MBW complexes impinge on anthocyanidin reductase gene regulation for proanthocyanidin biosynthesis in persimmon fruit

[EN] MBW protein complexes containing MYB, bHLH and WD40 repeat factors are known transcriptional regulators of secondary metabolites production such as proanthocyanidins and anthocyanins, and developmental processes such as trichome formation in many plant species. DkMYB2 and DkMYB4 (MYB-type), DkMYC1 (bHLH-type) and DkWDR1 (WD40-type) factors have been proposed by different authors to take part of persimmon MBW complexes for proanthocyanidin accumulation in immature fruit, leading to its characteristic astringent flavour with important agronomical and ecological effects. We have confirmed the nuclear localization of these proteins and their mutual physical interaction by bimolecular fluorescence complementation analysis. In addition, transient expression of DkMYB2, DkMYB4 and DkMYC1 cooperatively increase the expression of a persimmon anthocyanidin reductase gene (ANR), involved in the biosynthesis of cis-flavan-3-ols, the structural units of proanthocyanidin compounds. Collectively, these data support the presence of MBW complexes in persimmon fruit and suggest their coordinated participation in ANR regulation for proanthocyanidin production.This work was funded by the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA)-FEDER (grant no. RF2013-00043-C02-02 and RTA2017-00011-C03-01). FG-M was funded by a fellowship co-financed by the Generalitat Valenciana and European Social Fund (2014 2020) (grant no. ACIF/2016/115).Gil Muñoz, F.; Sanchez Navarro, JA.; Besada Ferreiro, CM.; Salvador Perez, AA.; Badenes Catala, M.; Naval Merino, MDM.; Rios Garcia, G. (2020). MBW complexes impinge on anthocyanidin reductase gene regulation for proanthocyanidin biosynthesis in persimmon fruit. Scientific Reports. 10:1-11. https://doi.org/10.1038/s41598-020-60635-wS11110Dixon, R. A., Xie, D.-Y. & Sharma, S. B. Proanthocyanidins–a final frontier in flavonoid research? New Phytol. 165, 9–28 (2005).Yonemori, K. & Matsushima, J. Property of development of the tannin cells in non-astringent type fruits of Japanese persimmon (Diospyros kaki) and its relationship to natural deastringency. J. Jpn. Soc. Hortic. Sci. 54, 201–208 (1985).Salvador, A. et al. Physiological and structural changes during ripening and deastringency treatment of persimmon fruit cv. ‘Rojo Brillante’. Postharvest Biol. Tec. 46, 181–188 (2007).Bernays, E. A., Driver, G. C. & Bilgener, M. Herbivores and plant tannins. In Advances in Ecological Research (eds. Begon, M., Fitter, A. H., Ford, E. D. & MacFadyen, A.) 19, 263–302 (Academic Press, 1989).Tessmer, M. A. et al. Microstructural changes while persimmon fruits mature and ripen. Comparison between astringent and non-astringent cultivars. Postharvest Biol. Tec. 120, 52–60 (2016).Nishiyama, S. et al. Characterization of a gene regulatory network underlying astringency loss in persimmon fruit. Planta 247, 733–743 (2018).Sugiura, A., Yonemori, K., Harada, H. & Tomama, T. Changes of ethanol and acetaldehyde contents in Japanese persimmon fruits and their relation to natural deastringency. Studies from Inst. Hort. Kyoto Univ. 9, 41–47 (1979).Sugiura, A. & Tomana, T. Relationships of ethanol production by seeds of different types of Japanese persimmons and their tannin content. HortSci. 