149 research outputs found
Searching for molecular mechanisms sustaining tumor formation and progression in Neurofibromatosis type 1
No full textSUMMARY
Neurofibromatosis type 1 (NF1, OMIM # 162200), also known as von Recklinghausen, is an autosomal dominant disease caused by mutations of the NF1 gene coding a 2818 amino acid protein, neurofibromin (Nf1). More than 900 different mutations in the NF1 gene have been identified (HGMD, Human Genetic Mutation Database). Mutations of NF1 gene cause a variety of clinical manifestations such as the optic gliomas, neoplasms of the haematopoietic system and learning disabilities. However, the hallmark of NF1 is the development of multiple benign peripheral nerve sheath tumors called neurofibromas. Neurofibromas are complex tumors arising from peripheral nerve sheaths and mainly composed of Schwann Cells (SCs) homozygous for mutated NF1, mast cells (MCs) and fibroblasts (FBRs) both heterozygous for the same mutation. The plexiform variety can progress to highly malignant sarcomas termed Malignant Peripheral Nerve Sheath Tumors (MPNSTs), which are almost invariably lethal.
Up to now, any effective therapy able to either reduces neurofibroma size and its incidence or to counteract its formation, has not been developed yet. The main feature of neurofibroma is a rigid structure due to massive deposition of collagen of different types by activated FBRs. These cells, named myofibroblasts (mFBRs), are massively stimulated by mast cell-secreting Transcription Growth Factor-Beta (TGF-Beta) to produce growth factors such as Platelet Growth Factor (PDGF), Fibroblast Growth Factor (FGF) and collagen. This leads to both potent SCs proliferation and deposition of rigid extracellular matrix (ECM).
Cells’ haploinsufficient for Nf1 display hyper-activation of Rat Sarcoma (Ras), which further increases when Loss of Heterozigozyty (LOH) of NF1 occurs. Thus, the activation of Ras/ Rapidly Accelerated Fibrosarcoma (Raf) /Extracellular signal-regulated Kinase (ERK) signaling in SCs is sufficient to make them more susceptible to proliferative signals provided by a NF1+/- niche. However, the physiological response to Ras hyper-activation is cell-cycle arrest and/or senescence rather than transformation. Ras-mediated transformation of SCs probably relies on a step-wise process that integrates circuits of amplification signals from the local niche. A major component of the niche is the ECM, a complex network of macromolecules whose the elasticity (ranging from soft to stiff and rigid),contributes to development and cancer. ECM elasticity determines how a cell senses and perceives external forces and thus provides a major environmental cue that determines cell behavior. Indeed, the focal adhesion complex, which consists of integrins, multicomplex of adaptors and signaling proteins, can be viewed as a mechanosensor linking the actomyosin cytoskeleton with the ECM. How lack of Nf1 may impact on the complexity of ECM-cell dynamic and how the great rigidity of the ECM in neurofibromas influences SCs’ behavior, is still unknown. Among the three functional domains described in the Nf1 protein, a Focal Adhesion Kinas (FAK) binding domain has been identified and Nf1 has been shown to interact with FAK, paving the way for the enunciation of new hypothesis aimed to explain the route of SCs transformation toward cancer.
Rational: as in other tumors {Lu, 2012 #289}, {Yu, 2011 #292}), also in the plexiform neurofibromas, the tumorigenic phenotype of SCs is fostered by the amplification of integrated signaling pathways triggered by loss of Nf1, Ras hyper activation and deregulated ECM. Changes of the mechanical properties of ECM due to increased collagen secretion by mFBRs might actively contribute to tumor progression by influencing gene expression profile of the cells through the enhancement of Ras signaling pathway triggered by FAK. The deep investigation of these biological changes triggered in SCs by ECM formation is the goal of the present project.
Project Goals: To shed light into this issue, we intend 1) to generate a novel three-dimensional experimental model in vitro reproducing the multicellular complexity of neurofibromas with primary cells. Immortalized cells, indeed, are not suitable for our aims since the molecular oncologists consider the immortalization process as the first hit leading to tumorigenic phenotype, because of the changes which made for cell cycle control in gene expression 2) to assess the requirement ECM for SCs transformation in this new in vitro system identifying the proper ECM composition and stiffness in matrigel (structural and non structural components) required for neurofibroma’s formation.
Results:
Isolation of primary SCs and FBRs from Neurofibromas and their biological characterization:
1) We have already isolated and cultured in 2D our SCs and FBRs NF1+/- according to Serra methodology {Serra, 2000 #210}. These cells have been isolated from plexiform neurofibroma biopsies after informed consent of patients by our Milan and Rome University collaborators.
