Biophysical studies of the tachykinin peptides : structural characterization and membrane interactions /

En aquesta tesi doctoral, s'han aplicat metodologies biofísiques per estudiar i caracteritzar l'estructura dels pèptids substància P (SP), neuroquinina A (NKA) i scyliorinina I (ScyI), que pertanyen a la família de les taquiquinines (TK), així com la seva manera d'interacció amb membranes model. Els pèptids TKS són agonistes dels receptors de neuroquinina acoblats a la proteïna G. Els TKS estan involucrats en diversos processos fisiològics i malalties com el càncer, malalties neurodegeneratives i respostes inflamatòries, i això els converteix en un objecte de gran interès per a l'estudi estructural en la recerca d'agents terapèuticament rellevants. Els tres pèptids SP, NKA i ScyI mostren una seqüència comuna en el domini C-terminal i es diferencien en el seu domini N-terminal. Per tant, sorgeixen preguntes: Què determina el seu diferent potencial d'activació? Quina és la conformació activa dels pèptids quan interactuen amb el receptor de NK per transferir la senyal? Quina és la seva manera d'interacció amb la superfície de la membrana? La superfície de la membrana, afecta la conformació del pèptid? Tenen els pèptids capacitat d'associar-se i si és així, quin tipus d'estructures formen i en quines condicions? A la primera part dels resultats i discussió, s'utilitzen diferents mètodes d'espectroscòpia de fluorescència, per estudiar les interaccions dels sistemes de membranes amb TKS mimètics (micel·les SDS i vesícules DMPG / DMPC). Les cadenes laterals Trp i Phe CN es van utilitzar com fluoròfors intrínsecs, mentre la fluoresceïna fosfatidiletanolamina (FPE) i els lípids bromats es van utilitzar com sondes externes. Ja que SP i NKA no posseeixen el residu Trp, es va substituir el residu Phe en la posició 6 i 8 amb Trp, respectivament per als pèptids SP i NKA. L'espectroscòpia CD va confirmar la similitud de l'estructura general de SP i NKA amb els seus anàlegs. A més, mitjançant l'ús d'espectroscòpia de fluorescència de Trp (principalment λmax), es demostra que, en solució i en estat sub-micel·lar de SDS, la cadena lateral de Trp en SPW i NKAW està en un entorn hidròfob, mentre que apareix desplaçat a ambient hidrofílic després de la formació de micel·les. D'altra banda, l'espectroscòpia de CD mostra la transició de l'estructura PPII dominant en solució, a estructura α helicoïdal (en cas de SP i ScyI) o a la barreja de conformació desordenada i d'hèlix α (en el cas de NKA) una vegada es formen micel · les. Aplicant una metodologia de fluorescència diferent, ha sigut possible separar el procés d'unió del pèptid a la superfície de la membrana, del procés d'inserció del pèptid / plegament al nucli hidrofòbic. SP, NKA i ScyI interaccionen amb DMPC i amb els liposomes amb càrrega negativa DMPG. No obstant això, les afinitats d'unió dels pèptids als liposomes de DMPC estan en el rang de 20-40 vegades menor, en comparació amb les afinitats a DMPG. A més, les afinitats d'unió de SP, NKA i ScyI correlacionen amb les seves càrregues netes, quan interactuen amb DMPG, però no amb DMPC. A la segona part dels resultats i discussions, els factors que regeixen les estructures secundàries de les taquiquinines en estat monomèric (com el medi, la càrrega neta del pèptid i la càrrega superficial de la membrana) s'estudien per espectroscòpia CD. A més, es va aplicar la dispersió de raigs X d'angle petit per determinar l'estructura secundària del NKA en solució. En solució aquosa, l'estructura dominant de totes les taquiquininas és PPII. Per espectroscòpia d'infraroig, l'estructura flexible desordenada es va detectar per les taquiquininas en una concentració de 1,5 mM en solució. A més, en aquestes condicions, les estructures girs β i estructures esteses de làmina β es van detectar, respectivament, per SP i ScyI. En TFE, l'estructura dominant de les taquiqinines és helicoïdal, indicant la propensió helicoïdal intrínsec dels pèptids. Igual que en solució, les taquiquinines mostren estructura PPII en presència de vesícules d'ions híbrids. En els liposomes carregats negativament, SP i ScyI posseeixen estructura α mentre NKA mostra una barreja