18, 319–321 (1983).Ben-Arie, R. & Sonego, L. Temperature affects astringency removal and recurrence in persimmon. J. Food Sci. 58, 1397–1400 (1993).Matsuo, T. & Itoo, S. A model experiment for de-astringency of persimmon fruit with high carbon dioxide treatment: in vitro gelation of kaki-tannin by reacting with acetaldehyde. Agr. Biol. Chem. Tokyo 46, 683–689 (1982).Pesis, E. & Ben-Arie, R. Involvement of acetaldehyde and ethanol accumulation during induced deastringency of persimmon fruits. J. Food Sci. 49, 896–899 (1984).Kanzaki, S., Yonemori, K., Sugiura, A., Sato, A. & Yamada, M. Identification of molecular markers linked to the trait of natural astringency loss of Japanese persimmon (Diospyros kaki) fruit. J. Am. Soc. Hortic. Sci. 126, 51–55 (2001).Yamada, M. & Sato, A. Segregation for fruit astringency type in progenies derived from crosses of ‘Nishimurawase’×pollination constant non-astringent genotypes in oriental persimmon (Diospyros kaki Thunb.). Sci. Hortic.-Amsterdam 92, 107–111 (2002).Besada, C. et al. Chloride stress triggers maturation and negatively affects the postharvest quality of persimmon fruit. Involvement of calyx ethylene production. Plant Physiol. Biochem. 100, 105–112 (2016).Lepiniec, L. et al. Genetics and biochemistry of seed flavonoids. Annu. Rev. Plant Biol. 57, 405–430 (2006).Tanner, G. J. et al. Proanthocyanidin biosynthesis in plants. Purification of legume leucoanthocyanidin reductase and molecular cloning of its cDNA. J. Biol. Chem. 278, 31647–31656 (2003).Xie, D.-Y., Sharma, S. B., Paiva, N. L., Ferreira, D. & Dixon, R. A. Role of anthocyanidin reductase, encoded by BANYULS in plant flavonoid biosynthesis. Science 299, 396–399 (2003).Ikegami, A., Eguchi, S., Kitajima, A., Inoue, K. & Yonemori, K. Identification of genes involved in proanthocyanidin biosynthesis of persimmon (Diospyros kaki) fruit. Plant Science 172, 1037–1047 (2007).Akagi, T. et al. Expression balances of structural genes in shikimate and flavonoid biosynthesis cause a difference in proanthocyanidin accumulation in persimmon (Diospyros kaki Thunb.) fruit. Planta 230, 899–915 (2009).Baudry, A. et al. TT2, TT8, and TTG1 synergistically specify the expression of BANYULS and proanthocyanidin biosynthesis in Arabidopsis thaliana. Plant J. 39, 366–380 (2004).Xu, W. et al. Complexity and robustness of the flavonoid transcriptional regulatory network revealed by comprehensive analyses of MYB-bHLH-WDR complexes and their targets in Arabidopsis seed. New Phytol. 202, 132–144 (2014).Xu, W., Dubos, C. & Lepiniec, L. Transcriptional control of flavonoid biosynthesis by MYB-bHLH-WDR complexes. Trends Plant Sci. 20, 176–185 (2015).Hichri, I. et al. The basic helix-loop-helix transcription factor MYC1 is involved in the regulation of the flavonoid biosynthesis pathway in grapevine. Mol. Plant 3, 509–523 (2010).Schaart, J. G. et al. Identification and characterization of MYB-bHLH-WD40 regulatory complexes controlling proanthocyanidin biosynthesis in strawberry (Fragaria × ananassa) fruits. New Phytol. 197, 454–467 (2013).Gesell, A., Yoshida, K., Tran, L. T. & Constabel, C. P. Characterization of an apple TT2-type R2R3 MYB transcription factor functionally similar to the poplar proanthocyanidin regulator PtMYB134. Planta 240, 497–511 (2014).Naval, M. et al. A WD40-repeat protein from persimmon interacts with the regulators of proanthocyanidin biosynthesis DkMYB2 and DkMYB4. Tree Genet. Genomes 12, 13 (2016).Akagi, T. et al. DkMyb4 is a Myb transcription factor involved in proanthocyanidin biosynthesis in persimmon fruit. Plant Physiol. 151, 2028–2045 (2009).Akagi, T., Ikegami, A. & Yonemori, K. DkMyb2 wound-induced transcription factor of persimmon (Diospyros kaki Thunb.), contributes to proanthocyanidin regulation. Planta 232, 1045–1059 (2010).Su, F., Hu, J., Zhang, Q. & Luo, Z. Isolation and characterization of a basic Helix–Loop–Helix transcription factor gene potentially involved in proanthocyanidin biosynthesis regulation in persimmon (Diospyros kaki Thunb.). Sci. Hortic.