To get two populations of SCs and FBRs we have cultured cells in selective Medium (according to {Serra, 2000 #210}, and our new unpublished protocol) and characterized them biochemically by: S100B {Tucker, 2011 #321} and p75 markers specifically recognizing SCs and collagen I secretion, alpha smooth muscle actin (α-SMA) expression, Smad2/3 activation, Abl kinase activation characterizing mFBR activity {Kojima, 2010 #150}.
2) We have already obtained colonies of SCs growing in 3D in vitro system as described in step 1 and 2 (in transwell-like chambers to permit autocrine stimulation between mFBRs and SCs). Our preliminary data show that primary SCs generate colonies only when plated in an ECM/reconstituted basement membrane Collagen I-Matrigel of at list 3 mg/ml. However, we have still to set up the culture conditions to keep cells in highly proliferating state.
Preliminary indications in immortalized Mouse Embrionic Fibroblasts (MEFs)
In other cellular models as in mouse FBRs NF1-/-, we have found that the absence of Neurofibromin correlates with deregulation of FAK Y397 and Y925 phosphorylation both in absence of integrin clustering and after ligand stimulation. Further, the tumorigenesis assay showed that MEFNF1-/-ability to form colonies is affected by both MECK inhibitor and FAK inhibitor (Y15) indicating the cooperative role of FAK and PDGFBB growth factor in the tumorigenesis process mediated by Nf1. Consistently, immunoprecipitation experiments showed that in Nf1 null cells, Growth factor receptor-bound protein2 (Grb-2), the RAS pathway initiator, interacts with FAK also in absence of collagen in a PDGFBB ligand-dependent way, thus suggesting that FAK and growth factor receptors can cooperate to increase the Ras activity to a threshold required to induce tumorigenesis.SOMMARIO
Neurofibromatosi tipo 1 (NF1, OMIM # 162200), nota anche come di von Recklinghausen, è una malattia autosomica dominante causata da mutazioni del gene NF1 che codifica una proteina coi 2818 aminoacidi , detta neurofibromina (Nf). Più di 900 diverse mutazioni nel gene NF1 sono state identificate (HGMD, Database di mutazione genetica umana). Mutazioni del gene NF1 causano una varietà di manifestazioni cliniche quali il glioma ottico, neoplasie del sistema ematopoietico e disabilità dell'apprendimento. Tuttavia, il segno distintivo della NF1 è lo sviluppo dei tumori benigni nella guaina dei nervi periferici, chiamati neurofibromi. I neurofibromi sono tumori complessi originati da guaine nervose periferiche e costituiti prevalentemente da cellule di Schwann omozigote mutate per NF1, mastociti e fibroblasti entrambi eterozigoti per la stessa mutazione. I plessiformi possono progredire a sarcomi altamente maligni denominati MPNSTs (schwannomi maligni), che sono quasi sempre letali.
Ad oggi non e’ ancora stata sviluppata alcuna terapia efficace in grado di ridurre la dimensione e incidenza dei neurofibromi, o atta a contrastarne la formazione. La caratteristica principale dei neurofibromi è la loro struttura rigida conseguente alla massiccia deposizione di collagene prodotto dai fibroblasti attivati. Queste cellule, denominate miofibroblasti, sono fortemente stimolate da mastociti che producono fattore di crescita trascrizionale-Beta (TGF-Beta) per produrre poi fattori di crescita, come fattore di crescita piastrinico, fattore di crescita dei fibroblasti e collagene. Ciò comporta sia la potente proliferazione di cellule di Schwann che la deposizione di matrice extracellulare rigida.
Cellule aploinsufficienti per Nf1 comportano iperattivazione di Ras, che aumenta ulteriormente con LOH. L'attivazione di vie di segnale di Ras/Raf/ERK in cellule di Schwann rende le cellule più suscettibili ai segnali proliferativi forniti dalla nicchia NF1+/-. Tuttavia, la risposta fisiologica a Ras iperattivato è l’arresto del ciclo cellulare e/o senescenza piuttosto che trasformazione. La trasformazione Ras-mediata di cellule di Schwann probabilmente si basa su un procedimento che integra diversi segnali dipendenti da circuiti di amplificazione della nicchia stessa. Uno dei più importanti componenti della nicchia è la matrice extracellulare (ECM), una rete complessa di macromolecole con plasticità variabile che contribuisce alla progressione tumorale. L’elasticità di ECM determina la modalità con cui una cellula percepisce le forze esterne e quindi fornisce un importante spunto ambientale che determina il comportamento cellulare. In effetti le adesioni focali, che consistono di integrine, adattatori multicomplesi e proteine di segnale, possono essere visti come meccano-sensori che collegano il citoscheletro con la ECM. Come la mancanza di Nf1 possa avere un impatto significativo sulla complessità di dinamismo di ECM-cellula o come la grande rigidezza dell'ECM in neurofibroma influenzi il comportamento delle cellule di Schwann, è ancora sconosciuto. Tra i tre domini funzionali descritti nella proteina, un dominio di legame, FAK, sulla proteina è stato identificato e Nf1 ha mostrato di interagire con FAK, spianando la strada per l'enunciazione di una nuova ipotesi per spiegare il percorso trasformazionale delle cellule di Schwann verso il cancro.
Razionale: come in altri tumori {Lu, 2012 #289}, {Yu, 2011 #292}), anche nei neurofibromi plessiformi il fenotipo trasformato di SCs è favorito dall'amplificazione della segnalazione di percorsi integrati attivati sia da perdita di Nf1, Ras iperattivazione che deregolamentato di matrice extracellulare (ECM). Le modifiche delle proprietà meccaniche di ECM a causa dell'aumento di secrezione di collagene dai miofibroblasti potrebbe contribuire attivamente alla progressione del tumore, influenzando profili di espressione genica delle cellule attraverso la valorizzazione di segnale di Ras pathway generato dall'adesione focale (FAK). L'indagine in profondità di queste modificazioni biologiche attivate in SCs dalla formazione di ECM è l'obiettivo del presente progetto.
Al fine di far luce su questo argomento, abbiamo intenzione di 1) generare un nuovo modello sperimentale tridimensionale in vitro che riproduce la complessità di neurofibroma pluricellulari con le cellule primarie. Cellule immortalizzate, infatti, non sono adatte per i nostri scopi poiché gli oncologi molecolari consideranno il processo di immortalizzazione come il primo colpo che conduce al fenotipo oncogenico, a causa dei cambiamenti che sono stati fatti per il controllo del ciclo cellulare di espressione genica; 2) valutare l'esigenza di ECM nella trasformazione di cellule di Schwann cell (SCs) in questo nuovo sistema in vitro identificando la corretta composizione dell'ECM e rigidità in matrigel (strutturali e non strutturali) per formazione di neurofibroma.
Risultati:
Isolamento delle cellule di Schwann e Fibroblasti primarie da Neurofibromi e la loro caratterizzazione biologica:
1) Abbiamo già isolato e coltivato in 2D le nostre cellule di Schwann e Fibroblasti NF1+/- secondo la metodologia di Serra {Serra, 2000 #210}. Queste cellule sono state isolate da biopsie di neurofibromi plessiformi dopo aver consenso informato dei pazienti mediante i nostri collaboratori presso Università di Milano e di Roma.
Per ottenere due popolazioni delle cellule di Schwann e Fibroblasti abbiamo coltivato le cellule in terreno selettivo (secondo {Serra, 2000 #210}, e il nostro nuovo protocollo inedito) e caratterizzato dal punto di vista biochimico: S100B {Tucker, 2011 #321} e p75 marcatori che riconoscono specificamente le cellule di Schwann e secrezione del collagene di tipo I, espressione dell’actìna alfa del muscolo liscio (α-SMA), attivazione di Smad2/3, attivazione di abl chinasi e caratterizzare l'attività di myo-fibroblasti {Kojima, 2010 #150}.
2) abbiamo già ottenuto le colonie di cellule di Schwann cresciute nel sistema 3D in vitro come descritto nella fase 1 e 2 (in transwell-like chamber per permettere la stimolazione autocrina tra myofibroblasti e le cellule di Schwann). I nostri dati preliminari mostrano che le cellule primarie di Schwann generano delle colonie solo quando piastrate in una ECM/ membrana basale ricostituita del collagene di tipo I di Matrigel di almeno 3 mg/ml. Tuttavia, dobbiamo ancora impostare le condizioni migliori di cultura per mantenere le cellule altamente proliferanti.