d'estructura desordenada i conformacions en hèlix α. Els canvis conformacionals de les taquiquinines en augmentar la fracció de DMPG de la vesícula composta de DMPC / DMPG demostren clarament que l'estructura α dels pèptids depèn fortament de la quantitat relativa de DMPG aniònic en les vesícules. Això reflecteix la importància de les interaccions electrostàtiques dels pèptids amb els caps de la membrana. A la part III dels resultats i discussió, s'estudia l'estat d'agregació de les taquiquinines. Es mostra que les taquiquinines són capaces de formar estructures fibril·lars. En solució, les taquiquinines a una concentració de 3 mM formen fibril·les amb diferent morfologia. En SP, es veuen llargues fibril·les retorçades i filaments individuals rectes, mentre que en ScyI i NKA només s'observen fibril·les rectes. Les taquiquinines en una concentració per sobre de 1,5 mm formen fibril·les immediatament en presència de vesícules de càrrega negativa, mentre que no es van detectar en les fibril·les de DMPC. Aquest fet indica la importància de les càrregues negatives en el procés de fibril·lizació. L'espectroscòpia FTIR mostra un augment significatiu de l'estructura de làmina β per les taquiquinines a una concentració de 3 mM i en presència de les vesícules de DMPG, que s'atribueix a la formació de fibril·les. A més, en aquesta condició, FTIR mostra estructura helicoïdal en tots els TKS i algunes conformacions de gir β per SP i NKA. Sobre la base de TEM i espectroscòpia de CD, es mostra que la fibril·lizació de SP (100 mM) es produeix durant la transició d'estructura PPII a fulla β després de la incubació en concentracions de SDS prop de la CMC. En contrast, SPW no mostra fibril·lizació en les mateixes condicions. Sobre la base d'assaig THT, es van detectar fibril·les amiloides per NKA però de moment no tenim cap evidència sobre la formació amiloide en SP i ScyI. Els resultats indiquen que la formació d'amiloide en NKA disminueix a pH alcalí. En contrast, NKAW és capaç de formar fibril·les amiloides a pH àcid i alcalí però no a pH neutre. Analitzant l'activitat metabòlica de la línia cel·lular PC12 mitjançant la prova de T03, es demostra que NKA a una concentració de més de 25 µM pot induir toxicitat, mentre que no es va observar cap disminució significativa de l'activitat metabòlica en presència de fins a 250 µM de SP o de ScyIIn this doctoral thesis, biophysical methodologies were applied to study and characterize the structures of substance P (SP), neurokinin A (NKA) and scyliorhinin I (ScyI) peptides, which belong to the tachykinin (TK) family, and their mode of interaction with model membranes. The TKs peptides are agonists of Neurokinin G-protein coupling receptors. TKs are involved in several physiological processes and diseases such as neurodegenerative disorders, cancer and inflammatory responses, what make them an object of high interest for structural study in search of relevant therapeutically agents. The three peptides SP, NKA and ScyI are homologous sharing common C domain -terminal and differ in their N terminal domain. Therefore, questions arise: What determine their different activity potential? What is the active conformation of the peptides when they interact with the NK receptor to transfer the signal? What is their mode of interaction with the membrane surface? Does the membrane surface affect the peptide conformation? Do the peptides self associate and if they have these ability, what kind of structure they form and at which conditions? In part I of the Results and Discussion, by using different fluorescence spectroscopy approaches, the mode of the interactions of TKs with membrane mimetic systems (SDS micelles and DMPG/DMPC vesicles) were studied. The Trp and Phe-CN amino acids were used as intrinsic fluorophores, while fluorescein phosphatidylethanolamine (FPE) and brominated lipids were used as external probes. Since SP and NKA lack the intrinsic Trp residue, we substituted Phe residue in position 6 and 8 with Trp, respectively for SP and NKA peptides. CD spectroscopy confirmed the similarity of the overall structure of SP and NKA with their analogues. Furthermore, by using Trp fluorescence spectroscopy (mainly λmax), we understood that in solution and in sub-micellar state of SDS, the Trp side chain of SPW and NKAW are in a hydrophobic environment, while they appear displaced to hydrophilic environment upon formation of micelles. On the other hand, CD spectroscopy show the transition of the dominant PPII helical structure in solution to α helical structure (in case of SP and ScyI) or to the mixture of unordered and α helical conformation (in the case of NKA) upon formation of micelles. Applying different fluorescence methodology it was possible to separate the process of peptide binding to a membrane surface from the process of peptide insertion/folding into the hydrophobic core. SP, NKA and ScyI bind to both zwitterionic DMPC and negatively charged DMPG liposomes. However, binding affinities of the peptides to DMPC liposomes are in the range 20-40 times lower, compared to the affinities to DMPG. Moreover the binding affinities of SP, NKA and ScyI correlate with their net charges, when they interact with DMPG, but not with DMPC. In part II of the Results and Discussions, the factors governing the secondary structures of the tachykinins in monomeric state (such as environment, peptide net charge and membrane surface charge) are studied by CD spectroscopy. Moreover, small angle X-ray scattering was applied to determine the NKA secondary structure in solution. In aqueous solution, the dominant structure of all tachykinins is PPII. By FTIR spectroscopy, flexible unordered structure was detected for tachykinins in a concentration of 1.5 mM in solution. Moreover, in these condition, β turn and extended β sheet structures were detected, respectively for SP and ScyI. In the TFE the dominant structure of tachykinins is alpha helical which indicates the intrinsic helical propensity of peptides. Like in solution, tachykinins have PPII structure in the presence of the zwitterionic vesicles. In negatively charged liposomes, SP and ScyI are in α helical structure while NKA shows a mixture of the unordered and α helical conformations. Conformational changes of tachykinins upon increasing of the DMPG fraction of the vesicle composed of DMPC/DMPG demonstrate clearly that the α helical fold of peptides strongly depends on the relative amount of anionic DMPG in the vesicles and reflecting the importance of the electrostatic interactions of peptides with headgroup of the membrane. In part III of the Results and Discussion, the aggregation state of the tachykinins is studied. We understood that tachykinins are able to form fibrillar structures. In solution, 3 mM of tachykinins formed fibrils with different morphology. In SP long twisted fibrils and straight single filaments were seen while in ScyI and NKA fibrils are only single-straight. Tachykinins in a concentration of above 1.5 mM formed fibrils immediately in the presence of negatively charge vesicles, while no fibrils were detected in DMPC for any tachykinins. This fact indicates the importance of the negatively surface charges on fibrillization. FTIR spectroscopy shows a significant increase of the β sheet structure for tachykinins in a concentration of 3 mM and in the presence of the DMPG vesicles which is attributed to the fibrils formation. Moreover, in this condition, FTIR shows helical structure in all TKs and some β turn conformations for SP and NKA. Based on TEM and CD spectroscopy, we understood that fibrillization of SP (100 µM) occurs upon transition of PPII structure of peptide to β sheet after incubation in SDS concentrations close to CMC. In contrast, SPW was not able to make fibrils in the same condition. Based on ThT assay, amiloid fibrils were detected for NKA but at the moment we do not have any evidence about the amiloid formation of SP and ScyI. Moreover we found that amyloid formation of NKA decreases at alkaline pH. In contrast, NKAW is able to form amyloid fibrils at acidic and alkaline pH but not at the neutral pH. Analyzing of the PC12 cell line metabolic activity by TMM test indicates that NKA in a concentration of more than 25 µM can induce toxicity, while no significant decrease of metabolic activity was seen in the presence of up to 250 µM SP or ScyI