-Amsterdam 136, 115–121 (2012).Hribal, J., Zavrtanik, M., Simćić, M. & Vidrih, R. Changes during storing and astringency removal of persimmon fruit Diospyros kaki L. Acta Aliment. Hung. 29, 123–136 (2000).Nesi, N., Jond, C., Debeaujon, I., Caboche, M. & Lepiniec, L. The Arabidopsis TT2 gene encodes an R2R3 MYB domain protein that acts as a key determinant for proanthocyanidin accumulation in developing seed. Plant Cell 13, 2099–2114 (2001).Zhao, M., Morohashi, K., Hatlestad, G., Grotewold, E. & Lloyd, A. The TTG1-bHLH-MYB complex controls trichome cell fate and patterning through direct targeting of regulatory loci. Development 135, 1991–1999 (2008).Weill, U. et al. Assessment of GFP tag position on protein localization and growth Fitness in yeast. J. Mol. Biol. 431, 636–641 (2019).Wang, P. et al. A sucrose-induced MYB (SIMYB) transcription factor promoting proanthocyanidin accumulation in the tea plant (Camellia sinensis). J. Agric. Food Chem. 67, 1418–1428 (2019).Baudry, A., Caboche, M. & Lepiniec, L. TT8 controls its own expression in a feedback regulation involving TTG1 and homologous MYB and bHLH factors, allowing a strong and cell-specific accumulation of flavonoids in Arabidopsis thaliana. Plant J. 46, 768–779 (2006).Albert, N. W. et al. A conserved network of transcriptional activators and repressors regulates anthocyanin pigmentation in eudicots. Plant Cell 26, 962–980 (2014).Bellini, E. Cultural practices for persimmon production. In Options Méditerranéennes. Série A: Séminaires Méditerranéens (CIHEAM) (eds. Bellini, E. & Giordani, E.) 51. 39–52 (CIHEAM-IAMZ, 2002).Taira, S. Astringency in Persimmon. In Fruit Analysis (eds. Linskens, H. F. & Jackson, J. F.) 97–110 (Springer Berlin Heidelberg, 1995).Arnal, L. & Rio, M. A. D. Quality of persimmon fruit cv. Rojo brillante during storage at different temperatures. Span. J. Agric. Res. 2, 243–247 (2004).Akagi, T., Henry, I. M., Tao, R. & Comai, L. A Y-chromosome–encoded small RNA acts as a sex determinant in persimmons. Science 346, 646–650 (2014).Doyle, J. J. & Doyle, J. L. A rapid DNA isolation procedure for small quantities of fresh leaf tissue. Phytochemical Bulletin 19, 11–15 (1987).Herranz, M. C., Sanchez-Navarro, J. A., Aparicio, F. & Pallás, V. Simultaneous detection of six stone fruit viruses by non-isotopic molecular hybridization using a unique riboprobe or ‘polyprobe’. J. Virol. Methods 124, 49–55 (2005).Leastro, M. O., Pallás, V., Resende, R. O. & Sánchez-Navarro, J. A. The movement proteins (NSm) of distinct tospoviruses peripherally associate with cellular membranes and interact with homologous and heterologous NSm and nucleocapsid proteins. Virology 478, 39–49 (2015).Knoester, M. et al. Ethylene-insensitive tobacco lacks nonhost resistance against soil-borne fungi. Proc. Natl. Acad. Sci. USA 95, 1933–1937 (1998).Hellens, R. P., Edwards, E. A., Leyland, N. R., Bean, S. & Mullineaux, P. M. pGreen: a versatile and flexible binary Ti vector for Agrobacterium-mediated plant transformation. Plant Mol. Biol. 42, 819–832 (2000).Hamilton, C. M., Frary, A., Lewis, C. & Tanksley, S. D. Stable transfer of intact high molecular weight DNA into plant chromosomes. Proc. Natl. Acad. Sci. USA 93, 9975–9979 (1996).Genovés, A., Pallás, V. & Navarro, J. A. Contribution of topology determinants of a viral movement protein to its membrane association, intracellular traffic, and viral cell-to-cell movement. J. Virol. 85, 7797–7809 (2011).Aparicio, F., Sánchez-Navarro, J. A. & Pallás, V. In vitro and in vivo mapping of the Prunus necrotic ringspot virus coat protein C-terminal dimerization domain by bimolecular fluorescence complementation. J. Gen. Virol. 87, 1745–1750 (2006).Laemmli, U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).Gambino, G., Perrone, I. & Gribaudo, I. A Rapid and effective method for RNA extraction from different tissues of grapevine and other woody plants. Phytochem. Anal. 19, 520–525 (2008)