Indicazioni preliminari in fibroblasti Embrionali immortalati Murini (MEFs)
In altri modelli cellulari come nel fibroblasti NF1-/- murini (MEFs), abbiamo trovato che l'assenza di neurofibromina scorrela con la deregolata di fosforilazione del FAK in Y397 e Y925 sia in assenza di raggruppamento di integrine che dopo la stimolazione con ligando. Inoltre, il saggio di tumorigenesi mostrava che la capacità di cellule di MEFNf1-/- di formare colonie è influenzata sia da inibitore di MECK che inibitore FAK Y15 indicante il ruolo di cooperatzione di FAK e PDGFBB, fattore di crescita, nel processo di tumorigenesi mediato da NF1. Coerentemente, gli esperimenti di immunoprecipitazione hanno mostrato che in cellule null NF1, il recettore del fattore di crescita di proteina legata2 (Grb-2), l’iniziatore di via di segnale di RAS, interagisce con FAK anche in assenza di collagene in un modo PDGFBB ligando-dipendente, suggerendo così che FAK e recettori di fattori di crescita possono cooperare per aumentare l'attività di Ras con un valore di soglia necessario per indurre la tumorigenesi
New technologies help the functional reconstruction in advanced-stage mandibular medication-related osteonecrosis of the jaw (MRONJ)
No full textA few words of friendship for Hoshyar Nooshin
No full text The aim of this paper is to evoke some events that the author shared with Professor Hoshyar Nooshin during more than forty years. Beyond scientific aspects, human relationships constituted the founding of an enthusiastic cooperation. </jats:p
Exposure to antiresorptive therapy with bisphosphonates does not induce histological changes in human alveolar jawbone
No full textAim: The identification of specific alterations in the alveolar jawbone of patients treated with nitrogen-containing bisphosphonates (NBP) but without bisphosphonate-related osteonecrosis of the jaw (BRONJ) may help to identify the early steps of BRONJ and to select patients at risk for it.
Materials and Methods: We performed a case-control study. Cases were 60 individuals treated with NBP without clinical and radiological signs of BRONJ and requiring surgical tooth extraction. Controls were 60 individuals never treated with NBP and requiring tooth extraction. Cases and controls were matched by sex (same) and age (within 5 years). 18 categorical (basophile reversal lines, osteoblasts, osteoblastic lines, osteocytes, empty osteocytic lacunae, osteoclasts, Howship’s lacunae, vessel dilatation, vascular congestion, arteriolar thickening, intravascular fat globules, calcific fat necrosis, fatty bone marrow, ruptured adipocytes, granular cytoplasm of adipocytes, oil cysts, perivascular fibrosis, diffuse fibrous metaplasia) and 2 ordinal histopathological variables (inflammation and bone maturation) were investigated. Exact univariable and multivariable (correction for gender and age) logistic regression was used to test the association between NBP use and the histopathological variables. Because of multiple comparisons, the critical p-value was set to 0.0025 (0.05/20).
Results: Cases and controls did not differ for any study variable except for vascular congestion that was significantly associated with NBP use (multivariable OR = 0.24, exact 95% CI 0.10 to 0.57 for cases vs. controls, p = 0.0006).
Conclusions: Use of NBP does not produce specific histological alveolar bone alterations in the absence of overt BRONJ disease
Elevation in Serum Irisin Levels after a Single Bout of Exercise do not Modulate Resting Energy Expenditure and Diet-induced Thermogenesis in Healthy Young Adults
No full text
Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017
No full textBackground 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 systetns, sample registration systetns, 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 8259 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 analysed separately and then incorporated into the estimation. We analyse 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 standardised and improved; and the analysis has been extended backwards 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 1000 livebirths in 1950 to 38.9 deaths (35.6-42.83) per 1000 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 tnales, 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, wotnen, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing
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
No full textBackground 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 39% (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-hatin 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
Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017
No full textBackground
Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017.
Methods
The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries—Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised.
Findings
At the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22·7% (21·5–23·9), representing an additional 7·61 million (7·20–8·01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7·9% (7·0–8·8). The number of deaths for CMNN causes decreased by 22·2% (20·0–24·0) and the death rate by 31·8% (30·1–33·3). Total deaths from injuries increased by 2·3% (0·5–4·0) between 2007 and 2017, and the death rate from injuries decreased by 13·7% (12·2–15·1) to 57·9 deaths (55·9–59·2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000–289 000) globally in 2007 to 352 000 (334 000–363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118·0% (88·8–148·6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36·4% (32·2–40·6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33·6% (31·2–36·1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990—neonatal disorders, lower respiratory infections, and diarrhoeal diseases—were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases.
Interpretation
Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade.
Funding
Bill & Melinda Gates Foundation
Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017
No full textBackground 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 synthesising 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 behavioural, 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 randomised 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 modelling 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 behavioural 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 121 billion (144-1.28) 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 (ie, population growth and ageing), 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-standardised 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 programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing 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 synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning
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