The global, regional, and national burden of stomach cancer in 195 countries, 1990-2017 : a systematic analysis for the Global Burden of Disease study 2017

Background: Stomach cancer is a major health problem in many countries. Understanding the current burden of stomach cancer and the differential trends across various locations is essential for formulating effective preventive strategies. We report on the incidence, mortality, and disability-adjusted life-years (DALYs) due to stomach cancer in 195 countries and territories from 21 regions between 1990 and 2017. Methods: Estimates from GBD 2017 were used to analyse the incidence, mortality, and DALYs due to stomach cancer at the global, regional, and national levels. The rates were standardised to the GBD world population and reported per 100 000 population as age-standardised incidence rates, age-standardised death rates, and age-standardised DALY rates. All estimates were generated with 95% uncertainty intervals (UIs). Findings: In 2017, more than 1·22 million (95% UI 1·19–1·25) incident cases of stomach cancer occurred worldwide, and nearly 865 000 people (848 000–885 000) died of stomach cancer, contributing to 19·1 million (18·7–19·6) DALYs. The highest age-standardised incidence rates in 2017 were seen in the high-income Asia Pacific (29·5, 28·2–31·0 per 100 000 population) and east Asia (28·6, 27·3–30·0 per 100 000 population) regions, with nearly half of the global incident cases occurring in China. Compared with 1990, in 2017 more than 356 000 more incident cases of stomach cancer were estimated, leading to nearly 96 000 more deaths. Despite the increase in absolute numbers, the worldwide age-standardised rates of stomach cancer (incidence, deaths, and DALYs) have declined since 1990. The drop in the disease burden was associated with improved Socio-demographic Index. Globally, 38·2% (21·1–57·8) of the age-standardised DALYs were attributable to high-sodium diet in both sexes combined, and 24·5% (20·0–28·9) of the age-standardised DALYs were attributable to smoking in males. Interpretation: Our findings provide insight into the changing burden of stomach cancer, which is useful in planning local strategies and monitoring their progress. To this end, specific local strategies should be tailored to each country's risk factor profile. Beyond the current decline in age-standardised incidence and death rates, a decrease in the absolute number of cases and deaths will be possible if the burden in east Asia, where currently almost half of the incident cases and deaths occur, is further reduced. Funding: Bill & Melinda Gates Foundation

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

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

The unfinished agenda of communicable diseases among children and adolescents before the COVID-19 pandemic, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019

BACKGROUND: Communicable disease control has long been a focus of global health policy. There have been substantial reductions in the burden and mortality of communicable diseases among children younger than 5 years, but we know less about this burden in older children and adolescents, and it is unclear whether current programmes and policies remain aligned with targets for intervention. This knowledge is especially important for policy and programmes in the context of the COVID-19 pandemic. We aimed to use the Global Burden of Disease (GBD) Study 2019 to systematically characterise the burden of communicable diseases across childhood and adolescence. METHODS: In this systematic analysis of the GBD study from 1990 to 2019, all communicable diseases and their manifestations as modelled within GBD 2019 were included, categorised as 16 subgroups of common diseases or presentations. Data were reported for absolute count, prevalence, and incidence across measures of cause-specific mortality (deaths and years of life lost), disability (years lived with disability [YLDs]), and disease burden (disability-adjusted life-years [DALYs]) for children and adolescents aged 0-24 years. Data were reported across the Socio-demographic Index (SDI) and across time (1990-2019), and for 204 countries and territories. For HIV, we reported the mortality-to-incidence ratio (MIR) as a measure of health system performance. FINDINGS: In 2019, there were 3·0 million deaths and 30·0 million years of healthy life lost to disability (as measured by YLDs), corresponding to 288·4 million DALYs from communicable diseases among children and adolescents globally (57·3% of total communicable disease burden across all ages). Over time, there has been a shift in communicable disease burden from young children to older children and adolescents (largely driven by the considerable reductions in children younger than 5 years and slower progress elsewhere), although children younger than 5 years still accounted for most of the communicable disease burden in 2019. Disease burden and mortality were predominantly in low-SDI settings, with high and high-middle SDI settings also having an appreciable burden of communicable disease morbidity (4·0 million YLDs in 2019 alone). Three cause groups (enteric infections, lower-respiratory-tract infections, and malaria) accounted for 59·8% of the global communicable disease burden in children and adolescents, with tuberculosis and HIV both emerging as important causes during adolescence. HIV was the only cause for which disease burden increased over time, particularly in children and adolescents older than 5 years, and especially in females. Excess MIRs for HIV were observed for males aged 15-19 years in low-SDI settings. INTERPRETATION: Our analysis supports continued policy focus on enteric infections and lower-respiratory-tract infections, with orientation to children younger than 5 years in settings of low socioeconomic development. However, efforts should also be targeted to other conditions, particularly HIV, given its increased burden in older children and adolescents. Older children and adolescents also experience a large burden of communicable disease, further highlighting the need for efforts to extend beyond the first 5 years of life. Our analysis also identified substantial morbidity caused by communicable diseases affecting child and adolescent health across the world. FUNDING: The Australian National Health and Medical Research Council Centre for Research Excellence for Driving Investment in Global Adolescent Health and the Bill & Melinda Gates Foundation

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.Peer reviewe

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe