Репозиторий Университета

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

In this paper, we propose a computational approach for description of radiation transfer in a quasi-ordered medium and study the impact of scattering on electromagnetic wave propagation and image formation. It combines finite-difference time-domain method, Monte Carlo simulations, and radiative transfer theory. Using as an example terahertz imaging, we analyze modulation transfer function (MTF) of imaging system operated at 0.25 THz for scattering material layers placed between the object and the imaging plane. We experimentally study imaging of bar-pattern test-objects through a quasi-ordered scattering medium. Both numerical and experimental results are in good agreement and demonstrate an impact of quasi-ordered scatterers on quality of THz images, i.e. particular combination of the electromagnetic wavelength and parameters of scattering materials could enhance MTF compared with ones with random particle structures.

Terahertz (THz) frequency range opens significant opportunities in various fundamental and applied fields including condensed matter physics and chemistry, biology and medicine, public security and nondestructive testing. Despite significant advances in THz instrumentation, the problem of THz sensing in harsh environments, particularly at high temperatures and pressures, remains acute due to the lack of THz materials and optical components capable for operation under the extreme conditions. To address this problem, the THz hollow‐core photonic crystal sapphire waveguides that are fabricated using shaped crystal growth technique are developed. Numerical analysis and experimental study show that the proposed waveguides operate in a few‐mode regime and allow for the broadband transmission of THz pulses with small dispersions and low propagation losses. Thanks to the unique physical properties of sapphire, the proposed waveguides are capable of operating in a variety of aggressive environments. As an example, the developed waveguides are used to conduct the intra‐waveguide interferometric sensing of phase transitions in sodium nitrite films at high temperatures. It is believed that the proposed sapphire‐based material's platform has strong potential for developing THz guided optics for applications in intra‐waveguide spectroscopy, interferometry, and remote sensing in aggressive environments. In order to address the problem of terahertz (THz) sensing in harsh environments, the hollow‐core photonic crystal sapphire waveguides are developed and fabricated using shaped crystal growth technique. Thanks to the unique physical properties of sapphire, the developed THz waveguides can be used in intra‐waveguide spectroscopy, interferometry, and remote sensing in aggressive environments, at high temperatures and pressures.

We have developed a method of terahertz (THz) solid immersion (SI) microscopy for continuous-wave reflection-mode imaging of soft biological tissues with a sub-wavelength spatial resolution. In order to achieve strong reduction in the dimensions of the THz beam caustic, an electromagnetic wave is focused into the evanescent field volume behind a medium with a high refractive index. We have experimentally demonstrated a 0.15λ-resolution of the proposed imaging modality at λ = 500 μm, which is beyond the Abbe diffraction limit and represents a considerable improvement over the previously-reported arrangements of SI imaging setups. The proposed technique does not involve any sub-wavelength near-field probes and diaphragms, thus, avoiding the THz beam attenuation due to such elements. We have applied the developed method for THz imaging of various soft tissues: a plant leaf blade, cell spheroids, and tissues of the breast ex vivo. Our THz images clearly reveal sub-wavelength features in tissues, therefore, promising applications of THz SI microscopy in biology and medicine.

In this review, we describe dielectric properties of biological tissues and liquids in the context of terahertz (THz) biophotonics. We discuss a model of the THz dielectric permittivity of water and water-containing media, which yields analysis of the relaxation and damped resonant molecules modes. We briefly describe modern techniques of THz spectroscopy and imaging employed in biophotonics with a strong emphasize on a THz time-domain spectroscopy. Furthermore, we consider the methods of sub-wavelength resolution THz imaging and the problem of THz wave delivery to hard to access tissues and internal organs. We consider the THz dielectric properties of biological solutions and liquids. Although strong absorption by water molecules prevents THz-waves from penetration of hydrated tissues and probing biological molecules in aqueous solutions, we discuss approaches for overcoming these drawbacks – novel techniques of freezing and temporal dehydration by application of hyperosmotic agents which have a potential for cancer detection. We review recent applications of THz technology in diagnosis of malignancies and aiding histology paying particular attention to the origin of contrast observed between healthy and pathological tissues. We consider recent applications of THz reflectometry in sensing the thinning dynamics of human pre-corneal tear film. Modern modalities of THz imaging, which relies on the concepts of multi-spectral and multi-temporal domains and employing the principles of color vision, phase analysis and tomography are discussed. Novel methods of THz spectra analysis based on machine learning, pattern recognition, chemical imaging and the revealing of the spatial distribution of various substances in a tissue, are analyzed. Advanced thermal model describing biological object irradiated by THz waves and phantoms mimicking the optical properties of tissues at THz frequencies are presented. Finally, application of the high-resolution THz spectroscopy in analytic chemistry, biology and medicine are described.

