Author: "Medical Research Council (Reino Unido)" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Medical Research Council (Reino Unido)"' showing total 90 results

Start Over Author "Medical Research Council (Reino Unido)"

90 results on '"Medical Research Council (Reino Unido)"'

1. Electrocardiographic Imaging for Atrial Fibrillation: A Perspective From Computer Models and Animal Experiments to Clinical Value

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, EIT Health, European Commission, Generalitat Valenciana, British Heart Foundation, Instituto de Salud Carlos III, Agencia Estatal de Investigación, European Regional Development Fund, National Institutes of Health, EEUU, Medical Research Council, Reino Unido, National Heart, Lung, and Blood Institute, EEUU, Netherlands Organization for Scientific Research, Ministerio de Ciencia, Innovación y Universidades, National Institute of General Medical Sciences, EEUU, Fundação de Amparo à Pesquisa do Estado de São Paulo, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Salinet, Joao, Molero-Alabau, Rubén, Schlindwein, Fernando S., Karel, Joël, Rodrigo, Miguel, Rojo-Álvarez, José Luis, Berenfeld, Omer, Climent, Andreu M., Zenger, Brian, Vanheusden, Frederique, Siles Paredes, Jimena Gabriela, MacLeod, Rob, Atienza, Felipe, Guillem Sánchez, María Salud, Cluitmans, Matthijs, Bonizzi, Pietro, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, EIT Health, European Commission, Generalitat Valenciana, British Heart Foundation, Instituto de Salud Carlos III, Agencia Estatal de Investigación, European Regional Development Fund, National Institutes of Health, EEUU, Medical Research Council, Reino Unido, National Heart, Lung, and Blood Institute, EEUU, Netherlands Organization for Scientific Research, Ministerio de Ciencia, Innovación y Universidades, National Institute of General Medical Sciences, EEUU, Fundação de Amparo à Pesquisa do Estado de São Paulo, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Salinet, Joao, Molero-Alabau, Rubén, Schlindwein, Fernando S., Karel, Joël, Rodrigo, Miguel, Rojo-Álvarez, José Luis, Berenfeld, Omer, Climent, Andreu M., Zenger, Brian, Vanheusden, Frederique, Siles Paredes, Jimena Gabriela, MacLeod, Rob, Atienza, Felipe, Guillem Sánchez, María Salud, Cluitmans, Matthijs, and Bonizzi, Pietro
Abstract: [EN] Electrocardiographic imaging (ECGI) is a technique to reconstruct non-invasively the electrical activity on the heart surface from body-surface potential recordings and geometric information of the torso and the heart. ECGI has shown scientific and clinical value when used to characterize and treat both atrial and ventricular arrhythmias. Regarding atrial fibrillation (AF), the characterization of the electrical propagation and the underlying substrate favoring AF is inherently more challenging than for ventricular arrhythmias, due to the progressive and heterogeneous nature of the disease and its manifestation, the small volume and wall thickness of the atria, and the relatively large role of microstructural abnormalities in AF. At the same time, ECGI has the advantage over other mapping technologies of allowing a global characterization of atrial electrical activity at every atrial beat and non-invasively. However, since ECGI is time-consuming and costly and the use of electrical mapping to guide AF ablation is still not fully established, the clinical value of ECGI for AF is still under assessment. Nonetheless, AF is known to be the manifestation of a complex interaction between electrical and structural abnormalities and therefore, true electro-anatomical-structural imaging may elucidate important key factors of AF development, progression, and treatment. Therefore, it is paramount to identify which clinical questions could be successfully addressed by ECGI when it comes to AF characterization and treatment, and which questions may be beyond its technical limitations. In this manuscript we review the questions that researchers have tried to address on the use of ECGI for AF characterization and treatment guidance (for example, localization of AF triggers and sustaining mechanisms), and we discuss the technological requirements and validation. We address experimental and clinical results, limitations, and future challenges for fruitful application of ECGI fo
Published: 2021

2. You Talking to Me? Cadherin and Integrin Crosstalk in Biomaterial Design

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, UK Regenerative Medicine Platform, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Barcelona-Estaje, Eva, Dalby, Matthew J., Cantini, Marco, Salmerón Sánchez, Manuel, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, UK Regenerative Medicine Platform, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Barcelona-Estaje, Eva, Dalby, Matthew J., Cantini, Marco, and Salmerón Sánchez, Manuel
Abstract: [EN] While much work has been done in the design of biomaterials to control integrin-mediated adhesion, less emphasis has been put on functionalization of materials with cadherin ligands. Yet, cell-cell contacts in combination with cell-matrix interactions are key in driving embryonic development, collective cell migration, epithelial to mesenchymal transition, and cancer metastatic processes, among others. This review focuses on the incorporation of both cadherin and integrin ligands in biomaterial design, to promote what is called the "adhesive crosstalk." First, the structure and function of cadherins and their role in eliciting mechanotransductive processes, by themselves or in combination with integrin mechanosensing, are introduced. Then, biomaterials that mimic cell-cell interactions, and recent applications to get insights in fundamental biology and tissue engineering, are critically discussed.
Published: 2021

3. Biochemical- and Biophysical-Induced Barriergenesis in the Blood¿Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Heart Research UK, Stroke Association, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Schofield, Christina L., Rodrigo-Navarro, Aleixandre, Dalby, Matthew J., Van Agtmael, Tom, Salmerón Sánchez, Manuel, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Heart Research UK, Stroke Association, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Schofield, Christina L., Rodrigo-Navarro, Aleixandre, Dalby, Matthew J., Van Agtmael, Tom, and Salmerón Sánchez, Manuel
Abstract: [EN] Central nervous system (CNS) pathologies are a prevalent problem in aging populations, creating a need to understand the underlying events in these diseases and develop efficient CNS-targeting drugs. The importance of the blood-brain barrier (BBB) is evident, acting both as a physical barrier to drug entry into the CNS and potentially as the cause or aggravator of CNS diseases. The development of a biomimetic BBB invitro model is required for the understanding of BBB-related pathologies and in the screening of drugs targeting the CNS. There is currently great interest in understanding the influence of biochemical and biophysical factors, as these have the potential to greatly improve the barrier function of brain microvascular endothelial cells (BMECs). Recent advances in understanding how these may regulate barriergenesis in BMECs help promote the development of improved BBB invitro models and therefore novel interventional therapies for pathologies related to its disruption. Herein, an overview of specific biochemical and biomechanical cues in the formation of the BBB, with a focus on invitro models and how these might recapitulate the BBB function, is provided.
Published: 2021

4. Standardizing Single-Frame Phase Singularity Identification Algorithms and Parameters in Phase Mapping During Human Atrial Fibrillation

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, British Heart Foundation, Instituto de Salud Carlos III, Medical Research Council, Reino Unido, National Institute for Health Research, Reino Unido, Fundação de Amparo à Pesquisa do Estado de São Paulo, Li, Xin, Almeida, Tiago P., Dastagir, Nawshin, Guillem Sánchez, María Salud, Salinet, Joao, Chu, Gavin S., Stafford, Peter J., Schlindwein, Fernando S., Ng, G. André, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, British Heart Foundation, Instituto de Salud Carlos III, Medical Research Council, Reino Unido, National Institute for Health Research, Reino Unido, Fundação de Amparo à Pesquisa do Estado de São Paulo, Li, Xin, Almeida, Tiago P., Dastagir, Nawshin, Guillem Sánchez, María Salud, Salinet, Joao, Chu, Gavin S., Stafford, Peter J., Schlindwein, Fernando S., and Ng, G. André
Abstract: [EN] Purpose Recent investigations failed to reproduce the positive rotor-guided ablation outcomes shown by initial studies for treating persistent atrial fibrillation (persAF). Phase singularity (PS) is an important feature for AF driver detection, but algorithms for automated PS identification differ. We aim to investigate the performance of four different techniques for automated PS detection. Methods 2048-channel virtual electrogram (VEGM) and electrocardiogram signals were collected for 30 s from 10 patients undergoing persAF ablation. QRST-subtraction was performed and VEGMs were processed using sinusoidal wavelet reconstruction. The phase was obtained using Hilbert transform. PSs were detected using four algorithms: (1) 2D image processing based and neighbor-indexing algorithm; (2) 3D neighbor-indexing algorithm; (3) 2D kernel convolutional algorithm estimating topological charge; (4) topological charge estimation on 3D mesh. PS annotations were compared using the structural similarity index (SSIM) and Pearson's correlation coefficient (CORR). Optimized parameters to improve detection accuracy were found for all four algorithms usingF(beta)score and 10-fold cross-validation compared with manual annotation. Local clustering with density-based spatial clustering of applications with noise (DBSCAN) was proposed to improve algorithms 3 and 4. Results The PS density maps created by each algorithm with default parameters were poorly correlated. Phase gradient threshold and search radius (or kernels) were shown to affect PS detections. The processing times for the algorithms were significantly different (p< 0.0001). TheF(beta)scores for algorithms 1, 2, 3, 3 + DBSCAN, 4 and 4 + DBSCAN were 0.547, 0.645, 0.742, 0.828, 0.656, and 0.831. Algorithm 4 + DBSCAN achieved the best classification performance with acceptable processing time (2.0 +/- 0.3 s). Conclusion AF driver identification is dependent on the PS detection algorithms and their parameters, which could explai
Published: 2020

5. Data-driven discovery of changes in clinical code usage over time: a case-study on changes in cardiovascular disease recording in two English electronic health records databases (2001-2015)

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Wellcome Trust, Welsh Government, European Commission, Scottish Government, British Heart Foundation, Agencia Estatal de Investigación, Medical Research Council, Reino Unido, Economic and Social Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Rockenschaub, Patrick, Nguyen, Vincent, Aldridge, Robert W., Acosta, Dionisio, Garcia-Gomez, Juan M, Sáez Silvestre, Carlos, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Wellcome Trust, Welsh Government, European Commission, Scottish Government, British Heart Foundation, Agencia Estatal de Investigación, Medical Research Council, Reino Unido, Economic and Social Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Rockenschaub, Patrick, Nguyen, Vincent, Aldridge, Robert W., Acosta, Dionisio, Garcia-Gomez, Juan M, and Sáez Silvestre, Carlos
Abstract: [EN] Objectives To demonstrate how data-driven variability methods can be used to identify changes in disease recording in two English electronic health records databases between 2001 and 2015. Design Repeated cross-sectional analysis that applied data-driven temporal variability methods to assess month-by-month changes in routinely collected medical data. A measure of difference between months was calculated based on joint distributions of age, gender, socioeconomic status and recorded cardiovascular diseases. Distances between months were used to identify temporal trends in data recording. Setting 400 English primary care practices from the Clinical Practice Research Datalink (CPRD GOLD) and 451 hospital providers from the Hospital Episode Statistics (HES). Main outcomes The proportion of patients (CPRD GOLD) and hospital admissions (HES) with a recorded cardiovascular disease (CPRD GOLD: coronary heart disease, heart failure, peripheral arterial disease, stroke; HES: International Classification of Disease codes I20-I69/G45). Results Both databases showed gradual changes in cardiovascular disease recording between 2001 and 2008. The recorded prevalence of included cardiovascular diseases in CPRD GOLD increased by 47%-62%, which partially reversed after 2008. For hospital records in HES, there was a relative decrease in angina pectoris (-34.4%) and unspecified stroke (-42.3%) over the same time period, with a concomitant increase in chronic coronary heart disease (+14.3%). Multiple abrupt changes in the use of myocardial infarction codes in hospital were found in March/April 2010, 2012 and 2014, possibly linked to updates of clinical coding guidelines. Conclusions Identified temporal variability could be related to potentially non-medical causes such as updated coding guidelines. These artificial changes may introduce temporal correlation among diagnoses inferred from routine data, violating the assumptions of frequently used statistical methods. Temporal variabil
Published: 2020

6. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Author: Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, Generalitat Valenciana, Ministerio de Educación, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Ministerio de Economía y Empresa, Medical Research Council, Reino Unido, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, Muñoz-Espín, Daniel, Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, Generalitat Valenciana, Ministerio de Educación, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Ministerio de Economía y Empresa, Medical Research Council, Reino Unido, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, and Muñoz-Espín, Daniel
Abstract: [EN] Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal beta-galactosidase (SA-beta-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-beta-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
Published: 2020

7. Structural connectivity centrality changes mark the path towards Alzheimer's disease

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Ministerio de Educación, U.S. Department of Defense, Ministerio de Economía y Empresa, National Institutes of Health, EEUU, Medical Research Council, Reino Unido, National Institute for Health Research, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Peraza, Luis R., Díaz-Parra, Antonio, Kennion, Oliver, Moratal, David, Taylor, John-Paul, Kaiser, Marcus, Bauer, Roman, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Ministerio de Educación, U.S. Department of Defense, Ministerio de Economía y Empresa, National Institutes of Health, EEUU, Medical Research Council, Reino Unido, National Institute for Health Research, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Peraza, Luis R., Díaz-Parra, Antonio, Kennion, Oliver, Moratal, David, Taylor, John-Paul, Kaiser, Marcus, and Bauer, Roman
Abstract: [EN] Introduction: The pathophysiological process of Alzheimer's disease is thought to begin years before clinical decline, with evidence suggesting prion-like spreading processes of neurofibrillary tangles and amyloid plaques. Methods: Using diffusion magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative database, we first identified relevant features for dementia diagnosis. We then created dynamic models with the Nathan Kline Institute-Rockland Sample database to estimate the earliest detectable stage associated with dementia in the simulated disease progression. Results: A classifier based on centrality measures provides informative predictions. Strength and closeness centralities are the most discriminative features, which are associated with the medial temporal lobe and subcortical regions, together with posterior and occipital brain regions. Our model simulations suggest that changes associated with dementia begin to manifest structurally at early stages. Discussion: Our analyses suggest that diffusion magnetic resonance imaging-based centrality measures can offer a tool for early disease detection before clinical dementia onset.
Published: 2019

8. Functionalization of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Universitat Politècnica de València. Departamento de Termodinámica Aplicada - Departament de Termodinàmica Aplicada, UK Regenerative Medicine Platform, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Sprott, Mark Robert, Ferrer, GG, Dalby, Matthew J., Salmerón Sánchez, Manuel, Cantini, Marco, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Universitat Politècnica de València. Departamento de Termodinámica Aplicada - Departament de Termodinàmica Aplicada, UK Regenerative Medicine Platform, Medical Research Council, Reino Unido, Engineering and Physical Sciences Research Council, Reino Unido, Sprott, Mark Robert, Ferrer, GG, Dalby, Matthew J., Salmerón Sánchez, Manuel, and Cantini, Marco
Abstract: [EN] Poly-l-lactic acid (PLLA) has been used as a biodegradable polymer for many years; the key characteristics of this polymer make it a versatile and useful resource for regenerative medicine. However, it is not inherently bioactive. Thus, here, a novel process is presented to functionalize PLLA surfaces with poly(ethyl acrylate) (PEA) brushes to provide biological functionality through PEA's ability to induce spontaneous organization of the extracellular matrix component fibronectin (FN) into physiological-like nanofibrils. This process allows control of surface biofunctionality while maintaining PLLA bulk properties (i.e., degradation profile, mechanical strength). The new approach is based on surface-initiated atomic transfer radical polymerization, which achieves a molecularly thin coating of PEA on top of the underlying PLLA. Beside surface characterization via atomic force microscopy, X-ray photoelectron spectroscopy and water contact angle to measure PEA grafting, the biological activity of this surface modification is investigated. PEA brushes trigger FN organization into nanofibrils, which retain their ability to enhance adhesion and differentiation of C2C12 cells. The results demonstrate the potential of this technology to engineer controlled microenvironments to tune cell fate via biologically active surface modification of an otherwise bioinert biodegradable polymer, gaining wide use in tissue engineering applications.
Published: 2019

9. Exploring Hybrid Parallel Systems for Probabilistic Record Linkage

Author: Universitat Politècnica de València. Departamento de Sistemas Informáticos y Computación - Departament de Sistemes Informàtics i Computació, Royal Society, Reino Unido, Generalitat Valenciana, Bill and Melinda Gates Foundation, Medical Research Council, Reino Unido, European Cooperation in Science and Technology, Fundação de Amparo à Pesquisa do Estado da Bahia, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil, Ministerio de Economía y Competitividad, Boratto, Murilo, Alonso-Jordá, Pedro, Pinto, Clicia, Melo, Pedro, Barreto, Marcos, Denaxas, Spiros, Universitat Politècnica de València. Departamento de Sistemas Informáticos y Computación - Departament de Sistemes Informàtics i Computació, Royal Society, Reino Unido, Generalitat Valenciana, Bill and Melinda Gates Foundation, Medical Research Council, Reino Unido, European Cooperation in Science and Technology, Fundação de Amparo à Pesquisa do Estado da Bahia, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil, Ministerio de Economía y Competitividad, Boratto, Murilo, Alonso-Jordá, Pedro, Pinto, Clicia, Melo, Pedro, Barreto, Marcos, and Denaxas, Spiros
Abstract: [EN] Record linkage is a technique widely used to gather data stored in disparate data sources that presumably pertain to the same real world entity. This integration can be done deterministically or probabilistically, depending on the existence of common key attributes among all data sources involved. The probabilistic approach is very time-consuming due to the amount of records that must be compared, specifically in big data scenarios. In this paper, we propose and evaluate a methodology that simultaneously exploits multicore and multi-GPU architectures in order to perform the probabilistic linkage of large-scale Brazilian governmental databases. We present some algorithmic optimizations that provide high accuracy and improve performance by defining the best algorithm-architecture combination for a problem given its input size. We also discuss performance results obtained with different data samples, showing that a hybrid approach outperforms other configurations, providing an average speedup of 7.9 when linking up to 20.000 million records.
Published: 2019

10. No metabolic effects of mustard allyl-isothiocyanate compared with placebo in men

Author: Universitat Politècnica de València. Departamento de Estadística e Investigación Operativa Aplicadas y Calidad - Departament d'Estadística i Investigació Operativa Aplicades i Qualitat, National Institute for Health Research, Reino Unido, British Retail Consortium, European Commission, Wellcome Trust, Medical Research Council, Reino Unido, British Heart Foundation, Biotechnology and Biological Sciences Research Council, Reino Unido, Langeveld, Mirjam, Tan, Chong Yew, Soeters, Maarten R., Virtue, Samuel, Watson, Laura P. E., Murgatroyd, Peter R., Ambler, Graeme K., Vidal Puig, Santiago, Chatterjee, Krishna V., Vidal-Puig, Antonio, Universitat Politècnica de València. Departamento de Estadística e Investigación Operativa Aplicadas y Calidad - Departament d'Estadística i Investigació Operativa Aplicades i Qualitat, National Institute for Health Research, Reino Unido, British Retail Consortium, European Commission, Wellcome Trust, Medical Research Council, Reino Unido, British Heart Foundation, Biotechnology and Biological Sciences Research Council, Reino Unido, Langeveld, Mirjam, Tan, Chong Yew, Soeters, Maarten R., Virtue, Samuel, Watson, Laura P. E., Murgatroyd, Peter R., Ambler, Graeme K., Vidal Puig, Santiago, Chatterjee, Krishna V., and Vidal-Puig, Antonio
Abstract: [EN] Background: Induction of nonshivering thermogenesis can be used to influence energy balance to prevent or even treat obesity. The pungent component of mustard, allyl-isothiocyanate (AITC), activates the extreme cold receptor transient receptor potential channel, subfamily A, member 1 and may thus induce energy expenditure and metabolic changes. Objective: The objective of our study was to evaluate the potential of mustard AITC to induce thermogenesis (primary outcome) and alter body temperature, cold and hunger sensations, plasma metabolic parameters, and energy intake (secondary outcomes). Design: Energy expenditure in mice was measured after subcutaneous injection with vehicle, 1 mg norepinephrine/kg, or 5 mg AITC/kg. In our human crossover study, 11 healthy subjects were studied under temperature-controlled conditions after an overnight fast. After ingestion of 10 g of capsulated mustard or uncapsulated mustard or a capsulated placebo mixture, measurements of energy expenditure, substrate oxidation, core temperature, cold and hunger scores, and plasma parameters were repeated every 30 min during a 150-min period. Subjects were randomly selected for the placebo and capsulated mustard intervention; 9 of 11 subjects received the uncapsulated mustard as the final intervention because this could not be blinded. After the experiments, energy intake was measured with the universal eating monitor in a test meal. Results: In mice, AITC administration induced a 32% increase in energy expenditure compared with vehicle (17.5 +/- 4.9 J . min(-1) . mouse(-1) compared with 12.5 +/- 1.2 J . min(-1) . mouse(-1), P = 0.03). Of the 11 randomly selected participants, 1 was excluded because of intercurrent illness after the first visit and 1 withdrew after the second visit. Energy expenditure did not increase after ingestion of capsulated or uncapsulated mustard compared with placebo. No differences in substrate oxidation, core temperature, cold and hunger scores, or plasma para
Published: 2017

11. Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Medical Research Council, Reino Unido, Zemzemi, Nejib, Bernabeu, Miguel O., Saiz Rodríguez, Francisco Javier, Cooper, Jonathan, Pathmanathan, Pras, Mirams, Gary R., Pitt-Francis, Joe, Rodríguez, Blanca, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Medical Research Council, Reino Unido, Zemzemi, Nejib, Bernabeu, Miguel O., Saiz Rodríguez, Francisco Javier, Cooper, Jonathan, Pathmanathan, Pras, Mirams, Gary R., Pitt-Francis, Joe, and Rodríguez, Blanca
Abstract: BACKGROUND AND PURPOSE Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. EXPERIMENTAL APPROACH We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. KEY RESULTS Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected. CONCLUSIONS AND IMPLICATIONS Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.
Published: 2013

12. Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, European Commission, Generalitat Valenciana, Ministerio de Educación, Universitat Politècnica de València, Medical Research Council, Reino Unido, Romero Pérez, Lucia, Carbonell Pascual, Beatriz, Trenor Gomis, Beatriz Ana, Rodríguez, Blanca, Saiz Rodríguez, Francisco Javier, Ferrero De Loma-Osorio, José María, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, European Commission, Generalitat Valenciana, Ministerio de Educación, Universitat Politècnica de València, Medical Research Council, Reino Unido, Romero Pérez, Lucia, Carbonell Pascual, Beatriz, Trenor Gomis, Beatriz Ana, Rodríguez, Blanca, Saiz Rodríguez, Francisco Javier, and Ferrero De Loma-Osorio, José María
Abstract: [EN] Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca(2+) and Na(+) dynamics, and their rate dependence to variations (+/- 15% and +/- 30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K(+) current (I(K1)) whereas APD rate adaptation as well as [Na(+)](i) rate dependence is influenced by the Na(+)/K(+) pump current (I(NaK)). In addition, steady-state [Ca(2+)](i) levels, APD restitution properties and [Ca(2+)](i); rate dependence are strongly dependent on I(NaK), the L-Type Ca(2+) current (I(CaL)) and the Na(+)/Ca(2+) exchanger current (I(NaCa)), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of cellul
Published: 2011

13. Phylogenetic and genetic linkage between novel atypical dual-specificity phosphatases from non-metazoan organisms

Author: Universitat Politècnica de València. Instituto Universitario Mixto de Biología Molecular y Celular de Plantas - Institut Universitari Mixt de Biologia Molecular i Cel·lular de Plantes, Ministerio de Educación y Ciencia, Ministerio de Ciencia e Innovación, European Commission, Generalitat Valenciana, Medical Research Council, Reino Unido, European Regional Development Fund, UK Research and Innovation, Romá-Mateo, C, Sacristán-Reviriego, A, Beresford, N.J, Caparrós Martín, José Antonio, Culiañez Macia, Francisco Antonio, Martin, H, Molina, M, Tabernero, L, Pulido, R, Universitat Politècnica de València. Instituto Universitario Mixto de Biología Molecular y Celular de Plantas - Institut Universitari Mixt de Biologia Molecular i Cel·lular de Plantes, Ministerio de Educación y Ciencia, Ministerio de Ciencia e Innovación, European Commission, Generalitat Valenciana, Medical Research Council, Reino Unido, European Regional Development Fund, UK Research and Innovation, Romá-Mateo, C, Sacristán-Reviriego, A, Beresford, N.J, Caparrós Martín, José Antonio, Culiañez Macia, Francisco Antonio, Martin, H, Molina, M, Tabernero, L, and Pulido, R
Abstract: [EN] Dual-specificity phosphatases (DSPs) constitute a large protein tyrosine phosphatase (PTP) family, with examples in distant evolutive phyla. PFA-DSPs (Plant and Fungi Atypical DSPs) are a group of atypical DSPs present in plants, fungi, kinetoplastids, and slime molds, the members of which share structural similarity with atypical- and lipid phosphatase DSPs from mammals. The analysis of the PFA-DSPs from the plant Arabidopsis thaliana (AtPFA-DSPs) showed differential tissue mRNA expression, substrate specificity, and catalytic activity for these proteins, suggesting different functional roles among plant PFA-DSPs. Bioinformatic analysis revealed the existence of novel PFA-DSP-related proteins in fungi (Oca1, Oca2, Oca4 and Oca6 in Saccharomyces cerevisiae) and protozoa, which were segregated from plant PFADSPs. The closest yeast homolog for these proteins was the PFA-DSP from S. cerevisiae ScPFA-DSP1/Siw14/Oca3. Oca1, Oca2, Siw14/Oca3, Oca4, and Oca6 were involved in the yeast response to caffeine and rapamycin stresses. Siw14/Oca3 was an active phosphatase in vitro, whereas no phosphatase activity could be detected for Oca1. Remarkably, overexpression of Siw14/Oca3 suppressed the caffeine sensitivity of oca1, oca2, oca4, and oca6 deleted strains, indicating a genetic linkage and suggesting a functional relationship for these proteins. Functional studies on mutations targeting putative catalytic residues from the A. thaliana AtPFA-DSP1/At1g05000 protein indicated the absence of canonical amino acids acting as the general acid/base in the phosphor-ester hydrolysis, which suggests a specific mechanism of reaction for PFA-DSPs and related enzymes. Our studies demonstrate the existence of novel phosphatase protein families in fungi and protozoa, with active and inactive enzymes linked in common signaling pathways. This illustrates the catalytic and functional complexity of the expanding family of atypical dual-specificity phosphatases in non-metazoans, including p
Published: 2011

14. Characterization of IS1110, a highly mobile genetic element from Mycobacterium avium

Author: Universitat Politècnica de València. Departamento de Biotecnología - Departament de Biotecnologia, European Commission, Ministerio de Educación y Ciencia, Medical Research Council, Reino Unido, Hernández Pérez, Manuel, Fomukong, N.G., Hellyer, T., Brown, I., Dale, J.W., Universitat Politècnica de València. Departamento de Biotecnología - Departament de Biotecnologia, European Commission, Ministerio de Educación y Ciencia, Medical Research Council, Reino Unido, Hernández Pérez, Manuel, Fomukong, N.G., Hellyer, T., Brown, I., and Dale, J.W.
Abstract: [EN] A highly mobile insertion sequence designated IS1110 was detected in Mycobacterium avium strain LR541 following an observed increase in size of the plasmid pLR20. Genomic libraries of M. avium strains carrying either parental pLR20 or the modified plasmid (pLR20') were constructed and the sequence of the relevant clones was determined to characterize the insertion sequence and the target region. IS1110 Is a 1457bp element lacking terminal inverted repeats, and is related to IS900 (from Mycobacterium paratuberculosis), IS901 and IS902 (from M. avium) and to IS116 (from Streptomyces clavuligerus). LR541 carries several copies of IS1110. Individual colonies from the same plate show differences in Southern blot patterns when tested with an IS1110-derived probe; the ability to detect transposition events in random colonies, without any selection pressure, indicates an exceptionally high degree of mobility, which will be invaluable for transposon mutagenesis. Analyses of M. avium isolates from human, veterinary, and environmental sources showed that IS1110-hybridizing sequences are present in some M. avium isolates but they were not detected in strains of other mycobacterial species. The polymorphism exhibited in M. avium isolates suggests that this element may be useful for molecular epidemiological studies f M. avium infections.
Published: 1994

15. Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study

Author: Adam Trickey, Lei Zhang, M John Gill, Fabrice Bonnet, Greer Burkholder, Antonella Castagna, Matthias Cavassini, Piotr Cichon, Heidi Crane, Pere Domingo, Sophie Grabar, Jodie Guest, Niels Obel, Mina Psichogiou, Marta Rava, Peter Reiss, Christopher T Rentsch, Melchor Riera, Gundolf Schuettfort, Michael J Silverberg, Colette Smith, Melanie Stecher, Timothy R Sterling, Suzanne M Ingle, Caroline A Sabin, Jonathan A C Sterne, NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), Medical Research Council (Reino Unido), NIHR - Senior Investigator (Reino Unido), Wellcome Trust, Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Gilead Sciences (Spain), Ministère de la Santé (Francia), Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, Ministry of Health (Holanda), Ministry of Health Welfare and Sport (Países Bajos), German Center for Infection Research (Alemania), Instituto de Salud Carlos III, Red de Investigación Cooperativa en Investigación en Sida (España), Plan Nacional de I+D+i (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Institut National de la Santé et de la Recherche Médicale (Francia), Bristol-Myers Squibb, Merck, Sharp & Dohme, Ministerio de Sanidad (España), Swiss National Science Foundation, CFAR Network of Integrated Clinical Systems (CNICS), United States Department of Veterans Affairs, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), Global Health, AII - Infectious diseases, and APH - Aging & Later Life
Subjects: Adult, Male, Anti-HIV Agents, Epidemiology, Rilpivirine, Immunology, HIV Infections, Middle Aged, Cohort Studies, Europe, Infectious Diseases, Raltegravir Potassium, Virology, North America, Humans, Female, HIV Integrase Inhibitors, Darunavir
Abstract: Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. We would like to thank our funders (US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council) and all patients and the clinical teams associated with the participating cohort studies. The antiretroviral therapy cohort collaboration is funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). UK Collaborative HIV Cohort is funded by the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1). JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z). Funding for the individual antiretroviral therapy cohort collaboration cohorts included in this analysis was from Alberta Health, Gilead, National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Ministry of Health, the Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the TP-HIV by the German Centre for Infection Research (NCT02149004), Instituto de Salud Carlos III (through the Red Temática de Investigación Cooperativa en Sida [RD06/006, RD12/0017/0018, and RD16/0002/0006]) as part of the Plan Nacional I + D + i. Other funders of the individual cohorts participating data for this analysis are ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional, ViiV Healthcare, Preben og Anna Simonsens Fond, ANRS-Maladies infectieuses émergentes, Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Myers Squibb, Janssen, Merck, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026230), the Spanish Ministry of Health, the Swiss National Science Foundation (grant 33CS30_134277), Centers for AIDS Research Network of Integrated Clinical Systems (1R24 AI067039-1, P30-AI-027757), the US Department of Veterans Affairs, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026224, U01-AA026209, U24-AA020794), the Veterans Health Administration Office of Research and Development, and the US National Institute of Allergy and Infectious Diseases (Tennessee Center for AIDS Research P30 AI110527). Sí
Published: 2022

16. GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Author: Pairo-Castineira, Erola, Rawlik, Konrad, Bretherick, Andrew D, Qi, Ting, Wu, Yang, Nassiri, Isar, McConkey, Glenn A, Zechner, Marie, Klaric, Lucija, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Richmond, Anne, Millar, Jonathan, Russell, Clark D, Malinauskas, Tomas, Thwaites, Ryan, Morrice, Kirstie, Keating, Sean, Maslove, David, Nichol, Alistair, Semple, Malcolm G, Knight, Julian, Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter J M, Begg, Colin, Walsh, Timothy, Tenesa, Albert, Flores, Carlos, Riancho, José A, Rojas-Martinez, Augusto, Lapunzina, Pablo, Yang, Jian, Ponting, Chris P, Wilson, James F, Vitart, Veronique, Abedalthagafi, Malak, Luchessi, Andre D, Parra, Esteban J, Cruz, Raquel, Carracedo, Angel, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Pereira, Alexandre C, Law, Andy, Fairfax, Benjamin, Hendry, Sara Clohisey, Baillie, J Kenneth, GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, The 23andMe COVID-19 Team, Brochado-Kith, Oscar, Ceballos, Francisco C, Fernandez-Rodriguez, Amanda, Jimenez-Sousa, Maria Angeles, Martin-Vicente, Maria, Resino, Salvador, Virseda-Berdices, Ana, Meijome, Xose M, Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación Amancio Ortega, Banco Santander, Gobierno de Canarias (España), Fundación Canaria de Investigación Sanitaria, Centro de Supercomputación de Galicia, National Council for Scientific and Technological Development (Brasil), Sepsis Trust NZ, Wellcome Trust, Illumina (Reino Unido), Westlake Educational Foundation, British Heart Foundation, Biotechnology and Biological Sciences Research Council (Reino Unido), UK Research and Innovation, Medical Research Council (Reino Unido), LifeArc, and Department of Health and Social Care (Reino Unido)
Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0). We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements). Sí
Published: 2023

17. Genetic Architecture of Acute Myocarditis and the Overlap with Inherited Cardiomyopathy

Author: Amrit S. Lota, Mark R. Hazebroek, Pantazis Theotokis, Rebecca Wassall, Sara Salmi, Brian P. Halliday, Upasana Tayal, Job Verdonschot, Devendra Meena, Ruth Owen, Antonio de Marvao, Alma Iacob, Momina Yazdani, Daniel J. Hammersley, Richard E. Jones, Riccardo Wage, Rachel Buchan, Fredrik Vivian, Yakeen Hafouda, Michela Noseda, John Gregson, Tarun Mittal, Joyce Wong, Jan Lukas Robertus, A. John Baksi, Vassilios Vassiliou, Ioanna Tzoulaki, Antonis Pantazis, John G.F. Cleland, Paul J.R. Barton, Stuart A. Cook, Dudley J. Pennell, Pablo Garcia-Pavia, Leslie T. Cooper, Stephane Heymans, James S. Ware, Sanjay K. Prasad, MUMC+: MA Med Staf Artsass Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), British Heart Foundation, Medical Research Council (Reino Unido), Wellcome Trust, Fondation Leducq, Instituto de Salud Carlos III, Fundación ProCNIC, Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), and Ministerio de Ciencia (España)
Subjects: Cardiomyopathy, Dilated, Adult, Male, Cardiomyopathy, Arrhythmogenic right ventricular dysplasia, Heart failure, Heart, Stroke Volume, Middle Aged, Ventricular Function, Left, Myocarditis, Desmoplakins, Physiology (medical), Dilated, Humans, Female, Cardiology and Cardiovascular Medicine
Abstract: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with
Published: 2022

18. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author: de Boer, Elke, Ockeloen, Charlotte W., Matalonga, Leslie, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Peters, Sophia, Paramonov, Ida, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vitobello, Antonio, Rodenburg, Richard J., Coenen, Marieke J. H., Janssen, Mirian, Henssen, Dylan, Banka, Siddharth, Benetti, Elisa, Casari, Giorgio, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Ellwanger, Kornelia, Faivre, Laurence, Graessner, Holm, Haack, Tobias B., Hammarsjö, Anna, Havlovicova, Marketa, Hoischen, Alexander, Hugon, Anne, Jackson, Adam, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Macek, Milan, Morleo, Manuela, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Verloes, Alain, Vissers, Lisenka, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Trimouille, Aurélien, Vissers, Lisenka E. L. M., Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Research Council, Evelyn Trust, Newton Fund, European Project: 825619,AI4EU, Dutch Research Council (Holanda), Medical Research Council (Reino Unido), Lily Foundation, Unión Europea. Comisión Europea. H2020, Ockeloen, Charlotte W [0000-0003-0329-1520], Horvath, Rita [0000-0002-9841-170X], Rodenburg, Richard J [0000-0001-5227-3527], Gilissen, Christian [0000-0003-1693-9699], Steyaert, Wouter [0000-0001-8393-0788], Trimouille, Aurélien [0000-0002-3457-5684], Verloes, Alain [0000-0003-4819-0264], Vissers, Lisenka ELM [0000-0001-6470-5497], Apollo - University of Cambridge Repository, de Boer, E., Ockeloen, C. W., Matalonga, L., Horvath, R., Rodenburg, R. J., Coenen, M. J. H., Janssen, M., Henssen, D., Gilissen, C., Steyaert, W., Paramonov, I., Trimouille, A., Kleefstra, T., Verloes, A., Vissers, L. E. L. M., Nigro, V., Torella, A., and Banfi, S.
Subjects: Male, Proband, Mitochondrial DNA, RNA, Transfer, Leu, Brief Communication, Quadriplegia, Whole Exome Sequencing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Genetics research, Intellectual disability, Genetics, medicine, Humans, Genetics (clinical), Exome sequencing, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Neurodevelopmental disorders, 030305 genetics & heredity, Correction, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Translational research, medicine.disease, Heteroplasmy, 3. Good health, MT-TL1, Mutation, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Spastic tetraparesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological disorders, 030217 neurology & neurosurgery
Abstract: Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí
Published: 2021

19. Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020

Author: Dana Bryazka, Marissa B Reitsma, Max G Griswold, Kalkidan Hassen Abate, Cristiana Abbafati, Mohsen Abbasi-Kangevari, Zeinab Abbasi-Kangevari, Amir Abdoli, Mohammad Abdollahi, Abu Yousuf Md Abdullah, E S Abhilash, Eman Abu-Gharbieh, Juan Manuel Acuna, Giovanni Addolorato, Oladimeji M Adebayo, Victor Adekanmbi, Kishor Adhikari, Sangeet Adhikari, Qorinah Estiningtyas Sakilah Adnani, Saira Afzal, Wubetu Yimam Agegnehu, Manik Aggarwal, Bright Opoku Ahinkorah, Araz Ramazan Ahmad, Sajjad Ahmad, Tauseef Ahmad, Ali Ahmadi, Sepideh Ahmadi, Haroon Ahmed, Tarik Ahmed Rashid, Chisom Joyqueenet Akunna, Hanadi Al Hamad, Md Zakiul Alam, Dejene Tsegaye Alem, Kefyalew Addis Alene, Yousef Alimohamadi, Atiyeh Alizadeh, Kasim Allel, Jordi Alonso, Saba Alvand, Nelson Alvis-Guzman, Firehiwot Amare, Edward Kwabena Ameyaw, Sohrab Amiri, Robert Ancuceanu, Jason A Anderson, Catalina Liliana Andrei, Tudorel Andrei, Jalal Arabloo, Muhammad Arshad, Anton A Artamonov, Zahra Aryan, Malke Asaad, Mulusew A Asemahagn, Thomas Astell-Burt, Seyyed Shamsadin Athari, Desta Debalkie Atnafu, Prince Atorkey, Alok Atreya, Floriane Ausloos, Marcel Ausloos, Getinet Ayano, Martin Amogre ayanore Ayanore, Olatunde O Ayinde, Jose L Ayuso-Mateos, Sina Azadnajafabad, Melkalem Mamuye Azanaw, Mohammadreza Azangou-Khyavy, Amirhossein Azari Jafari, Ahmed Y Azzam, Ashish D Badiye, Nasser Bagheri, Sara Bagherieh, Mohan Bairwa, Shankar M Bakkannavar, Ravleen Kaur Bakshi, Awraris Hailu Balchut/Bilchut, Till Winfried Bärnighausen, Fabio Barra, Amadou Barrow, Pritish Baskaran, Luis Belo, Derrick A Bennett, Isabela M Benseñor, Akshaya Srikanth Bhagavathula, Neeraj Bhala, Ashish Bhalla, Nikha Bhardwaj, Pankaj Bhardwaj, Sonu Bhaskar, Krittika Bhattacharyya, Vijayalakshmi S Bhojaraja, Bagas Suryo Bintoro, Elena A Elena Blokhina, Belay Boda Abule Bodicha, Archith Boloor, Cristina Bosetti, Dejana Braithwaite, Hermann Brenner, Nikolay Ivanovich Briko, Andre R Brunoni, Zahid A Butt, Chao Cao, Yin Cao, Rosario Cárdenas, Andre F Carvalho, Márcia Carvalho, Joao Mauricio Castaldelli-Maia, Giulio Castelpietra, Luis F S Castro-de-Araujo, Maria Sofia Cattaruzza, Promit Ananyo Chakraborty, Jaykaran Charan, Vijay Kumar Chattu, Akhilanand Chaurasia, Nicolas Cherbuin, Dinh-Toi Chu, Nandita Chudal, Sheng-Chia Chung, Chuchu Churko, Liliana G Ciobanu, Massimo Cirillo, Rafael M Claro, Simona Costanzo, Richard G Cowden, Michael H Criqui, Natália Cruz-Martins, Garland T Culbreth, Berihun Assefa Dachew, Omid Dadras, Xiaochen Dai, Giovanni Damiani, Lalit Dandona, Rakhi Dandona, Beniam Darge Daniel, Anna Danielewicz, Jiregna Darega Gela, Kairat Davletov, Jacyra Azevedo Paiva de Araujo, Antonio Reis de Sá-Junior, Sisay Abebe Debela, Azizallah Dehghan, Andreas K Demetriades, Meseret Derbew Molla, Rupak Desai, Abebaw Alemayehu Desta, Diana Dias da Silva, Daniel Diaz, Lankamo Ena Digesa, Mengistie Diress, Milad Dodangeh, Deepa Dongarwar, Fariba Dorostkar, Haneil Larson Dsouza, Bereket Duko, Bruce B Duncan, Kristina Edvardsson, Michael Ekholuenetale, Frank J Elgar, Muhammed Elhadi, Mohamed A Elmonem, Aman Yesuf Endries, Sharareh Eskandarieh, Azin Etemadimanesh, Adeniyi Francis Fagbamigbe, Ildar Ravisovich Fakhradiyev, Fatemeh Farahmand, Carla Sofia e Sá Farinha, Andre Faro, Farshad Farzadfar, Ali Fatehizadeh, Nelsensius Klau Fauk, Valery L Feigin, Rachel Feldman, Xiaoqi Feng, Zinabu Fentaw, Simone Ferrero, Lorenzo Ferro Desideri, Irina Filip, Florian Fischer, Joel Msafiri Francis, Richard Charles Franklin, Peter Andras Gaal, Mohamed M Gad, Silvano Gallus, Fabio Galvano, Balasankar Ganesan, Tushar Garg, Mesfin Gebrehiwot Damtew Gebrehiwot, Teferi Gebru Gebremeskel, Mathewos Alemu Gebremichael, Tadele Regasa Gemechu, Lemma Getacher, Motuma Erena Getachew, Abera Getachew Obsa, Asmare Getie, Amir Ghaderi, Mansour Ghafourifard, Alireza Ghajar, Seyyed-Hadi Ghamari, Lilian A Ghandour, Mohammad Ghasemi Nour, Ahmad Ghashghaee, Sherief Ghozy, Franklin N Glozah, Ekaterina Vladimirovna Glushkova, Justyna Godos, Amit Goel, Salime Goharinezhad, Mahaveer Golechha, Pouya Goleij, Mohamad Golitaleb, Felix Greaves, Michal Grivna, Giuseppe Grosso, Temesgen Worku Gudayu, Bhawna Gupta, Rajeev Gupta, Sapna Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Nima Hafezi-Nejad, Arvin Haj-Mirzaian, Brian J Hall, Rabih Halwani, Tiilahun Beyene Handiso, Graeme J Hankey, Sanam Hariri, Josep Maria Haro, Ahmed I Hasaballah, Hossein Hassanian-Moghaddam, Simon I Hay, Khezar Hayat, Golnaz Heidari, Mohammad Heidari, Delia Hendrie, Claudiu Herteliu, Demisu Zenbaba Heyi, Kamal Hezam, Mbuzeleni Mbuzeleni Hlongwa, Ramesh Holla, Md Mahbub Hossain, Sahadat Hossain, Seyed Kianoosh Hosseini, Mehdi hosseinzadeh, Mihaela Hostiuc, Sorin Hostiuc, Guoqing Hu, Junjie Huang, Salman Hussain, Segun Emmanuel Ibitoye, Irena M Ilic, Milena D Ilic, Mustapha Immurana, Lalu Muhammad Irham, M Mofizul Islam, Rakibul M Islam, Sheikh Mohammed Shariful Islam, Hiroyasu Iso, Ramaiah Itumalla, Masao Iwagami, Roxana Jabbarinejad, Louis Jacob, Mihajlo Jakovljevic, Zahra Jamalpoor, Elham Jamshidi, Sathish Kumar Jayapal, Umesh Umesh Jayarajah, Ranil Jayawardena, Rime Jebai, Seyed Ali Jeddi, Alelign Tasew Jema, Ravi Prakash Jha, Har Ashish Jindal, Jost B Jonas, Tamas Joo, Nitin Joseph, Farahnaz Joukar, Jacek Jerzy Jozwiak, Mikk Jürisson, Ali Kabir, Robel Hussen Kabthymer, Bhushan Dattatray Kamble, Himal Kandel, Girum Gebremeskel Kanno, Neeti Kapoor, Ibraheem M Karaye, Salah Eddin Karimi, Bekalu Getnet Kassa, Rimple Jeet Kaur, Gbenga A Kayode, Mohammad Keykhaei, Himanshu Khajuria, Rovshan Khalilov, Imteyaz A Khan, Moien AB Khan, Hanna Kim, Jihee Kim, Min Seo Kim, Ruth W Kimokoti, Mika Kivimäki, Vitalii Klymchuk, Ann Kristin Skrindo Knudsen, Ali-Asghar Kolahi, Vladimir Andreevich Korshunov, Ai Koyanagi, Kewal Krishan, Yuvaraj Krishnamoorthy, G Anil Kumar, Narinder Kumar, Nithin Kumar, Ben Lacey, Tea Lallukka, Savita Lasrado, Jerrald Lau, Sang-woong Lee, Wei-Chen Lee, Yo Han Lee, Lee-Ling Lim, Stephen S Lim, Stany W Lobo, Platon D Lopukhov, Stefan Lorkowski, Rafael Lozano, Giancarlo Lucchetti, Farzan Madadizadeh, Áurea M Madureira-Carvalho, Soleiman Mahjoub, Ata Mahmoodpoor, Rashidul Alam Mahumud, Alaa Makki, Mohammad-Reza Malekpour, Narayana Manjunatha, Borhan Mansouri, Mohammad Ali Mansournia, Jose Martinez-Raga, Francisco A Martinez-Villa, Richard Matzopoulos, Pallab K Maulik, Mahsa Mayeli, John J McGrath, Jitendra Kumar Meena, Entezar Mehrabi Nasab, Ritesh G Menezes, Gert B M Mensink, Alexios-Fotios A Mentis, Atte Meretoja, Bedasa Taye Merga, Tomislav Mestrovic, Junmei Miao Jonasson, Bartosz Miazgowski, Ana Carolina Micheletti Gomide Nogueira de Sá, Ted R Miller, GK Mini, Andreea Mirica, Antonio Mirijello, Seyyedmohammadsadeq Mirmoeeni, Erkin M Mirrakhimov, Sanjeev Misra, Babak Moazen, Maryam Mobarakabadi, Marcello Moccia, Yousef Mohammad, Esmaeil Mohammadi, Abdollah Mohammadian-Hafshejani, Teroj Abdulrahman Mohammed, Nagabhishek Moka, Ali H Mokdad, Sara Momtazmanesh, Yousef Moradi, Ebrahim Mostafavi, Sumaira Mubarik, Erin C Mullany, Beemnet Tekabe Mulugeta, Efrén Murillo-Zamora, Christopher J L Murray, Julius C Mwita, Mohsen Naghavi, Mukhammad David Naimzada, Vinay Nangia, Biswa Prakash Nayak, Ionut Negoi, Ruxandra Irina Negoi, Seyed Aria Nejadghaderi, Samata Nepal, Sudan Prasad Prasad Neupane, Sandhya Neupane Kandel, Yeshambel T Nigatu, Ali Nowroozi, Khan M Nuruzzaman, Chimezie Igwegbe Nzoputam, Kehinde O Obamiro, Felix Akpojene Ogbo, Ayodipupo Sikiru Oguntade, Hassan Okati-Aliabad, Babayemi Oluwaseun Olakunde, Gláucia Maria Moraes Oliveira, Ahmed Omar Bali, Emad Omer, Doris V Ortega-Altamirano, Adrian Otoiu, Stanislav S Otstavnov, Bilcha Oumer, Mahesh P A, Alicia Padron-Monedero, Raffaele Palladino, Adrian Pana, Songhomitra Panda-Jonas, Anamika Pandey, Ashok Pandey, Shahina Pardhan, Tarang Parekh, Eun-Kee Park, Charles D H Parry, Fatemeh Pashazadeh Kan, Jay Patel, Siddhartha Pati, George C Patton, Uttam Paudel, Shrikant Pawar, Amy E Peden, Ionela-Roxana Petcu, Michael R Phillips, Marina Pinheiro, Evgenii Plotnikov, Pranil Man Singh Pradhan, Akila Prashant, Jianchao Quan, Amir Radfar, Alireza Rafiei, Pankaja Raghav Raghav, Vafa Rahimi-Movaghar, Azizur Rahman, Md Mosfequr Rahman, Mosiur Rahman, Amir Masoud Rahmani, Shayan Rahmani, Chhabi Lal Ranabhat, Priyanga Ranasinghe, Chythra R Rao, Drona Prakash Rasali, Mohammad-Mahdi Rashidi, Zubair Ahmed Ratan, David Laith Rawaf, Salman Rawaf, Lal Rawal, Andre M N Renzaho, Negar Rezaei, Saeid Rezaei, Mohsen Rezaeian, Seyed Mohammad Riahi, Esperanza Romero-Rodríguez, Gregory A Roth, Godfrey M Rwegerera, Basema Saddik, Erfan Sadeghi, Reihaneh Sadeghian, Umar Saeed, Farhad Saeedi, Rajesh Sagar, Amirhossein Sahebkar, Harihar Sahoo, Mohammad Ali Sahraian, KM Saif-Ur-Rahman, Sarvenaz Salahi, Hamideh Salimzadeh, Abdallah M Samy, Francesco Sanmarchi, Milena M Santric-Milicevic, Yaser Sarikhani, Brijesh Sathian, Ganesh Kumar Saya, Mehdi Sayyah, Maria Inês Schmidt, Aletta Elisabeth Schutte, Michaël Schwarzinger, David C Schwebel, Abdul-Aziz Seidu, Nachimuthu Senthil Kumar, SeyedAhmad SeyedAlinaghi, Allen Seylani, Feng Sha, Sarvenaz Shahin, Fariba Shahraki-Sanavi, Shayan Shahrokhi, Masood Ali Shaikh, Elaheh Shaker, Murad Ziyaudinovich Shakhmardanov, Mehran Shams-Beyranvand, Sara Sheikhbahaei, Rahim Ali Sheikhi, Adithi Shetty, Jeevan K Shetty, Damtew Solomon Shiferaw, Mika Shigematsu, Rahman Shiri, Reza Shirkoohi, K M Shivakumar, Velizar Shivarov, Parnian Shobeiri, Roman Shrestha, Negussie Boti Sidemo, Inga Dora Sigfusdottir, Diego Augusto Santos Silva, Natacha Torres da Silva, Jasvinder A Singh, Surjit Singh, Valentin Yurievich Skryabin, Anna Aleksandrovna Skryabina, David A Sleet, Marco Solmi, YONATAN SOLOMON, Suhang Song, Yimeng Song, Reed J D Sorensen, Sergey Soshnikov, Ireneous N Soyiri, Dan J Stein, Sonu Hangma Subba, Miklós Szócska, Rafael Tabarés-Seisdedos, Takahiro Tabuchi, Majid Taheri, Ker-Kan Tan, Minale Tareke, Elvis Enowbeyang Tarkang, Gebremaryam Temesgen, Worku Animaw Temesgen, Mohamad-Hani Temsah, Kavumpurathu Raman Thankappan, Rekha Thapar, Nikhil Kenny Thomas, Chalachew Tiruneh, Jovana Todorovic, Marco Torrado, Mathilde Touvier, Marcos Roberto Tovani-Palone, Mai Thi Ngoc Tran, Sergi Trias-Llimós, Jaya Prasad Tripathy, Alireza Vakilian, Rohollah Valizadeh, Mehdi Varmaghani, Shoban Babu Varthya, Tommi Juhani Vasankari, Theo Vos, Birhanu Wagaye, Yasir Waheed, Mandaras Tariku Walde, Cong Wang, Yanzhong Wang, Yuan-Pang Wang, Ronny Westerman, Nuwan Darshana Wickramasinghe, Abate Dargie Wubetu, Suowen Xu, Kazumasa Yamagishi, Lin Yang, Gesila Endashaw E Yesera, Arzu Yigit, Vahit Yiğit, Ayenew Engida Ayenew Engida Yimaw, Dong Keon Yon, Naohiro Yonemoto, Chuanhua Yu, Siddhesh Zadey, Mazyar Zahir, Iman Zare, Mikhail Sergeevich Zastrozhin, Anasthasia Zastrozhina, Zhi-Jiang Zhang, Chenwen Zhong, Mohammad Zmaili, Yves Miel H Zuniga, Emmanuela Gakidou, University of St Andrews. School of Medicine, University of St Andrews. Population and Behavioural Science Division, Department of Public Health, University of Helsinki, Hjelt Institute (-2014), Helsinki Inequality Initiative (INEQ), Clinicum, Helsinki University Hospital Area, Bill & Melinda Gates Foundation, King Edward Medical University (Pakistán), Alexander von Humboldt Foundation, University of Oxford (Reino Unido), Medical Research Council (Reino Unido), NIH - National Institute of Mental Health (NIMH) (Estados Unidos), Canada Research Chairs, National Health and Medical Research Council (Australia), National Heart Foundation of Australia, Ministry of Education, Science and Technological Development (Serbia), Wellcome Trust, NIH - National Institute on Aging (NIA) (Estados Unidos), Finlands Akademi (Finlandia), Panjab University (India), Federal Ministry of Education & Research (Alemania), National Council for Scientific and Technological Development (Brasil), Danish National Research Foundation, Queensland Centre for Mental Health Research (Australia), South African Medical Research Council, National Natural Science Foundation of China, Charles Sturt University (Australia), Ain Shams University (Egipto), Mizoram University (India), Kasturba Medical College (India), Manipal Academy of Higher Education (India), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (Brasil), Ministerio de Ciencia e Innovación (España), Collaborators, GBD 2020 Alcohol, Bryazka, Dana, Reitsma, Marissa B, Griswold, Max G, Abate, Kalkidan Hassen, Abbafati, Cristiana, Abbasi-Kangevari, Mohsen, Abbasi-Kangevari, Zeinab, Abdoli, Amir, Abdollahi, Mohammad, Abdullah, Abu Yousuf Md, Abhilash, E S, Abu-Gharbieh, Eman, Acuna, Juan Manuel, Addolorato, Giovanni, Adebayo, Oladimeji M, Adekanmbi, Victor, Adhikari, Kishor, Adhikari, Sangeet, Adnani, Qorinah Estiningtyas Sakilah, Afzal, Saira, Agegnehu, Wubetu Yimam, Aggarwal, Manik, Ahinkorah, Bright Opoku, Ahmad, Araz Ramazan, Ahmad, Sajjad, Ahmad, Tauseef, Ahmadi, Ali, Ahmadi, Sepideh, Ahmed, Haroon, Ahmed Rashid, Tarik, Akunna, Chisom Joyqueenet, Al Hamad, Hanadi, Alam, Md Zakiul, Alem, Dejene Tsegaye, Alene, Kefyalew Addi, Alimohamadi, Yousef, Alizadeh, Atiyeh, Allel, Kasim, Alonso, Jordi, Alvand, Saba, Alvis-Guzman, Nelson, Amare, Firehiwot, Ameyaw, Edward Kwabena, Amiri, Sohrab, Ancuceanu, Robert, Anderson, Jason A, Andrei, Catalina Liliana, Andrei, Tudorel, Arabloo, Jalal, Arshad, Muhammad, Artamonov, Anton A, Aryan, Zahra, Asaad, Malke, Asemahagn, Mulusew A, Astell-Burt, Thoma, Athari, Seyyed Shamsadin, Atnafu, Desta Debalkie, Atorkey, Prince, Atreya, Alok, Ausloos, Floriane, Ausloos, Marcel, Ayano, Getinet, Ayanore, Martin Amogre ayanore, Ayinde, Olatunde O, Ayuso-Mateos, Jose L, Azadnajafabad, Sina, Azanaw, Melkalem Mamuye, Azangou-Khyavy, Mohammadreza, Azari Jafari, Amirhossein, Azzam, Ahmed Y, Badiye, Ashish D, Bagheri, Nasser, Bagherieh, Sara, Bairwa, Mohan, Bakkannavar, Shankar M, Bakshi, Ravleen Kaur, Balchut/bilchut, Awraris Hailu, Bärnighausen, Till Winfried, Barra, Fabio, Barrow, Amadou, Baskaran, Pritish, Belo, Lui, Bennett, Derrick A, Benseñor, Isabela M, Bhagavathula, Akshaya Srikanth, Bhala, Neeraj, Bhalla, Ashish, Bhardwaj, Nikha, Bhardwaj, Pankaj, Bhaskar, Sonu, Bhattacharyya, Krittika, Bhojaraja, Vijayalakshmi S, Bintoro, Bagas Suryo, Blokhina, Elena A Elena, Bodicha, Belay Boda Abule, Boloor, Archith, Bosetti, Cristina, Braithwaite, Dejana, Brenner, Hermann, Briko, Nikolay Ivanovich, Brunoni, Andre R, Butt, Zahid A, Cao, Chao, Cao, Yin, Cárdenas, Rosario, Carvalho, Andre F, Carvalho, Márcia, Castaldelli-Maia, Joao Mauricio, Castelpietra, Giulio, Castro-de-Araujo, Luis F S, Cattaruzza, Maria Sofia, Chakraborty, Promit Ananyo, Charan, Jaykaran, Chattu, Vijay Kumar, Chaurasia, Akhilanand, Cherbuin, Nicola, Chu, Dinh-Toi, Chudal, Nandita, Chung, Sheng-Chia, Churko, Chuchu, Ciobanu, Liliana G, Cirillo, Massimo, Claro, Rafael M, Costanzo, Simona, Cowden, Richard G, Criqui, Michael H, Cruz-Martins, Natália, Culbreth, Garland T, Dachew, Berihun Assefa, Dadras, Omid, Dai, Xiaochen, Damiani, Giovanni, Dandona, Lalit, Dandona, Rakhi, Daniel, Beniam Darge, Danielewicz, Anna, Darega Gela, Jiregna, Davletov, Kairat, de Araujo, Jacyra Azevedo Paiva, de Sá-Junior, Antonio Rei, Debela, Sisay Abebe, Dehghan, Azizallah, Demetriades, Andreas K, Derbew Molla, Meseret, Desai, Rupak, Desta, Abebaw Alemayehu, Dias da Silva, Diana, Diaz, Daniel, Digesa, Lankamo Ena, Diress, Mengistie, Dodangeh, Milad, Dongarwar, Deepa, Dorostkar, Fariba, Dsouza, Haneil Larson, Duko, Bereket, Duncan, Bruce B, Edvardsson, Kristina, Ekholuenetale, Michael, Elgar, Frank J, Elhadi, Muhammed, Elmonem, Mohamed A, Endries, Aman Yesuf, Eskandarieh, Sharareh, Etemadimanesh, Azin, Fagbamigbe, Adeniyi Franci, Fakhradiyev, Ildar Ravisovich, Farahmand, Fatemeh, Farinha, Carla Sofia e Sá, Faro, Andre, Farzadfar, Farshad, Fatehizadeh, Ali, Fauk, Nelsensius Klau, Feigin, Valery L, Feldman, Rachel, Feng, Xiaoqi, Fentaw, Zinabu, Ferrero, Simone, Ferro Desideri, Lorenzo, Filip, Irina, Fischer, Florian, Francis, Joel Msafiri, Franklin, Richard Charle, Gaal, Peter Andra, Gad, Mohamed M, Gallus, Silvano, Galvano, Fabio, Ganesan, Balasankar, Garg, Tushar, Gebrehiwot, Mesfin Gebrehiwot Damtew, Gebremeskel, Teferi Gebru, Gebremichael, Mathewos Alemu, Gemechu, Tadele Regasa, Getacher, Lemma, Getachew, Motuma Erena, Getachew Obsa, Abera, Getie, Asmare, Ghaderi, Amir, Ghafourifard, Mansour, Ghajar, Alireza, Ghamari, Seyyed-Hadi, Ghandour, Lilian A, Ghasemi Nour, Mohammad, Ghashghaee, Ahmad, Ghozy, Sherief, Glozah, Franklin N, Glushkova, Ekaterina Vladimirovna, Godos, Justyna, Goel, Amit, Goharinezhad, Salime, Golechha, Mahaveer, Goleij, Pouya, Golitaleb, Mohamad, Greaves, Felix, Grivna, Michal, Grosso, Giuseppe, Gudayu, Temesgen Worku, Gupta, Bhawna, Gupta, Rajeev, Gupta, Sapna, Gupta, Veer Bala, Gupta, Vivek Kumar, Hafezi-Nejad, Nima, Haj-Mirzaian, Arvin, Hall, Brian J, Halwani, Rabih, Handiso, Tiilahun Beyene, Hankey, Graeme J, Hariri, Sanam, Haro, Josep Maria, Hasaballah, Ahmed I, Hassanian-Moghaddam, Hossein, Hay, Simon I, Hayat, Khezar, Heidari, Golnaz, Heidari, Mohammad, Hendrie, Delia, Herteliu, Claudiu, Heyi, Demisu Zenbaba, Hezam, Kamal, Hlongwa, Mbuzeleni Mbuzeleni, Holla, Ramesh, Hossain, Md Mahbub, Hossain, Sahadat, Hosseini, Seyed Kianoosh, Hosseinzadeh, Mehdi, Hostiuc, Mihaela, Hostiuc, Sorin, Hu, Guoqing, Huang, Junjie, Hussain, Salman, Ibitoye, Segun Emmanuel, Ilic, Irena M, Ilic, Milena D, Immurana, Mustapha, Irham, Lalu Muhammad, Islam, M Mofizul, Islam, Rakibul M, Islam, Sheikh Mohammed Shariful, Iso, Hiroyasu, Itumalla, Ramaiah, Iwagami, Masao, Jabbarinejad, Roxana, Jacob, Loui, Jakovljevic, Mihajlo, Jamalpoor, Zahra, Jamshidi, Elham, Jayapal, Sathish Kumar, Jayarajah, Umesh Umesh, Jayawardena, Ranil, Jebai, Rime, Jeddi, Seyed Ali, Jema, Alelign Tasew, Jha, Ravi Prakash, Jindal, Har Ashish, Jonas, Jost B, Joo, Tama, Joseph, Nitin, Joukar, Farahnaz, Jozwiak, Jacek Jerzy, Jürisson, Mikk, Kabir, Ali, Kabthymer, Robel Hussen, Kamble, Bhushan Dattatray, Kandel, Himal, Kanno, Girum Gebremeskel, Kapoor, Neeti, Karaye, Ibraheem M, Karimi, Salah Eddin, Kassa, Bekalu Getnet, Kaur, Rimple Jeet, Kayode, Gbenga A, Keykhaei, Mohammad, Khajuria, Himanshu, Khalilov, Rovshan, Khan, Imteyaz A, Khan, Moien AB, Kim, Hanna, Kim, Jihee, Kim, Min Seo, Kimokoti, Ruth W, Kivimäki, Mika, Klymchuk, Vitalii, Knudsen, Ann Kristin Skrindo, Kolahi, Ali-Asghar, Korshunov, Vladimir Andreevich, Koyanagi, Ai, Krishan, Kewal, Krishnamoorthy, Yuvaraj, Kumar, G Anil, Kumar, Narinder, Kumar, Nithin, Lacey, Ben, Lallukka, Tea, Lasrado, Savita, Lau, Jerrald, Lee, Sang-woong, Lee, Wei-Chen, Lee, Yo Han, Lim, Lee-Ling, Lim, Stephen S, Lobo, Stany W, Lopukhov, Platon D, Lorkowski, Stefan, Lozano, Rafael, Lucchetti, Giancarlo, Madadizadeh, Farzan, Madureira-Carvalho, Áurea M, Mahjoub, Soleiman, Mahmoodpoor, Ata, Mahumud, Rashidul Alam, Makki, Alaa, Malekpour, Mohammad-Reza, Manjunatha, Narayana, Mansouri, Borhan, Mansournia, Mohammad Ali, Martinez-Raga, Jose, Martinez-Villa, Francisco A, Matzopoulos, Richard, Maulik, Pallab K, Mayeli, Mahsa, Mcgrath, John J, Meena, Jitendra Kumar, Mehrabi Nasab, Entezar, Menezes, Ritesh G, Mensink, Gert B M, Mentis, Alexios-Fotios A, Meretoja, Atte, Merga, Bedasa Taye, Mestrovic, Tomislav, Miao Jonasson, Junmei, Miazgowski, Bartosz, Micheletti Gomide Nogueira de Sá, Ana Carolina, Miller, Ted R, Mini, Gk, Mirica, Andreea, Mirijello, Antonio, Mirmoeeni, Seyyedmohammadsadeq, Mirrakhimov, Erkin M, Misra, Sanjeev, Moazen, Babak, Mobarakabadi, Maryam, Moccia, Marcello, Mohammad, Yousef, Mohammadi, Esmaeil, Mohammadian-Hafshejani, Abdollah, Mohammed, Teroj Abdulrahman, Moka, Nagabhishek, Mokdad, Ali H, Momtazmanesh, Sara, Moradi, Yousef, Mostafavi, Ebrahim, Mubarik, Sumaira, Mullany, Erin C, Mulugeta, Beemnet Tekabe, Murillo-Zamora, Efrén, Murray, Christopher J L, Mwita, Julius C, Naghavi, Mohsen, Naimzada, Mukhammad David, Nangia, Vinay, Nayak, Biswa Prakash, Negoi, Ionut, Negoi, Ruxandra Irina, Nejadghaderi, Seyed Aria, Nepal, Samata, Neupane, Sudan Prasad Prasad, Neupane Kandel, Sandhya, Nigatu, Yeshambel T, Nowroozi, Ali, Nuruzzaman, Khan M, Nzoputam, Chimezie Igwegbe, Obamiro, Kehinde O, Ogbo, Felix Akpojene, Oguntade, Ayodipupo Sikiru, Okati-Aliabad, Hassan, Olakunde, Babayemi Oluwaseun, Oliveira, Gláucia Maria Morae, Omar Bali, Ahmed, Omer, Emad, Ortega-Altamirano, Doris V, Otoiu, Adrian, Otstavnov, Stanislav S, Oumer, Bilcha, P A, Mahesh, Padron-Monedero, Alicia, Palladino, Raffaele, Pana, Adrian, Panda-Jonas, Songhomitra, Pandey, Anamika, Pandey, Ashok, Pardhan, Shahina, Parekh, Tarang, Park, Eun-Kee, Parry, Charles D H, Pashazadeh Kan, Fatemeh, Patel, Jay, Pati, Siddhartha, Patton, George C, Paudel, Uttam, Pawar, Shrikant, Peden, Amy E, Petcu, Ionela-Roxana, Phillips, Michael R, Pinheiro, Marina, Plotnikov, Evgenii, Pradhan, Pranil Man Singh, Prashant, Akila, Quan, Jianchao, Radfar, Amir, Rafiei, Alireza, Raghav, Pankaja Raghav, Rahimi-Movaghar, Vafa, Rahman, Azizur, Rahman, Md Mosfequr, Rahman, Mosiur, Rahmani, Amir Masoud, Rahmani, Shayan, Ranabhat, Chhabi Lal, Ranasinghe, Priyanga, Rao, Chythra R, Rasali, Drona Prakash, Rashidi, Mohammad-Mahdi, Ratan, Zubair Ahmed, Rawaf, David Laith, Rawaf, Salman, Rawal, Lal, Renzaho, Andre M N, Rezaei, Negar, Rezaei, Saeid, Rezaeian, Mohsen, Riahi, Seyed Mohammad, Romero-Rodríguez, Esperanza, Roth, Gregory A, Rwegerera, Godfrey M, Saddik, Basema, Sadeghi, Erfan, Sadeghian, Reihaneh, Saeed, Umar, Saeedi, Farhad, Sagar, Rajesh, Sahebkar, Amirhossein, Sahoo, Harihar, Sahraian, Mohammad Ali, Saif-Ur-Rahman, Km, Salahi, Sarvenaz, Salimzadeh, Hamideh, Samy, Abdallah M, Sanmarchi, Francesco, Santric-Milicevic, Milena M, Sarikhani, Yaser, Sathian, Brijesh, Saya, Ganesh Kumar, Sayyah, Mehdi, Schmidt, Maria Inê, Schutte, Aletta Elisabeth, Schwarzinger, Michaël, Schwebel, David C, Seidu, Abdul-Aziz, Senthil Kumar, Nachimuthu, Seyedalinaghi, Seyedahmad, Seylani, Allen, Sha, Feng, Shahin, Sarvenaz, Shahraki-Sanavi, Fariba, Shahrokhi, Shayan, Shaikh, Masood Ali, Shaker, Elaheh, Shakhmardanov, Murad Ziyaudinovich, Shams-Beyranvand, Mehran, Sheikhbahaei, Sara, Sheikhi, Rahim Ali, Shetty, Adithi, Shetty, Jeevan K, Shiferaw, Damtew Solomon, Shigematsu, Mika, Shiri, Rahman, Shirkoohi, Reza, Shivakumar, K M, Shivarov, Velizar, Shobeiri, Parnian, Shrestha, Roman, Sidemo, Negussie Boti, Sigfusdottir, Inga Dora, Silva, Diego Augusto Santo, Silva, Natacha Torres da, Singh, Jasvinder A, Singh, Surjit, Skryabin, Valentin Yurievich, Skryabina, Anna Aleksandrovna, Sleet, David A, Solmi, Marco, Solomon, Yonatan, Song, Suhang, Song, Yimeng, Sorensen, Reed J D, Soshnikov, Sergey, Soyiri, Ireneous N, Stein, Dan J, Subba, Sonu Hangma, Szócska, Mikló, Tabarés-Seisdedos, Rafael, Tabuchi, Takahiro, Taheri, Majid, Tan, Ker-Kan, Tareke, Minale, Tarkang, Elvis Enowbeyang, Temesgen, Gebremaryam, Temesgen, Worku Animaw, Temsah, Mohamad-Hani, Thankappan, Kavumpurathu Raman, Thapar, Rekha, Thomas, Nikhil Kenny, Tiruneh, Chalachew, Todorovic, Jovana, Torrado, Marco, Touvier, Mathilde, Tovani-Palone, Marcos Roberto, Tran, Mai Thi Ngoc, Trias-Llimós, Sergi, Tripathy, Jaya Prasad, Vakilian, Alireza, Valizadeh, Rohollah, Varmaghani, Mehdi, Varthya, Shoban Babu, Vasankari, Tommi Juhani, Vos, Theo, Wagaye, Birhanu, Waheed, Yasir, Walde, Mandaras Tariku, Wang, Cong, Wang, Yanzhong, Wang, Yuan-Pang, Westerman, Ronny, Wickramasinghe, Nuwan Darshana, Wubetu, Abate Dargie, Xu, Suowen, Yamagishi, Kazumasa, Yang, Lin, Yesera, Gesila Endashaw E, Yigit, Arzu, Yiğit, Vahit, Yimaw, Ayenew Engida Ayenew Engida, Yon, Dong Keon, Yonemoto, Naohiro, Yu, Chuanhua, Zadey, Siddhesh, Zahir, Mazyar, Zare, Iman, Zastrozhin, Mikhail Sergeevich, Zastrozhina, Anasthasia, Zhang, Zhi-Jiang, Zhong, Chenwen, Zmaili, Mohammad, Zuniga, Yves Miel H, Gakidou, Emmanuela, Bryazka, D, Reitsma, Mb, Griswold, Mg, Abate, Kh, Abbafati, C, Kangevari, Ma, Kangevari, Za, Abdoli, A, Abdollahi, M, Abdullah, Am, Abhilash, E, Abu Gharbieh, E, Acuna, Jm, Addolorato, G, Adebayo, Om, Adekanmbi, V, Adhikari, K, Adhikari, S, Adnani, Qe, Afzal, S, Agegnehu, Wy, Aggarwal, M, Ahinkorah, Bo, Ahmad, Ar, Ahmad, S, Ahmad, T, Ahmadi, A, Ahmadi, S, Ahmed, H, Rashid, Ta, Akunna, Cj, Al Hamad, H, Alam, Mz, Alem, Dt, Alene, Ka, Alimohamadi, Y, Alizadeh, A, Allel, K, Alonso, J, Alvand, S, Guzman, Na, Amare, F, Ameyaw, Ek, Amiri, S, Ancuceanu, R, Anderson, Ja, Andrei, Cl, Andrei, T, Arabloo, J, Arshad, M, Artamonov, Aa, Aryan, Z, Asaad, M, Asemahagn, Ma, Burt, Ta, Athari, S, Atnafu, Dd, Atorkey, P, Atreya, A, Ausloos, F, Ausloos, M, Ayano, G, Ayanore, Ma, Ayinde, Oo, Mateos, Jla, Azadnajafabad, S, Azanaw, Mm, Khyavy, Ma, Jafari, Aa, Azzam, Ay, Badiye, Ad, Bagheri, N, Bagherieh, S, Bairwa, M, Bakkannavar, Sm, Bakshi, Rk, Balchut, Ah, Null, T, Barra, F, Barrow, A, Baskaran, P, Belo, L, Bennett, Da, Bensenor, Im, Bhagavathula, A, Bhala, N, Bhalla, A, Bhardwaj, N, Bhardwaj, P, Bhaskar, S, Bhattacharyya, K, Bhojaraja, V, Bintoro, B, Blokhina, Eae, Bodicha, Bba, Boloor, A, Bosetti, C, Braithwaite, D, Brenner, H, Briko, Ni, Brunoni, Ar, Butt, Za, Cao, C, Cao, Y, Cardenas, R, Carvalho, Af, Carvalho, M, Maia, Jmc, Castelpietra, G, de Araujo, Lfsc, Cattaruzza, M, Chakraborty, Pa, Charan, J, Chattu, Vk, Chaurasia, A, Cherbuin, N, Chu, Dt, Chudal, N, Chung, Sc, Churko, C, Ciobanu, Lg, Cirillo, M, Claro, Rm, Costanzo, S, Cowden, Rg, Criqui, Mh, Martins, Nc, Culbreth, Gt, Dachew, Ba, Dadras, O, Dai, Xc, Damiani, G, Dandona, L, Dandona, R, Daniel, Bd, Danielewicz, A, Gela, Jd, Davletov, K, de Araujo, Jap, de Sa, Ar, Debela, Sa, Dehghan, A, Demetriades, Ak, Molla, Md, Desai, R, Desta, Aa, da Silva, Dd, Diaz, D, Digesa, Le, Diress, M, Dodangeh, M, Dongarwar, D, Dorostkar, F, Dsouza, Hl, Duko, B, Duncan, Bb, Edvardsson, K, Ekholuenetale, M, Elgar, Fj, Elhadi, M, Elmonem, Ma, Endries, Ay, Eskandarieh, S, Etemadimanesh, A, Fagbamigbe, Af, Fakhradiyev, Ir, Farahmand, F, Farinha, Cse, Faro, A, Farzadfar, F, Fatehizadeh, A, Fauk, Nk, Feigin, Vl, Feldman, R, Feng, Xq, Fentaw, Z, Ferrero, S, Desideri, Lf, Filip, I, Fischer, F, Francis, Jm, Franklin, Rc, Gaal, Pa, Gad, Mm, Gallus, S, Galvano, F, Ganesan, B, Garg, T, Gebrehiwot, Mgd, Gebremeskel, Tg, Gebremichael, Ma, Gemechu, Tr, Getacher, L, Getachew, Me, Obsa, Ag, Getie, A, Ghaderi, A, Ghafourifard, M, Ghajar, A, Ghamari, Sh, Ghandour, La, Nour, Mg, Ghashghaee, A, Ghozy, S, Glozah, Fn, Glushkova, Ev, Godos, J, Goel, A, Goharinezhad, S, Golechha, M, Goleij, P, Golitaleb, M, Greaves, F, Grivna, M, Grosso, G, Gudayu, Tw, Gupta, B, Gupta, R, Gupta, S, Gupta, Vb, Gupta, Vk, Nejad, Nh, Mirzaian, Ah, Hall, Bj, Halwani, R, Handiso, Tb, Hankey, Gj, Hariri, S, Haro, Jm, Hasaballah, Ai, Moghaddam, Hh, Hay, Si, Hayat, K, Heidari, G, Heidari, M, Hendrie, D, Herteliu, C, Heyi, Dz, Hezam, K, Hlongwa, Mm, Holla, R, Hossain, Mm, Hossain, S, Hosseini, Sk, Hosseinzadeh, M, Hostiuc, M, Hostiuc, S, Hu, Gq, Huang, Jj, Hussain, S, Ibitoye, Se, Ilic, Im, Ilic, Md, Immurana, M, Irham, Lm, Islam, Mm, Islam, Rm, Islam, Sm, Iso, H, Itumalla, R, Iwagami, M, Jabbarinejad, R, Jacob, L, Jakovljevic, M, Jamalpoor, Z, Jamshidi, E, Jayapal, Sk, Jayarajah, Uu, Jayawardena, R, Jebai, R, Jeddi, Sa, Jema, At, Jha, Rp, Jindal, Ha, Jonas, Jb, Joo, T, Joseph, N, Joukar, F, Jozwiak, Jj, Jurisson, M, Kabir, A, Kabthymer, Rh, Kamble, Bd, Kandel, H, Kanno, Gg, Kapoor, N, Karaye, Im, Karimi, Se, Kassa, Bg, Kaur, Rj, Kayode, Ga, Keykhaei, M, Khajuria, H, Khalilov, R, Khan, Ia, Ab Khan, M, Kim, H, Kim, J, Kim, M, Kimokoti, Rw, Kivimaki, M, Klymchuk, V, Knudsen, Ak, Kolahi, Aa, Korshunov, Va, Koyanagi, A, Krishan, K, Krishnamoorthy, Y, Kumar, Ga, Kumar, N, Ben, Lacey, Lallukka, T, Lasrado, S, Lau, J, Lee, Sw, Lee, Wc, Lee, Yh, Lim, Ll, Lim, S, Lobo, Sw, Lopukhov, Pd, Lorkowski, S, Lozano, R, Lucchetti, G, Madadizadeh, F, Mahjoub, S, Mahmoodpoor, A, Mahumud, Ra, Makki, A, Malekpour, Mr, Manjunatha, N, Mansouri, B, Mansournia, Ma, Raga, Jm, Villa, Fam, Matzopoulos, R, Maulik, Pk, Mayeli, M, Mcgrath, Jj, Meena, Jk, Nasab, Em, Menezes, Rg, Mensink, Gbm, Mentis, Afa, Meretoja, A, Merga, Bt, Mestrovic, T, Jonasson, Jm, Miazgowski, B, de Sa, Acmgn, Miller, Tr, Mini, G, Mirica, A, Mirijello, A, Mirmoeeni, S, Mirrakhimov, Em, Misra, S, Moazen, B, Mobarakabadi, M, Moccia, M, Mohammad, Y, Mohammadi, E, Hafshejani, Am, Mohammed, Ta, Moka, N, Mokdad, Ah, Momtazmanesh, S, Moradi, Y, Mostafavi, E, Mubarik, S, Mullany, Ec, Mulugeta, Bt, Zamora, Em, Murray, Cjl, Mwita, Jc, Naghavi, M, Naimzada, Md, Nangia, V, Nayak, Bp, Negoi, I, Negoi, Ri, Nejadghaderi, Sa, Nepal, S, Neupane, Spp, Kandel, Sn, Nigatu, Yt, Nowroozi, A, Nuruzzaman, Km, Nzoputam, Ci, Obamiro, Ko, Ogbo, Fa, Oguntade, A, Aliabad, Ho, Olakunde, Bo, Oliveira, Gmm, Bali, Ao, Omer, E, Altamirano, Dvo, Otoiu, A, Otstavnov, S, Oumer, B, Mahesh, Pa, Monedero, Ap, Palladino, R, Pana, A, Jonas, Sp, Pandey, A, Pardhan, S, Parekh, T, Park, Ek, Parry, Cdh, Kan, Fp, Patel, J, Pati, S, Patton, Gc, Paudel, U, Pawar, S, Peden, Ae, Petcu, Ir, Phillips, Mr, Pinheiro, M, Plotnikov, E, Pradhan, Pm, Prashant, A, Quan, Jc, Radfar, A, Rafiei, A, Raghav, Pr, Movaghar, Vr, Rahman, A, Rahman, Mm, Rahman, M, Rahmani, Am, Rahmani, S, Ranabhat, Cl, Ranasinghe, P, Rao, Cr, Rasali, Dp, Rashidi, Mm, Ratan, Za, Rawaf, Dl, Rawaf, S, Rawal, L, Renzaho, Amn, Rezaei, N, Rezaei, S, Rezaeian, M, Riahi, Sm, Rodriguez, Er, Roth, Ga, Rwegerera, Gm, Saddik, B, Sadeghi, E, Sadeghian, R, Saeed, U, Saeedi, F, Sagar, R, Sahebkar, A, Sahoo, H, Sahraian, Ma, Rahman, Ksu, Salahi, S, Salimzadeh, H, Samy, Am, Sanmarchi, F, Milicevic, Mm, Sarikhani, Y, Sathian, B, Saya, Gk, Sayyah, M, Schmidt, Mi, Schutte, Ae, Schwarzinger, M, Schwebel, Dc, Seidu, Aa, Seyedalinaghi, S, Seylani, A, Sha, F, Shahin, S, Sanavi, F, Shahrokhi, S, Shaikh, Ma, Shaker, E, Shakhmardanov, Mz, Beyranvand, M, Sheikhbahaei, S, Sheikhi, Ra, Shetty, A, Shetty, Jk, Shiferaw, D, Shigematsu, M, Shiri, R, Shirkoohi, R, Shivakumar, Km, Shivarov, V, Shobeiri, P, Shrestha, R, Sidemo, Nb, Sigfusdottir, Id, Silva, Da, da Silva, Nt, Singh, Ja, Singh, S, Skryabin, Vy, Skryabina, Aa, Sleet, Da, Solmi, M, Solomon, Y, Song, S, Song, Ym, Sorensen, Rjd, Soshnikov, S, Soyiri, In, Stein, Dj, Subba, Sh, Szocska, M, Seisdedos, Rt, Tabuchi, T, Taheri, M, Tan, Kk, Tareke, M, Tarkang, Ee, Temesgen, G, Temesgen, Wa, Temsah, Mh, Thankappan, Kr, Thapar, R, Thomas, Nk, Tiruneh, C, Todorovic, J, Torrado, M, Touvier, M, Palone, Mrt, Tran, Mtn, Llimos, St, Tripathy, Jp, Vakilian, A, Valizadeh, R, Varmaghani, M, Varthya, Sb, Vasankari, Tj, Vos, T, Wagaye, B, Waheed, Y, Walde, Mt, Wang, C, Wang, Yz, Wang, Yp, Westerman, R, Wickramasinghe, Nd, Wubetu, Ad, Xu, S, Yamagishi, K, Yang, L, Yesera, Gee, Yigit, A, Yimaw, Ae, Yon, Dk, Yonemoto, N, Yu, Ch, Zadey, S, Zahir, M, Zare, I, Zastrozhin, M, Zastrozhina, A, Zhang, Zj, Zhong, Cw, Zmaili, M, Zuniga, Ymh, Gakidou, E, Madureira-Carvalho, Am, Ciobanu, LG, Gakidou, Emma, and GBD 2020 Alcohol Collaborators
Subjects: Adult, Male, Alcohol Drinking, CONTROL POLICIES, adult, Child, Preschool, Female, Geography, Global Burden of Disease, Global Health, Humans, Middle Aged, Quality-Adjusted Life Years, Risk Factors, NDAS, ALL-CAUSE, GUIDELINES, GBD 2020 Alcohol Collaborators, COST-EFFECTIVENESS, Medicine, General & Internal, DRINKING, SDG 3 - Good Health and Well-being, RA0421, General & Internal Medicine, Quality-Adjusted Life Year, RA0421 Public health. Hygiene. Preventive Medicine, DRINKERS, Child, Preschool, 11 Medical and Health Sciences, METAANALYSIS, MCC, Science & Technology, global burden of disease, Risk Factor, General Medicine, CANCER, alcohol drinking, AC, 3121 General medicine, internal medicine and other clinical medicine, REDUCED MORTALITY, Life Sciences & Biomedicine, Human
Abstract: Background: The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods: For this analysis, we constructed burden-weighted dose-response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15-95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings: The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15-39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0-0) and 0·603 (0·400-1·00) standard drinks per day, and the NDE varied between 0·002 (0-0) and 1·75 (0·698-4·30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0·114 (0-0·403) to 1·87 (0·500-3·30) standard drinks per day and an NDE that ranged between 0·193 (0-0·900) and 6·94 (3·40-8·30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59·1% (54·3-65·4) were aged 15-39 years and 76·9% (73·0-81·3) were male. Interpretation: There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Research reported in this publication was supported by the Bill & Melinda Gates Foundation. S Afzal acknowledges the support for intellectual contributions to this manuscript by the Department of Community Medicine and Epidemiology at King Edward Medical University, Lahore, Pakistan. T Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. L Belo acknowledges support from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of UCIBIO and the project LA/P/0140/2020 of i4HB. D Bennett is supported by the UK Medical Research Council Population Health Research Unit at the University of Oxford (Oxford, UK). M Carvalho acknowledges support from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of UCIBIO and the project LA/P/0140/2020 of i4HB. L Castro-de-Araujo was funded by the Medical Research Council (UK), Grant no. MR/T03355X/1 and by the National Institute of Mental Health Grant no. R01MH128911. FJ Elgar is supported by the Canada Research Chairs program. F Greaves acknowledges support from the NIHR Applied Research Collaboration for NW London. V K Gupta acknowledges funding support from the National Health and Medical Research Council (NHMRC), Australia. VB Gupta acknowledges funding support from the National Health and Medical Research Council (NHMRC), Australia. C Herteliu is partially supported by a grant from the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. C Herteliu is partially supported by a grant from the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. S Hussain was supported by the Operational Programme Research, Development and Education –Project, Postdoc2MUNI “(No. CZ.02.2.69/0.0/0.0/18_053/0016952). S M S Islam is funded by the National Health and Medical Research Council and received funding from the National Heart Foundation of Australia. The Serbian part of this GBD-related contribution has been co-financed through Grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. M Kivimaki was supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), the US National Institute on Aging (R01AG056477), and the Academy of Finland (350426). K Krishan is supported by the UGC Centre of Advanced Study (Phase II), awarded to the Department of Anthropology, Panjab University, Chandigarh, India. B Lacey acknowledges support from the UK Biobank, funded largely by the UK Medical Research Council and Wellcome. S Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research; grant agreement number 01EA1808A). G Lucchetti received a productivity scholarship from the Brazilian National Council for Scientific and Technological Development — CNPq (Level 1D). J McGrath was supported by the Danish National Research Foundation (Niels Bohr Professor). J McGrath is employed by the Queensland Centre for Mental Health Research (Australia), which receives support from the Queensland Health Department. C Parry acknowleges the South African Medical Research Council. A Peden is supported by a National Health and Medical Research Council Emerging Leadership Fellowship (Grant ID: APP2009306). M R Phillips was supported in part by the Global Alliance for Chronic Diseases - National Natural Science Foundation of China (NSFC. No. 81761128031). M Pinheiro acknowledges FCT for funding through program DL 57/2016 – Norma transitória. A Rahman acknowledges the support from the Data Science Research Unit in Charles Sturt University (Bathurst, NSW, Australia). U Saeed would like to acknowledge the International Center of Medical Sciences Research (ICMSR), Islamabad, Pakistan. A M Samy acknowledges support from Ain Shams University (Cairo, Egypt) and the Egyptian Fulbright Mission Program. N Senthil Kumar acknowledges the DBT, New Delhi sponsored Advanced State Level Biotech Hub (BT/NER/143/SP44475/2021), Mizoram University (Aizawl, Mizoram, India) for facilitating this work. F Sha is supported by the Shenzhen Science and Technology Program (Grant No. KQTD20190929172835662). A Shetty acknowledges Kasturba Medical College (Mangalore, India) and Manipal Academy of Higher Education (Manipal, India) for all the academic support. R Shrestha acknowledges a career development award from the National Institutes of Health (K01DA051346). D Silva was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES)-Finance Code 001 and is supported in part by CNPq - Brazil (309589/2021-5). D Sleet acknowledges partial support from Veritas Management Group, Inc and The Bizzell Group, LLC. S Trias-Llimós acknowledges research funding from the Juan de la Cierva-Formación program of the Spanish Ministry of Science and Innovation (FJC-2019-039314-I). Sí
Published: 2022

20. Neutrophil phenotypes and functions in cancer

Author: Daniela F. Quail, Borko Amulic, Monowar Aziz, Betsy J. Barnes, Evgeniy Eruslanov, Zvi G. Fridlender, Helen S. Goodridge, Zvi Granot, Andrés Hidalgo, Anna Huttenlocher, Mariana J. Kaplan, Ilaria Malanchi, Taha Merghoub, Etienne Meylan, Vivek Mittal, Mikael J. Pittet, Andrea Rubio-Ponce, Irina A. Udalova, Timo K. van den Berg, Denisa D. Wagner, Ping Wang, Arturo Zychlinsky, Karin E. de Visser, Mikala Egeblad, Paul Kubes, Canadian Institutes of Health Research, Terry Fox Research Institute, UK Research and Innovation, Medical Research Council (Reino Unido), National Institutes of Health (Estados Unidos), Israel Science Foundation, Rosetrees Trust, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación ProCNIC, Wellcome Trust, and Swiss National Science Foundation
Subjects: Model organisms, Inflammation, Phenotype, Neutrophils, Stem Cells, Neoplasms, Immunology, Humans, Immunity, Innate, Neoplasms/genetics, Immunology and Allergy, Tumour Biology, Genetics & Genomics
Abstract: Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer. Acknowledgments This consensus statement is dedicated to our esteemed colleagues, Zena Werb and Paul S. Frenette, who attended and participated in the Banbury Center meeting and encouraged a collective effort by attendees to write this report. Both made significant contributions to ideas and discussions that are represented here. The Banbury Center meeting was organized by M. Egeblad, P. Kubes, K.E. de Visser, R. Leshan, and Banbury Center staff. The meeting was supported financially by Cold Spring Harbor Laboratory Northwell Health Affiliation. The funder had no involvement with the writing of this consensus statement. D.F. Quail acknowledges funding from the Canadian Institutes of Health Research (PJT-159742, PJT-178306), Terry Fox Research Institute, and Tier II Canada Research Chair. B. Amulic acknowledges funding from the Medical Research Council (MR/R02149x/1). M. Aziz acknowledges funding from the National Institutes of Health (NIH; R01GM129633). B.J. Barnes acknowledges funding from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR065959-01) and Department of Defense (CDMRP LRP W81XWH-18-1-0674). E. Eruslanov acknowledges funding from the NIH National Cancer Institute (NCI; R01CA187392) and the Department of Defense (CDMRP W81XWH-15-1-0717). Z.G. Fridlender acknowledges funding from the the Israel Science Foundation (grant number 1708/20) and the Sasson and Luisa Naor Fund. H.S. Goodridge acknowledges funding from the NIH National Institute of Allergy and Infectious Diseases (R01AI134987). Z. Granot acknowledges funding from the Israel Science Foundation Grant 405/18, the Israel Cancer Research Fund, the Deutsche Forschungsgemeinschaft, and the Rosetrees Trust. A. Hidalgo acknowledges funding from FET-OPEN (861878) from the European Commission; the Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministerio de Ciencia e Innovacion and the Pro-CNIC Foundation. M.J. Kaplan acknowledges funding from the Intramural Research Program of the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIAAR041199). I. Malanchi acknowledges funding from the European Research Council grant (ERC CoG-H2020-725492) and from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001112), the UK Medical Research Council (FC001112), and the Wellcome Trust (FC001112). T. Merghoub acknowledges funding from the NIH/NCI Cancer Center Support Grant (P30 CA008748/NCI R01 CA056821), Swim Across America, Ludwig Institute for Cancer Research, Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, and Parker Institute for Cancer Immunotherapy. E. Meylan acknowledges funding from the Swiss National Science Foundation (310030_179324) and Fonds de la Recherche Scientifique (MISU F.6003.22). M.J. Pittet acknowledges funding from the Institut Suisse de Recherche Experimentale sur le Cancer Foundation, Ludwig Cancer Research, and the NIH (P01CA240239, R01CA218579). I.A. Udalova acknowledges funding from the Wellcome Trust Investigator Award (209422/Z/17/Z). T.K. van den Berg acknowledges funding from Byondis BV, the Dutch Ministry of Health, and the Dutch Cancer Society (10300). D.D. Wagner acknowledges funding from the NIH National Health, Lung and Blood Institute (R35HL135765). P. Wang acknowledges funding from the NIH National Institute of General Medical Sciences (R35GM118337). A. Zychlinsky acknowledges funding from the Max Planck Society. K.E. de Visser acknowledges funding from the Dutch Cancer Society (KWF10623, KWF10083, and KWF13191), Oncode Institute, and the Netherlands Organization for Scientific Research (NWO-VICI 91819616). M. Egeblad acknowledges funding from the Department of Defense, Congressional Directed Medical Research Program (W81XWH2010753). P. Kubes acknowledges funding from the Canadian Institutes of Health Research. Sí
Published: 2022

21. Integrative analysis of clinical and epigenetic biomarkers of mortality

Author: Huan, Tianxiao, Nguyen, Steve, Colicino, Elena, Ochoa-Rosales, Carolina, Hill, W David, Brody, Jennifer A, Soerensen, Mette, Zhang, Yan, Baldassari, Antoine, Elhadad, Mohamed Ahmed, Toshiko, Tanaka, Zheng, Yinan, Domingo-Relloso, Arce, Lee, Dong Heon, Ma, Jiantao, Yao, Chen, Liu, Chunyu, Hwang, Shih-Jen, Joehanes, Roby, Fornage, Myriam, Bressler, Jan, van Meurs, Joyce B J, Debrabant, Birgit, Mengel-From, Jonas, Hjelmborg, Jacob, Christensen, Kaare, Vokonas, Pantel, Schwartz, Joel, Gahrib, Sina A, Sotoodehnia, Nona, Sitlani, Colleen M, Kunze, Sonja, Gieger, Christian, Peters, Annette, Waldenberger, Melanie, Deary, Ian J, Ferrucci, Luigi, Qu, Yishu, Greenland, Philip, Lloyd-Jones, Donald M, Hou, Lifang, Bandinelli, Stefania, Voortman, Trudy, Hermann, Brenner, Baccarelli, Andrea, Whitsel, Eric, Pankow, James S, Levy, Daniel, Ochoa‐Rosales, Carolina, Hill, W. David, Brody, Jennifer A., Domingo‐Relloso, Arce, Hwang, Shih‐Jen, van Meurs, Joyce B.J., Mengel‐From, Jonas, Gahrib, Sina A., Sitlani, Colleen M., Deary, Ian J., Lloyd‐Jones, Donald M., Pankow, James S., Meurs, Joyce B.J., National Institutes of Health (Estados Unidos), NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), NIH - Center for Information Technology (Estados Unidos), NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos), NIH - National Institute on Aging (NIA) (Estados Unidos), Fundación Merck Salud, Laughlin Family, Alpha Phi Foundation, Locke Charitable Foundation, National Center for Advancing Translational Sciences (Estados Unidos), NIH - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Estados Unidos), Danish Council for Independent Research, Unión Europea. Comisión Europea. 7 Programa Marco, United States of Department of Health & Human Services, NIH - National Institute of Environmental Health Sciences (NIEHS) (Estados Unidos), Biotechnology and Biological Sciences Research Council (Reino Unido), Royal Society (Reino Unido), Scottish Government, Age UK (Reino Unido), Centre for Cognitive Ageing and Cognitive Epidemiology (Reino Unido), Wellcome Trust, University of Edinburgh (Reino Unido), University of Queensland (Australia), Medical Research Council (Reino Unido), United States Department of Veterans Affairs, Massachusetts Veterans Education Research and Information Center (MAVERIC), Epidemiology, and Internal Medicine
Subjects: Epigenomics, Male, Aging, DNA methylation, Cell Biology, DNA Methylation, Cardiovascular disease, Epigenesis, Genetic, SDG 3 - Good Health and Well-being, Cardiovascular Diseases, Neoplasms, Machine learning, Humans, Mortality, Dna Methylation, Cancer, Cardiovascular Disease, Machine Learning, Biomarkers
Abstract: DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p
Published: 2022

22. PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts

Author: Piberger, Ann Liza, Bowry, Akhil, Kelly, Richard D W, Walker, Alexandra K, González-Acosta, Daniel, Bailey, Laura J, Doherty, Aidan J, Méndez, Juan, Morris, Joanna R, Bryant, Helen E, Petermann, Eva, Mendez, Juan, German Research Foundation (DFG), UK Research & Innovation (UKRI), Medical Research Council UK (MRC), European Commission, Cancer Research UK, Wellcome Trust, Cancer Research UK Birmingham Centre Award, Deutsche Forschungsgemeinschaft (Alemania), UK Research and Innovation, Medical Research Council (Reino Unido), Unión Europea. Comisión Europea, and Cancer Research UK (Reino Unido)
Subjects: 0301 basic medicine, Genome instability, Genomic instability, DNA damage, Science, 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide, RAD51, General Physics and Astronomy, DNA, Single-Stranded, Sister chromatid exchange, DNA Primase, DNA-Directed DNA Polymerase, Quinolones, Genetic recombination, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, DNA Adducts, 0302 clinical medicine, Benz(a)Anthracenes, Sister chromatids, Humans, Homologous Recombination, lcsh:Science, 030304 developmental biology, Cancer, 0303 health sciences, Multidisciplinary, Chemistry, General Chemistry, DNA Replication Fork, Multifunctional Enzymes, 4-Nitroquinoline-1-oxide, Single Molecule Imaging, Cell biology, enzymes and coenzymes (carbohydrates), 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, lcsh:Q, Primase, Rad51 Recombinase, Homologous recombination, Sister Chromatid Exchange, 030217 neurology & neurosurgery, DNA
Abstract: Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance., Bulky DNA adducts are important replication-blocking lesions. Here the authors reveal that homologous recombination at bulky adducts in mammalian cells involves post-replicative gap repair in a PrimPol dependent manner.
Published: 2020

23. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019:A Systematic Analysis for the Global Burden of Disease Study 2019

Author: Global Burden of Disease 2019 Cancer Collaboration, Kocarnik, JM, Compton, K, Dean, FE, Fu, W, Gaw, BL, Harvey, JD, Henrikson, HJ, Lu, D, Pennini, A, Xu, R, Ababneh, E, Abbasi-Kangevari, M, Abbastabar, H, Abd-Elsalam, SM, Abdoli, A, Abedi, A, Abidi, H, Abolhassani, H, Adedeji, IA, Adnani, QES, Advani, SM, Afzal, MS, Aghaali, M, Ahinkorah, BO, Ahmad, S, Ahmad, T, Ahmadi, A, Ahmadi, S, Ahmed Rashid, T, Ahmed Salih, Y, Akalu, GT, Aklilu, A, Akram, T, Akunna, CJ, Al Hamad, H, Alahdab, F, Al-Aly, Z, Ali, S, Alimohamadi, Y, Alipour, V, Aljunid, SM, Alkhayyat, M, Almasi-Hashiani, A, Almasri, NA, Al-Maweri, SAA, Almustanyir, S, Alonso, N, Alvis-Guzman, N, Amu, H, Anbesu, EW, Ancuceanu, R, Ansari, F, Ansari-Moghaddam, A, Antwi, MH, Anvari, D, Anyasodor, AE, Aqeel, M, Arabloo, J, Arab-Zozani, M, Aremu, O, Ariffin, H, Aripov, T, Arshad, M, Artaman, A, Arulappan, J, Asemi, Z, Asghari Jafarabadi, M, Ashraf, T, Atorkey, P, Aujayeb, A, Ausloos, M, Awedew, AF, Ayala Quintanilla, BP, Ayenew, T, Azab, MA, Azadnajafabad, S, Azari Jafari, A, Azarian, G, Azzam, AY, Badiye, AD, Bahadory, S, Baig, AA, Baker, JL, Balakrishnan, S, Banach, M, Bärnighausen, TW, Barone-Adesi, F, Barra, F, Barrow, A, Behzadifar, M, Belgaumi, UI, Bezabhe, WMM, Bezabih, YM, Bhagat, DS, Bhagavathula, AS, Bhardwaj, N, Bhardwaj, P, Bhaskar, S, Bhattacharyya, K, Bhojaraja, VS, Bibi, S, Bijani, A, Biondi, A, Bisignano, C, Bjørge, T, Bleyer, A, Blyuss, O, Bolarinwa, OA, Bolla, SR, Braithwaite, D, Brar, A, Brenner, H, Bustamante-Teixeira, MT, Butt, NS, Butt, ZA, Caetano Dos Santos, FL, Cao, Y, Carreras, G, Catalá-López, F, Cembranel, F, Cerin, E, Cernigliaro, A, Chakinala, RC, Chattu, SK, Chattu, VK, Chaturvedi, P, Chimed-Ochir, O, Cho, DY, Christopher, DJ, Chu, D-T, Chung, MT, Conde, J, Cortés, S, Cortesi, PA, Costa, VM, Cunha, AR, Dadras, O, Dagnew, AB, Dahlawi, SMA, Dai, X, Dandona, L, Dandona, R, Darwesh, AM, Das Neves, J, De la Hoz, FP, Demis, AB, Denova-Gutiérrez, E, Dhamnetiya, D, Dhimal, ML, Dhimal, M, Dianatinasab, M, Diaz, D, Djalalinia, S, Do, HP, Doaei, S, Dorostkar, F, Dos Santos Figueiredo, FW, Driscoll, TR, Ebrahimi, H, Eftekharzadeh, S, El Tantawi, M, El-Abid, H, Elbarazi, I, Elhabashy, HR, Elhadi, M, El-Jaafary, SI, Eshrati, B, Eskandarieh, S, Esmaeilzadeh, F, Etemadi, A, Ezzikouri, S, Faisaluddin, M, Faraon, EJA, Fares, J, Farzadfar, F, Feroze, AH, Ferrero, S, Ferro Desideri, L, Filip, I, Fischer, F, Fisher, JL, Foroutan, M, Fukumoto, T, Gaal, PA, Gad, MM, Gadanya, MA, Gallus, S, Gaspar Fonseca, M, Getachew Obsa, A, Ghafourifard, M, Ghashghaee, A, Ghith, N, Gholamalizadeh, M, Gilani, SA, Ginindza, TG, Gizaw, ATT, Glasbey, JC, Golechha, M, Goleij, P, Gomez, RS, Gopalani, SV, Gorini, G, Goudarzi, H, Grosso, G, Gubari, MIM, Guerra, MR, Guha, A, Gunasekera, DS, Gupta, B, Gupta, VB, Gupta, VK, Gutiérrez, RA, Hafezi-Nejad, N, Haider, MR, Haj-Mirzaian, A, Halwani, R, Hamadeh, RR, Hameed, S, Hamidi, S, Hanif, A, Haque, S, Harlianto, NI, Haro, JM, Hasaballah, AI, Hassanipour, S, Hay, RJ, Hay, SI, Hayat, K, Heidari, G, Heidari, M, Herrera-Serna, BY, Herteliu, C, Hezam, K, Holla, R, Hossain, MM, Hossain, MBH, Hosseini, M-S, Hosseini, M, Hosseinzadeh, M, Hostiuc, M, Hostiuc, S, Househ, M, Hsairi, M, Huang, J, Hugo, FN, Hussain, R, Hussein, NR, Hwang, B-F, Iavicoli, I, Ibitoye, SE, Ida, F, Ikuta, KS, Ilesanmi, OS, Ilic, IM, Ilic, MD, Irham, LM, Islam, JY, Islam, RM, Islam, SMS, Ismail, NE, Isola, G, Iwagami, M, Jacob, L, Jain, V, Jakovljevic, MB, Javaheri, T, Jayaram, S, Jazayeri, SB, Jha, RP, Jonas, JB, Joo, T, Joseph, N, Joukar, F, Jürisson, M, Kabir, A, Kahrizi, D, Kalankesh, LR, Kalhor, R, Kaliyadan, F, Kalkonde, Y, Kamath, A, Kameran Al-Salihi, N, Kandel, H, Kapoor, N, Karch, A, Kasa, AS, Katikireddi, SV, Kauppila, JH, Kavetskyy, T, Kebede, SA, Keshavarz, P, Keykhaei, M, Khader, YS, Khalilov, R, Khan, G, Khan, M, Khan, MN, Khan, MAB, Khang, Y-H, Khater, AM, Khayamzadeh, M, Kim, GR, Kim, YJ, Kisa, A, Kisa, S, Kissimova-Skarbek, K, Kopec, JA, Koteeswaran, R, Koul, PA, Koulmane Laxminarayana, SL, Koyanagi, A, Kucuk Bicer, B, Kugbey, N, Kumar, GA, Kumar, N, Kurmi, OP, Kutluk, T, La Vecchia, C, Lami, FH, Landires, I, Lauriola, P, Lee, S-W, Lee, SWH, Lee, W-C, Lee, YH, Leigh, J, Leong, E, Li, J, Li, M-C, Liu, X, Loureiro, JA, Lunevicius, R, Magdy Abd El Razek, M, Majeed, A, Makki, A, Male, S, Malik, AA, Mansournia, MA, Martini, S, Masoumi, SZ, Mathur, P, McKee, M, Mehrotra, R, Mendoza, W, Menezes, RG, Mengesha, EW, Mesregah, MK, Mestrovic, T, Miao Jonasson, J, Miazgowski, B, Miazgowski, T, Michalek, IM, Miller, TR, Mirzaei, H, Mirzaei, HR, Misra, S, Mithra, P, Moghadaszadeh, M, Mohammad, KA, Mohammad, Y, Mohammadi, M, Mohammadi, SM, Mohammadian-Hafshejani, A, Mohammed, S, Moka, N, Mokdad, AH, Molokhia, M, Monasta, L, Moni, MA, Moosavi, MA, Moradi, Y, Moraga, P, Morgado-da-Costa, J, Morrison, SD, Mosapour, A, Mubarik, S, Mwanri, L, Nagarajan, AJ, Nagaraju, SP, Nagata, C, Naimzada, MD, Nangia, V, Naqvi, AA, Narasimha Swamy, S, Ndejjo, R, Nduaguba, SO, Negoi, I, Negru, SM, Neupane Kandel, S, Nguyen, CT, Nguyen, HLT, Niazi, RK, Nnaji, CA, Noor, NM, Nuñez-Samudio, V, Nzoputam, CI, Oancea, B, Ochir, C, Odukoya, OO, Ogbo, FA, Olagunju, AT, Olakunde, BO, Omar, E, Omar Bali, A, Omonisi, AEE, Ong, S, Onwujekwe, OE, Orru, H, Ortega-Altamirano, DV, Otstavnov, N, Otstavnov, SS, Owolabi, MO, P A, M, Padubidri, JR, Pakshir, K, Pana, A, Panagiotakos, D, Panda-Jonas, S, Pardhan, S, Park, E-C, Park, E-K, Pashazadeh Kan, F, Patel, HK, Patel, JR, Pati, S, Pattanshetty, SM, Paudel, U, Pereira, DM, Pereira, RB, Perianayagam, A, Pillay, JD, Pirouzpanah, S, Pishgar, F, Podder, I, Postma, MJ, Pourjafar, H, Prashant, A, Preotescu, L, Rabiee, M, Rabiee, N, Radfar, A, Radhakrishnan, RA, Radhakrishnan, V, Rafiee, A, Rahim, F, Rahimzadeh, S, Rahman, M, Rahman, MA, Rahmani, AM, Rajai, N, Rajesh, A, Rakovac, I, Ram, P, Ramezanzadeh, K, Ranabhat, K, Ranasinghe, P, Rao, CR, Rao, SJ, Rawassizadeh, R, Razeghinia, MS, Renzaho, AMN, Rezaei, N, Rezapour, A, Roberts, TJ, Rodriguez, JAB, Rohloff, P, Romoli, M, Ronfani, L, Roshandel, G, Rwegerera, GM, S, M, Sabour, S, Saddik, B, Saeed, U, Sahebkar, A, Sahoo, H, Salehi, S, Salem, MR, Salimzadeh, H, Samaei, M, Samy, AM, Sanabria, J, Sankararaman, S, Santric-Milicevic, MM, Sardiwalla, Y, Sarveazad, A, Sathian, B, Sawhney, M, Saylan, M, Schneider, IJC, Sekerija, M, Seylani, A, Shafaat, O, Shaghaghi, Z, Shaikh, MA, Shamsoddin, E, Shannawaz, M, Sharma, R, Sheikh, A, Sheikhbahaei, S, Shetty, A, Shetty, JK, Shetty, PH, Shibuya, K, Shirkoohi, R, Shivakumar, KM, Shivarov, V, Siabani, S, Siddappa Malleshappa, SK, Silva, DAS, Singh, JA, Sintayehu, Y, Skryabin, VY, Skryabina, AA, Soeberg, MJ, Sofi-Mahmudi, A, Sotoudeh, H, Steiropoulos, P, Straif, K, Subedi, R, Sufiyan, MB, Sultan, I, Sultana, S, Sur, D, Szerencsés, V, Szócska, M, Tabarés-Seisdedos, R, Tabuchi, T, Tadbiri, H, Taherkhani, A, Takahashi, K, Talaat, IM, Tan, K-K, Tat, VY, Tedla, BAA, Tefera, YG, Tehrani-Banihashemi, A, Temsah, M-H, Tesfay, FH, Tessema, GA, Thapar, R, Thavamani, A, Thoguluva Chandrasekar, V, Thomas, N, Tohidinik, HR, Touvier, M, Tovani-Palone, MR, Traini, E, Tran, BX, Tran, KB, Tran, MTN, Tripathy, JP, Tusa, BS, Ullah, I, Ullah, S, Umapathi, KK, Unnikrishnan, B, Upadhyay, E, Vacante, M, Vaezi, M, Valadan Tahbaz, S, Velazquez, DZ, Veroux, M, Violante, FS, Vlassov, V, Vo, B, Volovici, V, Vu, GT, Waheed, Y, Wamai, RG, Ward, P, Wen, YF, Westerman, R, Winkler, AS, Yadav, L, Yahyazadeh Jabbari, SH, Yang, L, Yaya, S, Yazie, TSY, Yeshaw, Y, Yonemoto, N, Younis, MZ, Yousefi, Z, Yu, C, Yuce, D, Yunusa, I, Zadnik, V, Zare, F, Zastrozhin, MS, Zastrozhina, A, Zhang, J, Zhong, C, Zhou, L, Zhu, C, Ziapour, A, Zimmermann, IR, Fitzmaurice, C, Murray, CJL, Force, LM, Value, Affordability and Sustainability (VALUE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Microbes in Health and Disease (MHD), Kocarnik, J, Compton, K, Dean, F, Fu, W, Gaw, B, Harvey, J, Henrikson, H, Lu, D, Pennini, A, Xu, R, Ababneh, E, Abbasi-Kangevari, M, Abbastabar, H, Abd-Elsalam, S, Abdoli, A, Abedi, A, Abidi, H, Abolhassani, H, Adedeji, I, Adnani, Q, Advani, S, Afzal, M, Aghaali, M, Ahinkorah, B, Ahmad, S, Ahmad, T, Ahmadi, A, Ahmadi, S, Ahmed Rashid, T, Ahmed Salih, Y, Akalu, G, Aklilu, A, Akram, T, Akunna, C, Al Hamad, H, Alahdab, F, Al-Aly, Z, Ali, S, Alimohamadi, Y, Alipour, V, Aljunid, S, Alkhayyat, M, Almasi-Hashiani, A, Almasri, N, Al-Maweri, S, Almustanyir, S, Alonso, N, Alvis-Guzman, N, Amu, H, Anbesu, E, Ancuceanu, R, Ansari, F, Ansari-Moghaddam, A, Antwi, M, Anvari, D, Anyasodor, A, Aqeel, M, Arabloo, J, Arab-Zozani, M, Aremu, O, Ariffin, H, Aripov, T, Arshad, M, Artaman, A, Arulappan, J, Asemi, Z, Asghari Jafarabadi, M, Ashraf, T, Atorkey, P, Aujayeb, A, Ausloos, M, Awedew, A, Ayala Quintanilla, B, Ayenew, T, Azab, M, Azadnajafabad, S, Azari Jafari, A, Azarian, G, Azzam, A, Badiye, A, Bahadory, S, Baig, A, Baker, J, Balakrishnan, S, Banach, M, Barnighausen, T, Barone-Adesi, F, Barra, F, Barrow, A, Behzadifar, M, Belgaumi, U, Bezabhe, W, Bezabih, Y, Bhagat, D, Bhagavathula, A, Bhardwaj, N, Bhardwaj, P, Bhaskar, S, Bhattacharyya, K, Bhojaraja, V, Bibi, S, Bijani, A, Biondi, A, Bisignano, C, Bjorge, T, Bleyer, A, Blyuss, O, Bolarinwa, O, Bolla, S, Braithwaite, D, Brar, A, Brenner, H, Bustamante-Teixeira, M, Butt, N, Butt, Z, Caetano Dos Santos, F, Cao, Y, Carreras, G, Catala-Lopez, F, Cembranel, F, Cerin, E, Cernigliaro, A, Chakinala, R, Chattu, S, Chattu, V, Chaturvedi, P, Chimed-Ochir, O, Cho, D, Christopher, D, Chu, D, Chung, M, Conde, J, Cortes, S, Cortesi, P, Costa, V, Cunha, A, Dadras, O, Dagnew, A, Dahlawi, S, Dai, X, Dandona, L, Dandona, R, Darwesh, A, Das Neves, J, De La Hoz, F, Demis, A, Denova-Gutierrez, E, Dhamnetiya, D, Dhimal, M, Dianatinasab, M, Diaz, D, Djalalinia, S, Do, H, Doaei, S, Dorostkar, F, Dos Santos Figueiredo, F, Driscoll, T, Ebrahimi, H, Eftekharzadeh, S, El Tantawi, M, El-Abid, H, Elbarazi, I, Elhabashy, H, Elhadi, M, El-Jaafary, S, Eshrati, B, Eskandarieh, S, Esmaeilzadeh, F, Etemadi, A, Ezzikouri, S, Faisaluddin, M, Faraon, E, Fares, J, Farzadfar, F, Feroze, A, Ferrero, S, Ferro Desideri, L, Filip, I, Fischer, F, Fisher, J, Foroutan, M, Fukumoto, T, Gaal, P, Gad, M, Gadanya, M, Gallus, S, Gaspar Fonseca, M, Getachew Obsa, A, Ghafourifard, M, Ghashghaee, A, Ghith, N, Gholamalizadeh, M, Gilani, S, Ginindza, T, Gizaw, A, Glasbey, J, Golechha, M, Goleij, P, Gomez, R, Gopalani, S, Gorini, G, Goudarzi, H, Grosso, G, Gubari, M, Guerra, M, Guha, A, Gunasekera, D, Gupta, B, Gupta, V, Gutierrez, R, Hafezi-Nejad, N, Haider, M, Haj-Mirzaian, A, Halwani, R, Hamadeh, R, Hameed, S, Hamidi, S, Hanif, A, Haque, S, Harlianto, N, Haro, J, Hasaballah, A, Hassanipour, S, Hay, R, Hay, S, Hayat, K, Heidari, G, Heidari, M, Herrera-Serna, B, Herteliu, C, Hezam, K, Holla, R, Hossain, M, Hosseini, M, Hosseinzadeh, M, Hostiuc, M, Hostiuc, S, Househ, M, Hsairi, M, Huang, J, Hugo, F, Hussain, R, Hussein, N, Hwang, B, Iavicoli, I, Ibitoye, S, Ida, F, Ikuta, K, Ilesanmi, O, Ilic, I, Ilic, M, Irham, L, Islam, J, Islam, R, Islam, S, Ismail, N, Isola, G, Iwagami, M, Jacob, L, Jain, V, Jakovljevic, M, Javaheri, T, Jayaram, S, Jazayeri, S, Jha, R, Jonas, J, Joo, T, Joseph, N, Joukar, F, Jurisson, M, Kabir, A, Kahrizi, D, Kalankesh, L, Kalhor, R, Kaliyadan, F, Kalkonde, Y, Kamath, A, Kameran Al-Salihi, N, Kandel, H, Kapoor, N, Karch, A, Kasa, A, Katikireddi, S, Kauppila, J, Kavetskyy, T, Kebede, S, Keshavarz, P, Keykhaei, M, Khader, Y, Khalilov, R, Khan, G, Khan, M, Khang, Y, Khater, A, Khayamzadeh, M, Kim, G, Kim, Y, Kisa, A, Kisa, S, Kissimova-Skarbek, K, Kopec, J, Koteeswaran, R, Koul, P, Koulmane Laxminarayana, S, Koyanagi, A, Kucuk Bicer, B, Kugbey, N, Kumar, G, Kumar, N, Kurmi, O, Kutluk, T, La Vecchia, C, Lami, F, Landires, I, Lauriola, P, Lee, S, Lee, W, Lee, Y, Leigh, J, Leong, E, Li, J, Li, M, Liu, X, Loureiro, J, Lunevicius, R, Magdy Abd El Razek, M, Majeed, A, Makki, A, Male, S, Malik, A, Mansournia, M, Martini, S, Masoumi, S, Mathur, P, Mckee, M, Mehrotra, R, Mendoza, W, Menezes, R, Mengesha, E, Mesregah, M, Mestrovic, T, Miao Jonasson, J, Miazgowski, B, Miazgowski, T, Michalek, I, Miller, T, Mirzaei, H, Misra, S, Mithra, P, Moghadaszadeh, M, Mohammad, K, Mohammad, Y, Mohammadi, M, Mohammadi, S, Mohammadian-Hafshejani, A, Mohammed, S, Moka, N, Mokdad, A, Molokhia, M, Monasta, L, Moni, M, Moosavi, M, Moradi, Y, Moraga, P, Morgado-Da-Costa, J, Morrison, S, Mosapour, A, Mubarik, S, Mwanri, L, Nagarajan, A, Nagaraju, S, Nagata, C, Naimzada, M, Nangia, V, Naqvi, A, Narasimha Swamy, S, Ndejjo, R, Nduaguba, S, Negoi, I, Negru, S, Neupane Kandel, S, Nguyen, C, Nguyen, H, Niazi, R, Nnaji, C, Noor, N, Nunez-Samudio, V, Nzoputam, C, Oancea, B, Ochir, C, Odukoya, O, Ogbo, F, Olagunju, A, Olakunde, B, Omar, E, Omar Bali, A, Omonisi, A, Ong, S, Onwujekwe, O, Orru, H, Ortega-Altamirano, D, Otstavnov, N, Otstavnov, S, Owolabi, M, P A, M, Padubidri, J, Pakshir, K, Pana, A, Panagiotakos, D, Panda-Jonas, S, Pardhan, S, Park, E, Pashazadeh Kan, F, Patel, H, Patel, J, Pati, S, Pattanshetty, S, Paudel, U, Pereira, D, Pereira, R, Perianayagam, A, Pillay, J, Pirouzpanah, S, Pishgar, F, Podder, I, Postma, M, Pourjafar, H, Prashant, A, Preotescu, L, Rabiee, M, Rabiee, N, Radfar, A, Radhakrishnan, R, Radhakrishnan, V, Rafiee, A, Rahim, F, Rahimzadeh, S, Rahman, M, Rahmani, A, Rajai, N, Rajesh, A, Rakovac, I, Ram, P, Ramezanzadeh, K, Ranabhat, K, Ranasinghe, P, Rao, C, Rao, S, Rawassizadeh, R, Razeghinia, M, Renzaho, A, Rezaei, N, Rezapour, A, Roberts, T, Rodriguez, J, Rohloff, P, Romoli, M, Ronfani, L, Roshandel, G, Rwegerera, G, Manjula, S, Sabour, S, Saddik, B, Saeed, U, Sahebkar, A, Sahoo, H, Salehi, S, Salem, M, Salimzadeh, H, Samaei, M, Samy, A, Sanabria, J, Sankararaman, S, Santric-Milicevic, M, Sardiwalla, Y, Sarveazad, A, Sathian, B, Sawhney, M, Saylan, M, Schneider, I, Sekerija, M, Seylani, A, Shafaat, O, Shaghaghi, Z, Shaikh, M, Shamsoddin, E, Shannawaz, M, Sharma, R, Sheikh, A, Sheikhbahaei, S, Shetty, A, Shetty, J, Shetty, P, Shibuya, K, Shirkoohi, R, Shivakumar, K, Shivarov, V, Siabani, S, Siddappa Malleshappa, S, Silva, D, Singh, J, Sintayehu, Y, Skryabin, V, Skryabina, A, Soeberg, M, Sofi-Mahmudi, A, Sotoudeh, H, Steiropoulos, P, Straif, K, Subedi, R, Sufiyan, M, Sultan, I, Sultana, S, Sur, D, Szerencses, V, Szocska, M, Tabares-Seisdedos, R, Tabuchi, T, Tadbiri, H, Taherkhani, A, Takahashi, K, Talaat, I, Tan, K, Tat, V, Tedla, B, Tefera, Y, Tehrani-Banihashemi, A, Temsah, M, Tesfay, F, Tessema, G, Thapar, R, Thavamani, A, Thoguluva Chandrasekar, V, Thomas, N, Tohidinik, H, Touvier, M, Tovani-Palone, M, Traini, E, Tran, B, Tran, K, Tran, M, Tripathy, J, Tusa, B, Ullah, I, Ullah, S, Umapathi, K, Unnikrishnan, B, Upadhyay, E, Vacante, M, Vaezi, M, Valadan Tahbaz, S, Velazquez, D, Veroux, M, Violante, F, Vlassov, V, Vo, B, Volovici, V, Vu, G, Waheed, Y, Wamai, R, Ward, P, Wen, Y, Westerman, R, Winkler, A, Yadav, L, Yahyazadeh Jabbari, S, Yang, L, Yaya, S, Yazie, T, Yeshaw, Y, Yonemoto, N, Younis, M, Yousefi, Z, Yu, C, Yuce, D, Yunusa, I, Zadnik, V, Zare, F, Zastrozhin, M, Zastrozhina, A, Zhang, J, Zhong, C, Zhou, L, Zhu, C, Ziapour, A, Zimmermann, I, Fitzmaurice, C, Murray, C, Force, L, Kocarnik J.M., Compton K., Dean F.E., Fu W., Gaw B.L., Harvey J.D., Henrikson H.J., Lu D., Pennini A., Xu R., Ababneh E., Abbasi-Kangevari M., Abbastabar H., Abd-Elsalam S.M., Abdoli A., Abedi A., Abidi H., Abolhassani H., Adedeji I.A., Adnani Q.E.S., Advani S.M., Afzal M.S., Aghaali M., Ahinkorah B.O., Ahmad S., Ahmad T., Ahmadi A., Ahmadi S., Ahmed Rashid T., Ahmed Salih Y., Akalu G.T., Aklilu A., Akram T., Akunna C.J., Al Hamad H., Alahdab F., Al-Aly Z., Ali S., Alimohamadi Y., Alipour V., Aljunid S.M., Alkhayyat M., Almasi-Hashiani A., Almasri N.A., Al-Maweri S.A.A., Almustanyir S., Alonso N., Alvis-Guzman N., Amu H., Anbesu E.W., Ancuceanu R., Ansari F., Ansari-Moghaddam A., Antwi M.H., Anvari D., Anyasodor A.E., Aqeel M., Arabloo J., Arab-Zozani M., Aremu O., Ariffin H., Aripov T., Arshad M., Artaman A., Arulappan J., Asemi Z., Asghari Jafarabadi M., Ashraf T., Atorkey P., Aujayeb A., Ausloos M., Awedew A.F., Ayala Quintanilla B.P., Ayenew T., Azab M.A., Azadnajafabad S., Azari Jafari A., Azarian G., Azzam A.Y., Badiye A.D., Bahadory S., Baig A.A., Baker J.L., Balakrishnan S., Banach M., Barnighausen T.W., Barone-Adesi F., Barra F., Barrow A., Behzadifar M., Belgaumi U.I., Bezabhe W.M.M., Bezabih Y.M., Bhagat D.S., Bhagavathula A.S., Bhardwaj N., Bhardwaj P., Bhaskar S., Bhattacharyya K., Bhojaraja V.S., Bibi S., Bijani A., Biondi A., Bisignano C., Bjorge T., Bleyer A., Blyuss O., Bolarinwa O.A., Bolla S.R., Braithwaite D., Brar A., Brenner H., Bustamante-Teixeira M.T., Butt N.S., Butt Z.A., Caetano dos Santos F.L., Cao Y., Carreras G., Catala-Lopez F., Cembranel F., Cerin E., Cernigliaro A., Chakinala R.C., Chattu S.K., Chattu V.K., Chaturvedi P., Chimed-Ochir O., Cho D.Y., Christopher D.J., Chu D.-T., Chung M.T., Conde J., Cortes S., Cortesi P.A., Costa V.M., Cunha A.R., Dadras O., Dagnew A.B., Dahlawi S.M.A., Dai X., Dandona L., Dandona R., Darwesh A.M., das Neves J., De la Hoz F.P., Demis A.B., Denova-Gutierrez E., Dhamnetiya D., Dhimal M.L., Dhimal M., Dianatinasab M., Diaz D., Djalalinia S., Do H.P., Doaei S., Dorostkar F., dos Santos Figueiredo F.W., Driscoll T.R., Ebrahimi H., Eftekharzadeh S., El Tantawi M., El-Abid H., Elbarazi I., Elhabashy H.R., Elhadi M., El-Jaafary S.I., Eshrati B., Eskandarieh S., Esmaeilzadeh F., Etemadi A., Ezzikouri S., Faisaluddin M., Faraon E.J.A., Fares J., Farzadfar F., Feroze A.H., Ferrero S., Ferro Desideri L., Filip I., Fischer F., Fisher J.L., Foroutan M., Fukumoto T., Gaal P.A., Gad M.M., Gadanya M.A., Gallus S., Gaspar Fonseca M., Getachew Obsa A., Ghafourifard M., Ghashghaee A., Ghith N., Gholamalizadeh M., Gilani S.A., Ginindza T.G., Gizaw A.T.T., Glasbey J.C., Golechha M., Goleij P., Gomez R.S., Gopalani S.V., Gorini G., Goudarzi H., Grosso G., Gubari M.I.M., Guerra M.R., Guha A., Gunasekera D.S., Gupta B., Gupta V.B., Gupta V.K., Gutierrez R.A., Hafezi-Nejad N., Haider M.R., Haj-Mirzaian A., Halwani R., Hamadeh R.R., Hameed S., Hamidi S., Hanif A., Haque S., Harlianto N.I., Haro J.M., Hasaballah A.I., Hassanipour S., Hay R.J., Hay S.I., Hayat K., Heidari G., Heidari M., Herrera-Serna B.Y., Herteliu C., Hezam K., Holla R., Hossain M.M., Hossain M.B.H., Hosseini M.-S., Hosseini M., Hosseinzadeh M., Hostiuc M., Hostiuc S., Househ M., Hsairi M., Huang J., Hugo F.N., Hussain R., Hussein N.R., Hwang B.-F., Iavicoli I., Ibitoye S.E., Ida F., Ikuta K.S., Ilesanmi O.S., Ilic I.M., Ilic M.D., Irham L.M., Islam J.Y., Islam R.M., Islam S.M.S., Ismail N.E., Isola G., Iwagami M., Jacob L., Jain V., Jakovljevic M.B., Javaheri T., Jayaram S., Jazayeri S.B., Jha R.P., Jonas J.B., Joo T., Joseph N., Joukar F., Jurisson M., Kabir A., Kahrizi D., Kalankesh L.R., Kalhor R., Kaliyadan F., Kalkonde Y., Kamath A., Kameran Al-Salihi N., Kandel H., Kapoor N., Karch A., Kasa A.S., Katikireddi S.V., Kauppila J.H., Kavetskyy T., Kebede S.A., Keshavarz P., Keykhaei M., Khader Y.S., Khalilov R., Khan G., Khan M., Khan M.N., Khan M.A.B., Khang Y.-H., Khater A.M., Khayamzadeh M., Kim G.R., Kim Y.J., Kisa A., Kisa S., Kissimova-Skarbek K., Kopec J.A., Koteeswaran R., Koul P.A., Koulmane Laxminarayana S.L., Koyanagi A., Kucuk Bicer B., Kugbey N., Kumar G.A., Kumar N., Kurmi O.P., Kutluk T., La Vecchia C., Lami F.H., Landires I., Lauriola P., Lee S.-W., Lee S.W.H., Lee W.-C., Lee Y.H., Leigh J., Leong E., Li J., Li M.-C., Liu X., Loureiro J.A., Lunevicius R., Magdy Abd El Razek M., Majeed A., Makki A., Male S., Malik A.A., Mansournia M.A., Martini S., Masoumi S.Z., Mathur P., McKee M., Mehrotra R., Mendoza W., Menezes R.G., Mengesha E.W., Mesregah M.K., Mestrovic T., Miao Jonasson J., Miazgowski B., Miazgowski T., Michalek I.M., Miller T.R., Mirzaei H., Mirzaei H.R., Misra S., Mithra P., Moghadaszadeh M., Mohammad K.A., Mohammad Y., Mohammadi M., Mohammadi S.M., Mohammadian-Hafshejani A., Mohammed S., Moka N., Mokdad A.H., Molokhia M., Monasta L., Moni M.A., Moosavi M.A., Moradi Y., Moraga P., Morgado-Da-Costa J., Morrison S.D., Mosapour A., Mubarik S., Mwanri L., Nagarajan A.J., Nagaraju S.P., Nagata C., Naimzada M.D., Nangia V., Naqvi A.A., Narasimha Swamy S., Ndejjo R., Nduaguba S.O., Negoi I., Negru S.M., Neupane Kandel S., Nguyen C.T., Nguyen H.L.T., Niazi R.K., Nnaji C.A., Noor N.M., Nunez-Samudio V., Nzoputam C.I., Oancea B., Ochir C., Odukoya O.O., Ogbo F.A., Olagunju A.T., Olakunde B.O., Omar E., Omar Bali A.O., Omonisi A.E.E., Ong S., Onwujekwe O.E., Orru H., Ortega-Altamirano D.V., Otstavnov N., Otstavnov S.S., Owolabi M.O., P A M., Padubidri J.R., Pakshir K., Pana A., Panagiotakos D., Panda-Jonas S., Pardhan S., Park E.-C., Park E.-K., Pashazadeh Kan F., Patel H.K., Patel J.R., Pati S., Pattanshetty S.M., Paudel U., Pereira D.M., Pereira R.B., Perianayagam A., Pillay J.D., Pirouzpanah S., Pishgar F., Podder I., Postma M.J., Pourjafar H., Prashant A., Preotescu L., Rabiee M., Rabiee N., Radfar A., Radhakrishnan R.A., Radhakrishnan V., Rafiee A., Rahim F., Rahimzadeh S., Rahman M., Rahman M.A., Rahmani A.M., Rajai N., Rajesh A., Rakovac I., Ram P., Ramezanzadeh K., Ranabhat K., Ranasinghe P., Rao C.R., Rao S.J., Rawassizadeh R., Razeghinia M.S., Renzaho A.M.N., Rezaei N., Rezapour A., Roberts T.J., Rodriguez J.A.B., Rohloff P., Romoli M., Ronfani L., Roshandel G., Rwegerera G.M., Manjula S., Sabour S., Saddik B., Saeed U., Sahebkar A., Sahoo H., Salehi S., Salem M.R., Salimzadeh H., Samaei M., Samy A.M., Sanabria J., Sankararaman S., Santric-Milicevic M.M., Sardiwalla Y., Sarveazad A., Sathian B., Sawhney M., Saylan M., Schneider I.J.J., Sekerija M., Seylani A., Shafaat O., Shaghaghi Z., Shaikh M.A., Shamsoddin E., Shannawaz M., Sharma R., Sheikh A., Sheikhbahaei S., Shetty A., Shetty J.K., Shetty P.H., Shibuya K., Shirkoohi R., Shivakumar K.M., Shivarov V., Siabani S., Siddappa Malleshappa S.K., Silva D.A.S., Singh J.A., Sintayehu Y., Skryabin V.Y., Skryabina A.A., Soeberg M.J., Sofi-Mahmudi A., Sotoudeh H., Steiropoulos P., Straif K., Subedi R., Sufiyan M.B., Sultan I., Sultana S., Sur D., Szerencses V., Szocska M., Tabares-Seisdedos R., Tabuchi T., Tadbiri H., Taherkhani A., Takahashi K., Talaat I.M., Tan K.-K., Tat V.Y., Tedla B.A.A., Tefera Y.G., Tehrani-Banihashemi A., Temsah M., Tesfay F.H., Tessema G.A., Thapar R., Thavamani A., Thoguluva Chandrasekar V., Thomas N., Tohidinik H.R., Touvier M., Tovani-Palone M.R., Traini E., Tran B.X., Tran K.B., Tran M.T.N., Tripathy J.P., Tusa B.S., Ullah I., Ullah S., Umapathi K.K., Unnikrishnan B., Upadhyay E., Vacante M., Vaezi M., Valadan Tahbaz S., Velazquez D.Z., Veroux M., Violante F.S., Vlassov V., Vo B., Volovici V., Vu G.T., Waheed Y., Wamai R.G., Ward P., Wen Y.F., Westerman R., Winkler A.S., Yadav L., Yahyazadeh Jabbari S.H., Yang L., Yaya S., Yazie T.S.Y., Yeshaw Y., Yonemoto N., Younis M.Z., Yousefi Z., Yu C., Yuce D., Yunusa I., Zadnik V., Zare F., Zastrozhin M.S., Zastrozhina A., Zhang J., Zhong C., Zhou L., Zhu C., Ziapour A., Zimmermann I.R., Fitzmaurice C., Murray C.J.L., Force L.M., Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, Kuwait University (Kuwait), National University of Malaysia (Malasia), Alexander von Humboldt Foundation, Federal Ministry of Education & Research (Alemania), NIH - National Cancer Institute (NCI) (Estados Unidos), Unión Europea. Comisión Europea. European Research Council (ERC), Unión Europea. Comisión Europea. H2020, Novo Nordisk Foundation, National Health and Medical Research Council (Australia), Jazan University (Arabia Saudí), Romanian National Authority for Scientific Research and Innovation, Ministry of Education (Brasil), National Heart Foundation of Australia, Ministry of Education, Science and Technological Development (Serbia), NHS - Research Scotland (Reino Unido), Medical Research Council (Reino Unido), Scottish Government (Reino Unido), Jatiya Kabi Kazi Nazrul Islam University (Bangladesh), Xiamen University (Malasia), Manipal Academy of Higher Education (India), Sistema Nacional de Investigación (Panamá), Secretaría Nacional de Ciencia, Tecnología e Innovación (Panamá), King College London, National Health Service (Reino Unido), Government of the Russian Federation, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil), National Council for Scientific and Technological Development (Brasil), Cancer Prevention and Research Institute of Texas (Estados Unidos), Fundação para a Ciência e Tecnologia (Portugal), Neurosurgery, Kocarnik, J. M., Compton, K., Dean, F. E., Fu, W., Gaw, B. L., Harvey, J. D., Henrikson, H. J., Lu, D., Pennini, A., Xu, R., Ababneh, E., Abbasi-Kangevari, M., Abbastabar, H., Abd-Elsalam, S. M., Abdoli, A., Abedi, A., Abidi, H., Abolhassani, H., Adedeji, I. A., Adnani, Q. E. S., Advani, S. M., Afzal, M. S., Aghaali, M., Ahinkorah, B. O., Ahmad, S., Ahmad, T., Ahmadi, A., Ahmadi, S., Ahmed Rashid, T., Ahmed Salih, Y., Akalu, G. T., Aklilu, A., Akram, T., Akunna, C. J., Al Hamad, H., Alahdab, F., Al-Aly, Z., Ali, S., Alimohamadi, Y., Alipour, V., Aljunid, S. M., Alkhayyat, M., Almasi-Hashiani, A., Almasri, N. A., Al-Maweri, S. A. A., Almustanyir, S., Alonso, N., Alvis-Guzman, N., Amu, H., Anbesu, E. W., Ancuceanu, R., Ansari, F., Ansari-Moghaddam, A., Antwi, M. H., Anvari, D., Anyasodor, A. E., Aqeel, M., Arabloo, J., Arab-Zozani, M., Aremu, O., Ariffin, H., Aripov, T., Arshad, M., Artaman, A., Arulappan, J., Asemi, Z., Asghari Jafarabadi, M., Ashraf, T., Atorkey, P., Aujayeb, A., Ausloos, M., Awedew, A. F., Ayala Quintanilla, B. P., Ayenew, T., Azab, M. A., Azadnajafabad, S., Azari Jafari, A., Azarian, G., Azzam, A. Y., Badiye, A. D., Bahadory, S., Baig, A. A., Baker, J. L., Balakrishnan, S., Banach, M., Barnighausen, T. W., Barone-Adesi, F., Barra, F., Barrow, A., Behzadifar, M., Belgaumi, U. I., Bezabhe, W. M. M., Bezabih, Y. M., Bhagat, D. S., Bhagavathula, A. S., Bhardwaj, N., Bhardwaj, P., Bhaskar, S., Bhattacharyya, K., Bhojaraja, V. S., Bibi, S., Bijani, A., Biondi, A., Bisignano, C., Bjorge, T., Bleyer, A., Blyuss, O., Bolarinwa, O. A., Bolla, S. R., Braithwaite, D., Brar, A., Brenner, H., Bustamante-Teixeira, M. T., Butt, N. S., Butt, Z. A., Caetano Dos Santos, F. L., Cao, Y., Carreras, G., Catala-Lopez, F., Cembranel, F., Cerin, E., Cernigliaro, A., Chakinala, R. C., Chattu, S. K., Chattu, V. K., Chaturvedi, P., Chimed-Ochir, O., Cho, D. Y., Christopher, D. J., Chu, D. -T., Chung, M. T., Conde, J., Cortes, S., Cortesi, P. A., Costa, V. M., Cunha, A. R., Dadras, O., Dagnew, A. B., Dahlawi, S. M. A., Dai, X., Dandona, L., Dandona, R., Darwesh, A. M., Das Neves, J., De La Hoz, F. P., Demis, A. B., Denova-Gutierrez, E., Dhamnetiya, D., Dhimal, M. L., Dhimal, M., Dianatinasab, M., Diaz, D., Djalalinia, S., Do, H. P., Doaei, S., Dorostkar, F., Dos Santos Figueiredo, F. W., Driscoll, T. R., Ebrahimi, H., Eftekharzadeh, S., El Tantawi, M., El-Abid, H., Elbarazi, I., Elhabashy, H. R., Elhadi, M., El-Jaafary, S. I., Eshrati, B., Eskandarieh, S., Esmaeilzadeh, F., Etemadi, A., Ezzikouri, S., Faisaluddin, M., Faraon, E. J. A., Fares, J., Farzadfar, F., Feroze, A. H., Ferrero, S., Ferro Desideri, L., Filip, I., Fischer, F., Fisher, J. L., Foroutan, M., Fukumoto, T., Gaal, P. A., Gad, M. M., Gadanya, M. A., Gallus, S., Gaspar Fonseca, M., Getachew Obsa, A., Ghafourifard, M., Ghashghaee, A., Ghith, N., Gholamalizadeh, M., Gilani, S. A., Ginindza, T. G., Gizaw, A. T. T., Glasbey, J. C., Golechha, M., Goleij, P., Gomez, R. S., Gopalani, S. V., Gorini, G., Goudarzi, H., Grosso, G., Gubari, M. I. M., Guerra, M. R., Guha, A., Gunasekera, D. S., Gupta, B., Gupta, V. B., Gupta, V. K., Gutierrez, R. A., Hafezi-Nejad, N., Haider, M. R., Haj-Mirzaian, A., Halwani, R., Hamadeh, R. R., Hameed, S., Hamidi, S., Hanif, A., Haque, S., Harlianto, N. I., Haro, J. M., Hasaballah, A. I., Hassanipour, S., Hay, R. J., Hay, S. I., Hayat, K., Heidari, G., Heidari, M., Herrera-Serna, B. Y., Herteliu, C., Hezam, K., Holla, R., Hossain, M. M., Hossain, M. B. H., Hosseini, M. -S., Hosseini, M., Hosseinzadeh, M., Hostiuc, M., Hostiuc, S., Househ, M., Hsairi, M., Huang, J., Hugo, F. N., Hussain, R., Hussein, N. R., Hwang, B. -F., Iavicoli, I., Ibitoye, S. E., Ida, F., Ikuta, K. S., Ilesanmi, O. S., Ilic, I. M., Ilic, M. D., Irham, L. M., Islam, J. Y., Islam, R. M., Islam, S. M. S., Ismail, N. E., Isola, G., Iwagami, M., Jacob, L., Jain, V., Jakovljevic, M. B., Javaheri, T., Jayaram, S., Jazayeri, S. B., Jha, R. P., Jonas, J. B., Joo, T., Joseph, N., Joukar, F., Jurisson, M., Kabir, A., Kahrizi, D., Kalankesh, L. R., Kalhor, R., Kaliyadan, F., Kalkonde, Y., Kamath, A., Kameran Al-Salihi, N., Kandel, H., Kapoor, N., Karch, A., Kasa, A. S., Katikireddi, S. V., Kauppila, J. H., Kavetskyy, T., Kebede, S. A., Keshavarz, P., Keykhaei, M., Khader, Y. S., Khalilov, R., Khan, G., Khan, M., Khan, M. N., Khan, M. A. B., Khang, Y. -H., Khater, A. M., Khayamzadeh, M., Kim, G. R., Kim, Y. J., Kisa, A., Kisa, S., Kissimova-Skarbek, K., Kopec, J. A., Koteeswaran, R., Koul, P. A., Koulmane Laxminarayana, S. L., Koyanagi, A., Kucuk Bicer, B., Kugbey, N., Kumar, G. A., Kumar, N., Kurmi, O. P., Kutluk, T., La Vecchia, C., Lami, F. H., Landires, I., Lauriola, P., Lee, S. -W., Lee, S. W. H., Lee, W. -C., Lee, Y. H., Leigh, J., Leong, E., Li, J., Li, M. -C., Liu, X., Loureiro, J. A., Lunevicius, R., Magdy Abd El Razek, M., Majeed, A., Makki, A., Male, S., Malik, A. A., Mansournia, M. A., Martini, S., Masoumi, S. Z., Mathur, P., Mckee, M., Mehrotra, R., Mendoza, W., Menezes, R. G., Mengesha, E. W., Mesregah, M. K., Mestrovic, T., Miao Jonasson, J., Miazgowski, B., Miazgowski, T., Michalek, I. M., Miller, T. R., Mirzaei, H., Mirzaei, H. R., Misra, S., Mithra, P., Moghadaszadeh, M., Mohammad, K. A., Mohammad, Y., Mohammadi, M., Mohammadi, S. M., Mohammadian-Hafshejani, A., Mohammed, S., Moka, N., Mokdad, A. H., Molokhia, M., Monasta, L., Moni, M. A., Moosavi, M. A., Moradi, Y., Moraga, P., Morgado-Da-Costa, J., Morrison, S. D., Mosapour, A., Mubarik, S., Mwanri, L., Nagarajan, A. J., Nagaraju, S. P., Nagata, C., Naimzada, M. D., Nangia, V., Naqvi, A. A., Narasimha Swamy, S., Ndejjo, R., Nduaguba, S. O., Negoi, I., Negru, S. M., Neupane Kandel, S., Nguyen, C. T., Nguyen, H. L. T., Niazi, R. K., Nnaji, C. A., Noor, N. M., Nunez-Samudio, V., Nzoputam, C. I., Oancea, B., Ochir, C., Odukoya, O. O., Ogbo, F. A., Olagunju, A. T., Olakunde, B. O., Omar, E., Omar Bali, A., Omonisi, A. E. E., Ong, S., Onwujekwe, O. E., Orru, H., Ortega-Altamirano, D. V., Otstavnov, N., Otstavnov, S. S., Owolabi, M. O., P A, M., Padubidri, J. R., Pakshir, K., Pana, A., Panagiotakos, D., Panda-Jonas, S., Pardhan, S., Park, E. -C., Park, E. -K., Pashazadeh Kan, F., Patel, H. K., Patel, J. R., Pati, S., Pattanshetty, S. M., Paudel, U., Pereira, D. M., Pereira, R. B., Perianayagam, A., Pillay, J. D., Pirouzpanah, S., Pishgar, F., Podder, I., Postma, M. J., Pourjafar, H., Prashant, A., Preotescu, L., Rabiee, M., Rabiee, N., Radfar, A., Radhakrishnan, R. A., Radhakrishnan, V., Rafiee, A., Rahim, F., Rahimzadeh, S., Rahman, M., Rahman, M. A., Rahmani, A. M., Rajai, N., Rajesh, A., Rakovac, I., Ram, P., Ramezanzadeh, K., Ranabhat, K., Ranasinghe, P., Rao, C. R., Rao, S. J., Rawassizadeh, R., Razeghinia, M. S., Renzaho, A. M. N., Rezaei, N., Rezapour, A., Roberts, T. J., Rodriguez, J. A. B., Rohloff, P., Romoli, M., Ronfani, L., Roshandel, G., Rwegerera, G. M., Manjula, S., Sabour, S., Saddik, B., Saeed, U., Sahebkar, A., Sahoo, H., Salehi, S., Salem, M. R., Salimzadeh, H., Samaei, M., Samy, A. M., Sanabria, J., Sankararaman, S., Santric-Milicevic, M. M., Sardiwalla, Y., Sarveazad, A., Sathian, B., Sawhney, M., Saylan, M., Schneider, I. J. C., Sekerija, M., Seylani, A., Shafaat, O., Shaghaghi, Z., Shaikh, M. A., Shamsoddin, E., Shannawaz, M., Sharma, R., Sheikh, A., Sheikhbahaei, S., Shetty, A., Shetty, J. K., Shetty, P. H., Shibuya, K., Shirkoohi, R., Shivakumar, K. M., Shivarov, V., Siabani, S., Siddappa Malleshappa, S. K., Silva, D. A. S., Singh, J. A., Sintayehu, Y., Skryabin, V. Y., Skryabina, A. A., Soeberg, M. J., Sofi-Mahmudi, A., Sotoudeh, H., Steiropoulos, P., Straif, K., Subedi, R., Sufiyan, M. B., Sultan, I., Sultana, S., Sur, D., Szerencses, V., Szocska, M., Tabares-Seisdedos, R., Tabuchi, T., Tadbiri, H., Taherkhani, A., Takahashi, K., Talaat, I. M., Tan, K. -K., Tat, V. Y., Tedla, B. A. A., Tefera, Y. G., Tehrani-Banihashemi, A., Temsah, M. -H., Tesfay, F. H., Tessema, G. A., Thapar, R., Thavamani, A., Thoguluva Chandrasekar, V., Thomas, N., Tohidinik, H. R., Touvier, M., Tovani-Palone, M. R., Traini, E., Tran, B. X., Tran, K. B., Tran, M. T. N., Tripathy, J. P., Tusa, B. S., Ullah, I., Ullah, S., Umapathi, K. K., Unnikrishnan, B., Upadhyay, E., Vacante, M., Vaezi, M., Valadan Tahbaz, S., Velazquez, D. Z., Veroux, M., Violante, F. S., Vlassov, V., Vo, B., Volovici, V., Vu, G. T., Waheed, Y., Wamai, R. G., Ward, P., Wen, Y. F., Westerman, R., Winkler, A. S., Yadav, L., Yahyazadeh Jabbari, S. H., Yang, L., Yaya, S., Yazie, T. S. Y., Yeshaw, Y., Yonemoto, N., Younis, M. Z., Yousefi, Z., Yu, C., Yuce, D., Yunusa, I., Zadnik, V., Zare, F., Zastrozhin, M. S., Zastrozhina, A., Zhang, J., Zhong, C., Zhou, L., Zhu, C., Ziapour, A., Zimmermann, I. R., Fitzmaurice, C., Murray, C. J. L., and Force, L. M.
Subjects: Cancer Research, GBD, 195 COUNTRIES, Global Health, 1117 Public Health and Health Services, Global Burden of Disease, SDG 3 - Good Health and Well-being, WORLDWIDE, Risk Factors, Neoplasms, SURVEILLANCE, SUPPORT, Global Burden of Disease 2019 Cancer Collaboration, Prevalence, Online First, cancer, Humans, 1112 Oncology and Carcinogenesis, public health, cancer, burden of diseases, PROGRESS, Original Investigation, Global burden, Science & Technology, CHALLENGES, Research, Incidence, Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 [VDP], COVID-19, 1112 Oncology and Carcinogenesis, 1117 Public Health and Health Services, Disability-Adjusted Life Years, mortality, STATISTICS, Oncology, Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019 A Systematic Analysis for the Global Burden of Disease Study 2019, HEALTH-CARE, TERRITORIES, Quality-Adjusted Life Years, Life Sciences & Biomedicine, Comments
Abstract: Key Points Question What was the burden of cancer globally and across Sociodemographic Index (SDI) groupings in 2019, and how has incidence, morbidity, and mortality changed since 2010? Findings In this systematic analysis, there were 23.6 million new global cancer cases in 2019 (17.2 million when excluding those with nonmelanoma skin cancer), 10.0 million cancer deaths, and an estimated 250 million disability-adjusted life years estimated to be due to cancer; since 2010, these represent increases of 26.3%, 20.9%, and 16.0%, respectively. Absolute cancer burden increased in all SDI quintiles since 2010, but the largest percentage increases occurred in the low and low-middle SDI quintiles. Meanings The study results suggest that increased cancer prevention and control efforts are needed to equitably address the evolving and increasing burden of cancer across the SDI spectrum., Importance The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. Objective To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. Evidence Review The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). Findings In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. Conclusions and Relevance The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world., The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 examines cancer burden and trends globally for 204 countries and territories and by Socio-demographic Index quintiles from 2010 to 2019.
Published: 2022

24. Regional excess mortality during the 2020 COVID-19 pandemic in five European countries

Author: Garyfallos Konstantinoudis, Michela Cameletti, Virgilio Gómez-Rubio, Inmaculada León Gómez, Monica Pirani, Gianluca Baio, Amparo Larrauri, Julien Riou, Matthias Egger, Paolo Vineis, Marta Blangiardo, Medical Research Council, National Institutes of Health, Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), NIHR - Imperial Biomedical Research Centre (Reino Unido), Junta de Castilla y León (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministerio de Ciencia e Innovación (España), and Swiss National Science Foundation
Subjects: Adult, Male, Epidemiology, Science, General Physics and Astronomy, 610 Medicine & health, DELAYS, General Biochemistry, Genetics and Molecular Biology, Article, 360 Social problems & social services, Cause of Death, Humans, UK, Pandemics, Aged, Aged, 80 and over, Multidisciplinary, Science & Technology, Geography, Greece, SARS-CoV-2, COVID-19, Bayes Theorem, General Chemistry, Middle Aged, CARE, Survival Rate, Multidisciplinary Sciences, Risk factors, England, Italy, Viral infection, Spain, Science & Technology - Other Topics, Female, HEALTH, Settore SECS-S/01 - Statistica, Switzerland
Abstract: The impact of the COVID-19 pandemic on excess mortality from all causes in 2020 varied across and within European countries. Using data for 2015–2019, we applied Bayesian spatio-temporal models to quantify the expected weekly deaths at the regional level had the pandemic not occurred in England, Greece, Italy, Spain, and Switzerland. With around 30%, Madrid, Castile-La Mancha, Castile-Leon (Spain) and Lombardia (Italy) were the regions with the highest excess mortality. In England, Greece and Switzerland, the regions most affected were Outer London and the West Midlands (England), Eastern, Western and Central Macedonia (Greece), and Ticino (Switzerland), with 15–20% excess mortality in 2020. Our study highlights the importance of the large transportation hubs for establishing community transmission in the first stages of the pandemic. Here, we show that acting promptly to limit transmission around these hubs is essential to prevent spread to other regions and countries., In this study, the authors estimate excess mortality at the regional level for five European countries (England, Greece, Italy, Spain, and Switzerland) in 2020. They identify the regions and time periods with highest excess mortality and show how these patterns evolved through different pandemic waves.
Published: 2022

25. Assessing performance of the Healthcare Access and Quality Index, overall and by select age groups, for 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019

Author: Lozano, R., Haakenstad, A., Yearwood, J. A., Fullman, N., Bintz, C., Bienhoff, K., Weaver, M. R., Nandakumar, V., Joffe, J. N., LeGrand, K. E., Knight, M., Abbafati, C., Abbasi-Kangevari, M., Abdoli, A., Zuniga, R. A. A., Adedeji, I. A., Adekanmbi, V., Adetokunboh, O. O., Afzal, M. S., Afzal, S., Agudelo-Botero, M., Ahinkorah, B. O., Ahmad, S., Ahmadi, A., Ahmadi, S., Ahmed, A., Rashid, T. A., Aji, B., Akande-Sholabi, W., Alam, K., Al Hamad, H., Alhassan, R. K., Ali, L., Alipour, V., Aljunid, S. M., Ameyaw, E. K., Amin, T. T., Amu, H., Amugsi, D. A., Ancuceanu, R., Andrade, P. P., Anjum, A., Arabloo, J., Arab-Zozani, M., Ariffin, H., Arulappan, J., Aryan, Z., Ashraf, T., Atnafu, D. D., Atreya, A., Ausloos, M., Avila-Burgos, L., Ayano, G., Ayanore, M. A., Azari, S., Badiye, A. D., Baig, A. A., Bairwa, M., Bakkannavar, S. M., Baliga, S., Banik, P. C., Barnighausen, T. W., Barra, F., Barrow, A., Basu, S., Bayati, M., Belete, R., Bell, A. W., Bhagat, D. S., Bhagavathula, A. S., Bhardwaj, P., Bhardwaj, N., Bhaskar, S., Bhattacharyya, K., Bhutta, Z. A., Bibi, S., Bijani, A., Bikbov, B., Biondi, A., Bolarinwa, O. A., Bonny, A., Brenner, H., Buonsenso, D., Burkart, K., Busse, R., Butt, Z. A., Butt, N. S., dos Santos, F. L. C., Cahuana Hurtado, Lucero, Camera, Luis Alberto, Cardenas, R., Carneiro, V. L. A., Catala-Lopez, F., Chandan, J. S., Charan, J., Chavan, P. P., Chen, S. M., Chen, S., Choudhari, S. G., Chowdhury, E. K., Chowdhury, M. A. K., Cirillo, M., Corso, B., Dadras, O., Dahlawi, S. M. A., Dai, X. C., Dandona, L., Dandona, R., Dangel, W. J., Davila-Cervantes, C. A., Davletov, K., Deuba, K., Dhimal, M., Dhimal, M. L., Djalalinia, S., Do, H. P., Doshmangir, L., Duncan, B. B., Effiong, A., Ehsani-Chimeh, E., Elgendy, I. Y., Elhadi, M., El Sayed, I., El Tantawi, M., Erku, D. A., Eskandarieh, S., Fares, J., Farzadfar, F., Ferrero, S., Desideri, L. F., Fischer, F., Foigt, N. A., Foroutan, M., Fukumoto, T., Gaal, P. A., Gaihre, S., Gardner, W. M., Garg, T., Obsa, A. G., Ghafourifard, M., Ghashghaee, A., Ghith, N., Gilani, S. A., Gill, P. S., Goharinezhad, S., Golechha, M., Guadamuz, J. S., Guo, Y. M., Das Gupta, R., Gupta, R., Gupta, V. K., Gupta, V. B., Hamiduzzaman, M., Hanif, A., Haro, J. M., Hasaballah, A. I., Hasan, M. M., Hasan, M. T., Hashi, A., Hay, S. I., Hayat, K., Heidari, M., Heidari, G., Henry, N. J., Herteliu, C., Holla, R., Hossain, S., Hossain, S. J., Hossain, M. B. H., Hosseinzadeh, M., Hostiuc, S., Hoveidamanesh, S., Hsieh, V. C. R., Hu, G. Q., Huang, J. J., Huda, M. M., Ifeagwu, S. C., Ikuta, K. S., Ilesanmi, O. S., Irvani, S. S. N., Islam, R. M., Islam, S. M. S., Ismail, N. E., Iso, H., Isola, G., Itumalla, R., Iwagami, M., Jahani, M. A., Jahanmehr, N., Jain, R., Jakovljevic, M., Janodia, M. D., Jayapal, S. K., Jayaram, S., Jha, R. P., Jonas, J. B., Joo, T., Joseph, N., Jurisson, M., Kabir, A., Kalankesh, L. R., Kalhor, R., Kamath, A. M., Kamenov, K., Kandel, H., Kantar, R. S., Kapoor, N., Karanikolos, M., Katikireddi, S. V., Kavetskyy, T., Kawakami, N., Kayode, G. A., Keikavoosi-Arani, L., Keykhaei, M., Khader, Y. S., Khajuria, H., Khalilov, R., Khammarnia, M., Khan, M. N., Khan, M. A. B., Khan, M., Khezeli, M., Kim, M. S., Kim, Y. J., Kisa, S., Kisa, A., Klymchuk, V., Koly, K. N., Korzh, O., Kosen, S., Koul, P. A., Defo, B. K., Kumar, G. A., Kusuma, D., Kyu, H. H., Larsson, A. O., Lasrado, S., Lee, W. C., Lee, Y. H., Lee, C. B., Li, S. S., Lucchetti, G., Mahajan, P. B., Majeed, A., Makki, A., Malekzadeh, R., Malik, A. A., Malta, D. C., Mansournia, M. A., Mantovani, L. G., Martinez-Valle, A., Martins-Melo, F. R., Masoumi, S. Z., Mathur, M. R., Maude, R. J., Maulik, P. K., McKee, M., Mendoza, W., Menezes, R. G., Mensah, G. A., Meretoja, A., Meretoja, T. J., Mestrovic, T., Michalek, I. M., Mirrakhimov, E. M., Misganaw, A., Misra, S., Moazen, B., Mohammadi, M., Mohammed, S., Moitra, M., Mokdad, A. H., Molokhia, M., Monasta, L., Moni, M. A., Moradi, G., Moreira, R. S., Mosser, J. F., Mostafavi, E., Mouodi, S., Nagarajan, A. J., Nagata, C., Naghavi, M., Nangia, V., Swamy, S. N., Narayana, A. I., Nascimento, B. R., Nassereldine, H., Nayak, B. P., Nazari, J., Negoi, I., Nepal, S., Kandel, S. N., Ngunjiri, J. W., Nguyen, H. L. T, Nguyen, C. T., Ningrum, D. N. A., Noubiap, J. J., Oancea, B., Oghenetega, O. B., Oh, I. H., Olagunju, A. T., Olakunde, B. O., Bali, A. O., Omer, E., Onwujekwe, O. E., Otoiu, A., Padubidri, J. R., Palladino, R., Pana, A., Panda-Jonas, S., Pandi-Perumal, S. R., Pardhan, S., Pasupula, D. K., Pathak, P. K., Patton, G. C., Pawar, S., Pereira, J., Pilania, M., Piroozi, B., Podder, V., Pokhrel, K. N., Postma, M. J., Prada, S. I., Syed, Z. Q., Rabiee, N., Radhakrishnan, R. A., Rahman, M. M., Rahman, M., Rahman, M. H. U., Rahmani, A. M., Ranabhat, C. L., Rao, C. R., Rao, S. J., Rasella, D., Rawaf, S., Rawaf, D. L., Rawal, L., Renzaho, A. M. N., Reshmi, B., Resnikoff, S., Rezapour, A., Riahi, S. M., Ripon, R. K., Sacco, S., Sadeghi, M., Saeed, U., Sahebkar, A., Sahiledengle, B., Sahoo, H., Sahu, M., Salama, J. S., Salamati, P., Samy, A. M., Sanabria, J., Santric-Milicevic, M. M., Sathian, B., Sawhney, M., Schmidt, M. I., Seidu, A. A., Sepanlou, S. G., Seylani, A., Shaikh, M. A., Sheikh, A., Shetty, A., Shigematsu, M., Shiri, R., Shivakumar, K. M., Shokri, A., Singh, J. A., Sinha, D. N., Skryabin, V. Y., Skryabina, A. A., Sofi-Mahmudi, A., Sousa, R. A. R. C., Stephens, J. H., Sun, J., Szocska, M., Tabares-Seisdedos, R., Tadbiri, H., Tamiru, A. T., Thankappan, K. R., Topor-Madry, R., Tovani-Palone, M. R., Tran, M. T. N., Tran, B. X., Tripathi, N., Tripathy, J. P., Troeger, C. E., Uezono, D. R., Ullah, S., Ullah, A., Unnikrishnan, B., Vacante, M., Tahbaz, S. V., Valdez, P. R., Vasic, M., Veroux, M., Vervoort, D., Violante, F. S., Vladimirov, S. K., Vlassov, V., Vo, B., Waheed, Y., Wamai, R. G., Wang, Y. P., Wang, Y. Z., Ward, P., Wiangkham, T., Yadav, L., Jabbari, S. H. Y., Yamagishi, K., Yaya, S., Yazdi-Feyzabadi, V., Yi, S. Y., Yigit, V., Yonemoto, N., Younis, M. Z., Yu, C. H., Yunusa, I., Bin Zaman, S., Zastrozhin, M. S., Zhang, Z. J., Zhong, C. W., Zuniga, Y. M. H., Lim, S. S., Murray, C. J. L., GBD 2019 Healthcare Access Quality, Clinicum, Department of Neurosciences, HUS Comprehensive Cancer Center, Haakenstad, Annie, Yearwood, Jamal Akeem, Fullman, Nancy, Bintz, Corinne, Bienhoff, Kelly, Weaver, Marcia R, Nandakumar, Vishnu, Joffe, Jonah N, Legrand, Kate E, Knight, Megan, Abbafati, Cristiana, Abbasi-Kangevari, Mohsen, Abdoli, Amir, Abeldaño Zuñiga, Roberto Ariel, Adedeji, Isaac Akinkunmi, Adekanmbi, Victor, Adetokunboh, Olatunji O, Afzal, Muhammad Sohail, Afzal, Saira, Agudelo-Botero, Marcela, Ahinkorah, Bright Opoku, Ahmad, Sajjad, Ahmadi, Ali, Ahmadi, Sepideh, Ahmed, Ali, Ahmed Rashid, Tarik, Aji, Budi, Akande-Sholabi, Wuraola, Alam, Khurshid, Al Hamad, Hanadi, Alhassan, Robert Kaba, Ali, Liaqat, Alipour, Vahid, Aljunid, Syed Mohamed, Ameyaw, Edward Kwabena, Amin, Tarek Tawfik, Amu, Hubert, Amugsi, Dickson A, Ancuceanu, Robert, Andrade, Pedro Prata, Anjum, Afifa, Arabloo, Jalal, Arab-Zozani, Morteza, Ariffin, Hany, Arulappan, Judie, Aryan, Zahra, Ashraf, Tahira, Atnafu, Desta Debalkie, Atreya, Alok, Ausloos, Marcel, Avila-Burgos, Leticia, Ayano, Getinet, Ayanore, Martin Amogre, Azari, Samad, Badiye, Ashish D, Baig, Atif Amin, Bairwa, Mohan, Bakkannavar, Shankar M, Baliga, Shrikala, Banik, Palash Chandra, Bärnighausen, Till Winfried, Barra, Fabio, Barrow, Amadou, Basu, Sanjay, Bayati, Mohsen, Belete, Rebuma, Bell, Arielle Wilder, Bhagat, Devidas S, Bhagavathula, Akshaya Srikanth, Bhardwaj, Pankaj, Bhardwaj, Nikha, Bhaskar, Sonu, Bhattacharyya, Krittika, Bhutta, Zulfiqar A, Bibi, Sadia, Bijani, Ali, Bikbov, Bori, Biondi, Antonio, Bolarinwa, Obasanjo Afolabi, Bonny, Aime, Brenner, Hermann, Buonsenso, Danilo, Burkart, Katrin, Busse, Reinhard, Butt, Zahid A, Butt, Nadeem Shafique, Caetano dos Santos, Florentino Luciano, Cahuana-Hurtado, Lucero, Cámera, Luis Alberto, Cárdenas, Rosario, Carneiro, Vera L A, Catalá-López, Ferrán, Chandan, Joht Singh, Charan, Jaykaran, Chavan, Prachi P, Chen, Simiao, Chen, Shu, Choudhari, Sonali Gajanan, Chowdhury, Enayet Karim, Chowdhury, Mohiuddin Ahsanul Kabir, Cirillo, Massimo, Corso, Barbara, Dadras, Omid, Dahlawi, Saad M A, Dai, Xiaochen, Dandona, Lalit, Dandona, Rakhi, Dangel, William Jame, Dávila-Cervantes, Claudio Alberto, Davletov, Kairat, Deuba, Keshab, Dhimal, Meghnath, Dhimal, Mandira Lamichhane, Djalalinia, Shirin, Do, Huyen Phuc, Doshmangir, Leila, Duncan, Bruce B, Effiong, Andem, Ehsani-Chimeh, Elham, Elgendy, Islam Y, Elhadi, Muhammed, El Sayed, Iman, El Tantawi, Maha, Erku, Daniel Asfaw, Eskandarieh, Sharareh, Fares, Jawad, Farzadfar, Farshad, Ferrero, Simone, Ferro Desideri, Lorenzo, Fischer, Florian, Foigt, Nataliya A, Foroutan, Masoud, Fukumoto, Takeshi, Gaal, Peter Andra, Gaihre, Santosh, Gardner, William M, Garg, Tushar, Getachew Obsa, Abera, Ghafourifard, Mansour, Ghashghaee, Ahmad, Ghith, Nermin, Gilani, Syed Amir, Gill, Paramjit Singh, Goharinezhad, Salime, Golechha, Mahaveer, Guadamuz, Jenny S, Guo, Yuming, Gupta, Rajat Da, Gupta, Rajeev, Gupta, Vivek Kumar, Gupta, Veer Bala, Hamiduzzaman, Mohammad, Hanif, Asif, Haro, Josep Maria, Hasaballah, Ahmed I, Hasan, Md Mehedi, Hasan, M Tasdik, Hashi, Abdiwahab, Hay, Simon I, Hayat, Khezar, Heidari, Mohammad, Heidari, Golnaz, Henry, Nathaniel J, Herteliu, Claudiu, Holla, Ramesh, Hossain, Sahadat, Hossain, Sheikh Jamal, Hossain, Mohammad Bellal Hossain, Hosseinzadeh, Mehdi, Hostiuc, Sorin, Hoveidamanesh, Soodabeh, Hsieh, Vivian Chia-rong, Hu, Guoqing, Huang, Junjie, Huda, M Mamun, Ifeagwu, Susan C, Ikuta, Kevin S, Ilesanmi, Olayinka Stephen, Irvani, Seyed Sina Naghibi, Islam, Rakibul M, Islam, Sheikh Mohammed Shariful, Ismail, Nahlah Elkudssiah, Iso, Hiroyasu, Isola, Gaetano, Itumalla, Ramaiah, Iwagami, Masao, Jahani, Mohammad Ali, Jahanmehr, Nader, Jain, Rajesh, Jakovljevic, Mihajlo, Janodia, Manthan Dilipkumar, Jayapal, Sathish Kumar, Jayaram, Shubha, Jha, Ravi Prakash, Jonas, Jost B, Joo, Tama, Joseph, Nitin, Jürisson, Mikk, Kabir, Ali, Kalankesh, Leila R, Kalhor, Rohollah, Kamath, Aruna M, Kamenov, Kaloyan, Kandel, Himal, Kantar, Rami S, Kapoor, Neeti, Karanikolos, Marina, Katikireddi, Srinivasa Vittal, Kavetskyy, Tara, Kawakami, Norito, Kayode, Gbenga A, Keikavoosi-Arani, Leila, Keykhaei, Mohammad, Khader, Yousef Saleh, Khajuria, Himanshu, Khalilov, Rovshan, Khammarnia, Mohammad, Khan, Md Nuruzzaman, Khan, Moien AB, Khan, Maseer, Khezeli, Mehdi, Kim, Min Seo, Kim, Yun Jin, Kisa, Sezer, Kisa, Adnan, Klymchuk, Vitalii, Koly, Kamrun Nahar, Korzh, Oleksii, Kosen, Soewarta, Koul, Parvaiz A, Kuate Defo, Barthelemy, Kumar, G Anil, Kusuma, Dian, Kyu, Hmwe Hmwe, Larsson, Anders O, Lasrado, Savita, Lee, Wei-Chen, Lee, Yo Han, Lee, Chiachi Bonnie, Li, Shanshan, Lucchetti, Giancarlo, Mahajan, Preetam Bhalchandra, Majeed, Azeem, Makki, Alaa, Malekzadeh, Reza, Malik, Ahmad Azam, Malta, Deborah Carvalho, Mansournia, Mohammad Ali, Mantovani, Lorenzo Giovanni, Martinez-Valle, Adolfo, Martins-Melo, Francisco Rogerlândio, Masoumi, Seyedeh Zahra, Mathur, Manu Raj, Maude, Richard Jame, Maulik, Pallab K, Mckee, Martin, Mendoza, Walter, Menezes, Ritesh G, Mensah, George A, Meretoja, Atte, Meretoja, Tuomo J, Mestrovic, Tomislav, Michalek, Irmina Maria, Mirrakhimov, Erkin M, Misganaw, Awoke, Misra, Sanjeev, Moazen, Babak, Mohammadi, Mokhtar, Mohammed, Shafiu, Moitra, Modhurima, Mokdad, Ali H, Molokhia, Mariam, Monasta, Lorenzo, Moni, Mohammad Ali, Moradi, Ghobad, Moreira, Rafael Silveira, Mosser, Jonathan F, Mostafavi, Ebrahim, Mouodi, Simin, Nagarajan, Ahamarshan Jayaraman, Nagata, Chie, Naghavi, Mohsen, Nangia, Vinay, Narasimha Swamy, Sreeniva, Narayana, Aparna Ichalangod, Nascimento, Bruno Ramo, Nassereldine, Hasan, Nayak, Biswa Prakash, Nazari, Javad, Negoi, Ionut, Nepal, Samata, Neupane Kandel, Sandhya, Ngunjiri, Josephine W, Nguyen, Huong Lan Thi, Nguyen, Cuong Tat, Ningrum, Dina Nur Anggraini, Noubiap, Jean Jacque, Oancea, Bogdan, Oghenetega, Onome Bright, Oh, In-Hwan, Olagunju, Andrew T, Olakunde, Babayemi Oluwaseun, Omar Bali, Ahmed, Omer, Emad, Onwujekwe, Obinna E, Otoiu, Adrian, Padubidri, Jagadish Rao, Palladino, Raffaele, Pana, Adrian, Panda-Jonas, Songhomitra, Pandi-Perumal, Seithikurippu R, Pardhan, Shahina, Pasupula, Deepak Kumar, Pathak, Praveen Kumar, Patton, George C, Pawar, Shrikant, Pereira, Jeevan, Pilania, Manju, Piroozi, Bakhtiar, Podder, Vivek, Pokhrel, Khem Narayan, Postma, Maarten J, Prada, Sergio I, Quazi Syed, Zahiruddin, Rabiee, Navid, Radhakrishnan, Raghu Anekal, Rahman, Md Mosfequr, Rahman, Mosiur, Rahman, Mahfuzar, Rahman, Mohammad Hifz Ur, Rahmani, Amir Masoud, Ranabhat, Chhabi Lal, Rao, Chythra R, Rao, Sowmya J, Rasella, Davide, Rawaf, Salman, Rawaf, David Laith, Rawal, Lal, Renzaho, Andre M N, Reshmi, Bhageerathy, Resnikoff, Serge, Rezapour, Aziz, Riahi, Seyed Mohammad, Ripon, Rezaul Karim, Sacco, Simona, Sadeghi, Masoumeh, Saeed, Umar, Sahebkar, Amirhossein, Sahiledengle, Biniyam, Sahoo, Harihar, Sahu, Maitreyi, Salama, Joseph S, Salamati, Payman, Samy, Abdallah M, Sanabria, Juan, Santric-Milicevic, Milena M, Sathian, Brijesh, Sawhney, Monika, Schmidt, Maria Inê, Seidu, Abdul-Aziz, Sepanlou, Sadaf G, Seylani, Allen, Shaikh, Masood Ali, Sheikh, Aziz, Shetty, Adithi, Shigematsu, Mika, Shiri, Rahman, Shivakumar, K M, Shokri, Azad, Singh, Jasvinder A, Sinha, Dhirendra Narain, Skryabin, Valentin Yurievich, Skryabina, Anna Aleksandrovna, Sofi-Mahmudi, Ahmad, Sousa, Raúl A R C, Stephens, Jacqueline H, Sun, Jing, Szócska, Mikló, Tabarés-Seisdedos, Rafael, Tadbiri, Hooman, Tamiru, Animut Tagele, Thankappan, Kavumpurathu Raman, Topor-Madry, Roman, Tovani-Palone, Marcos Roberto, Tran, Mai Thi Ngoc, Tran, Bach Xuan, Tripathi, Niharika, Tripathy, Jaya Prasad, Troeger, Christopher E, Uezono, Deinzel Roble, Ullah, Saif, Ullah, Anayat, Unnikrishnan, Bhaskaran, Vacante, Marco, Valadan Tahbaz, Sahel, Valdez, Pascual R, Vasic, Milena, Veroux, Massimiliano, Vervoort, Dominique, Violante, Francesco S, Vladimirov, Sergey Konstantinovitch, Vlassov, Vasily, Vo, Bay, Waheed, Yasir, Wamai, Richard G, Wang, Yuan-Pang, Wang, Yanzhong, Ward, Paul, Wiangkham, Taweewat, Yadav, Lalit, Yahyazadeh Jabbari, Seyed Hossein, Yamagishi, Kazumasa, Yaya, Sanni, Yazdi-Feyzabadi, Vahid, Yi, Siyan, Yiğit, Vahit, Yonemoto, Naohiro, Younis, Mustafa Z, Yu, Chuanhua, Yunusa, Ismaeel, Zaman, Sojib Bin, Zastrozhin, Mikhail Sergeevich, Zhang, Zhi-Jiang, Zhong, Chenwen, Zuniga, Yves Miel H, Lim, Stephen S, Murray, Christopher J L, Lozano, Rafael, Haakenstad, A, Yearwood, J, Fullman, N, Bintz, C, Bienhoff, K, Weaver, M, Nandakumar, V, Joffe, J, Legrand, K, Knight, M, Abbafati, C, Abbasi-Kangevari, M, Abdoli, A, Abeldano Zuniga, R, Adedeji, I, Adekanmbi, V, Adetokunboh, O, Afzal, M, Afzal, S, Agudelo-Botero, M, Ahinkorah, B, Ahmad, S, Ahmadi, A, Ahmadi, S, Ahmed, A, Ahmed Rashid, T, Aji, B, Akande-Sholabi, W, Alam, K, Al Hamad, H, Alhassan, R, Ali, L, Alipour, V, Aljunid, S, Ameyaw, E, Amin, T, Amu, H, Amugsi, D, Ancuceanu, R, Andrade, P, Anjum, A, Arabloo, J, Arab-Zozani, M, Ariffin, H, Arulappan, J, Aryan, Z, Ashraf, T, Atnafu, D, Atreya, A, Ausloos, M, Avila-Burgos, L, Ayano, G, Ayanore, M, Azari, S, Badiye, A, Baig, A, Bairwa, M, Bakkannavar, S, Baliga, S, Banik, P, Barnighausen, T, Barra, F, Barrow, A, Basu, S, Bayati, M, Belete, R, Bell, A, Bhagat, D, Bhagavathula, A, Bhardwaj, P, Bhardwaj, N, Bhaskar, S, Bhattacharyya, K, Bhutta, Z, Bibi, S, Bijani, A, Bikbov, B, Biondi, A, Bolarinwa, O, Bonny, A, Brenner, H, Buonsenso, D, Burkart, K, Busse, R, Butt, Z, Butt, N, Caetano dos Santos, F, Cahuana-Hurtado, L, Camera, L, Cardenas, R, Carneiro, V, Catala-Lopez, F, Chandan, J, Charan, J, Chavan, P, Chen, S, Choudhari, S, Chowdhury, E, Chowdhury, M, Cirillo, M, Corso, B, Dadras, O, Dahlawi, S, Dai, X, Dandona, L, Dandona, R, Dangel, W, Davila-Cervantes, C, Davletov, K, Deuba, K, Dhimal, M, Djalalinia, S, Do, H, Doshmangir, L, Duncan, B, Effiong, A, Ehsani-Chimeh, E, Elgendy, I, Elhadi, M, El Sayed, I, El Tantawi, M, Erku, D, Eskandarieh, S, Fares, J, Farzadfar, F, Ferrero, S, Ferro Desideri, L, Fischer, F, Foigt, N, Foroutan, M, Fukumoto, T, Gaal, P, Gaihre, S, Gardner, W, Garg, T, Getachew Obsa, A, Ghafourifard, M, Ghashghaee, A, Ghith, N, Gilani, S, Gill, P, Goharinezhad, S, Golechha, M, Guadamuz, J, Guo, Y, Gupta, R, Gupta, V, Hamiduzzaman, M, Hanif, A, Haro, J, Hasaballah, A, Hasan, M, Hashi, A, Hay, S, Hayat, K, Heidari, M, Heidari, G, Henry, N, Herteliu, C, Holla, R, Hossain, S, Hossain, M, Hosseinzadeh, M, Hostiuc, S, Hoveidamanesh, S, Hsieh, V, Hu, G, Huang, J, Huda, M, Ifeagwu, S, Ikuta, K, Ilesanmi, O, Irvani, S, Islam, R, Islam, S, Ismail, N, Iso, H, Isola, G, Itumalla, R, Iwagami, M, Jahani, M, Jahanmehr, N, Jain, R, Jakovljevic, M, Janodia, M, Jayapal, S, Jayaram, S, Jha, R, Jonas, J, Joo, T, Joseph, N, Jurisson, M, Kabir, A, Kalankesh, L, Kalhor, R, Kamath, A, Kamenov, K, Kandel, H, Kantar, R, Kapoor, N, Karanikolos, M, Katikireddi, S, Kavetskyy, T, Kawakami, N, Kayode, G, Keikavoosi-Arani, L, Keykhaei, M, Khader, Y, Khajuria, H, Khalilov, R, Khammarnia, M, Khan, M, Khezeli, M, Kim, M, Kim, Y, Kisa, S, Kisa, A, Klymchuk, V, Koly, K, Korzh, O, Kosen, S, Koul, P, Kuate Defo, B, Kumar, G, Kusuma, D, Kyu, H, Larsson, A, Lasrado, S, Lee, W, Lee, Y, Lee, C, Li, S, Lucchetti, G, Mahajan, P, Majeed, A, Makki, A, Malekzadeh, R, Malik, A, Malta, D, Mansournia, M, Mantovani, L, Martinez-Valle, A, Martins-Melo, F, Masoumi, S, Mathur, M, Maude, R, Maulik, P, Mckee, M, Mendoza, W, Menezes, R, Mensah, G, Meretoja, A, Meretoja, T, Mestrovic, T, Michalek, I, Mirrakhimov, E, Misganaw, A, Misra, S, Moazen, B, Mohammadi, M, Mohammed, S, Moitra, M, Mokdad, A, Molokhia, M, Monasta, L, Moni, M, Moradi, G, Moreira, R, Mosser, J, Mostafavi, E, Mouodi, S, Nagarajan, A, Nagata, C, Naghavi, M, Nangia, V, Narasimha Swamy, S, Narayana, A, Nascimento, B, Nassereldine, H, Nayak, B, Nazari, J, Negoi, I, Nepal, S, Neupane Kandel, S, Ngunjiri, J, Nguyen, H, Nguyen, C, Ningrum, D, Noubiap, J, Oancea, B, Oghenetega, O, Oh, I, Olagunju, A, Olakunde, B, Omar Bali, A, Omer, E, Onwujekwe, O, Otoiu, A, Padubidri, J, Palladino, R, Pana, A, Panda-Jonas, S, Pandi-Perumal, S, Pardhan, S, Pasupula, D, Pathak, P, Patton, G, Pawar, S, Pereira, J, Pilania, M, Piroozi, B, Podder, V, Pokhrel, K, Postma, M, Prada, S, Quazi Syed, Z, Rabiee, N, Radhakrishnan, R, Rahman, M, Rahmani, A, Ranabhat, C, Rao, C, Rao, S, Rasella, D, Rawaf, S, Rawaf, D, Rawal, L, Renzaho, A, Reshmi, B, Resnikoff, S, Rezapour, A, Riahi, S, Ripon, R, Sacco, S, Sadeghi, M, Saeed, U, Sahebkar, A, Sahiledengle, B, Sahoo, H, Sahu, M, Salama, J, Salamati, P, Samy, A, Sanabria, J, Santric-Milicevic, M, Sathian, B, Sawhney, M, Schmidt, M, Seidu, A, Sepanlou, S, Seylani, A, Shaikh, M, Sheikh, A, Shetty, A, Shigematsu, M, Shiri, R, Shivakumar, K, Shokri, A, Singh, J, Sinha, D, Skryabin, V, Skryabina, A, Sofi-Mahmudi, A, Sousa, R, Stephens, J, Sun, J, Szocska, M, Tabares-Seisdedos, R, Tadbiri, H, Tamiru, A, Thankappan, K, Topor-Madry, R, Tovani-Palone, M, Tran, M, Tran, B, Tripathi, N, Tripathy, J, Troeger, C, Uezono, D, Ullah, S, Ullah, A, Unnikrishnan, B, Vacante, M, Valadan Tahbaz, S, Valdez, P, Vasic, M, Veroux, M, Vervoort, D, Violante, F, Vladimirov, S, Vlassov, V, Vo, B, Waheed, Y, Wamai, R, Wang, Y, Ward, P, Wiangkham, T, Yadav, L, Yahyazadeh Jabbari, S, Yamagishi, K, Yaya, S, Yazdi-Feyzabadi, V, Yi, S, Yigit, V, Yonemoto, N, Younis, M, Yu, C, Yunusa, I, Zaman, S, Zastrozhin, M, Zhang, Z, Zhong, C, Zuniga, Y, Lim, S, Murray, C, Lozano, R, Bill & Melinda Gates Foundation, King Edward Medical University (Pakistán), Kuwait University (Kuwait), Romanian National Authority for Scientific Research and Innovation, Romanian Ministry of Research Innovation and Digitalization, Alexander von Humboldt Foundation, Federal Ministry of Education & Research (Alemania), Unión Europea. Comisión Europea. H2020, University of Aberdeen (Reino Unido), Novo Nordisk Foundation, National Health and Medical Research Council (Australia), National Research, Development and Innovation Office (Hungria), National Records of Scotland (Reino Unido), Medical Research Council (Reino Unido), Scottish Government (Reino Unido), Jatiya Kabi Kazi Nazrul Islam University (Bangladesh), Xiamen University Malaysia (Malasia), National Council for Scientific and Technological Development (Brasil), Ministero della Salute (Italia), Fondazione IRCCS. Istituto Nazionale dei Tumori, King College London, IRCCS Materno Infantile Burlo Garofolo (Italia), Edwards Lifesciences Foundation, Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Brasil), Manipal Academy of Higher Education (India), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Government of Catalonia (España), International Center of Medical Sciences Research (Pakistán), Ain Shams University (Egipto), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red - CIBERSAM (Salud Mental), INCLIVA Health Research Institute (España), Canadian Institutes of Health Research, Australian Government, and Ministry of Education, Science and Technological Development (Serbia)
Subjects: Adult, Adolescent, Population, Global Health, Health Services Accessibility, Global Burden of Disease, Health system quality, Young Adult, Nations, Health systems, health care access, Risk Factors, Quality-Adjusted Life Year, Humans, Child, Global Burden of Disease Study 2019, Health-care access, Aged, Quality of Health Care, quality, performance, The Healthcare Access and Quality Index, Risk Factor, Infant, Newborn, Infant, eu-repo/semantics/review [info], Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Health-care quality, Middle Aged, 3141 Health care science, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Indicator, Medical-care, Child, Preschool, Deaths, Amenable mortality, Quality-Adjusted Life Years, Age groups, Trends, Human
Abstract: Background: Health-care needs change throughout the life course. It is thus crucial to assess whether health systems provide access to quality health care for all ages. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we measured the Healthcare Access and Quality (HAQ) Index overall and for select age groups in 204 locations from 1990 to 2019. Methods: We distinguished the overall HAQ Index (ages 0-74 years) from scores for select age groups: the young (ages 0-14 years), working (ages 15-64 years), and post-working (ages 65-74 years) groups. For GBD 2019, HAQ Index construction methods were updated to use the arithmetic mean of scaled mortality-to-incidence ratios (MIRs) and risk-standardised death rates (RSDRs) for 32 causes of death that should not occur in the presence of timely, quality health care. Across locations and years, MIRs and RSDRs were scaled from 0 (worst) to 100 (best) separately, putting the HAQ Index on a different relative scale for each age group. We estimated absolute convergence for each group on the basis of whether the HAQ Index grew faster in absolute terms between 1990 and 2019 in countries with lower 1990 HAQ Index scores than countries with higher 1990 HAQ Index scores and by Socio-demographic Index (SDI) quintile. SDI is a summary metric of overall development. Findings: Between 1990 and 2019, the HAQ Index increased overall (by 19·6 points, 95% uncertainty interval 17·9-21·3), as well as among the young (22·5, 19·9-24·7), working (17·2, 15·2-19·1), and post-working (15·1, 13·2-17·0) age groups. Large differences in HAQ Index scores were present across SDI levels in 2019, with the overall index ranging from 30·7 (28·6-33·0) on average in low-SDI countries to 83·4 (82·4-84·3) on average in high-SDI countries. Similarly large ranges between low-SDI and high-SDI countries, respectively, were estimated in the HAQ Index for the young (40·4-89·0), working (33·8-82·8), and post-working (30·4-79·1) groups. Absolute convergence in HAQ Index was estimated in the young group only. In contrast, divergence was estimated among the working and post-working groups, driven by slow progress in low-SDI countries. Interpretation: Although major gaps remain across levels of social and economic development, convergence in the young group is an encouraging sign of reduced disparities in health-care access and quality. However, divergence in the working and post-working groups indicates that health-care access and quality is lagging at lower levels of social and economic development. To meet the needs of ageing populations, health systems need to improve health-care access and quality for working-age adults and older populations while continuing to realise gains among the young. O Adetokunboh acknowledges support from Department of Science and Innovation and National Research Foundation. S Afzal acknowledges the institutional support of King Edward Medical University. S Aljunid acknowledges Department of Health Policy and Management, College of Public Health, Health Science Centre, Kuwait University for the approval and support to participate in this research project. M Ausloos, C Herteliu, and A Pana acknowledge partial support by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. C Herteliu also acknowledges partial support by a grant of the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. T Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the Federal Ministry of Education and Research. B Bikbov acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No. 703226. Institute of Applied Health Sciences; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Scotland. The salary for N Ghith is covered by a grant from Novo Nordisk Foundation (NNF16OC0021856). V B Gupta acknowledges funding support from National Health and Medical Research Council (NHMRC) Australia. V K Gupta acknowledges funding support from National Health and Medical Research Council (NHMRC) Australia. T Joo acknowledges support from the National Research, Development and Innovation Office of Hungary under grant RRF-2.3.1-21-2022-00006 (Data-driven Health Division of Health Security National Laboratory). S Vittal Katikireddi acknowledges funding from a NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). M N Khan acknowledges the support of Jatiya Kabi Kazi Nazrul Islam University, Mymensingh, Bangladesh. Y J Kim acknowledges support from the Research Management Centre Xiamen University Malaysia [XMUMRF/2020-C6/ITCM/0004]. G Lucchetti is a grantee of the Brazilian National Council for Scientific and Technological Development Research Productivity - Level 1D. L Mantovani acknowledges support by Italian Ministry of Health Ricerca Corrente - IRCCS Multimedica. M Molokhia acknowledges support by the National Institute for Health Research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. L Monasta reports support for the present manuscript from the Italian Ministry of Health on project Ricerca Corrente 34/2017 and payments made to the Institute for Maternal and Child Health IRCCS Burlo Garofolo. R Moreira acknowledges the CNPQ productivity grant (316607/2021-5). B R Nascimento is partially supported by CNPq (Research Productivity Grant, 312382/2019-7), the Edwards Lifesciences Foundation (Improving the prevention and detection of Heart Valve disease across the Lifespan, 2021), and FAPEMIG (grant APQ-000627-20). J R Padubidri acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India for their constant support in conducting research. D Rasella reports financial support from the Spanish Ministry of Science and Innovation and State Research Agency through the Centro de Excelencia Severo Ochoa 2019-2023 programme (CEX2018-000806-S), and financial support from the Generalitat de Catalunya through the Centres de Recerca de Catalunya programme. U Saeed would like to acknowledge the International Center of Medical Sciences Research (ICMSR), Islamabad (44000), Pakistan. A M Samy acknowledges the support from Ain Shams University and the Egyptian Fulbright Mission Program. U Saeed would like to acknowledge Kasturba Medical College, Mangalore. Manipal Academy of Higher Education, Manipal for supporting research activities. R T-S is supported by the Spanish Ministry of Science and Innovation, Institute of Health Carlos III, CIBERSAM, INCLIVA (PID2021-129099OB-I00). D Vervoort is supported by the Canadian Institutes of Health Research (CIHR) Vanier Canada Graduate Scholarship. S B Zaman acknowledges receiving a scholarship from the Australian Government Research Training Program (RTP) in support of his academic career. Serbian part of this GBD contribution was co-financed through Grant OI 175 014 of the Ministry of Education Science and Technological Development of The Republic of Serbia. This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation OPP1152504. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Sí
Published: 2022

26. Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral therapy in high-income European settings

Author: Juan Berenguer, Christoph Wyen, M. John Gill, Sophie Abgrall, Ard van Sighem, Matthias Cavassini, Sophie Grabar, Jordi Casabona, Margaret T May, Julia del Amo, Antonella d'Arminio Monforte, Robert Zangerle, John Stover, Niels Obel, Jonathan A C Sterne, Fabrice Bonnet, Adam Trickey, Medical Research Council (Reino Unido), Department for International Development (Reino Unido), NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), National Institute for Health Research (Reino Unido), Unión Europea, Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Institut National de la Santé et de la Recherche Médicale (Francia), Ministero della Salute (Italia), Ministerio de Sanidad y Consumo (España), Ministerio de Ciencia e Innovación (España), Red de Investigación Cooperativa en Investigación en Sida (España), Swiss National Science Foundation, University of Bristol [Bristol], Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital General Universitario 'Gregorio Marañón' [Madrid], Instituto de Investigación Sanitaria Gregorio Marañón [Madrid, Spain] ( IiSGM), University Hospital of Cologne [Cologne], Centre d'Estudis Epidemiològics sobre les Infeccions de Transmissió Sexual i Sida de Catalunya (CEEISCAT), CIBER de Epidemiología y Salud Pública (CIBERESP), Università degli Studi di Milano = University of Milan (UNIMI), Ospedale San Paolo-Polo Universitario, ASST Santi Paolo e Carlo, Milan, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne = University of Lausanne (UNIL), Instituto de Salud Carlos III [Madrid] (ISC), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University of Calgary, Department of Infectious Diseases [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Gestionnaire, Hal Sorbonne Université, Medical Research Council (United Kingdom), Department for International Development (United Kingdom), National Institute on Alcohol Abuse and Alcoholism (United States), National Institute for Health Research (United Kingdom), European Union, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Institut National de la Santé et de la Recherche Médicale (France), and Red Española de Investigación en SIDA
Subjects: Adult, Male, 0301 basic medicine, Anti-HIV Agents, [SDV]Life Sciences [q-bio], Immunology, Population, HIV Infections, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Acquired immunodeficiency syndrome (AIDS), Risk Factors, death, cause-specific, medicine, Humans, Immunology and Allergy, 030212 general & internal medicine, Mortality, education, United Nations Programme on HIV/AIDS, education.field_of_study, Models, Statistical, business.industry, Developed Countries, Mortality rate, duration, HIV, cohort, Middle Aged, medicine.disease, Confidence interval, 3. Good health, AIDS, [SDV] Life Sciences [q-bio], Europe, Anti-HIV Agents/therapeutic use, Europe/epidemiology, Female, HIV Infections/drug therapy, HIV Infections/mortality, Mortality/trends, Editorial, 030104 developmental biology, Infectious Diseases, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Developed country, Demography, Cohort study
Abstract: Supplemental Digital Content is available in the text, Introduction: HIV cohort data from high-income European countries were compared with the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). Methods: Data from 2000 to 2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare all-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. Results: Analyses included 94 026 PLHIV with 585 784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000–2003 were 0.0121, reducing to 0.0078 in 2012–2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 [95% confidence interval (95% CI): 0.0130–0.0171] reducing to 0.0049 (95% CI: 0.0039–0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000–2003, dropping to 43.6% in 2012–2015. In the ART-CC, AIDS-related mortality constitutes 45.3% (95% CI: 38.4–52.9%) of mortality in 2000–2003 and 26.7% (95% CI: 19–46%) between 2012 and 2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95% CI: 60.3–95.2%) in 2000–2003 to 30.7% (95% CI: 25.5–63.7%) in 2012–2015. Conclusion: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000–2003 and decline more quickly to levels currently captured for recent years.
Published: 2019

27. In vitro functional analysis of gRNA sites regulating assembly of hepatitis B virus

Author: Nikesh Patel, Sam Clark, Eva U. Weiß, Carlos P. Mata, Jen Bohon, Erik R. Farquhar, Daniel P. Maskell, Neil A. Ranson, Reidun Twarock, Peter G. Stockley, UK Research and Innovation, Medical Research Council (Reino Unido), Wellcome Trust, Engineering and Physical Sciences Research Council (Reino Unido), Royal Society (Reino Unido), National Science Foundation (Estados Unidos), National Institutes of Health (Estados Unidos), United States Department of Energy, University of Leeds (Reino Unido), and Unión Europea. Comisión Europea
Subjects: Hepatitis B virus, QH301-705.5, Virus Assembly, Medicine (miscellaneous), Genome, Viral, Article, General Biochemistry, Genetics and Molecular Biology, stomatognathic diseases, Cryoelectron microscopy, RNA, RNA, Viral, Biology (General), General Agricultural and Biological Sciences, RNA, Guide, Kinetoplastida
Abstract: The roles of RNA sequence/structure motifs, Packaging Signals (PSs), for regulating assembly of an HBV genome transcript have been investigated in an efficient in vitro assay containing only core protein (Cp) and RNA. Variants of three conserved PSs, within the genome of a strain not used previously, preventing correct presentation of a Cp-recognition loop motif are differentially deleterious for assembly of nucleocapsid-like particles (NCPs). Cryo-electron microscopy reconstruction of the T = 4 NCPs formed with the wild-type gRNA transcript, reveal that the interior of the Cp shell is in contact with lower resolution density, potentially encompassing the arginine-rich protein domains and gRNA. Symmetry relaxation followed by asymmetric reconstruction reveal that such contacts are made at every symmetry axis. We infer from their regulation of assembly that some of these contacts would involve gRNA PSs, and confirmed this by X-ray RNA footprinting. Mutation of the ε stem-loop in the gRNA, where polymerase binds in vivo, produces a poor RNA assembly substrate with Cp alone, largely due to alterations in its conformation. The results show that RNA PSs regulate assembly of HBV genomic transcripts in vitro, and therefore may play similar roles in vivo, in concert with other molecular factors., Patel et al. investigate the role of RNA sequence/structure motif ‘Packaging Signals’ (PSs) in regulating the assembly of an HBV genome transcript using an in vitro assay containing only core protein (Cp) and RNA. They show that RNA PSs regulate assembly of HBV genomic transcripts in vitro, and therefore may play similar roles in vivo, in concert with other molecular factors.
Published: 2021

28. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019

Author: Emma Nichols, Jaimie D Steinmetz, Stein Emil Vollset, Kai Fukutaki, Julian Chalek, Foad Abd-Allah, Amir Abdoli, Ahmed Abualhasan, Eman Abu-Gharbieh, Tayyaba Tayyaba Akram, Hanadi Al Hamad, Fares Alahdab, Fahad Mashhour Alanezi, Vahid Alipour, Sami Almustanyir, Hubert Amu, Iman Ansari, Jalal Arabloo, Tahira Ashraf, Thomas Astell-Burt, Getinet Ayano, Jose L Ayuso-Mateos, Atif Amin Baig, Anthony Barnett, Amadou Barrow, Bernhard T Baune, Yannick Béjot, Woldesellassie M Mequanint Bezabhe, Yihienew Mequanint Bezabih, Akshaya Srikanth Bhagavathula, Sonu Bhaskar, Krittika Bhattacharyya, Ali Bijani, Atanu Biswas, Srinivasa Rao Bolla, Archith Boloor, Carol Brayne, Hermann Brenner, Katrin Burkart, Richard A Burns, Luis Alberto Cámera, Chao Cao, Felix Carvalho, Luis F S Castro-de-Araujo, Ferrán Catalá-López, Ester Cerin, Prachi P Chavan, Nicolas Cherbuin, Dinh-Toi Chu, Vera Marisa Costa, Rosa A S Couto, Omid Dadras, Xiaochen Dai, Lalit Dandona, Rakhi Dandona, Vanessa De la Cruz-Góngora, Deepak Dhamnetiya, Diana Dias da Silva, Daniel Diaz, Abdel Douiri, David Edvardsson, Michael Ekholuenetale, Iman El Sayed, Shaimaa I El-Jaafary, Khalil Eskandari, Sharareh Eskandarieh, Saman Esmaeilnejad, Jawad Fares, Andre Faro, Umar Farooque, Valery L Feigin, Xiaoqi Feng, Seyed-Mohammad Fereshtehnejad, Eduarda Fernandes, Pietro Ferrara, Irina Filip, Howard Fillit, Florian Fischer, Shilpa Gaidhane, Lucia Galluzzo, Ahmad Ghashghaee, Nermin Ghith, Alessandro Gialluisi, Syed Amir Gilani, Ionela-Roxana Glavan, Elena V Gnedovskaya, Mahaveer Golechha, Rajeev Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Mohammad Rifat Haider, Brian J Hall, Samer Hamidi, Asif Hanif, Graeme J Hankey, Shafiul Haque, Risky Kusuma Hartono, Ahmed I Hasaballah, M Tasdik Hasan, Amr Hassan, Simon I Hay, Khezar Hayat, Mohamed I Hegazy, Golnaz Heidari, Reza Heidari-Soureshjani, Claudiu Herteliu, Mowafa Househ, Rabia Hussain, Bing-Fang Hwang, Licia Iacoviello, Ivo Iavicoli, Olayinka Stephen Ilesanmi, Irena M Ilic, Milena D Ilic, Seyed Sina Naghibi Irvani, Hiroyasu Iso, Masao Iwagami, Roxana Jabbarinejad, Louis Jacob, Vardhmaan Jain, Sathish Kumar Jayapal, Ranil Jayawardena, Ravi Prakash Jha, Jost B Jonas, Nitin Joseph, Rizwan Kalani, Amit Kandel, Himal Kandel, André Karch, Ayele Semachew Kasa, Gizat M Kassie, Pedram Keshavarz, Moien AB Khan, Mahalaqua Nazli Khatib, Tawfik Ahmed Muthafer Khoja, Jagdish Khubchandani, Min Seo Kim, Yun Jin Kim, Adnan Kisa, Sezer Kisa, Mika Kivimäki, Walter J Koroshetz, Ai Koyanagi, G Anil Kumar, Manasi Kumar, Hassan Mehmood Lak, Matilde Leonardi, Bingyu Li, Stephen S Lim, Xuefeng Liu, Yuewei Liu, Giancarlo Logroscino, Stefan Lorkowski, Giancarlo Lucchetti, Ricardo Lutzky Saute, Francesca Giulia Magnani, Ahmad Azam Malik, João Massano, Man Mohan Mehndiratta, Ritesh G Menezes, Atte Meretoja, Bahram Mohajer, Norlinah Mohamed Ibrahim, Yousef Mohammad, Arif Mohammed, Ali H Mokdad, Stefania Mondello, Mohammad Ali Ali Moni, Md Moniruzzaman, Tilahun Belete Mossie, Gabriele Nagel, Muhammad Naveed, Vinod C Nayak, Sandhya Neupane Kandel, Trang Huyen Nguyen, Bogdan Oancea, Nikita Otstavnov, Stanislav S Otstavnov, Mayowa O Owolabi, Songhomitra Panda-Jonas, Fatemeh Pashazadeh Kan, Maja Pasovic, Urvish K Patel, Mona Pathak, Mario F P Peres, Arokiasamy Perianayagam, Carrie B Peterson, Michael R Phillips, Marina Pinheiro, Michael A Piradov, Constance Dimity Pond, Michele H Potashman, Faheem Hyder Pottoo, Sergio I Prada, Amir Radfar, Alberto Raggi, Fakher Rahim, Mosiur Rahman, Pradhum Ram, Priyanga Ranasinghe, David Laith Rawaf, Salman Rawaf, Nima Rezaei, Aziz Rezapour, Stephen R Robinson, Michele Romoli, Gholamreza Roshandel, Ramesh Sahathevan, Amirhossein Sahebkar, Mohammad Ali Sahraian, Brijesh Sathian, Davide Sattin, Monika Sawhney, Mete Saylan, Silvia Schiavolin, Allen Seylani, Feng Sha, Masood Ali Shaikh, KS Shaji, Mohammed Shannawaz, Jeevan K Shetty, Mika Shigematsu, Jae Il Shin, Rahman Shiri, Diego Augusto Santos Silva, João Pedro Silva, Renata Silva, Jasvinder A Singh, Valentin Yurievich Skryabin, Anna Aleksandrovna Skryabina, Amanda E Smith, Sergey Soshnikov, Emma Elizabeth Spurlock, Dan J Stein, Jing Sun, Rafael Tabarés-Seisdedos, Bhaskar Thakur, Binod Timalsina, Marcos Roberto Tovani-Palone, Bach Xuan Tran, Gebiyaw Wudie Tsegaye, Sahel Valadan Tahbaz, Pascual R Valdez, Narayanaswamy Venketasubramanian, Vasily Vlassov, Giang Thu Vu, Linh Gia Vu, Yuan-Pang Wang, Anders Wimo, Andrea Sylvia Winkler, Lalit Yadav, Seyed Hossein Yahyazadeh Jabbari, Kazumasa Yamagishi, Lin Yang, Yuichiro Yano, Naohiro Yonemoto, Chuanhua Yu, Ismaeel Yunusa, Siddhesh Zadey, Mikhail Sergeevich Zastrozhin, Anasthasia Zastrozhina, Zhi-Jiang Zhang, Christopher J L Murray, Theo Vos, Nichols, E., Steinmetz, J. D., Vollset, S. E., Fukutaki, K., Chalek, J., Abd-Allah, F., Abdoli, A., Abualhasan, A., Abu-Gharbieh, E., Akram, T. T., Al Hamad, H., Alahdab, F., Alanezi, F. M., Alipour, V., Almustanyir, S., Amu, H., Ansari, I., Arabloo, J., Ashraf, T., Astell-Burt, T., Ayano, G., Ayuso-Mateos, J. L., Baig, A. A., Barnett, A., Barrow, A., Baune, B. T., Bejot, Y., Bezabhe, W. M. M., Bezabih, Y. M., Bhagavathula, A. S., Bhaskar, S., Bhattacharyya, K., Bijani, A., Biswas, A., Bolla, S. R., Boloor, A., Brayne, C., Brenner, H., Burkart, K., Burns, R. A., Camera, L. A., Cao, C., Carvalho, F., Castro-de-Araujo, L. F. S., Catala-Lopez, F., Cerin, E., Chavan, P. P., Cherbuin, N., Chu, D. -T., Costa, V. M., Couto, R. A. S., Dadras, O., Dai, X., Dandona, L., Dandona, R., De la Cruz-Gongora, V., Dhamnetiya, D., Dias da Silva, D., Diaz, D., Douiri, A., Edvardsson, D., Ekholuenetale, M., El Sayed, I., El-Jaafary, S. I., Eskandari, K., Eskandarieh, S., Esmaeilnejad, S., Fares, J., Faro, A., Farooque, U., Feigin, V. L., Feng, X., Fereshtehnejad, S. -M., Fernandes, E., Ferrara, P., Filip, I., Fillit, H., Fischer, F., Gaidhane, S., Galluzzo, L., Ghashghaee, A., Ghith, N., Gialluisi, A., Gilani, S. A., Glavan, I. -R., Gnedovskaya, E. V., Golechha, M., Gupta, R., Gupta, V. B., Gupta, V. K., Haider, M. R., Hall, B. J., Hamidi, S., Hanif, A., Hankey, G. J., Haque, S., Hartono, R. K., Hasaballah, A. I., Hasan, M. T., Hassan, A., Hay, S. I., Hayat, K., Hegazy, M. I., Heidari, G., Heidari-Soureshjani, R., Herteliu, C., Househ, M., Hussain, R., Hwang, B. -F., Iacoviello, L., Iavicoli, I., Ilesanmi, O. S., Ilic, I. M., Ilic, M. D., Irvani, S. S. N., Iso, H., Iwagami, M., Jabbarinejad, R., Jacob, L., Jain, V., Jayapal, S. K., Jayawardena, R., Jha, R. P., Jonas, J. B., Joseph, N., Kalani, R., Kandel, A., Kandel, H., Karch, A., Kasa, A. S., Kassie, G. M., Keshavarz, P., Khan, M. A., Khatib, M. N., Khoja, T. A. M., Khubchandani, J., Kim, M. S., Kim, Y. J., Kisa, A., Kisa, S., Kivimaki, M., Koroshetz, W. J., Koyanagi, A., Kumar, G. A., Kumar, M., Lak, H. M., Leonardi, M., Li, B., Lim, S. S., Liu, X., Liu, Y., Logroscino, G., Lorkowski, S., Lucchetti, G., Lutzky Saute, R., Magnani, F. G., Malik, A. A., Massano, J., Mehndiratta, M. M., Menezes, R. G., Meretoja, A., Mohajer, B., Mohamed Ibrahim, N., Mohammad, Y., Mohammed, A., Mokdad, A. H., Mondello, S., Moni, M. A. A., Moniruzzaman, M., Mossie, T. B., Nagel, G., Naveed, M., Nayak, V. C., Neupane Kandel, S., Nguyen, T. H., Oancea, B., Otstavnov, N., Otstavnov, S. S., Owolabi, M. O., Panda-Jonas, S., Pashazadeh Kan, F., Pasovic, M., Patel, U. K., Pathak, M., Peres, M. F. P., Perianayagam, A., Peterson, C. B., Phillips, M. R., Pinheiro, M., Piradov, M. A., Pond, C. D., Potashman, M. H., Pottoo, F. H., Prada, S. I., Radfar, A., Raggi, A., Rahim, F., Rahman, M., Ram, P., Ranasinghe, P., Rawaf, D. L., Rawaf, S., Rezaei, N., Rezapour, A., Robinson, S. R., Romoli, M., Roshandel, G., Sahathevan, R., Sahebkar, A., Sahraian, M. A., Sathian, B., Sattin, D., Sawhney, M., Saylan, M., Schiavolin, S., Seylani, A., Sha, F., Shaikh, M. A., Shaji, K. S., Shannawaz, M., Shetty, J. K., Shigematsu, M., Shin, J. I., Shiri, R., Silva, D. A. S., Silva, J. P., Silva, R., Singh, J. A., Skryabin, V. Y., Skryabina, A. A., Smith, A. E., Soshnikov, S., Spurlock, E. E., Stein, D. J., Sun, J., Tabares-Seisdedos, R., Thakur, B., Timalsina, B., Tovani-Palone, M. R., Tran, B. X., Tsegaye, G. W., Valadan Tahbaz, S., Valdez, P. R., Venketasubramanian, N., Vlassov, V., Vu, G. T., Vu, L. G., Wang, Y. -P., Wimo, A., Winkler, A. S., Yadav, L., Yahyazadeh Jabbari, S. H., Yamagishi, K., Yang, L., Yano, Y., Yonemoto, N., Yu, C., Yunusa, I., Zadey, S., Zastrozhin, M. S., Zastrozhina, A., Zhang, Z. -J., Murray, C. J. L., Vos, T., Department of Public Health, Clinicum, Helsinki University Hospital Area, Bill & Melinda Gates Foundation, University of Porto (Portugal), Medical Research Council (Reino Unido), Fundação para a Ciência e Tecnologia (Portugal), King College London, University College London Hospitals NHS Foundation Trust, NIHR - Oxford Biomedical Research Centre (Reino Unido), Novo Nordisk Foundation, National Health and Medical Research Council (Australia), Jazan University (Arabia Saudí), Romanian National Authority for Scientific Research and Innovation, Xiamen University Malaysia (Malasia), Wellcome Trust, Fogarty International Center (Estados Unidos), Federal Ministry of Education & Research (Alemania), Ministero della Salute (Italia), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (Brasil), Nichols, E, D Steinmetz, J, Emil Vollset, S, Fukutaki, K, Chalek, J, Abd-Allah, F, Abdoli, A, Abualhasan, A, Abu-Gharbieh, E, Tayyaba Akram, T, Al Hamad, H, Alahdab, F, Mashhour Alanezi, F, Alipour, V, Almustanyir, S, Amu, H, Ansari, I, Arabloo, J, Ashraf, T, Astell-Burt, T, Ayano, G, L Ayuso-Mateos, J, Amin Baig, A, Barnett, A, Barrow, A, T Baune, B, Béjot, Y, M Mequanint Bezabhe, W, Mequanint Bezabih, Y, Srikanth Bhagavathula, A, Bhaskar, S, Bhattacharyya, K, Bijani, A, Biswas, A, Rao Bolla, S, Boloor, A, Brayne, C, Brenner, H, Burkart, K, A Burns, R, Alberto Cámera, L, Cao, C, Carvalho, F, S Castro-de-Araujo, L, Catalá-López, F, Cerin, E, P Chavan, P, Cherbuin, N, Chu, D, Marisa Costa, V, S Couto, R, Dadras, O, Dai, X, Dandona, L, Dandona, R, De la Cruz-Góngora, V, Dhamnetiya, D, Dias da Silva, D, Diaz, D, Douiri, A, Edvardsson, D, Ekholuenetale, M, El Sayed, I, I El-Jaafary, S, Eskandari, K, Eskandarieh, S, Esmaeilnejad, S, Fares, J, Faro, A, Farooque, U, L Feigin, V, Feng, X, Fereshtehnejad, S, Fernandes, E, Ferrara, P, Filip, I, Fillit, H, Fischer, F, Gaidhane, S, Galluzzo, L, Ghashghaee, A, Ghith, N, Gialluisi, A, Amir Gilani, S, Glăvan, I, V Gnedovskaya, E, Golechha, M, Gupta, R, Bala Gupta, V, Kumar Gupta, V, Rifat Haider, M, J Hall, B, Hamidi, S, Hanif, A, J Hankey, G, Haque, S, Kusuma Hartono, R, I Hasaballah, A, Tasdik Hasan, M, Hassan, A, I Hay, S, Hayat, K, I Hegazy, M, Heidari, G, Heidari-Soureshjani, R, Herteliu, C, Househ, M, Hussain, R, Hwang, B, Iacoviello, L, Iavicoli, I, Stephen Ilesanmi, O, M Ilic, I, D Ilic, M, Sina Naghibi Irvani, S, Iso, H, Iwagami, M, Jabbarinejad, R, Jacob, L, Jain, V, Kumar Jayapal, S, Jayawardena, R, Prakash Jha, R, B Jonas, J, Joseph, N, Kalani, R, Kandel, A, Kandel, H, Karch, A, Semachew Kasa, A, M Kassie, G, Keshavarz, P, B Khan, M, Nazli Khatib, M, Ahmed Muthafer Khoja, T, Khubchandani, J, Seo Kim, M, Jin Kim, Y, Kisa, A, Kisa, S, Kivimäki, M, J Koroshetz, W, Koyanagi, A, Anil Kumar, G, Kumar, M, Mehmood Lak, H, Leonardi, M, Li, B, S Lim, S, Liu, X, Liu, Y, Logroscino, G, Lorkowski, S, Lucchetti, G, Lutzky Saute, R, Giulia Magnani, F, Azam Malik, A, Massano, J, Mohan Mehndiratta, M, G Menezes, R, Meretoja, A, Mohajer, B, Mohamed Ibrahim, N, Mohammad, Y, Mohammed, A, H Mokdad, A, Mondello, S, Ali Moni, M, Moniruzzaman, M, Belete Mossie, T, Nagel, G, Naveed, M, C Nayak, V, Neupane Kandel, S, Huyen Nguyen, T, Oancea, B, Otstavnov, N, S Otstavnov, S, O Owolabi, M, Panda-Jonas, S, Pashazadeh Kan, F, Pasovic, M, K Patel, U, Pathak, M, P Peres, M, Perianayagam, A, B Peterson, C, R Phillips, M, Pinheiro, M, A Piradov, M, Dimity Pond, C, H Potashman, M, Hyder Pottoo, F, I Prada, S, Radfar, A, Raggi, A, Rahim, F, Rahman, M, Ram, P, Ranasinghe, P, Laith Rawaf, D, Rawaf, S, Rezaei, N, Rezapour, A, R Robinson, S, Romoli, M, Roshandel, G, Sahathevan, R, Sahebkar, A, Ali Sahraian, M, Sathian, B, Sattin, D, Sawhney, M, Saylan, M, Schiavolin, S, Seylani, A, Sha, F, Ali Shaikh, M, S Shaji, K, Shannawaz, M, K Shetty, J, Shigematsu, M, Il Shin, J, Shiri, R, Augusto Santos Silva, D, Pedro Silva, J, Silva, R, A Singh, J, Yurievich Skryabin, V, Aleksandrovna Skryabina, A, E Smith, A, Soshnikov, S, Elizabeth Spurlock, E, J Stein, D, Sun, J, Tabarés-Seisdedos, R, Thakur, B, Timalsina, B, Roberto Tovani-Palone, M, Xuan Tran, B, Wudie Tsegaye, G, Valadan Tahbaz, S, R Valdez, P, Venketasubramanian, N, Vlassov, V, Thu Vu, G, Gia Vu, L, Wang, Y, Wimo, A, Sylvia Winkler, A, Yadav, L, Hossein Yahyazadeh Jabbari, S, Yamagishi, K, Yang, L, Yano, Y, Yonemoto, N, Yu, C, Yunusa, I, Zadey, S, Sergeevich Zastrozhin, M, Zastrozhina, A, Zhang, Z, L Murray, C, and Vos, T
Subjects: Blood Glucose, EUROPE, Sociodemographic Factors, Prevalence forecasts, Population Dynamics, UNITED-STATES, DIAGNOSIS, Global Health, Body Mass Index, Global Burden of Disease, SDG 3 - Good Health and Well-being, Risk Factors, SYSTEMATIC ANALYSIS, Humans, METAANALYSIS, Public, Environmental & Occupational Health, RISK, Population ageing, Public health, Population Dynamic, Sociodemographic Factor, Science & Technology, Risk Factor, Smoking, Public Health, Environmental and Occupational Health, Dementia forecasts, Educational Statu, TRENDS, 3142 Public health care science, environmental and occupational health, ALZHEIMERS-DISEASE, INSIGHTS, Educational Status, Dementia, Public aspects of medicine, RA1-1270, Life Sciences & Biomedicine, MIXED BRAIN PATHOLOGIES, MIDLIFE, Human
Abstract: Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4-65·1) million cases globally in 2019 to 152·8 (130·8-175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [-7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64-1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52-1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41-67]) and western Europe (74% [58-90]), and the largest in north Africa and the Middle East (367% [329-403]) and eastern sub-Saharan Africa (357% [323-395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. F Carvalho and E F Fernandes acknowledge support from the University of Porto (UID/MULTI/04378/2019 and UID/QUI/50006/2019 with funding from FCT/MCTES through national funds). L F S Castro-de-Araujo acknowledges support from the Medical Research Council (London; grant number MC_PC_MR/T03355X/1). V M Costa acknowledges her 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). A Douiri acknowledges support from the NIHR Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust and the Royal College of Physicians, as well as the support from the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. N Ghith acknowledges her salary as a postdoc is covered by a grant to her research group provided by Novo Nordisk Foundation. V K Gupta and V B Gupta acknowledge funding support from National Health and Medical Research Council (NHMRC), Australia. S Haque acknowledges support from Jazan University, Saudi Arabia, for providing access to the Saudi Digital Library for this study. C Herteliu is partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation (CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084). Y J Kim was supported by the Research Management Centre, Xiamen University, Malaysia (No. XMUMRF/2020-C6/ITCM/0004). M Kivimäki was supported by the MRC (S011676) and the Wellcome Trust (221854/Z/20/Z). M Kumar acknowledges support from Fogarty International Center (K43 TW010716-04). S Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research, grant agreement number 01EA1808A). S Mondello was supported by the Italian Ministry of Health (GR-2013-02354960). A Raggi acknowledges support from a grant from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C. Besta, Linea – Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche). D A S Silva acknowledges support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES; Finance Code 001 / CAPES-PRINT). J P Silva acknowledges support from the Applied Molecular Biosciences Unit (UCIBIO; grant number UIDB/04378/2020), supported through Portuguese national funds via FCT/MCTES. Sí
Published: 2021

29. Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects

Author: Chris Power, Shelley A. Cole, M Molokhia, Ana Navas-Acien, C. Christiansen, Jane Maddock, Juan E. Castillo-Fernandez, Caroline L Relton, Rebecca Hardy, George B. Ploubidis, Arce Domingo-Relloso, J. S. El-Sayed Moustafa, Sharon L.R. Kardia, Karin Haack, Kerrin S. Small, D Kuh, Jordana T. Bell, Jennifer A. Smith, Alissa Goodman, Zhao W, P-C Tsai, Maria Tellez-Plaza, Matthew Suderman, Andrew Wong, Economic and Social Research Council (Reino Unido), Wellcome Trust, Medical Research Council (Reino Unido), NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), National Institutes of Health (Estados Unidos), Fundación La Caixa, Economic and Social Research Council, Medical Research Council (United Kingdom), National Heart, Lung, and Blood Institute (United States), and National Institutes of Health (United States)
Subjects: Oncology, Male, Epigenesis, Genetic, Cohort Studies, Epigenome, 0302 clinical medicine, Risk Factors, Genetics (clinical), 0303 health sciences, education.field_of_study, Smokers, DNA methylation, Smoking, Middle Aged, 3. Good health, CpG site, 030220 oncology & carcinogenesis, Cohort, SLAMF7, Female, Epigenetics, medicine.medical_specialty, Population, Environment, White People, 03 medical and health sciences, Signaling Lymphocytic Activation Molecule Family, Internal medicine, Genetics, medicine, Tobacco Smoking, Humans, education, Molecular Biology, American Indian or Alaska Native, 030304 developmental biology, 1970 British Cohort Study, Aged, business.industry, Research, Environmental Exposure, Lifestyle, Human genetics, United Kingdom, Black or African American, Genetic epidemiology, Case-Control Studies, CpG Islands, business, Developmental Biology, Genome-Wide Association Study
Abstract: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk. This study was supported by the Economic and Social Research Council (ESRC, Grant Number ES/N000404/1 to J.T.B). Data governance for access to UK birth cohort data was provided by the METADAC data access committee, funded by ESRC, Wellcome and MRC (2015–2018: Grant Number MR/N01104X/1 2018–2020: Grant Number ES/S008349/1). This work made use of data and samples generated by the 1958 Birth Cohort (NCDS), which is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the ESRC (Grant Number ES/M001660/1); blood sample collection was funded by MRC (Grant G0000934). Access to these resources was enabled via the Wellcome Trust and MRC: 58FORWARDS Grant (108439/Z/15/Z). Before 2015 biomedical resources were maintained under the Wellcome Trust and Medical Research Council 58READIE Project (Grant Numbers WT095219MA and G1001799). Work undertaken at Great Ormond Street Hospital/University College London, Institute of Child Health, is in part supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The UK Medical Research Council also provided core funding for the MRC National Survey of Health and Development (Grant MC_UU_00019/1). The TwinsUK study is supported by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013); the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The SHS study received support from the National Heart, Lung, and Blood Institute (NHLBI) of the USA (under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029 and 75N92019D00030) and previous Grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282 and R01HL109319 and Cooperative Agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520 and U01HL65521), from the National Institutes of Health Sciences of the USA (R01ES021367, R01ES025216, P42ES010349, P30ES009089) and from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). The GENOA study received funding from U01HL054457, RC1HL100185, R01HL119443, R01HL133221, R01HL141292. Sí
Published: 2021

30. Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD

Author: Sebastian Deindl, Christopher D.O. Cooper, Lucia Sommerova, Ellie Herbert, Harshil Patel, Antonia Tomás-Loba, Stephen J. Pettitt, Ivan Ahel, Tohru Takaki, Robert J. Goldstone, Gordon Stamp, Kasper Fugger, Phil Ruis, Stephen C. West, Rachel Brough, Roberto Bellelli, Dragana Ahel, Christopher J. Lord, Graeme Hewitt, Laura C. Lehmann, Valerie Borel, J. Ross Chapman, Kang Zhu, Aleksandra Vancevska, Simon J. Boulton, Deborah Schneider-Luftman, Sandra Segura-Bayona, Wellcome Trust, Cancer Research UK (Reino Unido), The Francis Crick Institute, Medical Research Council (Reino Unido), European Molecular Biology Organization, and Unión Europea. Comisión Europea
Subjects: DNA Replication, DNA damage, DNA repair, Cellbiologi, education, Biology, Poly(ADP-ribose) Polymerase Inhibitors, CHD1L, Article, PARPs, 03 medical and health sciences, Mice, 0302 clinical medicine, poly(ADP)-ribosylation, DNA-(Apurinic or Apyrimidinic Site) Lyase, Animals, DNA damage repair, homologous recombination defieciency, Homologous Recombination, chromatin remodeler, Molecular Biology, health care economics and organizations, 030304 developmental biology, Mice, Knockout, 0303 health sciences, DNA replication, DNA Helicases, DNA gycosylases, Neoplasms, Experimental, BRCAs, Cell Biology, Chromatin Assembly and Disassembly, base excsion repair, synthetic lethality, Chromatin, Cell biology, Neoplasm Proteins, Nucleosomes, DNA-Binding Proteins, ALC1, DNA glycosylase, PARP inhibitor, Poly(ADP-ribose) Polymerases, Homologous recombination, 030217 neurology & neurosurgery
Abstract: Summary Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers., Graphical Abstract, Highlights • Loss of ALC1 nucleosome remodeling confers PARPi, MMS, and formyl-dU sensitivity • ALC1 is required after lesion excision by DNA glycosylases prior to APEX1 • Loss of ALC1 is synthetic lethal with homologous recombination deficiency (HRD) • Endogenous alkylated base damage is a source of synthetic lethality with HRD, Hewitt et al. report that loss of the chromatin-remodeling enzyme ALC1 leads to persistent BER intermediates and a critical dependency on HR for repair. Combined loss of ALC1 and HR is synthetic lethal, which can be partially rescued by blocking excision of endogenous alkylation damage by the glycosylase MPG.
Published: 2021

31. 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales

Author: Kuhn, Jens H, Adkins, Scott, Agwanda, Bernard R, Al Kubrusli, Rim, Alkhovsky, Sergey V, Amarasinghe, Gaya K, Avšič-Županc, Tatjana, Ayllón, María A, Bahl, Justin, Balkema-Buschmann, Anne, Ballinger, Matthew J, Basler, Christopher F, Bavari, Sina, Beer, Martin, Bejerman, Nicolas, Bennett, Andrew J, Bente, Dennis A, Bergeron, Éric, Bird, Brian H, Blair, Carol D, Blasdell, Kim R, Blystad, Dag-Ragnar, Bojko, Jamie, Borth, Wayne B, Bradfute, Steven, Breyta, Rachel, Briese, Thomas, Brown, Paul A, Brown, Judith K, Buchholz, Ursula J, Buchmeier, Michael J, Bukreyev, Alexander, Burt, Felicity, Büttner, Carmen, Calisher, Charles H, Cao, Mengji, Casas, Inmaculada, Chandran, Kartik, Charrel, Rémi N, Cheng, Qi, Chiaki, Yuya, Chiapello, Marco, Choi, Il-Ryong, Ciuffo, Marina, Clegg, J Christopher S, Crozier, Ian, Dal Bó, Elena, de la Torre, Juan Carlos, de Lamballerie, Xavier, de Swart, Rik L, Debat, Humberto, Dheilly, Nolwenn M, Di Cicco, Emiliano, Di Paola, Nicholas, Di Serio, Francesco, Dietzgen, Ralf G, Digiaro, Michele, Dolnik, Olga, Drebot, Michael A, Drexler, J Felix, Dundon, William G, Duprex, W Paul, Dürrwald, Ralf, Dye, John M, Easton, Andrew J, Ebihara, Hideki, Elbeaino, Toufic, Ergünay, Koray, Ferguson, Hugh W, Fooks, Anthony R, Forgia, Marco, Formenty, Pierre B H, Fránová, Jana, Freitas-Astúa, Juliana, Fu, Jingjing, Fürl, Stephanie, Gago-Zachert, Selma, Gāo, George Fú, García, María Laura, García-Sastre, Adolfo, Garrison, Aura R, Gaskin, Thomas, Gonzalez, Jean-Paul J, Griffiths, Anthony, Goldberg, Tony L, Groschup, Martin H, Günther, Stephan, Hall, Roy A, Hammond, John, Han, Tong, Hepojoki, Jussi, Hewson, Roger, Hong, Jiang, Hong, Ni, Hongo, Seiji, Horie, Masayuki, Hu, John S, Hu, Tao, Hughes, Holly R, Hüttner, Florian, Hyndman, Timothy H, Ilyas, M, Jalkanen, Risto, Jiāng, Dàohóng, Jonson, Gilda B, Junglen, Sandra, Kadono, Fujio, Kaukinen, Karia H, Kawate, Michael, Klempa, Boris, Klingström, Jonas, Kobinger, Gary, Koloniuk, Igor, Kondō, Hideki, Koonin, Eugene V, Krupovic, Mart, Kubota, Kenji, Kurath, Gael, Laenen, Lies, Lambert, Amy J, Langevin, Stanley L, Lee, Benhur, Lefkowitz, Elliot J, Leroy, Eric M, Li, Shaorong, Li, Longhui, Lǐ, Jiànróng, Liu, Huazhen, Lukashevich, Igor S, Maes, Piet, de Souza, William Marciel, Marklewitz, Marco, Marshall, Sergio H, Marzano, Shin-Yi L, Massart, Sebastien, McCauley, John W, Melzer, Michael, Mielke-Ehret, Nicole, Miller, Kristina M, Ming, Tobi J, Mirazimi, Ali, Mordecai, Gideon J, Mühlbach, Hans-Peter, Mühlberger, Elke, Naidu, Rayapati, Natsuaki, Tomohide, Navarro, José A, Netesov, Sergey V, Neumann, Gabriele, Nowotny, Norbert, Nunes, Márcio R T, Olmedo-Velarde, Alejandro, Palacios, Gustavo, Pallás, Vicente, Pályi, Bernadett, Papa, Anna, Paraskevopoulou, Sofia, Park, Adam C, Parrish, Colin R, Patterson, David A, Pauvolid-Corrêa, Alex, Pawęska, Janusz T, Payne, Susan, Peracchio, Carlotta, Pérez, Daniel R, Postler, Thomas S, Qi, Liying, Radoshitzky, Sheli R, Resende, Renato O, Reyes, Carina A, Rima, Bertus K, Luna, Gabriel Robles, Romanowski, Víctor, Rota, Paul, Rubbenstroth, Dennis, Rubino, Luisa, Runstadler, Jonathan A, Sabanadzovic, Sead, Sall, Amadou Alpha, Salvato, Maria S, Sang, Rosemary, Sasaya, Takahide, Schulze, Angela D, Schwemmle, Martin, Shi, Mang, Shí, Xiǎohóng, Shí, Zhènglì, Shimomoto, Yoshifumi, Shirako, Yukio, Siddell, Stuart G, Simmonds, Peter, Sironi, Manuela, Smagghe, Guy, Smither, Sophie, Song, Jin-Won, Spann, Kirsten, Spengler, Jessica R, Stenglein, Mark D, Stone, David M, Sugano, Jari, Suttle, Curtis A, Tabata, Amy, Takada, Ayato, Takeuchi, Shigeharu, Tchouassi, David P, Teffer, Amy, Tesh, Robert B, Thornburg, Natalie J, Tomitaka, Yasuhiro, Tomonaga, Keizō, Tordo, Noël, Torto, Baldwyn, Towner, Jonathan S, Tsuda, Shinya, Tu, Changchun, Turina, Massimo, Tzanetakis, Ioannis E, Uchida, Janice, Usugi, Tomio, Vaira, Anna Maria, Vallino, Marta, van den Hoogen, Bernadette, Varsani, Arvind, Vasilakis, Nikos, Verbeek, Martin, von Bargen, Susanne, Wada, Jiro, Wahl, Victoria, Walker, Peter J, Wang, Lin-Fa, Wang, Guoping, Wang, Yanxiang, Wang, Yaqin, Waqas, Muhammad, Wèi, Tàiyún, Wen, Shaohua, Whitfield, Anna E, Williams, John V, Wolf, Yuri I, Wu, Jiangxiang, Xu, Lei, Yanagisawa, Hironobu, Yang, Caixia, Yang, Zuokun, Zerbini, F Murilo, Zhai, Lifeng, Zhang, Yong-Zhen, Zhang, Song, Zhang, Jinguo, Zhang, Zhe, Zhou, Xueping, Kuhn, Jens H., Agwanda, Bernard R., Alkhovsky, Sergey V., Amarasinghe, Gaya K., Ayllón, María A., Ballinger, Matthew J., Basler, Christopher F., Bennett, Andrew J., Bente, Dennis A., Bird, Brian H., Blair, Carol D., Blasdell, Kim R., Borth, Wayne B., Brown, Paul A., Brown, Judith K., Buchholz, Ursula J., Buchmeier, Michael J., Calisher, Charles H., Charrel, Rémi N., Clegg, J. Christopher S., de Swart, Rik L., Dheilly, Nolwenn M., Dietzgen, Ralf G., Drebot, Michael A., Drexler, J. Felix, Dundon, William G., Duprex, W. Paul, Dye, John M., Easton, Andrew J., Ferguson, Hugh W., Fooks, Anthony R., Formenty, Pierre B. H., Garrison, Aura R., Gonzalez, Jean-Paul J., Goldberg, Tony L., Groschup, Martin H., Hall, Roy A., Hu, John S., Hughes, Holly R., Hyndman, Timothy H., Ilyas, M., Jonson, Gilda B., Kaukinen, Karia H., Koonin, Eugene V., Lambert, Amy J., Langevin, Stanley L., Lefkowitz, Elliot J., Leroy, Eric M., Lukashevich, Igor S., Marshall, Sergio H., Marzano, Shin-Yi L., McCauley, John W., Miller, Kristina M., Ming, Tobi J., Mordecai, Gideon J., Navarro, José A., Netesov, Sergey V., Nunes, Márcio R. T., Park, Adam C., Parrish, Colin R., Patterson, David A., Pawęska, Janusz T., Pérez, Daniel R., Postler, Thomas S., Radoshitzky, Sheli R., Resende, Renato O., Reyes, Carina A., Rima, Bertus K., Runstadler, Jonathan A., Salvato, Maria S., Schulze, Angela D., Siddell, Stuart G., Spengler, Jessica R., Stenglein, Mark D., Stone, David M., Suttle, Curtis A., Tchouassi, David P., Tesh, Robert B., Thornburg, Natalie J., Towner, Jonathan S., Tzanetakis, Ioannis E., Walker, Peter J., Whitfield, Anna E., Williams, John V., Wolf, Yuri I., Zerbini, F. Murilo, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), NIH - National Cancer Institute (NCI) (Estados Unidos), National Institutes of Health (Estados Unidos), United States Department of Agriculture. National Institute of Food and Agriculture, Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), Wellcome Trust, Mississippi State University (Estados Unidos), Battelle National Biodefense Institute, National Biodefense Analysis and Countermeasures Center, Tunnell Government Services (Estados Unidos), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), U.S. Horticultural Research Laboratory ( Fort Pierce, USA), United States Department of Agriculture (USDA), Jomo Kenyatta University of Agriculture and Technology (JKUAT), National Museums of Kenya, Humboldt University Of Berlin, Ministry of Health and Social Development of Russian Federation [Moscow], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Ljubljana, Universidad Politécnica de Madrid (UPM), University of Georgia [USA], Institute of Novel and Emerging Infectious Diseases (INNT), Friedrich-Loeffler-Institut (FLI), Laboratoire de Ploufragan-Plouzané-Niort [ANSES], Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Virologie des archées - Archaeal Virology, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Stratégies antivirales, Institut Pasteur [Paris] (IP), Centre collaborateur de l'OMS Arbovirus et Fièvres Hémorragiques virales - Stratégies antivirales (CC-OMS), NIAID under Contract No. HHSN272201800013C, NCI, NIH under Contract No. 75N91019D00024, NIH contract HHSN272201000040I/HHSN27200004/D04 and grant R24AI120942, US Department of Agriculture, Hatch Project 1021494, Cancer Research UK (FC001030), UK Medical Research Council (FC001030), Wellcome Trust (FC001030), Integrated Research Facility at Fort Detrick (IRF-Frederick), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), ARS, Medical School, University of Ljubljana, École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Virology
Subjects: Phylum, Identification, Alpharhabdovirinae, Strains, Field-collected mosquitos, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Article, MESH: Viruses, ICTV, 03 medical and health sciences, Biointeractions and Plant Health, MESH: Mononegavirales, Taxonomy of Viruses, Virology, Life Science, Humans, Crepuscuviridae, Myriaviridae, ComputingMilieux_MISCELLANEOUS, Taxonomy, 030304 developmental biology, Bunyavirales, 2. Zero hunger, 0303 health sciences, Virome, 030306 microbiology, Borne virus-infectons, Betarhabdovirinae, Rhabdovirus, General Medicine, Taxonomía de Virus, Merida virus, 3. Good health, Negarnaviricota, Aliusviridae, Triniti-virus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viruses, Queensland, Mononegavirales, Hantavirus
Abstract: In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV. Instituto de Patología Vegetal Fil: Kuhn, Jens H. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Integrated Research Facility at Fort Detrick; Estados Unidos Fil: Adkins, Scott. United States Department of Agriculture. Agricultural Research Service. US Horticultural Research Laboratory; Estados Unidos Fil: Agwanda, Bernard R. National Museums of Kenya. Zoology Department; Kenia Fil: Agwanda, Bernard R. Jomo Kenyatta University of Agriculture & Technology; Kenia Fil: Kubrusli, Rim Al. Humboldt-Universität zu Berlin. Faculty of Life Sciences. Division Phytomedicine; Alemania Fil: Alkhovsky, Sergey V. D.I. Ivanovsky Institute of Virology of N.F. Gamaleya National Center on Epidemiology and Microbiology of Ministry of Health of Russian Federation; Rusia Fil: Amarasinghe, Gaya K. Washington University School of Medicine. Department of Pathology and Immunology; Estados Unidos Fil: Avšič-Županc, Tatjana. University of Ljubljana. Faculty of Medicine; Eslovenia Fil: Ayllón, María A. Universidad Politécnica de Madrid—Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria. Campus de Montegancedo. Centro de Biotecnología y Genómica de Plantas; España Fil: Ayllón, María A. Universidad Politécnica de Madrid. Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas. Departamento de Biotecnología-Biología Vegetal; España Fil: Bahl, Justin. University of Georgia. Center for Ecology of Infectious Diseases, Department of Infectious Diseases, Department of Epidemiology and Biostatistics, Insitute of Bioinformatics; Estados Unidos Fil: Balkema-Buschmann, Anne. Institute of Novel and Emerging Infectious Diseases. Friedrich-Loeffler-Institut. Federal Research Institute for Animal Health; Alemania Fil: Bejerman, Nicolas Esteban. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patología Vegetal; Argentina Fil: Bejerman, Nicolas Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Fitopatología y Modelización Agrícola (UFyMA); Argentina Fil: Debat, Humberto Julio. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patología Vegetal; Argentina Fil: Debat, Humberto Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Fitopatología y Modelización Agrícola (UFyMA); Argentina Fil: Zhou, Xueping. Chinese Academy of Agricultural Sciences. Institute of Plant Protection. State Key Laboratory for Biology of Plant Diseases and Insect Pests; China
Published: 2021

32. Global mortality from dementia : Application of a new method and results from the Global Burden of Disease Study 2019

Author: Nichols, Emma, Abd‐Allah, Foad, Abdoli, Amir, Abosetugn, Akine Eshete, Abrha, Woldu Aberhe, Abualhasan, Ahmed, Abu‐Gharbieh, Eman, Akinyemi, Rufus Olusola, Alahdab, Fares, Alanezi, Fahad Mashhour, Alipour, Vahid, Ansari, Iman, Arabloo, Jalal, Ashraf‐Ganjouei, Amir, Avan, Abolfazl, Ayano, Getinet, Babar, Zaheer‐Ud‐Din, Baig, Atif Amin, Banach, Maciej, Barboza, Miguel A., Barker‐Collo, Suzanne Lyn, Baune, Bernhard T., Bhagavathula, Akshaya Srikanth, Bhattacharyya, Krittika, Bijani, Ali, Biondi, Antonio, Birhan, Tsegaye Adane, Biswas, Atanu, Bolla, Srinivasa Rao, Boloor, Archith, Brayne, Carol, Brenner, Hermann, Burkart, Katrin, Burns, Richard A., Nagaraja, Sharath Burugina, Carvalho, Felix, Castro‐de‐Araujo, Luis F. S., Catala-Lopez, Ferran, Cerin, Ester, Cernigliaro, Achille, Cherbuin, Nicolas, Choi, Jee‐Young Jasmine, Chu, Dinh‐Toi, Dagnew, Baye, Dai, Xiaochen, Dandona, Lalit, Dandona, Rakhi, Diaz, Daniel, Forooshani, Zahra Sadat Dibaji, Douiri, Abdel, Duncan, Bruce B., Edvardsson, David, El‐Jaafary, Shaimaa I., Eskandari, Khalil, Eskandarieh, Sharareh, Feigin, Valery L., Fereshtehnejad, Seyed‐Mohammad, Fernandes, Eduarda, Ferrara, Pietro, Filip, Irina, Fischer, Florian, Gaidhane, Shilpa, Gebregzabiher, Kidane Zereabruk, Ghashghaee, Ahmad, Gholamian, Asadollah, Gnedovskaya, Elena V., Golechha, Mahaveer, Gupta, Rajeev, Hachinski, Vladimir, Hamidi, Samer, Hankey, Graeme J., Haro, Josep Maria, Hassan, Amr, Hay, Simon I., Heidari, Golnaz, Heidari‐Soureshjani, Reza, Househ, Mowafa, Hussain, Rabia, Hwang, Bing‐Fang, Ilic, Irena M., Ilic, Milena D., Irvani, Seyed Sina Naghibi, Iso, Hiroyasu, Iwagami, Masao, Jha, Ravi Prakash, Kalani, Rizwan, Kandel, Himal, Karch, André, Kasa, Ayele Semachew, Kengne, Andre Pascal, Kim, Young‐Eun, Kim, Yun Jin, Kisa, Sezer, Kisa, Adnan, Kivimäki, Mika, Komaki, Hamidreza, Koyanagi, Ai, Kukull, Walter A, Kumar, G. Anil, Kumar, Manasi, Landires, Iván, Leonardi, Matilde, Lim, Stephen S., Liu, Xuefeng, Logroscino, Giancarlo, Lopez, Alan D., Lorkowski, Stefan, Loy, Clement T., Amin, Hawraz Ibrahim M., Manafi, Navid, Manjunatha, Narayana, Mehndiratta, Man Mohan, Menezes, Ritesh G, Meretoja, Atte, Merkin, Alexander, Metekiya, Workua Mekonnen, Misganaw, Awoke Temesgen, Mohajer, Bahram, Ibrahim, Norlinah Mohamed, Mohammad, Yousef, Mohapatra, Archisman, Mohebi, Farnam, Mokdad, Ali H., Mondello, Stefania, Mossie, Tilahun Belete, Mulugeta, Anwar, Nagel, Gabriele, Naveed, Muhammad, Nayak, Vinod C., Kandel, Sandhya Neupane, Nguyen, Son Hoang, Nguyen, Huong Lan Thi, Nuñez‐Samudio, Virginia, Ogbo, Felix Akpojene, Olagunju, Andrew T., Orru, Hans, Ostojic, Sergej M., Ostroff, Samuel M., Otstavnov, Nikita, Otstavnov, Stanislav S, Owolabi, Mayowa O., Pathak, Mona, Toroudi, Hamidreza Pazoki, Peterson, Carrie B., Pham, Hai Quang, Phillips, Michael R., Piradov, Michael A., Pottoo, Faheem Hyder, Prada, Sergio I., Pribadi, Dimas Ria Angga, Radfar, Amir, Raggi, Alberto, Rahim, Fakher, Ram, Pradhum, Rana, Juwel, Rashedi, Vahid, Rawaf, Salman, Rawaf, David Laith, Reinig, Nickolas, Rezaei, Nima, Robinson, Stephen R, Romoli, Michele, Sachdev, Perminder S., Sahathevan, Ramesh, Sahebkar, Amirhossein, Sahraian, Mohammad Ali, Sattin, Davide, Saylan, Mete, Sayyah, Mehdi, Schiavolin, Silvia, Schmidt, Maria Inês, Shahid, Izza, Shaikh, Masood Ali, Shigematsu, Mika, Shin, Jae Il, Shiri, Rahman, Siddiqi, Tariq Jamal, Silva, João Pedro, Singh, Jasvinder A., Soheili, Amin, Spurlock, Emma Elizabeth, Szoeke, Cassandra E I, Tabarés‐Seisdedos, Rafael, Taddele, Biruk Wogayehu, Thakur, Bhaskar, ThekkePurakkal, Akhil Soman, Tovani‐Palone, Marcos Roberto, Tran, Bach Xuan, Travillian, Ravensara S., Tripathi, Manjari, Tsegaye, Gebiyaw Wudie, Usman, Muhammad Shariq, Vacante, Marco, Velazquez, Diana Zuleika, Venketasubramanian, Narayanaswamy, Vidale, Simone, Vlassov, Vasily, Wang, Yuan‐Pang, Wei, Jingkai, Weiss, Jordan, Weldemariam, Abrha Hailay, Wimo, Anders, Wu, Chenkai, Yadollahpour, Ali, Yamagishi, Kazumasa, Yeshitila, Yordanos Gizachew, Yonemoto, Naohiro, Zadey, Siddhesh, Zhang, Zhi‐Jiang, Murray, Christopher J. L., Vos, Theo, GBD 2019 Collaborators, Department of Public Health, Clinicum, HUS Neurocenter, Neurologian yksikkö, Bill & Melinda Gates Foundation, Royal Society (Reino Unido), African Academy of Sciences, National Institutes of Health (Estados Unidos), Fundação para a Ciência e Tecnologia (Portugal), Wellcome Trust, Center of Data and Knowledge Integration for Health, Oswaldo Cruz Foundation, National Institute for Health Research (Reino Unido), King College London, Xiamen University Malaysia (Malasia), Medical Research Council (Reino Unido), NIH - National Institute on Aging (NIA) (Estados Unidos), Secretaría Nacional de Ciencia, Tecnología e Innovación (Panamá), Federal Ministry of Education & Research (Alemania), Ministero della Salute (Italia), National Natural Science Foundation of China, National Health and Medical Research Council (Australia), Alzheimers Association, University of Melbourne (Australia), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Nichols, E, Abd-Allah, F, Abdoli, A, Abosetugn, A, Abrha, W, Abualhasan, A, Abu-Gharbieh, E, Akinyemi, R, Alahdab, F, Alanezi, F, Alipour, V, Ansari, I, Arabloo, J, Ashraf-Ganjouei, A, Avan, A, Ayano, G, Babar, Z, Baig, A, Banach, M, Barboza, M, Barker-Collo, S, Baune, B, Srikanth Bhagavathula, A, Bhattacharyya, K, Bijani, A, Biondi, A, Birhan, T, Biswas, A, Bolla, S, Boloor, A, Brayne, C, Brenner, H, Burkart, K, Burns, R, Nagaraja, S, Carvalho, F, Castro-De-araujo, L, Catala-Lopez, F, Cerin, E, Cernigliaro, A, Cherbuin, N, Jasmine Choi, J, Chu, D, Dagnew, B, Dai, X, Dandona, L, Dandona, R, Diaz, D, Dibaji Forooshani, Z, Douiri, A, Duncan, B, Edvardsson, D, El-Jaafary, S, Eskandari, K, Eskandarieh, S, Feigin, V, Fereshtehnejad, S, Fernandes, E, Ferrara, P, Filip, I, Fischer, F, Gaidhane, S, Gebregzabiher, K, Ghashghaee, A, Gholamian, A, Gnedovskaya, E, Golechha, M, Gupta, R, Hachinski, V, Hamidi, S, Hankey, G, Haro, J, Hassan, A, Hay, S, Heidari, G, Heidari-Soureshjani, R, Househ, M, Hussain, R, Hwang, B, Ilic, I, Ilic, M, Naghibi Irvani, S, Iso, H, Iwagami, M, Jha, R, Kalani, R, Kandel, H, Karch, A, Kasa, A, Kengne, A, Kim, Y, Kisa, S, Kisa, A, Kivimaki, M, Komaki, H, Aikoyanagi, Kukull, W, Kumar, G, Kumar, M, Landires, I, Leonardi, M, Lim, S, Liu, X, Logroscino, G, Lopez, A, Lorkowski, S, Loy, C, Amin, H, Manafi, N, Manjunatha, N, Mehndiratta, M, Menezes, R, Meretoja, A, Merkin, A, Metekiya, W, Misganaw, A, Mohajer, B, Ibrahim, N, Mohammad, Y, Mohapatra, A, Mohebi, F, Mokdad, A, Mondello, S, Mossie, T, Mulugeta, A, Nagel, G, Naveed, M, Nayak, V, Kandel, S, Nguyen, S, Nguyen, H, Nunez-Samudio, V, Ogbo, F, Olagunju, A, Orru, H, Ostojic, S, Ostroff, S, Otstavnov, N, Otstavnov, S, Owolabi, M, Pathak, M, Toroudi, H, Peterson, C, Pham, H, Phillips, M, Piradov, M, Pottoo, F, Prada, S, Angga Pribadi, D, Radfar, A, Raggi, A, Rahim, F, Ram, P, Rana, J, Rashedi, V, Rawaf, S, Rawaf, D, Reinig, N, Rezaei, N, Robinson, S, Romoli, M, Sachdev, P, Sahathevan, R, Sahebkar, A, Sahraian, M, Sattin, D, Saylan, M, Sayyah, M, Schiavolin, S, Schmidt, M, Shahid, I, Shaikh, M, Shigematsu, M, Shin, J, Shiri, R, Siddiqi, T, Silva, J, Singh, J, Soheili, A, Spurlock, E, Szoeke, C, Tabares-Seisdedos, R, Taddele, B, Thakur, B, Thekke Purakkal, A, Tovani-Palone, M, Tran, B, Travillian, R, Tripathi, M, Tsegaye, G, Usman, M, Vacante, M, Velazquez, D, Venketasubramanian, N, Vidale, S, Vlassov, V, Wang, Y, Wei, J, Weiss, J, Weldemariam, A, Wimo, A, Wu, C, Yadollahpour, A, Yamagishi, K, Yeshitila, Y, Yonemoto, N, Zadey, S, Zhang, Z, Murray, C, Vos, T, Fundação para a Ciência e a Tecnologia (Portugal), Center for Data and Knowledge Integration for Health (CIDACS), Imperial College London (Reino Unido), University Hospitals Bristol NHS Foundation Trust, South African Medical Research Council, NIH - National Institute of Mental Health (NIMH) (Estados Unidos), Alzheimer's Association, Australian Research Council, European Regional Development Fund, Ministry of Science and Technology (Shanghái), Nichols, Emma, Abd-Allah, Foad, Abdoli, Amir, Abosetugn, Akine Eshete, Mulugeta, Anwar, and Vos, Theo
Subjects: MILD COGNITIVE IMPAIRMENT, Clinical Neurology, Global health, global health, burden of disease, ALL-CAUSE, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, CLINICALLY DIAGNOSED DEMENTIA, mental disorders, 030212 general & internal medicine, REPORTING DEMENTIA, Mortality, RC346-429, GBD 2019 Collaborators, PREDICTORS, Research Articles, POPULATION, Science & Technology, DEATH CERTIFICATES, RC952-954.6, Neurosciences, Burden of disease, 3112 Neurosciences, NURSING-HOME RESIDENTS, mortality, 3. Good health, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Disease burdens, Geriatrics, SURVIVAL, Dementia, Neurology. Diseases of the nervous system, Neurosciences & Neurology, Neurology (clinical), Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article, dementia
Abstract: Introduction: Dementia is currently one of the leading causes of mortality globally, and mortality due to dementia will likely increase in the future along with corresponding increases in population growth and population aging. However, large inconsistencies in coding practices in vital registration systems over time and between countries complicate the estimation of global dementia mortality. Methods: We meta-analyzed the excess risk of death in those with dementia and multiplied these estimates by the proportion of dementia deaths occurring in those with severe, end-stage disease to calculate the total number of deaths that could be attributed to dementia. Results: We estimated that there were 1.62 million (95% uncertainty interval [UI]: 0.41-4.21) deaths globally due to dementia in 2019. More dementia deaths occurred in women (1.06 million [0.27-2.71]) than men (0.56 million [0.14-1.51]), largely but not entirely due to the higher life expectancy in women (age-standardized female-to-male ratio 1.19 [1.10-1.26]). Due to population aging, there was a large increase in all-age mortality rates from dementia between 1990 and 2019 (100.1% [89.1-117.5]). In 2019, deaths due to dementia ranked seventh globally in all ages and fourth among individuals 70 and older compared to deaths from other diseases estimated in the Global Burden of Disease (GBD) study. Discussion: Mortality due to dementia represents a substantial global burden, and is expected to continue to grow into the future as an older, aging population expands globally. This work was funded by the Bill and Melinda Gates Foundation, Seattle, WA, and by Gates Ventures, Seattle, WA. R. Akinyemi is supported as a FLAIR Research Fellow by the UK Royal Society and the African Academy of Science (Grants FLR/R1/191813 and FCG/R1/201034) U01HG010273 and from the National Institutes of Health (NIH), USA as part of the H3Africa Consortium. F. Carvalho and E. Fernandes acknowledge support from UID/MULTI/04378/2019 and UID/QUI/50006/2019 support with funding from FCT/MCTES, through national funds. L. F. S. Castro-de-Araujo is funded by The Wellcome Trust (Grant 202912/Z/16Z) via a research associate scholarship at Center of Data and Knowledge Integration for Health (CIDACS), Fundação Oswaldo Cruz (Fiocruz). A. Douiri acknowledges financial support from the National Institute for Health Research (NIHR) Biomedical Research and from the NIHR Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust. The views expressed are those of the author and not necessarily those of the King’s College London, NHS, the NIHR or the Department of Health. B. B. Duncan was supported in part by IATS/FAPERGS (465518/2014-1). A. P. Kengne is supported by the South African Medical Research Council. Y. J. Kim was funded by a grant from the Research Management Centre, Xiamen University Malaysia (Grant number: XMUMRF/2020-C6/ITCM/0004). M. Kivimäki reports grants from the UK Medical Research Council (MRC S011676), the US National Institutes on Ageing (NIA R01AG056477) and NordForsk. W. Kukull acknowledges support from U01 AG016976. M Kumar acknowledges support from FIC/NIMHK43 TW010716-03. I. Landires is member of the Sistema Nacional de Investigación (SNI), which is supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT), Panamá. S. Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research; grant agreement number 01EA1808A). S. Mondello acknowledges support by grant number GR-2013-02354960 from the Italian Ministry of Health. M. R. Phillips is supported in part by Global Alliance for Chronic Diseases-National Natural Science Foundation of China (NSFC. No. 81761128031). P. S. Sachdev acknowledges funding support from NHMRC Australia (grant no 1093086). J. P. Silva acknowledges support from grant number UIDB/04378/2020 from the Applied Molecular Biosciences Unit (UCIBIO), supported through Portuguese national funds via FCT/MCTES. C. E. I. Szoeke is supported by the National Med ical Health and Research Council, the Alzheimer’s Association, and The University of Melbourne. R. Tabarés-Seisdedos was supported in part by grant PI17/00719 from ISCIII-FEDER. C. Wu acknowledges support from the Ministry of Science and Technology (2020YFC2005600) and Suzhou Municipal Science and Technology Bureau (SS2019069). Sí
Published: 2021

33. Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM

Author: López-Perrote, Andres, Hug, Nele, González-Corpas, Ana, Rodríguez, Carlos F, Serna, Marina, García-Martín, Carmen, Caceres, Javier F, Llorca, Oscar, Boskovic, Jasminka, Fernandez-Leiro, Rafael, Llorca Blanco, Oscar Antonio, Medical Research Council (Reino Unido), UK Research and Innovation, Comunidad de Madrid (España), Ministerio de Ciencia, Innovación y Universidades (España), Medical Research Council UK (MRC), UK Research & Innovation (UKRI), and Ministerio de Ciencia, Innovacion y Universidades (MICIU)
Subjects: DHX34, QH301-705.5, Structural Biology and Molecular Biophysics, Science, Protein subunit, Nonsense-mediated decay, Mutant, General Biochemistry, Genetics and Molecular Biology, Gene Expression Regulation, Enzymologic, ATP hydrolysis, RUVBL2, Humans, Nucleotide, AAA+ ATPases, Biology (General), Cloning, Molecular, RUVBL1-RUVBL2, chemistry.chemical_classification, General Immunology and Microbiology, Chemistry, General Neuroscience, HEK 293 cells, Cryoelectron Microscopy, DNA Helicases, General Medicine, RNA Helicase A, AAA proteins, In vitro, Cell biology, HEK293 Cells, Medicine, ATPases Associated with Diverse Cellular Activities, Carrier Proteins, RNA Helicases, Research Article, Human, nonsense mediated mRNA decay
Abstract: Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that degrades aberrant mRNAs and also regulates the expression of a wide range of physiological transcripts. RUVBL1 and RUVBL2 AAA-ATPases form an hetero-hexameric ring that is part of several macromolecular complexes such as INO80, SWR1, and R2TP. Interestingly, RUVBL1-RUVBL2 ATPase activity is required for NMD activation by an unknown mechanism. Here, we show that DHX34, an RNA helicase regulating NMD initiation, directly interacts with RUVBL1-RUVBL2 in vitro and in cells. Cryo-EM reveals that DHX34 induces extensive changes in the N-termini of every RUVBL2 subunit in the complex, stabilizing a conformation that does not bind nucleotide and thereby down-regulates ATP hydrolysis of the complex. Using ATPase-deficient mutants, we find that DHX34 acts exclusively on the RUVBL2 subunits. We propose a model, where DHX34 acts to couple RUVBL1-RUVBL2 ATPase activity to the assembly of factors required to initiate the NMD response. Spanish Ministry of Science and Innovation SAF2017-82632-P Andres Lopez-Perrote Carlos F Rodriguez Marina Serna Oscar Llorca. Autonomous Government of Madrid Y2018/BIO4747 Ana Gonzalez-Corpas Oscar Llorca. Autonomous Government of Madrid P2018/NMT4443 Ana Gonzalez-Corpas Oscar Llorca MRC Core funding Javier F Caceres Spanish Ministry of Science and Innovation BES-2015-071348 Carlos F Rodriguez The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Sí
Published: 2020

34. Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics

Author: John M. Starr, Paul F. Jacques, Ian J. Deary, Qing Liu, Alba Fernández-Sanlés, Simin Liu, Kenneth Westerman, Roberto Elosua, Paola Sebastiani, Prasad Patil, Dawn L. DeMeo, Jose M. Ordovas, United States Department of Agriculture, National Institutes of Health (Estados Unidos), NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Medical Research Council (Reino Unido), and Wellcome Trust
Subjects: Epigenomics, Male, Epidemiology, Myocardial Infarction, Disease, 030204 cardiovascular system & hematology, Proof of Concept Study, Risk Assessment, Epigenesis, Genetic, Epigenome, risk prediction, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Predictive Value of Tests, cardiovascular disease, Prevalence, Genetics, Humans, Medicine, Risk factor, Aged, Original Research, 030304 developmental biology, 0303 health sciences, DNA methylation, Framingham Risk Score, business.industry, Proportional hazards model, Incidence, Hazard ratio, Reproducibility of Results, Computational Biology, Odds ratio, Middle Aged, Cardiovascular Diseases, Heart Disease Risk Factors, epigenomics, Cohort, Female, Epigenetics, Cardiology and Cardiovascular Medicine, business, Biomarkers, Genome-Wide Association Study, Demography
Abstract: Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics. This work was supported by the US Department of Agriculture, Agriculture Research Service (8050–51000-098-00D). Dr. Westerman was additionally supported by National Institutes of Health predoctoral training grant 5T32HL069772-14. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This article was prepared in collaboration with investigators of the WHI but has not been reviewed by the WHI and does not necessarily reflect the opinions of the WHI investigators or the National Heart, Lung, and Blood Institute. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or National Heart, Lung, and Blood Institute. The LBC 1936 is supported by Age UK (Disconnected Mind program) and the Medical Research Council (MR/M01311/1). Methylation typing in LBC 1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. LBC 1936 work was conducted in the Centre for Cognitive Ageing and Cognitive Epidemiology, which supported Dr. Deary and is supported by the medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1). Sí
Published: 2020

35. Cause-specific mortality after diagnosis of cancer among HIV-positive patients: a collaborative analysis of cohort studies

Author: Peter Reiss, Margaret T May, Matthias Cavassini, Sophie Grabar, Christoph Wyen, Sophie Abgrall, Fabrice Bonnet, Julia del Amo, Amy C. Justice, Antonella d'Arminio Monforte, Ferdinand W. N. M. Wit, Katharina Grabmeier-Pfistershammer, Leah Shepherd, Ramón Teira, Juan Berenguer, M. John Gill, Adam Trickey, Jodie L. Guest, Janne Vehreschild, Dominique Costagliola, Jonathan A C Sterne, Gestionnaire, Hal Sorbonne Université, University of Bristol [Bristol], University of Calgary, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Groupe hospitalier Broca, University Hospital of Cologne [Cologne], German Centre for Infection Research (DZIF), University of Amsterdam [Amsterdam] (UvA), Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], VU University Medical Center [Amsterdam], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Université de Lausanne = University of Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Medizinische Universität Wien = Medical University of Vienna, Emory University School of Medicine, Emory University [Atlanta, GA], University College of London [London] (UCL), Università degli Studi di Milano = University of Milan (UNIMI), Institute of Health Carlos III, Yale School of Medicine [New Haven, Connecticut] (YSM), VA Connecticut Healthcare System, Department for International Development (Reino Unido), NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), Medical Research Council (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Institut National de la Santé et de la Recherche Médicale (Francia), Swiss National Science Foundation, Ministerio de Sanidad y Consumo (España), Red de Investigación Cooperativa en Investigación en Sida (España), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Global Health, Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Università degli Studi di Milano [Milano] (UNIMI), Yale University School of Medicine, United Kingdom Department for International Development, National Institute on Alcohol Abuse and Alcoholism (United States), Medical Research Council (United Kingdom), 7º Programa Marco - Comisión Europea, Institut National de la Santé et de la Recherche Médicale, Red Española de Investigación en SIDA, and National Institutes of Health (United States)
Subjects: Cancer Research, Lung Neoplasms, ADM, Human immunodeficiency virus (HIV), Uterine Cervical Neoplasms, medicine.disease_cause, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medical diagnosis, Cancer, Lymphoma, AIDS-Related, education.field_of_study, Mortality rate, Liver Neoplasms, Cohort, cohort, Middle Aged, Prognosis, Hodgkin Disease, 3. Good health, Survival Rate, NADM, PLHIV, cancer, mortality, Infectious Causes of Cancer, Oncology, 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Cohort study, Adult, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, IDLIC, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Mortality, education, Acquired Immunodeficiency Syndrome, business.industry, medicine.disease, United Kingdom, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: People living with HIV (PLHIV) are more likely than the general population to develop AIDS‐defining malignancies (ADMs) and several non‐ADMs (NADMs). Information is lacking on survival outcomes and cause‐specific mortality after cancer diagnosis among PLHIV. We investigated causes of death within 5 years of cancer diagnosis in PLHIV enrolled in European and North American HIV cohorts starting antiretroviral therapy (ART) 1996–2015, aged ≥16 years, and subsequently diagnosed with cancer. Cancers were grouped: ADMs, viral NADMs and nonviral NADMs. We calculated cause‐specific mortality rates (MR) after diagnosis of specific cancers and compared 5‐year survival with the UK and France general populations. Among 83,856 PLHIV there were 4,436 cancer diagnoses. Of 603 deaths after ADM diagnosis, 292 (48%) were due to an ADM. There were 467/847 (55%) and 74/189 (39%) deaths that were due to an NADM after nonviral and viral NADM diagnoses, respectively. MR were higher for diagnoses between 1996 and 2005 versus 2006–2015: ADMs 102 (95% CI 92–113) per 1,000 years versus 88 (78–100), viral NADMs 134 (106–169) versus 111 (93–133) and nonviral NADMs 264 (232–300) versus 226 (206–248). Estimated 5‐year survival for PLHIV diagnosed with liver (29% [19–39%]), lung (18% [13–23%]) and cervical (75% [63–84%]) cancer was similar to general populations. Survival after Hodgkin's lymphoma diagnosis was lower in PLHIV (75% [67–81%]). Among ART‐treated PLHIV diagnosed with cancer, MR and causes of death varied by cancer type, with mortality highest for liver and lung cancers. Deaths within 5 years of NADM diagnoses were more likely to be from cancer than AIDS., What's new? People with HIV live longer than they used to, thanks to advances in antiretroviral therapy. These improvements reduced the incidence of AIDS‐defining malignancies, such as Kaposi's sarcoma, but the increased life expectancy has led to more diagnoses of cancers not traditionally associated with HIV. Here, the authors studied cause‐specific mortality among people with HIV diagnosed with cancer. For those people, within 5 years after a cancer diagnosis, cause of death was more likely to be cancer than AIDS. Survival rates after diagnosis varied by cancer type, but were similar to rates among the general population.
Published: 2020

36. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study

Author: Roth, Gregory A, Mensah, George A, Johnson, Catherine Owens, Addolorato, Giovanni, Ammirati, Enrico, Baddour, Larry M, Barengo, Noël C, Beaton, Andrea Z, Benjamin, Emelia J, Benziger, Catherine P, Bonny, Aimé, Brauer, Michael, Brodmann, Marianne, Cahill, Thomas J, Carapetis, Jonathan, Catapano, Alberico, Chugh, Sumeet S, Cooper, Leslie T, Coresh, Josef, Criqui, Michael, DeCleene, Nicole, Eagle, Kim A, Emmons-Bell, Sophia, Feigin, Valery L, Fernandez-Sola, Joaquim, Fowkes, Gerry, Gakidou, Emmanuela, Grundy, Scott M, He, Feng J, Howard, George, Hu, Frank, Inker, Lesley, Karthikeyan, Ganesan, Kassebaum, Nicholas, Koroshetz, Walter, Lavie, Carl, Lloyd-Jones, Donald, Lu, Hong S, Mirijello, Antonio, Temesgen, Awoke Misganaw, Mokdad, Ali H, Moran, Andrew E, Muntner, Paul, Narula, Jagat, Neal, Bruce, Ntsekhe, Mpiko, Moraes de Oliveira, Glaucia, Otto, Catherine, Owolabi, Mayowa Ojo, Pratt, Michael, Rajagopalan, Sanjay, Reitsma, Marissa, Ribeiro, Antonio Luiz P, Rigotti, Nancy, Rodgers, Anthony, Sable, Craig, Shakil, Saate, Sliwa-Hahnle, Karen, Stark, Benjamin, Sundström, Johan, Timpel, Patrick, Tleyjeh, Imad M, Valgimigli, Marco, Vos, Theo, Whelton, Paul K, Yacoub, Magdi, Zuhlke, Liesl, Murray, Christopher J L, Fuster, Valentin, Aegerion, Akcea, American Heart Association, Amgen Inc., Amryt, AstraZeneca, Bill & Melinda Gates Foundation, CNPq, Daiichi Sankyo Co. Ltd, Eli Lilly and Company, ERA NET, Esperion, FAPEMIG, Fondazione Cariplo, George Medicines Pty Ltd (GM), Horizon 2020, Ionis Pharmaceuticals, Kowa, Menarini, Merck KGaA, Ministry of Health - Ricerca Corrente Multimedica, Mylan, National Heart, Lung, and Blood Institute (United States), National Kidney Foundation, National Institutes of Health (United States), Novartis Farmaceutica S.A., Recordati, Regeneron, Sandoz, Sanofi Regeneron, Sanofi, The George Institute for Global Health (TGI), United Kingdom Department for International Development, United Kingdom Medical Research Council, UpToDate, Inc., Aegerion Pharmaceuticals (Estados Unidos), Akcea Therapeutics, Amgen, Amryt Pharma, National Council for Scientific and Technological Development (Brasil), Daiichi Sankyo, Eli Lilly, Esperion Therapeutics (Estados Unidos), Fundação de Amparo à Pesquisa do Estado de São Paulo Minas Gerais (Brasil), Unión Europea. Comisión Europea. H2020, Kowa (Japón), Grupo Menarini, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), National Kidney Foundation (Estados Unidos), National Institutes of Health (Estados Unidos), Novartis, Regeneron (Estados Unidos), Sandoz Farmacéutica, George Institute for Global Health, Department for International Development (Reino Unido), and Medical Research Council (Reino Unido)
Subjects: Cardiovascular diseases, SDG 3 - Good Health and Well-being, Population health, Global health, Health policy
Abstract: Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases. This study was funded by the Bill and Melinda Gates Foundation. Dr. Benjamin has received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (R01HL092577, 1R01HL128914) and American Heart Association (18SFRN34110082). Dr. Brauer has received a grant from the Bill and Melinda Gates Foundation. Dr. Catapano has received support from Fondazione Cariplo 2015-0524 and 2015-0564, H2020 REPROGRAM PHC-03-2015/667837-2, ERA NET ER-2017-2364981, GR-2011- 02346974, Ministry of Health - Ricerca Corrente Multimedica; has received research grant/support from Sanofi, Sanofi Regeneron, Amgen, Mylan, Menarini, and Eli Lilly; has served on the speakers bureau for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron, Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; has received honoraria from Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; and has served as a consultant/on the Advisory Board for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, Genzyme, Aegerion, and Sandoz. Dr. Coresh has received funding from the NIH and National Kidney Foundation; and has served as an advisor to Healthy.io. Dr. Fowkes has served on the Advisory Board for AstraZeneca. Dr. Muntner has received grants and personal fees from Amgen Inc. Dr. Ribeiro has received partial support by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17). Dr. Zuhlke has received funding by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and the National Research Foundation of South Africa. Dr. Rigotti has served as a consultant to Achieve Life Sciences; and has received royalties from UpToDate, Inc. Dr. Rodgers is employed by The George Institute for Global Health (TGI) and seconded part time to George Medicines Pty Ltd (GM); TGI has submitted patent applications with respect to low-fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease and is listed as one of the inventors; George Health Enterprises Pty. Ltd. (GHE) and its subsidiary, GM, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs; GHE is the social enterprise arm of TGI (Dr. Rodgers does not have a direct financial interest in these patent applications or investments). Dr. Sundström holds ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Bayer, Pfizer, and AstraZeneca, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sí
Published: 2020

37. Predicting the environmental suitability for onchocerciasis in Africa as an aid to elimination planning

Author: Fereshteh Ansari, Richard C. Franklin, Naznin Hossain, Rodrigo Sarmiento-Suárez, Mahdi Bohluli, Irena Ilic, Anwar Faraj, Soosanna Kumary Chattu, Sanni Yaya, Hagos Degefa Hidru, Morteza Shamsizadeh, Ehsan Sadeghi, Bach Xuan Tran, Leila Zaki, Mohammad Miri, Maha El Tantawi, Maciej Banach, Hasan Yusefzadeh, Kira A Barbre, Chigozie Jesse Uneke, Mehdi Naderi, Behzad Karami Matin, Yunquan Zhang, Vahid Yazdi-Feyzabadi, Emma Elizabeth Spurlock, Zahid A Butt, Nuruzzaman Khan, Robert L. Thompson, Mehdi Hosseinzadeh, Rovshan Khalilov, Usman Iqbal, K M Shivakumar, Leili Tapak, Chris A Schmidt, Priya Rathi, Shanshan Li, Bhaskaran Unnikrishnan, Chuanhua Yu, Elizabeth A. Cromwell, Davood Anvari, Hoa Thi Do, Abdullah Al Mamun, Obinna Onwujekwe, Serge Resnikoff, Majid Fasihi Harandi, Joshua C. P. Osborne, Farahnaz Joukar, Aso Mohammad Darwesh, Rohollah Kalhor, Turki Alanzi, Katie M Donkers, Amir Kasaeian, Eirini Skiadaresi, Aleksandra Barac, Simon I. Hay, Paul S. F. Yip, Tomislav Mestrovic, Zhi-Jiang Zhang, Katherine Gass, Cuong Tat Nguyen, Gurudatta Naik, Joshua Longbottom, Somayeh Bohlouli, Aziz Rezapour, Huong Lan Thi Nguyen, Khaled Khatab, Mohammed Ibrahim Mohialdeen Gubari, Ahmed Omar Bali, Temesgen Yihunie Akalu, Paul H. Lee, Vahid Alipour, Kebede Deribe, Megan F. Schipp, Ziyad Al-Aly, Biagio Simonetti, Masoud Moradi, Jalal Arabloo, Reza Rawassizadeh, Saif Ullah, Seth Christopher Yaw Appiah, Demelash Abewa Elemineh, Abedin Saghafipour, Fakher Rahim, Tinuke O Olagunju, Kimberly B. Johnson, Souranshu Chatterjee, Salvatore Rubino, Nataliya Foigt, Olayinka Stephen Ilesanmi, Taras Kavetskyy, Carlo La Vecchia, Eduarda Fernandes, Mohsen Mazidi, Claudiu Herteliu, Sojib Bin Zaman, Aziz Sheikh, Yong Yu, David Laith Rawaf, Hassan Magdy Abd El Razek, Natalie V S Vinkeles Melchers, Samath D Dharmaratne, Enrico Rubagotti, Fahad Alanezi, Masood Ali Shaikh, Masoud Foroutan, B. Suresh Kumar Shetty, Milena Ilic, Melese Abate Reta, Dian Kusuma, Ali Manafi, Krittika Bhattacharyya, Giovanni Damiani, Kanaan Hamagharib Abdullah, Desalegn Tadese Mengistu, Van C. Lansingh, Till Bärnighausen, Benjamin F. Arnold, Natalie Maria Cormier, Zulfiqar A Bhutta, Ahmad Daryani, Ali Bijani, Jae Il Shin, Samer Hamidi, Jasvinder A. Singh, Mohsen Bayati, Tomohide Yamada, Zubair Kabir, Muhammed Magdy Abd El Razek, Jonathan F. Mosser, Gbenga A. Kayode, Martin Amogre Ayanore, Shahin Soltani, Arvin Haj-Mirzaian, Mohammad Ali Mansournia, Salah Eddin Karimi, Alan J Thomson, Daniel Diaz, Ahamarshan Jayaraman Nagarajan, Adrian Pana, Salman Rawaf, Oliver J. Brady, Birhanu Geta Meharie, Yousef Fatahi, Sadia Bibi, Bogdan Oancea, Masoud Moghadaszadeh, Kelemu Tilahun Kibret, Valery L. Feigin, Saad M.A. Dahlawi, Ted R. Miller, Nicola Luigi Bragazzi, Atif Amin Baig, Maryam Zamanian, Kate E. LeGrand, Salahuddin Mohammed, Yuming Guo, Irfan Ullah, Hebat Allah Salah A. Yousof, Mowafa Househ, Ionut Negoi, Naohiro Yonemoto, Reza Mohammadpourhodki, Hadi Pourjafar, Navid Manafi, Neda Kianipour, Abraham Getachew Kelbore, Victor Adekanmbi, Seid Tiku Mereta, Olalekan A. Uthman, Arash Ziapour, Olatunji O. Adetokunboh, Trang Huyen Nguyen, Seyed Sina Naghibi Irvani, Francesco Saverio Violante, Monika Sawhney, Paula Moraga, Rahmatollah Moradzadeh, Mu'awiyyah Babale Sufiyan, Mohammad Hifz Ur Rahman, María-Gloria Basáñez, Vijay Kumar Chattu, Mustafa Geleto Ansha, Mona M. Khater, Andrew T Olagunju, Ejaz Ahmad Khan, Davide Guido, Kiomars Sharafi, S. Mohammad Sajadi, Francisco Rogerlândio Martins-Melo, Tarig B. Higazi, Afshin Maleki, Abdollah Mohammadian-Hafshejani, Soewarta Kosen, Amin Soheili, Félix Carvalho, Yun Jin Kim, Catalina Liliana Andrei, Ali Kazemi Karyani, Ehsan Ahmadpour, Thomas R. Unnasch, Mohsen Afarideh, Takahiro Tabuchi, Shreya Shirude, Marcel Ausloos, Maysaa El Sayed Zaki, Haileab Fekadu Wolde, Amira Shaheen, Shafiu Mohammed, Rajan Nikbakhsh, Tewodros Eshete Wonde, Endalkachew Worku Mengesha, Jacek Jerzy Jozwiak, Muktar Beshir Ahmed, Eugenio Traini, Leila R Kalankesh, Kris J. Krohn, Colm McAlinden, Walter Mendoza, Maryam Keramati, Ravi Prakash Jha, David M. Pigott, Elex Hill, Abdallah M. Samy, Farah Daoud, Wanji, Samuel, Public Health, Bill & Melinda Gates Foundation, Medical Research Council (Reino Unido), Department for International Development (Reino Unido), Unión Europea, Cromwell E.A., Osborne J.C.P., Unnasch T.R., Basanez M., Gass K.M., Barbre K.A., Hill E., Johnson K.B., Donkers K.M., Shirude S., Schmidt C.A., Adekanmbi V., Adetokunboh O.O., Afarideh M., Ahmadpour E., Beshir Ahmed M., Yihunie Akalu T., Al-Aly Z., Alanezi F.M., Alanzi T.M., Alipour V., Andrei C.L., Ansari F., Ansha M.G., Anvari D., Yaw Appiah S.C., Arabloo J., Arnold B.F., Ausloos M., Ayanore M.A., Amin Baig A., Banach M., Barac A., Barnighausen T.W., Bayati M., Bhattacharyya K., Bhutta Z.A., Bibi S., Bijani A., Bohlouli S., Bohluli M., Brady O.J., Bragazzi N.L., Butt Z.A., Carvalho F., Chatterjee S., Chattu V.K., Chattu S.K., Cormier N.M., Dahlawi S.M.A., Damiani G., Daoud F., Darwesh A.M., Daryani A., Deribe K., Dharmaratne S.D., Diaz D., Do H.T., El Sayed Zak M., El Tantawi M., Elemineh D.A., Faraj A., Harandi M.F., Fatahi Y., Feigin V.L., Fernandes E., Foigt N.A., Foroutan M., Franklin R.C., Mohialdeen Gubari M.I., Guido D., Guo Y., Haj-Mirzaian A., Abdullah K.H., Hamidi S., Herteliu C., De Hidru H.D., Higazi T.B., Hossain N., Hosseinzadeh M., Househ M., Ilesanmi O.S., Ilic M.D., Ilic I.M., Iqbal U., Naghibi Irvani S.S., Jha R.P., Joukar F., Jozwiak J.J., Kabir Z., Kalankesh L.R., Kalhor R., Matin B.K., Karimi S.E., Kasaeian A., Kavetskyy T., Kayode G.A., Karyani A.K., Kelbore A.G., Keramati M., Khalilov R., Khan E.A., Nuruzzaman Khan M.N., Khatab K., Khater M.M., Kianipour N., Kibret K.T., Kim Y.J., Kosen S., Krohn K.J., Kusuma D., Vecchia C.L., Lansingh Van C., Lee P.H., Legrand K.E., Li S., Longbottom J., Abd El Razek H.M., Abd El Razek M.M., Maleki A., Mamun A.A., Manafi A., Manafi N., Mansournia M.A., Martins-Melo F.R., Mazidi M., McAlinden C., Meharie B.G., Mendoza W., Mengesha E.W., Mengistu D.T., Mereta S.T., Mestrovic T., Miller T.R., Miri M., Moghadaszadeh M., Hafshejani A.M., Mohammadpourhodki R., Mohammed S., Moradi M., Moradzadeh R., Moraga P., Mosser J.F., Naderi M., Nagarajan A.J., Naik G., Negoi I., Nguyen C.T., Nguyen H.L.T., Nguyen T.H., Nikbakhsh R., Oancea B., Olagunju T.O., Olagunju A.T., Bali A.O., Onwujekwe O.E., Pana A., Pourjafar H., Rahim F., Ur Rahman M.H., Rathi P., Rawaf S., Rawaf D.L., Rawassizadeh R., Resnikoff S., Reta M.A., Rezapour A., Rubagotti E., Rubino S., Sadeghi E., Saghafipour A., Sajadi S.M., Samy A.M., Sarmiento-Suarez R., Sawhney M., Schipp M.F., Shaheen A.A., Shaikh M.A., Shamsizadeh M., Sharafi K., Sheikh A., Kumar Shetty B.S., Shin J.I., Shivakumar K.M., Simonetti B., Singh J.A., Skiadaresi E., Soheili A., Soltani S., Spurlock E.E., Sufiyan M.B., Tabuchi T., Tapak L., Thompson R.L., Thomson A.J., Traini E., Tran B.X., Ullah I., Ullah S., Uneke C.J., Unnikrishnan B., Uthman O.A., Melchers N.V.S.V., Violante F.S., Wolde H.F., Wonde T.E., Yamada T., Yaya S., Yazdi Feyzabadi V., Yip P., Yonemoto N., Yousof H.-A.S.A., Yu C., Yu Y., Yusefzadeh H., Zaki L., Zaman S.B., Zamanian M., Zhang Z.-J., Zhang Y., Ziapour A., Hay S.I., Pigott D.M., and Cuidado de la Salud y Desarrollo Sostenible
Subjects: Oncocercosis, Decision Analysis, RC955-962, Onchocerciasis, law.invention, Geographical Locations, Medical Conditions, 0302 clinical medicine, law, Arctic medicine. Tropical medicine, Medicine and Health Sciences, 030212 general & internal medicine, Onchocerca, 11 Medical and Health Sciences, Data Management, biology, Pharmaceutics, wc_695, Enfermedades Parasitarias, Onchocerciasi, 3. Good health, Infectious Diseases, Geography, Transmission (mechanics), Helminth Infections, Engineering and Technology, Mass Drug Administration, Public aspects of medicine, RA1-1270, Management Engineering, Cartography, Human, Research Article, Neglected Tropical Diseases, Computer and Information Sciences, Drug Administration, 030231 tropical medicine, Decision tree, wa_395, Dermatology, wc_765, Environment, wc_885, Research and Analysis Methods, Skin Diseases, 03 medical and health sciences, Drug Therapy, SDG 3 - Good Health and Well-being, Diagnostic Medicine, Tropical Medicine, Parasitic Diseases, medicine, Humans, Disease Eradication, Spatial analysis, Ivermectin, Data collection, Receiver operating characteristic, Data Visualization, Decision Trees, Public Health, Environmental and Occupational Health, 06 Biological Sciences, Elimination planning, Africa, Implementation units, Public health, Tropical Diseases, medicine.disease, biology.organism_classification, Health Care, ROC Curve, People and Places, Health Statistics, Morbidity, Scale (map), Forecasting
Abstract: Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 0·71 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 50·2% exceed this threshold for suitability in at least one 5 × 5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify., Author summary As of 2018, it was unknown if onchocerciasis transmission occurred among approximately 2 400 implementation units (IUs; typically, second administrative-level units, such as districts) considered potentially endemic. These IUs have either never been surveyed for onchocerciasis or historical data are not sufficient to define contemporary endemicity status. Given the large number of IUs for which baseline data collection is likely required to achieve continental elimination, there is a need to prioritise areas for surveys to ensure that those suitable for endemic transmission, and therefore potentially eligible for mass drug administration, are able to initiate interventions as soon as possible. We used boosted regression trees to predict environmental suitability for onchocerciasis, with corresponding measures of uncertainty. We summarized the fine scale spatial predictions at the IU level by using receiver operating characteristic (ROC) curve analysis to identify a threshold that maximized agreement with the occurrence locations to identify IUs that may warrant prioritisation for mapping surveys. This analysis suggests that approximately half of the IUs considered for surveys could be classified as environmentally suitable for onchocerciasis. In order to develop an elimination strategy, many national onchocerciasis elimination programmes (NOEPs) need a mechanism to synthesise historical data to define priority areas for surveys.
Published: 2021

38. Global benchmarking of children's exposure to television advertising of unhealthy foods and beverages across 22 countries

Author: Bridget Kelly, Simón Barquera, María Victoria Tiscornia, Zandile Mchiza, Miguel Ángel Royo-Bordonada, Igor Pravst, Jason C.G. Halford, Melissa L. Jensen, Lingxia Zeng, Irina Zamora-Corrales, Nongnuch Jaichuen, Sascha Reiff, Putthipanya Rueangsom, Lizbeth Tolentino-Mayo, Laura I. González-Zapata, See Hoe Ng, Asha Kaur, Stefanie Vandevijvere, Emma Boyland, Tilakavati Karupaiah, Teresa Correa, Whadi-ah Parker, Monique Potvin Kent, Daniel Cauchi, Jean Adams, Emma Lucia Cosenza-Quintana, Luciana Castronuovo, Camila Corvalán, Jillian Wate, Marcela Reyes, Lorena Allemandi, Liliana Bahena-Espina, Carlos Fernández-Escobar, Krista Miklavec, Boyd Swinburn, Martin White, Peter Scarborough, Manuel Ramirez-Zea, Paul Calleja, Isabel Cristina Carmona-Garcés, Maria F Kroker-Lobos, International Development Research Centre, Universidad de Antioquia (Colombia), Ministry of Higher Education (Malasia), Ministry of Health (Eslovenia), Slovenian Research Agency, Instituto de Salud Carlos III, Organización de consumidores y usuarios (España), British Heart Foundation, Cancer Research UK (Reino Unido), Economic and Social Research Council (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Wellcome Trust, United Kingdom Clinical Research Collaboration, Kelly, Bridget [0000-0003-3111-6279], Vandevijvere, Stefanie [0000-0003-3225-7524], Adams, Jean [0000-0002-5733-7830], Barquera, Simon [0000-0003-1854-4615], Cauchi, Daniel [0000-0003-3930-7272], Corvalán, Camila [0000-0003-3766-7709], Scarborough, Peter [0000-0002-2378-2944], White, Martin [0000-0002-1861-6757], Swinburn, Boyd [0000-0002-2131-045X], and Apollo - University of Cambridge Repository
Subjects: Food industry, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, World health, Beverages, 03 medical and health sciences, 0302 clinical medicine, Advertising, Humans, 030212 general & internal medicine, Television advertising, INFORMAS, Child, 2. Zero hunger, Obesity prevention, business.industry, Public Health, Environmental and Occupational Health, Benchmarking, 3. Good health, Food, Supplement Article, Television, Public Health, business
Abstract: Restricting children's exposures to marketing of unhealthy foods and beverages is a global obesity prevention priority. Monitoring marketing exposures supports informed policymaking. This study presents a global overview of children's television advertising exposure to healthy and unhealthy products. Twenty-two countries contributed data, captured between 2008 and 2017. Advertisements were coded for the nature of foods and beverages, using the 2015 World Health Organization (WHO) Europe Nutrient Profile Model (should be permitted/not-permitted to be advertised). Peak viewing times were defined as the top five hour timeslots for children. On average, there were four times more advertisements for foods/beverages that should not be permitted than for permitted foods/beverages. The frequency of food/beverages advertisements that should not be permitted per hour was higher during peak viewing times compared with other times (P
Published: 2019

39. Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

Author: Garcia-Pavia, P, Kim, Y, Restrepo-Cordoba, MA, Lunde, IG, Wakimoto, H, Smith, AM, Toepfer, CN, Getz, K, Gorham, J, Patel, P, Ito, K, Willcox, JA, Arany, Z, Li, J, Owens, AT, Govind, R, Nuñez, B, Mazaika, E, Bayes-Genis, A, Walsh, R, Finkelman, B, Lupon, J, Whiffin, N, Serrano, I, Midwinter, W, Wilk, A, Bardaji, A, Ingold, N, Buchan, R, Tayal, U, Pascual-Figal, DA, De Marvao, A, Ahmad, M, Garcia-Pinilla, JM, Pantazis, A, Dominguez, F, John Baksi, A, O'Regan, DP, Rosen, SD, Prasad, SK, Lara-Pezzi, E, Provencio, M, Lyon, AR, Alonso-Pulpon, L, Cook, SA, DePalma, SR, Barton, PJR, Aplenc, R, Seidman, JG, Ky, B, Ware, JS, Seidman, CE, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Wellcome Trust, Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Imperial College London (Reino Unido), Fondation Leducq, British Heart Foundation, National Institutes of Health (Estados Unidos), Howard Hughes Medical Institute, Fundación ProCNIC, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Department of Health, Royal Brompton & Harefield NHS Foundation Trust, Imperial College Healthcare NHS Trust- BRC Funding, Rosetrees Trust, and The Academy of Medical Sciences
Subjects: CARDIOTOXICITY, cardiomyopathies, Adult, Male, Cardiac & Cardiovascular Systems, FAMILIAL DILATED CARDIOMYOPATHY, Antineoplastic Agents, Mice, Transgenic, TITIN, 1117 Public Health and Health Services, Cohort Studies, Mice, Neoplasms, A-BAND TRUNCATION, Animals, Humans, genetics, titin, Prospective Studies, AMERICAN SOCIETY, 1102 Cardiorespiratory Medicine and Haematology, POLYMORPHISMS, Aged, Retrospective Studies, Science & Technology, CONGESTIVE-HEART-FAILURE, MUTATIONS, Genetic Variation, 1103 Clinical Sciences, CHEMOTHERAPY, Middle Aged, medical oncology, drug therapy, Mice, Inbred C57BL, Peripheral Vascular Disease, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Female, ECHOCARDIOGRAPHY, Cardiomyopathies, Life Sciences & Biomedicine
Abstract: BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P
Published: 2019

40. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, G., Bogliolo, M., Catucci, I., Caleca, L., Lasheras, S. V., Pujol, R., Kiiski, J. I., Muranen, T. A., Barnes, D. R., Dennis, J., Michailidou, K., Bolla, M. K., Leslie, G., Aalfs, C. M., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C. S., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Adank, M. A., Adlard, J., Agata, S., Cadoo, K., Agnarsson, B. A., Ahearn, T., Aittomaki, K., Ambrosone, C. B., Andrews, L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Arnold, N., Aronson, K. J., Arun, B. K., Asseryanis, E., Auber, B., Auvinen, P., Azzollini, J., Balmana, J., Barkardottir, R. B., Barrowdale, D., Barwell, J., Beane Freeman, L. E., Beauparlant, C. J., Beckmann, M. W., Behrens, S., Benitez, J., Berger, R., Bermisheva, M., Blanco, A. M., Blomqvist, C., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bonanni, B., Borg, A., Brady, A. F., Brauch, H., Brenner, H., Bruning, T., Burwinkel, B., Buys, S. S., Caldes, T., Caliebe, A., Caligo, M. A., Campa, D., Campbell, I. G., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Claes, K. B. M., Clarke, C. L., Collavoli, A., Conner, T. A., Cox, D. G., Cybulski, C., Czene, K., Daly, M. B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dite, G. S., Ditsch, N., Domchek, S. M., Dorfling, C. M., dos-Santos-Silva, I., Durda, K., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Flyger, H., Foulkes, W. D., Friebel, T. M., Friedman, E., Gabrielson, M., Gaddam, P., Gago-Dominguez, M., Gao, C., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Gayther, S. A., Belotti, M., Bertrand, O., Birot, A. -M., Buecher, B., Caputo, S., Dupre, A., Fourme, E., Gauthier-Villars, M., Golmard, L., Le Mentec, M., Moncoutier, V., de Pauw, A., Saule, C., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Bressac-de-Paillerets, B., Caron, O., Guillaud-Bataille, M., Bignon, Y. -J., Uhrhammer, N., Bonadona, V., Lasset, C., Berthet, P., Castera, L., Vaur, D., Bourdon, V., Nogues, C., Noguchi, T., Popovici, C., Remenieras, A., Sobol, H., Coupier, I., Pujol, P., Adenis, C., Dumont, A., Revillion, F., Muller, D., Barouk-Simonet, E., Bonnet, F., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Guimbaud, R., Feillel, V., Toulas, C., Dreyfus, H., Leroux, C. D., Peysselon, M., Rebischung, C., Legrand, C., Baurand, A., Bertolone, G., Coron, F., Faivre, L., Jacquot, C., Lizard, S., Kientz, C., Lebrun, M., Prieur, F., Fert-Ferrer, S., Mari, V., Venat-Bouvet, L., Bezieau, S., Delnatte, C., Mortemousque, I., Colas, C., Coulet, F., Soubrier, F., Warcoin, M., Bronner, M., Sokolowska, J., Collonge-Rame, M. -A., Damette, A., Gesta, P., Lallaoui, H., Chiesa, J., Molina-Gomes, D., Ingster, O., Manouvrier-Hanu, S., Lejeune, S., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Guenel, P., Gutierrez-Barrera, A. M., Haeberle, L., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Harrington, P. A., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hopper, J. L., Hosgood, H. D., Howell, A., Hu, C., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., Aghmesheh, M., Greening, S., Amor, D., Gattas, M., Botes, L., Buckley, M., Friedlander, M., Koehler, J., Meiser, B., Saleh, M., Salisbury, E., Trainer, A., Tucker, K., Antill, Y., Dobrovic, A., Fellows, A., Fox, S., Harris, M., Nightingale, S., Phillips, K., Sambrook, J., Thorne, H., Armitage, S., Arnold, L., Kefford, R., Kirk, J., Rickard, E., Bastick, P., Beesley, J., Hayward, N., Spurdle, A., Walker, L., Beilby, J., Saunders, C., Bennett, I., Blackburn, A., Bogwitz, M., Gaff, C., Lindeman, G., Pachter, N., Scott, C., Sexton, A., Visvader, J., Taylor, J., Winship, I., Brennan, M., Brown, M., French, J., Edwards, S., Burgess, M., Burke, J., Patterson, B., Butow, P., Culling, B., Caldon, L., Callen, D., Chauhan, D., Eisenbruch, M., Heiniger, L., Chauhan, M., Christian, A., Dixon, J., Kidd, A., Cohen, P., Colley, A., Fenton, G., Crook, A., Dickson, R., Field, M., Cui, J., Cummings, M., Dawson, S. -J., Defazio, A., Delatycki, M., Dudding, T., Edkins, T., Farshid, G., Flanagan, J., Fong, P., Forrest, L., Gallego-Ortega, D., George, P., Gill, G., Kollias, J., Haan, E., Hart, S., Jenkins, M., Hunt, C., Lakhani, S., Lipton, L., Lobb, L., Mann, G., Mclachlan, S. A., O'Connell, S., O'Sullivan, S., Pieper, E., Robinson, B., Saunus, J., Scott, E., Shelling, A., Williams, R., Young, M. A., Isaacs, C., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Karlan, B. Y., Khusnutdinova, E., Kitahara, C. M., Konstantopoulou, I., Koutros, S., Kraft, P., Lambrechts, D., Lazaro, C., Le Marchand, L., Lester, J., Lesueur, F., Lilyquist, J., Loud, J. T., K. H., Lu, Luben, R. N., Lubinski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martens, J. W. M., Maurer, T., Mavroudis, D., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Newman, W. G., Nguyen-Dumont, T., Nielsen, F. C., Nielsen, S., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Olshan, A. F., Olson, J. E., Olsson, H., Osorio, A., Ottini, L., Peissel, B., Peixoto, A., Peto, J., Plaseska-Karanfilska, D., Pocza, T., Presneau, N., Pujana, M. A., Punie, K., Rack, B., Rantala, J., Rashid, M. U., Rau-Murthy, R., Rennert, G., Lejbkowicz, F., Rhenius, V., Romero, A., Rookus, M. A., Ross, E. A., Rossing, M., Rudaitis, V., Ruebner, M., Saloustros, E., Sanden, K., Santamarina, M., Scheuner, M. T., Schmutzler, R. K., Schneider, M., Senter, L., Shah, M., Sharma, P., Shu, X. -O., Simard, J., Singer, C. F., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Steele, L., Stoppa-Lyonnet, D., Tapper, W. J., Teixeira, M. R., Terry, M. B., Thomassen, M., Thompson, J., Thull, D. L., Tischkowitz, M., Tollenaar, R. A. E. M., Torres, D., Troester, M. A., Truong, T., Tung, N., Untch, M., Vachon, C. M., van Rensburg, E. J., van Veen, E. M., Vega, A., Viel, A., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Wieme, G., Wolk, A., Yang, X. R., Zheng, W., Ziogas, A., Zorn, K. K., Dunning, A. M., Lush, M., Wang, Q., Mcguffog, L., Parsons, M. T., Pharoah, P. D. P., Fostira, F., Toland, A. E., Andrulis, I. L., Ramus, S. J., Swerdlow, A. J., Greene, M. H., Chung, W. K., Milne, R. L., Chenevix-Trench, G., Dork, T., Schmidt, M. K., Easton, D. F., Radice, P., Hahnen, E., Antoniou, A. C., Couch, F. J., Nevanlinna, H., Surralles, J., Peterlongo, P., Caleca, Laura [0000-0002-3381-7493], Muranen, Taru A. [0000-0002-5895-1808], Dennis, Joe [0000-0003-4591-1214], Adlard, Julian [0000-0002-1693-0435], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Devilee, Peter [0000-0002-8023-2009], Foulkes, William D. [0000-0001-7427-4651], Isaacs, Claudine [0000-0002-9646-1260], Jakimovska, Milena [0000-0002-1506-0669], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Menon, Usha [0000-0003-3708-1732], Miller, Austin [0000-0001-9739-8462], Peto, Julian [0000-0002-1685-8912], Punie, Kevin [0000-0002-1162-7963], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Viel, Alessandra [0000-0003-2804-0840], Wieme, Greet [0000-0003-2718-5300], Zheng, Wei [0000-0003-1226-070X], Ziogas, Argyrios [0000-0003-4529-3727], Greene, Mark H. [0000-0003-1852-9239], Nevanlinna, Heli [0000-0002-0916-2976], Peterlongo, Paolo [0000-0001-6951-6855], Apollo - University of Cambridge Repository, Medical Oncology, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Yorkshire Regional Genetics Service, Department of Pathology, University Hospital and University of Iceland School of Medicine, Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig–Holstein, Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], University of Iceland [Reykjavik]-Landspitali - University Hospital, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Leicestershire Clinical Genetics Service, University Hospitals Leicester, Occupational and Environmental Epidemiology Branch [Bethesda, Maryland], Division of Cancer Epidemiology and Genetics [Bethesda, Maryland], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Chaim Sheba Medical Center, Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Department of Oncology, Department of Obstetrics and Gynaecology (MHH), Hannover Medical School [Hannover] (MHH), Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, North West Thames Regional Genetics, Northwick Park Hospital, Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology [Stuttgart], Division of Clinical Epidemiology and Aging Research, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Molecular Epidemiology Research Group, Department of Internal Medicine, Huntsman Cancer Institute, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Cancer Epidemiology, Division of Cancer Epidemiology, Division of Cancer Epidemiology and Genetics, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Division of Population Science, Fox Chase Cancer Center, Department of Human Genetics & Department of Pathology, Leiden University Medical Center (LUMC), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Department of Obstetrics and Gynecology [Munich, Germany], University-Hospital Munich-Großhadern [München]-Ludwig Maximilian University [Munich] (LMU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Wessex clinical genetics service, Lund University Hospital, Department of Genomic Medicine, University of Manchester [Manchester], Department of Breast Surgery, Herlev and Gentofte Hospital, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, National Institutes of Health [Bethesda] (NIH), Epidemiology Research Program, American Cancer Society, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), University of Melbourne, Ontario Cancer Genetics Network, Cancer Care Ontario, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], International Agency for Cancer Research (IACR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of OB/Gyn, University Breast Center Franconia, Univeristy Hospital Erlangen, Molecular Genetics of Breast Cancer, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, The Christie, Department of Statistics, Penn State University, University of Pennsylvania [Philadelphia], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Department of Gynecology and Obstetrics, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Department of Epidemiology, Cancer Prevention Institute of California, Unit of Nutrition and Cancer, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Institute of Biochemistry and Genetics [Bashkortostan Republic, Russia], Russian Academy of Sciences / Ufa Scientific Centre [Bashkortostan Republic, Russia]], National Center for Scientific Research 'Demokritos' (NCSR), Harvard School of Public Health, Laboratory for translational genetics Leuven, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, University of Hawai‘i [Mānoa] (UHM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Genetics Branch, Strangeways Research Laboratory, Unit of Medical Genetics, Fondazione IRCCS INT, Department of Gynaecology and Obstetrics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institute for Women's Health [London], University College London Hospitals (UCLH), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Department of Population Sciences, Beckman Research Institute of City of Hope, Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Department of Molecular Genetics and Department of Chemotherapy, National Institute of Oncology, University of Chicago, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human Genetics Group, Spanish National Cancer Research Centre, Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Genetics, Portuguese Oncology Institute, Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine (LSHTM), University of Munich, Karolinska University Hospital [Stockholm], Umm Al-Qura University, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Netherlands Cancer Institute, IT University of Copenhagen (ITU), Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Queen's University [Belfast] (QUB), Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University School of Medicine [Nashville], Laboratoire de Génomique des Cancers, Université Laval [Québec] (ULaval), Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Universität Heidelberg [Heidelberg], Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto = University of Porto, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Columbia University [New York], Odense University Hospital, Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), HELIOS Hospital Berlin-Buch, Cancer Genetics Laboratory, University of Pretoria [South Africa], Genomic Medicine Group, Universidade de Santiago de Compostela [Spain] (USC ), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, Center for Astrophysical Sciences [Baltimore], Johns Hopkins University (JHU), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of Science and Technology Beijing [Beijing] (USTB), University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Université de Pau et des Pays de l'Adour (UPPA), Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, The institute of cancer research [London], Department of Medical Genetics, Mayo Clinic, Cancer Epidemiology Centre, Cancer Council Victoria, Queensland Institute of Medical Research, Cancer Research U.K. Genetic Epidemiology Unit, Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medici, Department of Laboratory Medicine and Pathology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Muranen, Taru A [0000-0002-5895-1808], Foulkes, William D [0000-0001-7427-4651], Greene, Mark H [0000-0003-1852-9239], Institut Català de la Salut, [Figlioli G, Catucci I] IFOM - the FIRC Institute for Molecular Oncology, Genome Diagnostics Program, Milan, Italy. [Bogliolo M, Pujol R] Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain. Institute of Biomedical Research, Sant Pau Hospital, Barcelona, Spain. [Caleca L] Fondazione IRCCS Istituto Nazionale dei Tumori, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Milan, Italy. [Lasheras SV] Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Genètica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Hospital Universitari Vall d'Hebron, University of Iceland [Reykjavik], Università degli Studi di Milano = University of Milan (UNIMI), Universiteit Leiden-Universiteit Leiden, University of Pennsylvania-University of Pennsylvania, University of Pennsylvania, Georgetown University [Washington] (GU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universität Heidelberg [Heidelberg] = Heidelberg University, European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), Human Genetics, Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, Universitat Autònoma de Barcelona [Barcelona] (UAB), Università degli studi di Milano [Milano], University Hospitals of Leicester, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Biology, University of Pisa, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pomeranian Medical University-International Hereditary Cancer Centre, McGill University, University of Kansas Medical Center [Lawrence], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology-University of Cambridge [UK] (CAM), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Technical University of Munich (TUM), Università degli Studi di Roma 'La Sapienza' [Rome], IT University of Copenhagen, Laval University [Québec], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Pontificia Universidad Javeriana, University of Santiago de Compostela, Læknadeild (HÍ), Faculty of Medicine (UI), Biomedical Center (UI), Lífvísindasetur (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MINES ParisTech - École nationale supérieure des mines de Paris, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Universidade do Porto, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea, Against Breast Cancer, Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea. H2020, Cancer UK Grant, Canadian Institutes of Health Research, Ministère de Économie, de la science et de innovation (Canadá), NIH - National Cancer Institute (NCI) (Estados Unidos), Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Xunta de Galicia (España), Canadian Cancer Society, California Breast Cancer Research Program, California Department of Public Health, Medical Research Council (Reino Unido), Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilization Diseases), Federal Ministry of Education & Research (Alemania), German Cancer Aid, Helsinki University Central Hospital Research Fund, Finlands Akademi (Finlandia), Deutsche Forschungsgemeinschaft (Alemania), Russian Foundation for Basic Research, Ministry of Science and Higher Education (Rusia), National Health and Medical Research Council (Australia), Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Estée Lauder Companies’ Breast Cancer Campaign, Swedish Research Council, NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Lon V. Smith Foundation, Research Coincil of Lithuania, Italian Association for Cancer Research, University of Kansas. Cancer Center (Estados Unidos), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), French National Cancer Institute, Netherlands Organisation for Health Research and Development, Pink Ribbons Project, United States of Department of Health & Human Services, HUS Gynecology and Obstetrics, Clinicum, University of Helsinki, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, University Management, HUS Comprehensive Cancer Center, Biosciences, Helsinki University Hospital, and Lietuvos Mokslo Taryba (Lituania)
Subjects: 0301 basic medicine, Gene mutation, Càncer - Aspectes genètics, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Mama - Càncer, Fanconi anemia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Brjóstakrabbamein, Medicine and Health Sciences, Pharmacology (medical), FANCM, 631/208/68, skin and connective tissue diseases, Cancer genetics, Triple-negative breast cancer, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Manchester Cancer Research Centre, Otros calificadores::Otros calificadores::/genética [Otros calificadores], article, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Life Sciences & Biomedicine, 3122 Cancers, ABCTB Investigators, lcsh:RC254-282, KConFab, Olaparib, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, SDG 3 - Good Health and Well-being, 631/67/68, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Erfðafræði, Radiology, Nuclear Medicine and imaging, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, ddc:610, Risk factor, CHEK2, Krabbamein, Cancer och onkologi, FancM, Science & Technology, cancer, MUTATIONS, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Biology and Life Sciences, nutritional and metabolic diseases, cancer genetics, medicine.disease, GENE, Expressió gènica, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES], 030104 developmental biology, chemistry, 692/4028/67/68, Cancer and Oncology, FANCONI-ANEMIA, Cancer research, gene expression, C.5791C-GREATER-THAN-T, business
Abstract: Publisher's version (útgefin grein), Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors., Peterlongo laboratory is supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo and by a fellowship from Fondazione Umberto Veronesi to G. Figlioli. Surrallés laboratory is supported by the ICREA-Academia program, the Spanish Ministry of Health (projects FANCOSTEM and FANCOLEN), the Spanish Ministry of Economy and Competiveness (projects CB06/07/0023 and RTI2018-098419-B-I00), the European Commission (EUROFANCOLEN project HEALTH-F5-2012-305421 and P-SPHERE COFUND project), the Fanconi Anemia Research Fund Inc, and the “Fondo Europeo de Desarrollo Regional, una manera de hacer Europa” (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III, Spain. BCAC: we thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCFS thank Maggie Angelakos, Judi Maskiell, Tu Nguyen-Dumont is a National Breast Cancer Foundation (Australia) Career Development Fellow. ABCS thanks the Blood bank Sanquin, The Netherlands. Samples are made available to researchers on a non-exclusive basis. BCEES thanks Allyson Thomson, Christobel Saunders, Terry Slevin, BreastScreen Western Australia, Elizabeth Wylie, Rachel Lloyd. The BCINIS study would not have been possible without the contributions of Dr. Hedy Rennert, Dr. K. Landsman, Dr. N. Gronich, Dr. A. Flugelman, Dr. W. Saliba, Dr. E. Liani, Dr. I. Cohen, Dr. S. Kalet, Dr. V. Friedman, Dr. O. Barnet of the NICCC in Haifa, and all the contributing family medicine, surgery, pathology and oncology teams in all medical institutes in Northern Israel. The BREOGAN study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Muñoz Garzón, Alejandro Novo Domínguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Peña Fernández, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), José Antúnez, Máximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigación Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaquín González-Carreró and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. BSUCH thanks Peter Bugert, Medical Faculty Mannheim. CBCS thanks study participants, co-investigators, collaborators and staff of the Canadian Breast Cancer Study, and project coordinators Agnes Lai and Celine Morissette. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. Investigators from the CPS-II cohort thank the participants and Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, and Eunjung Lee at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine, and Fred Schumacher at Case Western University. DIETCOMPLYF thanks the patients, nurses and clinical staff involved in the study. The DietCompLyf study was funded by the charity Against Breast Cancer (Registered Charity Number 1121258) and the NCRN. We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. FHRISK thanks NIHR for funding. GC-HBOC thanks Stefanie Engert, Heide Hellebrand, Sandra Kröber and LIFE - Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber). The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany [HB, Wing-Yee Lo], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [HB], Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2180 - 390900677 [HB], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. HABCS thanks Michael Bremer. HEBCS thanks Heidi Toiminen, Kristiina Aittomäki, Irja Erkkilä and Outi Malkavaara. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Shamil Gantsev. KARMA thanks the Swedish Medical Research Counsel. KBCP thanks Eija Myöhänen, Helena Kemiläinen. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MABCS thanks Milena Jakimovska (RCGEB “Georgi D. Efremov), Katerina Kubelka, Mitko Karadjozov (Adzibadem-Sistina” Hospital), Andrej Arsovski and Liljana Stojanovska (Re-Medika” Hospital) for their contributions and commitment to this study. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG (Milan Breast Cancer Study Group) thanks Daniela Zaffaroni, Irene Feroce, and the personnel of the Cogentech Cancer Genetic Test Laboratory. We thank the coordinators, the research staff and especially the MMHS participants for their continued collaboration on research studies in breast cancer. MSKCC thanks Marina Corines and Lauren Jacobs. MTLGEBCS would like to thank Martine Tranchant (CHU de Québec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. NBHS thanks study participants and research staff for their contributions and commitment to the studies. We would like to thank the participants and staff of the Nurses’ Health Study and Nurses’ Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors assume full responsibility for analyses and interpretation of these data. OFBCR thanks Teresa Selander and Nayana Weerasooriya. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank staff in the Experimental Cancer Medicine Centre (ECMC) supported Faculty of Medicine Tissue Bank and the Faculty of Medicine DNA Banking resource. PREFACE thanks Sonja Oeser and Silke Landrith. PROCAS thanks NIHR for funding. RBCS thanks Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. We thank the SUCCESS Study teams in Munich, Duessldorf, Erlangen and Ulm. SZBCS thanks Ewa Putresza. UCIBCS thanks Irene Masunaka. UKBGS thanks Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. CIMBA: we are grateful to all the families and clinicians who contribute to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; all the individuals and the researchers who took part in CONSIT TEAM (Consorzio Italiano Tumori Ereditari Alla Mammella), thanks in particular: Giulia Cagnoli, Roberta Villa, Irene Feroce, Mariarosaria Calvello, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato, Isabella Marchi, Elena Bandieri, Antonio Russo, Daniele Calistri and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FPGMX: members of the Cancer Genetics group (IDIS): Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Diana Torres, Ignacio Briceno, Fabian Gil). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study. Drs.Sofia Khan, Irja Erkkilä and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez-Garcia, M.J. Blok; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. Overbeek; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; HVH (University Hospital Vall d’Hebron) the authors acknowledge the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron, Miguel Servet Progam (CP10/00617), and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab investigators, research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, Amber Aielts, and Michelle O’Conor; Christina Selkirk; Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Carole Pye, Patricia Harrington and Eva Wozniak. OSUCCG thanks Kevin Sweet, Caroline Craven, Julia Cooper, Michelle O’Conor and Amber Aeilts. BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) was supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia. For the BCFR-NY, BCFR-PA, BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BCINIS study was funded by the BCRF (The Breast Cancer Research Foundation, USA). The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, K05 CA136967, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the German Research Foundation (Do 761/10-1). The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014 and 17-44-020498. E.K was supported by the program for support the bioresource collections №007-030164/2 and study was performed as part of the assignment of the Ministry of Science and Higher Education of Russian Federation (№АААА-А16-116020350032-1). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. LMBC is supported by the ‘Stichting tegen Kanker’. DL is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286 and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, U01 CA179715), and the North Carolina University Cancer Research Fund. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation and the Swedish Research Council [grant 2017-00644 for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER)]. The SZBCS is financially supported under the program of Minister of Science and Higher Education “Regional Initiative of Excellence” in years 2019-2022, Grant No 002/RID/2018/19. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. CIMBA CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015 and Nr. P-MIP-19-164. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’) to S. Manoukian. UNIROMA1: Italian Association for Cancer Research (AIRC; grant no. 21389) to L. Ottini. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: NIH/NCI grant P30-CA006927. The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. Ana Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the French National Institute of Cancer (INCa) (grants AOR 01 082, 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015) and the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365). GEORGETOWN: the Survey, Recruitment and Biospecimen Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008) and the Fisher Center for Hereditary Cancer and Clinical Genomics Research. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. HVH (University Hospital Vall d’Hebron) This work was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds: FIS PI12/02585 and PI15/00355. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, P18/01029, and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, 2017SGR449, and PERIS Project MedPerCan), and CERCA program. IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5 × 1000” Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-45012). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: was funded by the Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Researc h UK. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124.
Published: 2019

41. The hematopoietic stem-cell niche in health and leukemia

Author: Simón Méndez-Ferrer, Abel Sanchez-Aguilera, Wellcome Trust, Medical Research Council (Reino Unido), Ministerio de Economía y Competitividad (España), Fundación ProCNIC, Red de Investigación Cooperativa en Terapia Celular (España), Comunidad de Madrid (España), Unión Europea. Comisión Europea, European Hematology Association, Howard Hughes Medical Institute, Méndez-Ferrer, Simón [0000-0002-9805-9988], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Cell type, Hematopoietic stem cell niche, education, ENDOTHELIAL NICHES, Leukemia stem cell, MESENCHYMAL STROMAL CELLS, MICROENVIRONMENT, Review, ACUTE MYELOID-LEUKEMIA, Biology, Hematopoietic stem cell, 03 medical and health sciences, Cellular and Molecular Neuroscience, Bone Marrow, Tumor Microenvironment, medicine, Animals, Humans, BONE-MARROW NICHE, Molecular Biology, health care economics and organizations, IN-VIVO, Bone marrow microenvironment, Pharmacology, Tumor microenvironment, Leukemia, CHRONIC MYELOGENOUS LEUKEMIA, Stem cell niche, MOUSE MODEL, Cell Biology, Hematopoietic Stem Cells, medicine.disease, 3. Good health, Cell biology, SELF-RENEWAL, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, PROGENITOR CELLS, Hematologic Neoplasms, Immunology, Neoplastic Stem Cells, Molecular Medicine, Bone marrow, Stem cell
Abstract: Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment. We thank members of the SM-F group for helpful discussions. This work was supported by core support grants from the Wellcome Trust and MRC to the Cambridge Stem Cell Institute, the Spanish Ministry of Economy and Competitiveness (SAF-2011-30308), Pro-CNIC Foundation, Severo Ochoa Center of Excellence award SEV-2015-0505 to CNIC, TerCel (Spanish Cell Therapy Network), Ramon y Cajal Program grants RYC-2011-09726 to AS-A and RYC-2009-04703 to SM-F), Marie Curie Career Integration Program grants (FP7-PEOPLE-2011-RG-294262/294096) to AS-A and SM-F; and a ConSEPOC-Comunidad de Madrid grant (S2010/BMD-2542) and Horizon2020 (ERC-2014-CoG-64765 grant to SM-F. This research was partly funded by a European Hematology Association Research Fellowship awarded to AS-A and an International Early Career Scientist Grant from the Howard Hughes Medical Institute to SM-F. Sí
Published: 2016

42. Genetic Etiology for Alcohol-Induced Cardiac Toxicity

Author: Ware, James S., Amor-Salamanca, Almudena, Tayal, Upasana, Govind, Risha, Serrano, Isabel, Salazar-Mendiguchía, Joel, García-Pinilla, José Manuel, Pascual-Figal, Domingo A., Núñez, Julio, Guzzo-Merello, Gonzalo, González-Vioque, Emiliano, Bardají, Alfredo, Manito, Nicolas, López-Garrido, Miguel A., Padron-Barthe, Laura, Edwards, Elizabeth, Whiffin, Nicola, Walsh, Roddy, Buchan, Rachel J., Midwinter, William, Wilk, Alicja, Prasad, Sanjay, Pantazis, Antonis, Baski, John, O'Regan, Declan P., Alonso-Pulpón, Luis, Cook, Stuart A., Lara-Pezzi, Enrique, Barton, Paul J., García-Pavia, Pablo, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Wellcome Trust, British Heart Foundation, Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Ministerio de Economía, Industria y Competitividad (España), Fundación ProCNIC, and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Subjects: Adult, Male, ACM, alcoholic cardiomyopathy, Cohort Studies, ExAC, Exome Aggregation Consortium, LVEF, left ventricular ejection fraction, Humans, Genetic Predisposition to Disease, genetics, titin, cardiovascular diseases, Prospective Studies, DCM, dilated cardiomyopathy, Aged, MUTATIONS, alcohol, Cardiomyopathy, Alcoholic, CONSUMPTION, Middle Aged, Cardiotoxicity, dilated cardiomyopathy, variant, cardiovascular system, TTNtv, titin truncating variant, Female, Self Report, GENOMICS
Abstract: BACKGROUND Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. OBJECTIVES This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. METHODS The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. RESULTS Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5\% vs. 2.9\%; p = 1.2 x10(-5)), but similar between patients with ACM and DCM (19.4\%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9\%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7\% absolute reduction in ejection fraction (95\% confidence interval: -2.3\% to -15.1\%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. CONCLUSIONS TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.(C)2018 The Authors. This work was supported by the Instituto de Salud Carlos III (ISCIII) (PI15/01551), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT), the Wellcome Trust (107469/Z/15/Z), the British Heart Foundation (SP/10/10/28431), the Medical Research Council, the National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit based at Royal Brompton \& Harefield NHS Foundation Trust and Imperial College London, the NIHR Biomedical Research Centre based at Imperial College London Healthcare NHS Trust and Imperial College London, the Fondation Leducq (11 CVD-01), and a Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, United Kingdom (HICF-R6-373). The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) ``Away of making Europe.´´ The Hospital Universitario Puerta de Hierro Majadahonda and Hospital Virgen de la Arrixaca are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). The funders played no role in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Prof. Cook is cofounder and a shareholder of Enleofen Bio. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Published: 2018

43. Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils

Author: Eva M. Janssen-Megens, Myrto Kostadima, Marta Gut, Farzin Pourfarzad, Sebastian Ullrich, Mattia Frontini, Luigi Grassi, Daniel Rico, Ida H. Hiemstra, Alfonso Valencia, Ehsan Habibi, Juliane Perner, Anton T.J. Tool, Hinri Kerstens, Angelika Merkel, Ivo Gut, Paul Flicek, Erik Mul, Taco W. Kuijpers, Ernesto Lowy, Enrique Carrillo-de-Santa-Pau, Joost H.A. Martens, Kim Berentsen, Laura Clarke, Marie-Laure Yaspo, Timo K. van den Berg, Willem H. Ouwehand, Avik Datta, Guoqiang Yi, Hendrik G. Stunnenberg, Dirk Roos, Martin Vingron, Matthias Linser, Simon Heath, Felipe Were, Dutch Cancer Foundation, European Research Council, British Health Foundation, Wellcome Trust, European Molecular Biology Organization, Bristol-Myers Squibb, Medical Research Council (Reino Unido), Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, ARD - Amsterdam Reproduction and Development, Molecular cell biology and Immunology, Pediatric surgery, APH - Aging & Later Life, Grassi, Luigi [0000-0002-6308-7540], Frontini, Mattia [0000-0001-8074-6299], Ouwehand, Willem [0000-0002-7744-1790], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Myeloid, Neutrophils, epigenome, Bone Marrow Cells, Biology, Myeloid differentiation, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, 03 medical and health sciences, Epigenome, 0302 clinical medicine, medicine, Transcriptional regulation, Cytotoxic T cell, Humans, Epigenetics, lcsh:QH301-705.5, Molecular Biology, Neutrophil, neutrophil, Cell Differentiation, Chromatin, 3. Good health, Respiratory burst, Cell biology, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), Gene Expression Regulation, 030220 oncology & carcinogenesis, myeloid differentiation, Bone marrow, transcriptome
Abstract: Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils. The work presented here was supported by the Landsteiner Foundation forBlood Transfusion Research (LSBR-1121 to T.W.K.) and by the Dutch CancerFoundation (KUN 2011-4 937 to J.H.A.M.). The work was funded by a grantfrom the European Commission 7th Framework Program (FP72007-2013,grant 282510, BLUEPRINT). M.F. ssupported sh Heart Foundation(BHF) Cambridge Centre of Excellence (RE/13/6/30180). Additional support wasrovided by the Wellcome Trust (WT108749/Z/15/Z to P.F.) and by the Eu-ropean Molecular Biology Laboratory (E.L., A.D.,L.C., P.F.). Research in theOuwehand laboratory is also supported by grants from Bristol-Myers Squibb,the British Heart Foundation, the Medical Research Council, the National Insti-tutefor Health Research (NIHR) (W.H.O. is senior investigator), and NHSBlood and Transplant (NHSB T). Sí
Published: 2018

44. Increased non-AIDS mortality among persons with AIDS-defining events after antiretroviral therapy initiation

Author: Peter Reiss, François Dabis, Amy C. Justice, Matthias Cavasinni, Michael Gill, José M. Miró, Suzanne M Ingle, Robert Zangerle, Colette Smith, Heidi M. Crane, Julia del Amo, Antonella d'Arminio Monforte, Jonathan A C Sterne, Sophie Abgrall, Margaret T May, Michael S. Saag, Bryan E. Shepherd, David M. Moore, Jodie L. Guest, Niels Obel, Gerd Fätkenheuer, April C. Pettit, Mark J. Giganti, Leah Shepherd, Ramón Teira, Timothy R. Sterling, AII - Infectious diseases, APH - Aging & Later Life, Infectious diseases, Global Health, AII - Amsterdam institute for Infection and Immunity, Medical Research Council (Reino Unido), Department for International Development (Reino Unido), National Institutes of Health (Estados Unidos), Vanderbilt University Medical Center (Estados Unidos), Ministerio de Sanidad y Consumo (España), Instituto de Salud Carlos III, Red de Investigación Cooperativa en Investigación en Sida (España), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Stichting HIV Monitoring (Netherlands), Augustinus Foundation, Antiretroviral Therapy Cohort Collaboration (ART-CC) investigators, and Universitat de Barcelona
Subjects: Male, marginal structural model, 0301 basic medicine, non‐Hodgkin's lymphoma, Marginal structural model, Cohort Studies, 0302 clinical medicine, 030212 general & internal medicine, Research Articles, AIDS patients, Lymphoma, Non-Hodgkin, Pneumonia, Pneumocystis, Hazard ratio, Antiretrovirals, Non-Hodgkin's lymphoma, Middle Aged, 3. Good health, AIDS defining events, Infectious Diseases, tuberculosis, non‐AIDS mortality, Cohort, Female, Research Article, Acquired Immunodeficiency Syndrome/complications, Acquired Immunodeficiency Syndrome/drug therapy, Adult, Anti-HIV Agents/therapeutic use, Humans, Lymphoma, Non-Hodgkin/mortality, Pneumonia, Pneumocystis/mortality, Tuberculosis/mortality, AIDS-defining events, Pneumocystis jiroveci pneumonia, non-AIDS mortality, non-Hodgkin's lymphoma, Cohort study, AIDS‐defining events, medicine.medical_specialty, Tuberculosis, Anti-HIV Agents, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Mortalitat, medicine, Mortality, Malalts de sida, Acquired Immunodeficiency Syndrome, business.industry, Public Health, Environmental and Occupational Health, non-Hodgkin’s lymphoma, medicine.disease, Antiretroviral agents, 030112 virology, Confidence interval, Non-AIDS mortality, business
Abstract: INTRODUCTION: HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. METHODS: We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. RESULTS: The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). CONCLUSIONS: In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival. We would like to thank the following cohorts for participating in this study; the AIDS Therapy Evaluation Project Netherlands (ATHENA); ANRS CO4 French Hospital Database on HIV (FHDH); ANRS CO3 Aquitaine Cohort, France; Departments of Internal Medicine at University of Cologne and Bonn, Germany; K€oln/Bonn Cohort, Germany; Italian Cohort of Antiretroviral-Na€ıve Patients (ICONA); CORIS, Spain; Proyecto para la Informatizaci on del Seguimiento Cl ınico-epidemiol ogico de la Infecci on por HIV y SIDA (PISCIS), Spain; Royal Free Hospital Cohort, London UK; Swiss HIV Cohort Study (SHCS); The Multicenter Study Group on EuroSIDA; Southern Alberta Clinic, Canada; HIV Atlanta Veterans affairs Cohort Study (HAVACS), USA; UAB 1917 Clinic Cohort, Birmingham, Alabama, USA; Veterans Ageing Cohort Study (VACS8),USA; Vanderbilt- Meharry and Tennessee Center for AIDS Research, Nashville, Tennessee, USA; University of Washington Harborview Medical Center, USA; € Osterreichische HIV-Kohortenstudie (OEHIVKOS), Austria; Danish HIV Cohort Study, Denmark; VACH, (Spain); and HAART Observational Medical Evaluation and Research (HOMER), British Columbia, Canada. We would also like to thank the ART-CC Steering group. Sí
Published: 2018

45. Myeloid cell deficiency of p38 gamma/p38 delta protects against candidiasis and regulates antifungal immunity

Author: Pilar Fajardo, Susana Alemany, Alejandra Escós, Mihai G. Netea, Dayanira Alsina-Beauchamp, Juan Jose Sanz-Ezquerro, Carlos del Fresno, Jorge Domínguez-Andrés, Noelia Aparicio, Natalia Shpiro, Diego Gonzalez‐Romero, Ana Cuenda, Miguel A. Martín-Serrano, Ana Risco, Carlos Ardavín, Ester Díaz-Mora, Rafal Zur, Gordon D. Brown, Ministerio de Economía y Competitividad (España), Fundación La Marató TV3, European Research Council, Dutch Research Council (Holanda), Wellcome Trust, Medical Research Council (Reino Unido), Fundació La Marató de TV3, Netherlands Organization for Scientific Research, Medical Research Council (UK), University of Aberdeen, Fundación 'la Caixa', and European Commission
Subjects: 0301 basic medicine, Medicine (General), Myeloid, Neutrophils, Cell, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Nitric Oxide Synthase Type II, QH426-470, Mitogen-Activated Protein Kinase 13, Mitogen-Activated Protein Kinase 12, Candida albicans, Medicine, Myeloid Cells, signalling, Research Articles, IN-VIVO, Mice, Knockout, P38-DELTA, biology, INVASIVE CANDIDIASIS, Candidiasis, Microbiology, Virology & Host Pathogen Interaction, 3. Good health, medicine.anatomical_structure, Host-Pathogen Interactions, p38MAPK, Molecular Medicine, Female, Infection, Research Article, Signal Transduction, Antifungal, medicine.drug_class, kinase inhibitor, Immunology, CROSS-TALK, TNF-ALPHA PRODUCTION, Signalling, Sepsis, 03 medical and health sciences, R5-920, All institutes and research themes of the Radboud University Medical Center, INFLAMMATION, Immunity, Genetics, Animals, PATTERN-RECOGNITION RECEPTORS, Pharmacology & Drug Discovery, Kinase inhibitor, Innate immune system, business.industry, Septic shock, Macrophages, P38-GAMMA, LOCI-2 TPL2 KINASE, medicine.disease, biology.organism_classification, infection, Mice, Inbred C57BL, 030104 developmental biology, INNATE IMMUNITY, business, Reactive Oxygen Species
Abstract: Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans., This work was supported by grants from the MINECO [SAF2013‐45331‐R and SAF2016‐79792‐R (AEI/FEDER, UE)] to AC and JJS‐E, La Marató TV3 Foundation (20133431) to AC and (SAF2014‐52009‐R) to SA. ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research to MGN, and Wellcome Trust, the Medical Research Council (MRC; UK), the MRC Centre for Medical Mycology at the University of Aberdeen to GDB. DAB and AE receive MINECO FPI fellowships, AR a MINECO Juan de la Cierva award and JD‐A a La Caixa Foundation PhD fellowship.
Published: 2018

46. TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression

Author: Van T. M. Nguyen, Elisa Giovannetti, Niccola Funel, Thomas M. Gress, Adam E Frampton, Hugang Feng, Long R. Jiao, Christopher Heeschen, Alexander de Giorgio, Nicholas R. Lemoine, Jonathan Krell, Silvia Ottaviani, Justin Stebbing, Leandro Castellano, Sara Trabulo, Luca Magnani, Sladjana Zagorac, Ylenia Lombardo, Action Against Cancer, Pancreatic Cancer UK, Academy of Medical Sciences (Reino Unido), Royal College of Surgeons of Edinburgh, Colin McDavid Family Trust, No Surrender Cancer Trust, Ralph Bates Pancreatic Cancer Research Fund, Dutch Cancer Society (Holanda), Italian Association for Cancer Research, Tumour Institute of Tuscany (Italia), Regione Toscana 'Progetto DIAMANTE'/FAS grant, Medical Research Council (Reino Unido), Medical oncology laboratory, AGEM - Re-generation and cancer of the digestive system, AII - Inflammatory diseases, Royal College of Surgeons Edinburgh, The Academy of Medical Sciences, Imperial College London, Cancer Research UK, and Imperial College Trust
Subjects: 0301 basic medicine, EXPRESSION, LASER MICRODISSECTION, MICRORNAS, Science, BIOGENESIS, General Physics and Astronomy, RNA-binding protein, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cancer stem cell, CANCER STEM-CELLS, MD Multidisciplinary, microRNA, medicine, lcsh:Science, PANCREATIC TUMOR-GROWTH, Regulation of gene expression, MESENCHYMAL TRANSITION, Science & Technology, Multidisciplinary, Q0180.55.M3, ADENOCARCINOMA, General Chemistry, 3. Good health, Cell biology, Multidisciplinary Sciences, SELF-RENEWAL, 030104 developmental biology, TARGET, 030220 oncology & carcinogenesis, embryonic structures, Science & Technology - Other Topics, lcsh:Q, Signal transduction, Carcinogenesis, Transforming growth factor
Abstract: TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell–cell junctions’ pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis., In pancreatic ductal adenocarcinoma, TGF-β/Activin induce epithelial-to-mesenchymal transition (EMT) and stemness. Here, the authors show that TGF-β induces pro-tumourigenic miR-100 and miR-125b, but blocks anti-tumourigenic let-7a maturation via LIN28B, regulating pathways to promote stemness, EMT and tumourigenesis.
Published: 2018

47. Transplantation of allogeneic pericytes improves myocardial vascularization and reduces interstitial fibrosis in a swine model of reperfused acute myocardial infarction

Author: Alvino, Valeria Vincenza, Fernández-Jiménez, Rodrigo, Rodriguez-Arabaolaza, Iker, Slater, Sadie, Mangialardi, Giuseppe, Avolio, Elisa, Spencer, Helen, Culliford, Lucy, Hassan, Sakinah, Sueiro Ballesteros, Lorena, Herman, Andrew, Ayaon-Albarrán, Ali, Galán-Arriola, Carlos, Sánchez-González, Javier, Hennessey, Helena, Delmege, Catherine, Ascione, Raimondo, Emanueli, Costanza, Angelini, Gianni Davide, Ibanez, Borja, Madeddu, Paolo, British Heart Foundation, Medical Research Council (Reino Unido), National Health Service (Reino Unido), Ministerio de Economía, Industria y Competitividad (España), Fundación Jesús Serra, Fundacion Interhospitalaria de Investigacion Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, and Fundación ProCNIC
Subjects: Male, Cardiac & Cardiovascular Systems, Sus scrofa, Cell- and Tissue-Based Therapy, Myocardial Infarction, ISCHEMIC-HEART-DISEASE, MOUSE, THERAPY, Vascular Medicine, Ventricular Function, Left, angiogenesis, Cells, Cultured, Original Research, Aged, 80 and over, Ventricular Remodeling, Middle Aged, myocardial infarction, large animal models, Centre for Surgical Research, cardiovascular system, Heterografts, Female, Life Sciences & Biomedicine, Neovascularization, Physiologic, Myocardial Reperfusion Injury, BTC (Bristol Trials Centre), pericytes, MESENCHYMAL STEM-CELLS, REGENERATION, Vascular Biology, Animals, Humans, Transplantation, Homologous, OPTIMIZATION, Aged, Science & Technology, Allogeneic Cells, Myocardium, Stroke Volume, Recovery of Function, Fibrosis, Myocardial Contraction, LIMB ISCHEMIA, CARDIOMYOCYTE PROLIFERATION, Disease Models, Animal, PROGENITOR CELLS, Cardiovascular System & Cardiology, ISCHEMIA/REPERFUSION, cell therapy
Abstract: Background-Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model. Methods and Results-We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following invitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone. Conclusions-Immunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements. Madeddu is the recipient of grants from the British Heart Foundation and the Medical Research Council in support of research on human and swine APCs. Angelini is the recipient of a grant from the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust, which partially supported the present study. Fernandez-Jimenez was the recipient of nonoverlapping grants from the Ministry of Economy, Industry, and Competitiveness through the Instituto de Salud Carlos III (Rio Hortega fellowship); and the Fundacion Jesus Serra, the Fundacion Interhospitalaria de Investigacion Cardiovascular (FIC), and the CNIC (FICNIC fellowship). The use of QMass software was partly supported by a scientific collaboration between the CNIC and Medis Medical Imaging Systems BV. This study forms part of a Master Research Agreement (MRA) between the CNIC and Philips Healthcare. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Sí
Published: 2018

48. Hypothalamic AMPK-ER Stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance

Author: Juan Carlos Roa, Luis M. Varela, Patricia Seoane-Collazo, Tomás Sobrino, Eva Rial-Pensado, Miguel López, Roger J. Davis, Vidya Velagapudi, Andrew J. Whittle, Pablo B. Martínez de Morentin, Gema Medina-Gómez, Carlos Dieguez, Rubén Nogueiras, Kamal Rahmouni, Laura Liñares-Pose, Antonio Vidal-Puig, Rafael Vázquez-Martínez, Teresa C. Delgado, Ismael González-García, Matej Orešič, Guadalupe Sabio, Cristina Contreras, Y. C. Loraine Tung, Xabier Buqué, Patricia Aspichueta, Igor Aurrekoetxea, Beatriz Gomez-Santos, Francesc Villarroya, Núria Casals, Noelia Martínez-Sánchez, Donald A. Morgan, Manuel Tena-Sempere, Anthony P. Coll, María L. Martínez-Chantar, Peter J. Voshol, Tania López-González, Joan Villarroya, María M. Malagón, Francisco Gonzalez, Jens Mittag, Krishna Chatterjee, University of Helsinki, Institute for Molecular Medicine Finland, Chatterjee, Krishna [0000-0002-2654-8854], Coll, Anthony [0000-0003-2594-7463], Vidal-Puig, Antonio [0000-0003-4220-9577], Apollo - University of Cambridge Repository, Unión Europea. Comisión Europea, Xunta de Galicia (España), Regional Government of Andalusia (España), Basque Government (España), EITB - Radio Televisión Pública Vasca, Instituto de Salud Carlos III, Government of Catalonia (España), Fundación La Marató TV3, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Medical Research Council (Reino Unido), Wellcome Trust, Deutsche Forschungsgemeinschaft (Alemania), National Institutes of Health (Estados Unidos), American Heart Association, Fraternal Order of Eagles (Estados Unidos), European Foundation for the Study of Diabetes, Fundación AstraZeneca, Atresmedia, Fundación ProCNIC, and University of Iowa (Estados Unidos)
Subjects: 0301 basic medicine, AMPK, Male, HOMEOSTASIS, Adipose Tissue, Brown/metabolism, Physiology, Obesidad, Neurones, AMPK, BAT, ER stress, JNK1, SF1, VMH, autonomic nervous system, ceramides, liver, thyroid hormones, Inbred C57BL, Neuronas, Rats, Sprague-Dawley, Mice, 0302 clinical medicine, Adipose Tissue, Brown, Brown adipose tissue, NEURONS, Mitogen-Activated Protein Kinase 8/metabolism, Metabolismo, Neurons, INSULIN-RESISTANCE, Triiodothyronine, Thermogenesis, Metabolisme, SF1, medicine.anatomical_structure, Thyroid Hormones/metabolism, Lipogenesis, Obesitat, ER stress, Signal Transduction, Liver/metabolism, ADIPOSE-TISSUE THERMOGENESIS, medicine.medical_specialty, DIET-INDUCED OBESITY, Tejido adiposo, Hypothalamus, RAT-LIVER, Adipose tissue, Biology, METABOLISM, liver, Resistencia a la insulina, Article, 03 medical and health sciences, Lipid oxidation, BROWN FAT, Brown/metabolism, Internal medicine, medicine, Animals, Mitogen-Activated Protein Kinase 8, Obesity, Molecular Biology, VLDL SECRETION, thyroid hormones, Insulinoresistència, ceramides, Hypothalamus/metabolism, RECEPTOR, autonomic nervous system, ta1182, JNK1, BAT, Lipid metabolism, Insulin resistance, Cell Biology, Triiodothyronine/metabolism, VMH, Lipid Metabolism, Rats, Mice, Inbred C57BL, Teixit adipós, 030104 developmental biology, Endocrinology, Metabolism, Unfolded protein response, 1182 Biochemistry, cell and molecular biology, Sprague-Dawley, 3111 Biomedicine, Energy Metabolism, 030217 neurology & neurosurgery
Abstract: Summary Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism., Graphical Abstract, Highlights • Central T3 regulates lipogenesis in liver via the parasympathetic nervous system • Central T3 regulates lipid oxidation in BAT via the sympathetic nervous system • Ablation of AMPK in SF1 neurons of the VMH recapitulates the effects of T3 • Hypothalamic JNK1 and ceramides/ER stress mediate T3 actions on liver and BAT, Martínez-Sánchez et al. show that thyroid hormones act in the hypothalamus to regulate hepatic lipogenesis and brown fat lipid oxidation via the parasympathetic and sympathetic nervous systems. These peripheral effects are orchestrated by two distinct signaling pathways in the VMH, JNK1 and ceramides/ER stress, which are under AMPK control.
Published: 2017

49. Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

Author: Alessandra Ferlini, David Salgado, Velina Guergueltcheva, Olivia Schreiber-Katz, Zaïda Koeks, Grace McMacken, Hugh Dawkins, Jan Kirschner, Angela Stringer, Vedrana Milic Rasic, Teodora Chamova, Sophelia H. S. Chan, Hanns Lochmüller, Lawrence Korngut, Jan J.G.M. Verschuuren, Maggie C. Walter, Clemens Bloetzer, Jordi Díaz-Manera, Veronika Karcagi, Nina Barišić, Tunca Oznur, Andriy V. Shatillo, Ann Martin, Rasha El Sherif, Yi Dai, Kyriaki Kekou, Jaana Lahdetie, Andrea Klein, Rosário Santos, Holly L. Peay, Haluk Topaloglu, Elena Neagu, Maria E. Foncuberta, Richard Roxburgh, Kevin M. Flanigan, Miriam Rodrigues, Kate Bushby, Farhad Bayat, Petr Brabec, Christophe Béroud, Catherine L. Bladen, Jen Wang, Matthew I. Bellgard, Venkatarman Viswanathan, Svetlana Artemieva, Anna Lusakowska, Konstantina Kosma, Manuel Posada, Agnes Herczegfalvi, Soledad Monges, Anna Kostera-Pruszczyk, Dina Vojinovic, Volker Straub, Anna J. Roy, En Kimura, Janneke C. van den Bergen, Filippo Buccella, Leanne Lamont, Erik W. van Zwet, Craig Campbell, Oksana Pogoryelova, Eduard Gallardo, Marta Garami, Ayşe Karaduman, Unión Europea. Comisión Europea. 6 Programa Marco, Unión Europea. Comisión Europea. 7 Programa Marco, Medical Research Council (Reino Unido), Department of Medical Statistics and Bioinformatics, Leiden University Medical Center (LUMC), Neuropaediatrics, Garrahan National Paediatric Hospital, Centre for Comparative Genomics, Murdoch University, Ctr Comparat Genom, Department of Neurology, Ludwig-Maximilians-Universität München (LMU)-Friedrich-Baur-Institute, Department of Reproduction and Growth, UOL of Medical Genetics (University Hospital St Anna, Ferrara), University of Ferrara at St. Anna Hospital, Medicina Pediátrica y del Desarrollo, Instituto de Investigación en Enfermedades Raras (IIER)-Instituto de Salud Carlos III [Madrid] (ISC), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden-Universiteit Leiden, Department of Biological and Environmental Engineering, Cornell University [New York], Università degli Studi di Ferrara = University of Ferrara (UniFE), Department of Embryology [Warsaw], Institute of Zoology [Warsaw], Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW)-Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW), Instituto de Salud Carlos III [Madrid] (ISC)-Instituto de Investigación en Enfermedades Raras (IIER), and Fizyoterapi ve Rehabilitasyon
Subjects: 0301 basic medicine, Research Report, Male, Neurology, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], Cardiomyopathy, Disease, computer.software_genre, 0302 clinical medicine, Adrenal Cortex Hormones, Child, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Database, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Neuromuscular diseases, Treatment Outcome, Databases as Topic, Child, Preschool, Cohort, DMD, TREAT-NMD, Neurology (clinical), musculoskeletal diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Population, Socio-culturale, 610 Medicine & health, Adrenal Cortex Hormones/therapeutic use, Cross-Sectional Studies, Humans, Infant, Infant, Newborn, Muscular Dystrophy, Duchenne/epidemiology, Muscular Dystrophy, Duchenne/genetics, Muscular Dystrophy, Duchenne/therapy, Young Adult, 03 medical and health sciences, 360 Social problems & social services, medicine, education, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Clinical trial, Muscular Dystrophy, Duchenne, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, 030217 neurology & neurosurgery, Rare disease
Abstract: Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. This work was supported by TREAT-NMD operating grants, FP6 LSHM-CT-2006-036825, 20123307 UNEW FY2013 and AFM 16104. Further support came from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics) and Medical Research Council UK (reference G1002274, grant ID 98482). Sí
Published: 2017

50. beta-Blockers and Mortality After Acute Myocardial Infarction in Patients Without Heart Failure or Ventricular Dysfunction

Author: Dondo, Tatendashe B., Hall, Marlous, West, Robert M., Jernberg, Tomas, Lindahl, Bertil, Bueno, Hector, Danchin, Nicolas, Deanfield, John E., Hemingway, Harry, Fox, Keith A. A., Timmis, Adam D., Gale, Chris P., British Health Foundation, National Institute for Health Research (Reino Unido), and Medical Research Council (Reino Unido)
Subjects: OUTCOMES, Kardiologi, METOPROLOL, average treatment effect, GUIDELINES, THERAPY, survival, DISEASE, STEMI, NSTEMI, preserved left ventricular systolic function, MANAGEMENT, TRIAL, Cardiac and Cardiovascular Systems, ELEVATION, INTERVENTION, propensity score
Abstract: BACKGROUND For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if beta-blockers are associated with reduced mortality. OBJECTIVES The goal of this study was to determine the association between beta-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD). METHODS This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of beta-blockers and 1-year mortality. RESULTS Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non-ST-segment elevation myocardial infarction, 88,542 (96.4\%) and 81,933 (93.2\%) received beta-blockers, respectively. For the entire cohort, with> 163,772 person-years of observation, there were 9,373 deaths (5.2\%). Unadjusted 1-year mortality was lower for patients who received beta-blockers compared with those who did not (4.9\% vs. 11.2\%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without beta-blocker use (average treatment effect [ATE] coefficient: 0.07; 95\% confidence interval [CI]: -0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95\% CI: -0.98 to 1.58; p = 0.637) and non-ST-segment elevation myocardial infarction (ATE coefficient: -0.07; 95\% CI: -0.68 to 0.54; p = 0.819). CONCLUSIONS Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of beta-blockers was not associated with a lower risk of death at any time point up to 1 year. (beta-Blocker Use and Mortality in Hospital Survivors of Acute Myocardial Infarction Without Heart Failure; (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. The authors gratefully acknowledge the contribution of all hospitals and health care professions who participate in the MINAP registry. They also acknowledge the MINAP Academic Group and the National Institute for Cardiovascular Outcomes Research for their contribution to this research and to the funders, including the British Health Foundation, the National Institute for Health Research, and the Medical Research Council. Sí
Published: 2017

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

90 results on '"Medical Research Council (Reino Unido)"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources