Adjuvants : Their Interactions with Immune Competent Cells and their Effect on Mitochondrial Activity

Background:Studies revealing the immune stimulatory properties of aluminium-based adjuvants (ABAs) have been impaired by the absence ofsimple and reliable methods of tracing the adjuvants and their effect on biochemical processes upon endocytosis.Objective:To verify that labelling of ABAs with lumogallion doesn’t affect the physicochemical properties of the adjuvant; tracing cellularinteraction with aluminium adjuvants; explore their effect on metabolic activity upon endocytosis.Methods:Physicochemical characterization by Z-potential and size distribution of ABAs labelled with lumogallion. Cellular interactions withABAs by flow cytometry and confocal microscopy. Metabolic activity explored by measuring transformation of tetrazolium intoformazan.Results:No or minor change of zeta potential and average particle size of lumogallion labelled aluminium oxyhydroxide, AlO(OH) andaluminium hydroxyphosphate, Al(OH)x(PO4)y. Both phagocytosing and non-phagocytosing leukocytes became associated withABAs at concentrations expected after in vivo administration of a vaccine. The ABAs were relatively toxic, affecting bothlymphocytes and monocytes, and Al(OH)x(PO4)y was more toxic than AlO(OH). Endocytosed aluminium adjuvant particles werenot secreted from the cells and remained intracellular throughout several cell divisions. The presence of ABAs increased themitochondrial activity of the monocytic cell line THP-1 and peripheral monocytes, as based on the transformation of tetrazolium intoformazan.Conclusion:Lumogallion labelled ABAs is a valuable tool tracing interactions between ABAs and cells. Labelled ABAs can be tracedintracellularly and ABAs are likely to remain intracellular for a long period of time. Intracellular ABAs increase the mitochondrialactivity and the presence of intracellular Al ions is suggested to cause an increased mitochondrial activity.Keywords: Aluminium based adjuvant, Lumogallion, Mitochondrial activity, MTT assay, Phagocytosis, ABAS, Zeolites