For efficient manufacturing of fibrous collagen‐based materials by electrospinning, the search on optimal rheological parameters is of the great importance. Rheological characteristics and denaturation of collagen in aqueous dispersions were studied as a function of shear rate and acetic acid concentration in the range of 3‐9% w/w at temperature from 20 to 40°C. It was shown that an increase in temperature, acetic acid concentration of the collagen dispersion leads to a significant decrease in its viscosity. It was found that helical conformation of the collagen macromolecules is preserved up to 31°C. An increase in acetic acid concentration leads to a reduction of denaturation temperature. The complex viscosity of collagen dispersions exhibits a sharp drop, followed by a rapid growth of damping factor in the temperature range from 22 to 35°C. Both storage (G') and loss (G”) moduli increase with frequency and collagen concentration. It was revealed that optimal parameters for electrospinning of highly concentrated collagen dispersions can be achieved by adjusting of the concentration of acetic acid, temperature and stirring speed. As a result, collagen nonwoven materials with diameter from 100 to 700 nm were obtained. This article is protected by copyright. All rights reserved.

Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.

Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage.

Department of Medical Biochemistry and Biophysics, Section for Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.

Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the α3(XI) chain is identical to the α1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures.

Methods: Mice expressing the susceptible immune response gene were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments.

Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of α3(XI) or α1(II) chain. The L10D9 antibody binds cartilage and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis.

The first example of an unusual addition of chromone‐substituted acrylic acid to enamines is described. The process shows high versatility concerning both enamines and chromones. The reaction is catalyzed by tertiary amines and is highly likely of Morita–Baylis–Hillman‐type. The described compounds show combined moderate inhibitory action on BChE and antagonism towards NMDA receptors which makes them a perspective group for the development of anti‐Alzheimer drugs. An unusual addition of enamines to chromone‐substituted acrylic acid is an efficient and versatile method of synthesis of allylamine derivatives. The reaction is catalyzed by amines and is highly likely of Morita–Baylis–Hillman‐type. The described compounds show combined moderate inhibitory action on BChE and antagonism towards NMDA receptors

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. View Full-Text

Purpose

The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon.

Methods

Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis.

Certolizumab pegol (CZP) is a PEGylated antigen-binding fragment-fragment of a humanized mAb neutralizing TNF. It lacks Fc-fragment and has a very low potential to cross the placenta. We aimed to report the efficacy and safety of CZP in a case series of patients with refractory Takayasu arteritis (TA).

Background

Small intestinal bacterial overgrowth (SIBO) was detected in cirrhosis in many studies. The aim is to perform a systematic review and meta-analysis on the prevalence of SIBO in cirrhosis and on the relationship of SIBO with features of cirrhosis.

Methods

PUBMED search (until 14 January 2018) was performed. Specific search terms were: ‘(cirrhosis) AND (SIBO OR bacterial overgrowth)’. Studies not relating to cirrhosis or SIBO, animal studies, and non-original articles were excluded. A meta-analysis of all studies was performed using a random-effects model.

Results

117 references were identified by the PUBMED search. 3 references were added after handsearching the reference lists of all the articles. 99 references were excluded. 21 studies (included in total 1264 cirrhotics and 306 controls) remained for qualitative analysis and quantitative synthesis. Prevalence of SIBO for cirrhosis was 40.8% (95% CI 34.8–47.1), while the prevalence of SIBO for controls was 10.7% (95% CI 5.7–19.0). OR 6.83 (95% CI 4.16–11.21; p < 0.001). Prevalence of SIBO for decompensated cirrhosis was higher than prevalence of SIBO for compensated cirrhosis (50.5% vs. 31.2%; p < 0.001). SIBO in cirrhosis was associated with ascites (p < 0.001), minimal hepatic encephalopathy (p = 0.001), bacterial translocation (p = 0.026), spontaneous bacterial peritonitis (p = 0.008), prolonged orocecal transit time (p < 0.001), and was not associated with hypocoagulation. Further studies are required to clarify the relationship of SIBO with hyperbilirubinemia, hypoalbuminemia, overt hepatic encephalopathy in past, esophageal varices and systemic inflammation.

Conclusion

Small intestinal bacterial overgrowth is more often detected in cirrhosis than in healthy persons and is associated with some features of cirrhosis.

Abstract

Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally.

Methods

The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8,259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analyzed separately and then incorporated into the estimation. We analyze the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardized and improved; and the analysis has been extended backward in time by two decades to start in 1950.

Findings

Globally, 18.7% (95% uncertainty interval 18.4–19.0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58.8% (58.2–59.3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48.1 years (46.5–49.6) to 70.5 years (70.1–70.8) for men and from 52.9 years (51.7–54.0) to 75.6 years (75.3–75.9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49.1 years (46.5–51.7) for men in the Central African Republic to 87.6 years (86.9–88.1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216.0 deaths (196.3–238.1) per 1,000 livebirths in 1950 to 38.9 deaths (35.6–42.8) per 1,000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5.4 million (5.2–5.6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development.

Interpretation

This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Abstract

Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind,” it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analyzed global attainment.

Methods 

We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2.5th percentile and 100 as the 97.5th percentile of 1,000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualized rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1,000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualized rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualized rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator.

Findings

The global median health-related SDG index in 2017 was 59.4 (IQR 35.4–67.3), ranging from a low of 11.6 (95% uncertainty interval 9.6–14.0) to a high of 84.9 (83.1–86.7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For 14 indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualized rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualized rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1,000 population by 2030.

Interpretation

The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—toward multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.

Abstract

Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardized estimates of mortality. We present single calendar-year and single-year of age estimates of fertility and population by sex with standardized and replicable methods.

Methods

We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardized and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7,817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1,000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1,257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories.

Findings

From 1950 to 2017, TFRs decreased by 49.4% (95% uncertainty interval [UI] 46.4–52.0). The TFR decreased from 4.7 livebirths (4.5–4.9) to 2.4 livebirths (2.2–2.5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1,000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83.8 million people per year since 1985. The global population increased by 197.2% (193.3–200.8) since 1950, from 2.6 billion (2.5–2.6) to 7.6 billion (7.4–7.9) people in 2017; much of this increase was in the proportion of the global population in South Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2.0%; this rate then remained nearly constant until 1970 and then decreased to 1.1% in 2017. Population growth rates in the Southeast Asia, East Asia, and Oceania GBD super-region decreased from 2.5% in 1963 to 0.7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2.7%. The global average age increased from 26.6 years in 1950 to 32.1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59.9% to 65.3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1.0 livebirths (95% UI 0.9–1.2) in Cyprus to a high of 7.1 livebirths (6.8–7.4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0.08 livebirths (0.07–0.09) in South Korea to 2.4 livebirths (2.2–2.6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0.3 livebirths (0.3–0.4) in Puerto Rico to a high of 3.1 livebirths (3.0–3.2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in Central, Eastern, and Western Europe, whereas population growth rates of more than 2.0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger.

Interpretation

Population trends create demographic dividends and headwinds (i.e., economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision-making and to monitor progress.

Abstract

How long one lives, how many years of life are spent in good and poor health, and how the population’s state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years.

Methods

We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analyzed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males.

Findings

Globally, from 1990 to 2017, life expectancy at birth increased by 7.4 years (95% uncertainty interval 7.1–7.8), from 65.6 years (65.3–65.8) in 1990 to 73.0 years (72.7–73.3) in 2017. The increase in years of life varied from 5.1 years (5.0–5.3) in high SDI countries to 12.0 years (11.3–12.8) in low SDI countries. Of the additional years of life expected at birth, 26.3% (20.1–33.1) were expected to be spent in poor health in high SDI countries compared with 11.7% (8.8–15.1) in low-middle SDI countries. HALE at birth increased by 6.3 years (5.9–6.7), from 57.0 years (54.6–59.1) in 1990 to 63.3 years (60.5–65.7) in 2017. The increase varied from 3.8 years (3.4–4.1) in high SDI countries to 10.5 years (9.8–11.2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1.0 year (0.4–1.7) in Saint Vincent and the Grenadines (62.4 years [59.9–64.7] in 1990 to 63.5 years [60.9–65.8] in 2017) to 23.7 years (21.9–25.6) in Eritrea (30.7 years [28.9–32.2] in 1990 to 54.4 years [51.5–57.1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1.4 years (0.6–2.3) in Algeria to 11.9 years (10.9–12.9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75.8 years [72.4–78.7]) and males (72.6 years [69.8–75.0]) and the lowest estimates were in Central African Republic (47.0 years [43.7–50.2] for females and 42.8 years [40.1–45.6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardized DALY rates decreased by 41.3% (38.8–43.5) for communicable diseases and by 49.8% (47.9–51.6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40.1% (36.8–43.0), although age-standardized DALY rates decreased by 18.1% (16.0–20.2).

Interpretation

With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximize HALE, such as risk prevention and attention to upstream determinants of health.

Abstract

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesizing evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations.

Methods

We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life years (DALYs), by age group, sex, year, and location for 84 behavioral, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46,749 randomized controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modeling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioral risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.

Findings

In 2017, 34.1 million (95% uncertainty interval [UI] 33.3–35.0) deaths and 1.21 billion (1.14–1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6–62.4) of deaths and 48.3% (46.3–50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39–11.5) deaths and 218 million (198–237) DALYs, followed by smoking (7.10 million [6.83–7.37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6.53 million [5.23–8.23] deaths and 171 million [144–201] DALYs), high body mass index (BMI; 4.72 million [2.99–6.70] deaths and 148 million [98.6–202] DALYs), and short gestation for birthweight (1.43 million [1.36–1.51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3–6.5) between 2007 and 2017. In the absence of demographic changes (i.e., population growth and aging), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardized DALY rates was high SBP in four super-regions: Central Europe, Eastern Europe, and Central Asia; North Africa and Middle East; South Asia; and Southeast Asia, East Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in North Africa and the Middle East were notably low.

Interpretation

By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and program efforts might have been successful and highlights current priorities for public health action. Decreases in behavioral, environmental, and occupational risks have largely offset the effects of population growth and aging, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population aging will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision-making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesizing data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.

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