Plant Breeding and Management Strategies to Minimize the Impact of Water Scarcity and Biotic Stress in Cereal Crops under Mediterranean Conditions

Wheat and rice are two main staple food crops that may suffer from yield losses due to drought episodes that are increasingly impacted by climate change, in addition to new epidemic outbreaks. Sustainable intensification of production will rely on several strategies, such as efficient use of water and variety improvement. This review updates the latest findings regarding complementary approaches in agronomy, genetics, and phenomics to cope with climate change challenges. The agronomic approach focuses on a case study examining alternative rice water management practices, with their impact on greenhouse gas emissions and biodiversity for ecosystem services. The genetic approach reviews in depth the latest technologies to achieve fungal disease resistance, as well as the use of landraces to increase the genetic diversity of new varieties. The phenomics approach explores recent advances in high-throughput remote sensing technologies useful in detecting both biotic and abiotic stress effects on breeding programs. The complementary nature of all these technologies indicates that only interdisciplinary work will ensure significant steps towards a more sustainable agriculture under future climate change scenarios.info:eu-repo/semantics/publishedVersio

Design and methodological characteristics of studies using observational routinely collected health data for investigating the link between cancer and neurodegenerative diseases: protocol for a meta-research study

Introduction: Health services generate large amounts of routine health data (eg, administrative databases, disease registries and electronic health records), which have important secondary uses for research. Increases in the availability and the ability to access and analyse large amounts of data represent a major opportunity for conducting studies on the possible relationships between complex diseases. The objective of this study will be to evaluate the design, methods and reporting of studies conducted using observational routinely collected health data for investigating the link between cancer and neurodegenerative diseases. Methods and analysis: This is the protocol for a meta-research study. We registered the study protocol within the Open Science Framework: https://osf.io/h2qjg. We will evaluate observational studies (eg, cohort and case-control) conducted using routinely collected health data for investigating the associations between cancer and neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis/motor neuron disease, Huntington's disease, multiple sclerosis and Parkinson's disease). The following electronic databases will be searched (from their inception onwards): MEDLINE, Embase and Web of Science Core Collection. Screening and selection of articles will be conducted by at least two researchers. Potential discrepancies will be resolved via discussion. Design, methods and reporting characteristics in each article will be extracted using a standardised data extraction form. Information on general, methodological and transparency items will be reported. We will summarise our findings with tables and graphs (eg, bar charts, forest plots). Ethics and dissemination: Due to the nature of the proposed study, no ethical approval will be required. We plan to publish the full study in an open access peer-reviewed journal and disseminate the findings at scientific conferences and via social media. All data will be deposited in a cross-disciplinary public repository.FC-L and RT-S are supported by the Institute of Health Carlos III/CIBERSAM. MJP is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200101618). MR and EB-D are partially funded by the Spanish Health Services Research on Chronic Patients Network (REDISSEC)/Institute of Health Carlos III.S

TEMÁTICA SEGURANÇA DO PACIENTE NAS MATRIZES CURRICULARES DE ESCOLAS DE GRADUAÇÃO EM ENFERMAGEM E OBSTETRÍCIA

Objetivos: categorizar a temática segurança do paciente nas matrizes curriculares de cursos de graduação em enfermagem e obstetrícia. Método: Estudo documental, desenvolvido em nove universidades no período de junho de 2013 a março de 2014. Foram elencadas 16 palavras-chave diretas e 12 indiretas e categorizadas conforme o Patient safety curriculum guide: multi-professional edition.  Resultados: As palavras-chave diretas e indiretas foram encontradas em 168 disciplinas, sendo Segurança do Paciente (20,4%) e Lei do Exercício Profissional (13,7%) as diretas mais frequentes, enquanto que as indiretas foram Sistematização da Assistência em Enfermagem (42,1%) e Biossegurança (10,0%). Conclusão: A temática segurança do paciente foi encontrada nos conteúdos programáticos analisados, porém de maneira desarticulada; tornando-se imperativo buscar estratégias de ensino, que repercutam na formação do estudante. Descritores: Segurança do paciente; Currículo; Enfermagem; Obstetrizes

Treatment of nonmetastatic unilateral retinoblastoma in children

IMPORTANCE: Multi-institutional collaborative studies that include large patient populations for the management of retinoblastoma with histopathological risk factors could provide important information for patient management. OBJECTIVE: To evaluate the implementation of a strategy for the management of nonmetastatic unilateral retinoblastoma in children based on standardized diagnostic and treatment criteria. DESIGN, SETTING, AND PARTICIPANTS: This single-arm prospective study applied a strategy based on a single-center experience. The setting was a multicenter study in Latin America (Grupo de America Latina de Oncologia Pediatrica [GALOP]). Participants were children with nonmetastatic unilateral retinoblastoma (staged with the International Retinoblastoma Staging System). The study opened on July 1, 2008, and closed on December 31, 2014. Follow-up was updated until June 30, 2017. INTERVENTIONS: Stage 0 patients (without enucleation) were given conservative therapy without a protocol. Stage I patients (with enucleation and no residual tumor) were divided into a high-risk group (retrolaminar invasion and/or scleral invasion) and a low-risk group (all remaining patients). High-risk children received adjuvant chemotherapy with 4 alternating cycles of regimen 1 (cyclophosphamide [65mg/kg/d] [plus sodium-2-mercaptoethane sulfonate], idarubicin hydrochloride [10mg/m2/d], and vincristine sulfate [0.05mg/kg/d]) and 4 cycles of regimen 2 (carboplatin [500mg/m2/d, days 1 and 2] and etoposide [100mg/m2/d, days 1-3]). Low-risk children did not receive adjuvant therapy. Children with buphthalmia received neoadjuvant and adjuvant chemotherapy for a total of 8 cycles. MAIN OUTCOMES AND MEASURES: Probability of event-free survival (extraocular relapse and death from any cause were considered events). RESULTS: Among 187 children registered in the study, 175 were evaluable (92 [52.5%] female; median age, 22 months; age range, 3-100 months). Forty-two were stage 0 children, 84 were stage I low-risk children, and 42 were stage I high-risk children; there were 7 children in the buphthalmia group. With a median follow-up of 46 months, the 3-year probability of event-free survival was 0.97 (95%CI, 0.94-0.99), and the probability of overall survival was 0.98 (95%CI, 0.94-1.00). Stage 0 patients had no events, stage I low-risk patients had 1 event (orbital relapse treated with second-line therapy), stage I high-risk patients had 2 events (1 central nervous system relapse and 1 death from sepsis), and the buphthalmia group had 1 event (orbital relapse, followed by central nervous relapse and death). CONCLUSIONS AND RELEVANCE: Adjuvant therapymay be effective for high-risk unilateral retinoblastoma but is toxic, and neoadjuvant chemotherapy for buphthalmus appears feasible.Fil: Pérez, Verónica. Hospital San Juan de Dios; ChileFil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Rey, Guadalupe. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Parareda Salles, Andreu. Hospital Sant Joan de Déu; EspañaFil: Kopp, Katherine. Hospital Dr. Luis Calvo Mackenna Hospital; ChileFil: Dabezies, Agustín P.. Hospital Pereyra Rossell; UruguayFil: Dufort, Gustavo. Hospital Pereyra Rossell; UruguayFil: Zelter, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: López, Juan P.. Hospital Calvo Mackenna; ChileFil: Urbieta, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Alcalde Ruiz, Elisa. Hospital Dr. Luis Calvo Mackenna Hospital; ChileFil: Catala Mora, Jaume. Hospital Sant Joan de Déu; EspañaFil: Suñol, Mariona. Hospital Sant Joan de Déu; EspañaFil: Ossandon, Diego. Hospital San Juan de Dios; ChileFil: Fandiño, Adriana Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Croxatto, Juan Oscar. Fundación Oftalmología Argentina "J. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: De Dávila, María T. G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Reaman, Gregory. Center for Drug Evaluation and Research; Estados UnidosFil: Ravindranath, Yaddanapudi. Children’s Hospital of Michigan; Estados UnidosFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Altered Antioxidant-Oxidant Status in the Aqueous Humor and Peripheral Blood of Patients with Retinitis Pigmentosa

Retinitis Pigmentosa is a common form of hereditary retinal degeneration constituting the largest Mendelian genetic cause of blindness in the developed world. It has been widely suggested that oxidative stress possibly contributes to its pathogenesis. We measured the levels of total antioxidant capacity, free nitrotyrosine, thiobarbituric acid reactive substances (TBARS) formation, extracellular superoxide dismutase (SOD3) activity, protein, metabolites of the nitric oxide/cyclic GMP pathway, heme oxygenase-I and inducible nitric oxide synthase expression in aqueous humor or/and peripheral blood from fifty-six patients with retinitis pigmentosa and sixty subjects without systemic or ocular oxidative stress-related disease. Multivariate analysis of covariance revealed that retinitis pigmentosa alters ocular antioxidant defence machinery and the redox status in blood. Patients with retinitis pigmentosa present low total antioxidant capacity including reduced SOD3 activity and protein concentration in aqueous humor. Patients also show reduced SOD3 activity, increased TBARS formation and upregulation of the nitric oxide/cyclic GMP pathway in peripheral blood. Together these findings confirmed the hypothesis that patients with retinitis pigmentosa present reduced ocular antioxidant status. Moreover, these patients show changes in some oxidative-nitrosative markers in the peripheral blood. Further studies are needed to clarify the relationship between these peripheral markers and retinitis pigmentosa

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

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, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury