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45 results on '"National Institute for Health Research (Reino Unido)"'

1. Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, European Commission, Generalitat Valenciana, National Science Foundation, EEUU, COMISION DE LAS COMUNIDADES EUROPEA, National Institute for Health Research, Reino Unido, Belletti, Rebecca, Romero Pérez, Lucia, Martínez-Mateu, Laura, Cherry, Elizabeth M., Fenton, Flavio H., Saiz Rodríguez, Francisco Javier, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, European Commission, Generalitat Valenciana, National Science Foundation, EEUU, COMISION DE LAS COMUNIDADES EUROPEA, National Institute for Health Research, Reino Unido, Belletti, Rebecca, Romero Pérez, Lucia, Martínez-Mateu, Laura, Cherry, Elizabeth M., Fenton, Flavio H., and Saiz Rodríguez, Francisco Javier
Abstract: [EN] Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation¿namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M¿using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters¿ value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor¿s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor¿s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor¿s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor¿s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhyth
Published: 2021

2. 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

3. First in-vivo Demonstration of Bilateral Blood-Brain Barrier Opening Using Acoustic Holograms in Mice

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Universitat Politècnica de València. Instituto de Instrumentación para Imagen Molecular - Institut d'Instrumentació per a Imatge Molecular, Generalitat Valenciana, Agencia Estatal de Investigación, European Regional Development Fund, National Institutes of Health, EEUU, Agència Valenciana de la Innovació, National Institute for Health Research, Reino Unido, Jiménez-Gambín, Sergio, Jimenez, Noe, Benlloch Baviera, Jose María, Camarena Femenia, Francisco, Pouliopoulos, Antonios N., Konofagou, Elisa E., Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Universitat Politècnica de València. Instituto de Instrumentación para Imagen Molecular - Institut d'Instrumentació per a Imatge Molecular, Generalitat Valenciana, Agencia Estatal de Investigación, European Regional Development Fund, National Institutes of Health, EEUU, Agència Valenciana de la Innovació, National Institute for Health Research, Reino Unido, Jiménez-Gambín, Sergio, Jimenez, Noe, Benlloch Baviera, Jose María, Camarena Femenia, Francisco, Pouliopoulos, Antonios N., and Konofagou, Elisa E.
Abstract: [EN] Focused ultrasound (FUS) with microbubbles allows for non-invasive targeted drug delivery into the central nervous system (CNS) by temporally and locally disrupting the bloodbrain barrier (BBB). However, current FUS technologies are not able to simultaneously target several brain structures. In this work, we open the BBB in two regions in a murine brain using a single-element transducer with a coupled 3D-printed holographic lens, which is designed to simultaneously create two symmetric foci in anesthetized mice in vivo. The proposed approach shows many advantages: (1) simple and low-cost; (2) correction of aberrations due to skull and water cone; and (3) multiple BBB opening (BBBO) locations with only one sonication, becoming a time- and cost-effective therapeutic system for neurological diseases. For the in-vivo experiment, contrast-enhanced, T1- weighted MRI scan was conducted following BBBO, showing gadolinium extravasation at two symmetric focal spots. The two BBBO regions were separated by 3.0 +- 0.7 mm (n=5 mice) compared to 5.3 mm in full-wave simulations. This work shows the capability of bifocal ultrasound generation in separate animals using a unique uCT scan. A bilateral BBBO was achieved with a single sonication using a holographic lens in mice, thus improving the efficiency and defining a new approach for several neurodegenerative diseases targeting symmetric brain structures, e.g. hippocampus, putamen or caudate. This study demonstrates the feasibility of hologram-assisted BBBO for targeted drug delivery in the CNS in symmetric regions in separate hemispheres.
Published: 2020

4. 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

5. Propagation of meandering rotors surrounded by areas of high dominant frequency in persistent atrial fibrillation

Author: Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, National Institute for Health Research, Reino Unido, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior, Brasil, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil, Salinet, Joao, Schlindwein, Fernando S., Stafford, Peter, Almeida, Tiago P., Li, Xin, Vanheusden, Frederique, Guillem Sánchez, María Salud, Ng, André, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, National Institute for Health Research, Reino Unido, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior, Brasil, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil, Salinet, Joao, Schlindwein, Fernando S., Stafford, Peter, Almeida, Tiago P., Li, Xin, Vanheusden, Frederique, Guillem Sánchez, María Salud, and Ng, André
Abstract: [EN] [Background] Identification of arrhythmogenic regions remains a challenge in persistent atrial fibrillation (persAF). Frequency and phase analysis allows identification of potential ablation targets. [Objective] This study aimed to investigate the spatiotemporal association between dominant frequency (DF) and reentrant phase activation areas. [Methods] A total of 8 persAF patients undergoing first-time catheter ablation procedure were enrolled. A noncontact array catheter was deployed into the left atrium (LA) and 2048 atrial fibrillation electrograms (AEGs) were acquired for 15 seconds following ventricular far-field cancellation. DF and phase singularity (PS) points were identified from the AEGs and tracked over consecutive frames. The spatiotemporal correlation of high DF areas and PS points was investigated, and the organization index at the core of high-DF areas was compared with that of their periphery. [Results] The phase maps presented multiple simultaneous PS points that drift over the LA, with preferential locations. Regions displaying higher PS concentration showed a degree of colocalization with DF sites, with PS and DF regions being neighbors in 61.8% and with PS and DF regions overlapping in 36.8% of the time windows. Sites with highest DF showed a greater degree of organization at their core compared with their periphery. After ablation, the PS incidence reduced over the entire LA (36.2% ± 23.2%, P < .05), but especially at the pulmonary veins (78.6% ± 22.2%, P < .05). [Conclusion] Multiple PS points drifting over the LA were identified with their clusters correlating spatially with the DF regions. After pulmonary vein isolation, the PS¿s complexity was reduced, which supports the notion that PS sites represent areas of relevance to the atrial substrate.
Published: 2017

6. 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

7. Method for automatic adjustment of an insulin bolus calculator: In silico robustness evaluation under intra-day variability

Author: Universitat Politècnica de València. Instituto Universitario de Automática e Informática Industrial - Institut Universitari d'Automàtica i Informàtica Industrial, Universitat Politècnica de València. Departamento de Ingeniería de Sistemas y Automática - Departament d'Enginyeria de Sistemes i Automàtica, Generalitat Valenciana, Wellcome Trust, National Institute for Health Research, Reino Unido, Herrero, Pau, Pesl, Peter, Bondía Company, Jorge, Reddy, Monika, Oliver, Nick, Georgiou, Pantelis, Toumazou, Christofer, Universitat Politècnica de València. Instituto Universitario de Automática e Informática Industrial - Institut Universitari d'Automàtica i Informàtica Industrial, Universitat Politècnica de València. Departamento de Ingeniería de Sistemas y Automática - Departament d'Enginyeria de Sistemes i Automàtica, Generalitat Valenciana, Wellcome Trust, National Institute for Health Research, Reino Unido, Herrero, Pau, Pesl, Peter, Bondía Company, Jorge, Reddy, Monika, Oliver, Nick, Georgiou, Pantelis, and Toumazou, Christofer
Abstract: Background and objective: Insulin bolus calculators are simple decision support software tools incorporated in most commercially available insulin pumps and some capillary blood glucose meters. Although their clinical benefit has been demonstrated, their utilisation has not been widespread and their performance remains suboptimal, mainly because of their lack of flexibility and adaptability. One of the difficulties that people with diabetes, clinicians and carers face when using bolus calculators is having to set parameters and adjust them on a regular basis according to changes in insulin requirements. In this work, we propose a novel method that aims to automatically adjust the parameters of a bolus calculator. Periodic usage of a continuous glucose monitoring device is required for this purpose. Methods: To test the proposed method, an in silico evaluation under real-life conditions was carried out using the FDA-accepted Type 1 diabetes mellitus (T1DM) UVa/Padova simulator. Since the T1DM simulator does not incorporate intra-subject variability and uncertainty, a set of modifications were introduced to emulate them. Ten adult and ten adolescent virtual subjects were assessed over a 3-month scenario with realistic meal variability. The glycaemic metrics: mean blood glucose; percentage time in target; percentage time in hypoglycaemia; risk index, low blood glucose index; and blood glucose standard deviation, were employed for evaluation purposes. A t-test statistical analysis was carried out to evaluate the benefit of the presented algorithm against a bolus calculator without automatic adjustment. Results: The proposed method statistically improved (p < 0.05) all glycemic metrics evaluating hypoglycaemia on both virtual cohorts: percentage time in hypoglycaemia (i.e. BG <70 mg/dl) (adults: 2.7 +/- 4.0 vs. 0.4 +/- 0.7, p=0.03; adolescents: 7.1 +/- 7.4 vs. 1.3 +/- 2.4, p=0.02) and low blood glucose index (LBGI) (adults: 1.1 +/- 1.3 vs. 0.3 +/- 0.2, p=0.002; adolescen
Published: 2015

8. Contribution of alcohol use in HIV/hepatitis C virus co-infection to all-cause and cause-specific mortality: A collaboration of cohort studies

Author: Trickey, Adam, Ingle, Suzanne M, Boyd, Anders, Gill, M John, Grabar, Sophie, Jarrin-Vera, Inmaculada, Obel, Niels, Touloumi, Giota, Zangerle, Robert, Rauch, Andri, Rentsch, Christopher T, Satre, Derek D, Silverberg, Michael J, Bonnet, Fabrice, Guest, Jodie, Burkholder, Greer, Crane, Heidi, Teira, Ramon, Berenguer, Juan, Wyen, Christoph, Abgrall, Sophie, Hessamfar, Mojgan, Reiss, Peter, d'Arminio Monforte, Antonella, McGinnis, Kathleen A, Sterne, Jonathan A C, Wittkop, Linda, Antiretroviral Therapy Cohort Collaboration, NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), United States Department of Veterans Affairs, 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), Swiss National Science Foundation, Ministerio de Sanidad (España), Janssen Cilag, Institut National de la Santé et de la Recherche Médicale (Francia), Wellcome Trust, Gilead Sciences (Spain), Ministère de la Santé (Francia), Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, German Center for Infection Research (Alemania), Ministry of Health Welfare and Sport (Países Bajos), National Institute for Health Research (Reino Unido), Alberta Health (Canadá), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), ViiV Healthcare, and Integrated Clinical Systems
Subjects: Hepatitis C virus, Cohort, HIV, Mortality, Alcohol, Cause-specific
Abstract: Among persons with HIV (PWH), higher alcohol use and having hepatitis C virus (HCV) are separately associated with increased morbidity and mortality. We investigated whether the association between alcohol use and mortality among PWH is modified by HCV. Data were combined from European and North American cohorts of adult PWH who started antiretroviral therapy (ART). Self-reported alcohol use data, collected in diverse ways between cohorts, were converted to grams/day. Eligible PWH started ART during 2001-2017 and were followed from ART initiation for mortality. Interactions between the associations of baseline alcohol use (0, 0.1-20.0, >20.0 g/day) and HCV status were assessed using multivariable Cox models. Of 58,769 PWH, 29,711 (51%), 23,974 (41%) and 5084 (9%) self-reported alcohol use of 0 g/day, 0.1-20.0 g/day, and > 20.0 g/day, respectively, and 4799 (8%) had HCV at baseline. There were 844 deaths in 37,729 person-years and 2755 deaths in 443,121 person-years among those with and without HCV, respectively. Among PWH without HCV, adjusted hazard ratios (aHRs) for mortality were 1.18 (95% CI: 1.08-1.29) for 0.0 g/day and 1.84 (1.62-2.09) for >20.0 g/day compared with 0.1-20.0 g/day. This J-shaped pattern was absent among those with HCV: aHRs were 1.00 (0.86-1.17) for 0.0 g/day and 1.64 (1.33-2.02) for >20.0 g/day compared with 0.1-20.0 g/day (interaction p
Published: 2023

9. The real-life effect of catechol-O-methyltransferase inhibition on non-motor symptoms in levodopa-treated Parkinson’s disease: opicapone versus entacapone

Author: Leta, Valentina, van Wamelen, Daniel J, Aureli, Federico, Metta, Vinod, Trivedi, Dhaval, Cortelli, Pietro, Rodriguez-Blazquez, Carmen, Rizos, Alexandra, Ray Chaudhuri, K, International Parkinson and Movement Disorder Society, National Institute for Health Research (Reino Unido), NIHR - UCL Biomedical Research Centre (Reino Unido), Parkinsons Foundation, King College London, and NHS - Foundation Trust
Subjects: Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, Neurology, Catechol-O-methyltransferase, Parkinson’s disease, Non-motor symptoms, Neurology (clinical), Sleep, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Entacapone, Opicapone, Biological Psychiatry
Abstract: Objective To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson’s disease (PwP). Methods A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson’s Disease Sleep Scale (PDSS) total and item scores after the same time span. Results Groups were comparable for baseline demographics and Parkinson’s-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05). Conclusions Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.
Published: 2023

10. Factor Analysis and Clustering of the Movement Disorder Society–Non‐Motor Rating Scale

Author: Carmen Rodriguez-Blazquez, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Anette Schrag, Daniel Weintraub, Alexandra Rizos, Jose Manuel Rojo-Abuin, International Parkinson and Movement Disorder Society, United Kingdom Clinical Research Collaboration, and National Institute for Health Research (Reino Unido)
Subjects: 0301 basic medicine, Parkinson's disease, Rating scale, Severity of Illness Index, Nonmotorsymptoms, Factor (chord), 03 medical and health sciences, Cluster analysis, 0302 clinical medicine, medicine, Cluster Analysis, Humans, Movement (music), Parkinson Disease, medicine.disease, Explained variation, Exploratory factor analysis, Confirmatory factor analysis, Cross-Sectional Studies, 030104 developmental biology, Neurology, Parkinson’s disease, Neurology (clinical), Factor analysis, Factor Analysis, Statistical, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Background: The primary validation of the Movement Disorder Society Non-Motor Rating Scale was recently published, but 2 important structural analyses were not included. The objective of this study was to examine the structural characteristics of the Movement Disorder Society Non-Motor Rating Scale by factor and cluster analyses. Methods: Data came from the validation study, an international multicenter cross-sectional study of 402 Parkinson's disease patients. Demographic and clinical data, the Movement Disorder Society Non-Motor Rating Scale, and Hoehn and Yahr staging were used. Exploratory and confirmatory factor analysis and nonhierarchical cluster analysis were performed. Results: The exploratory factor analysis showed that all 13 domains of the Movement Disorder Society Non-Motor Rating Scale, except 1, and the Non-Motor Fluctuations subscale performed as unidimensional (variance explained: 0.36, sleep and wakefulness; -0.82, orthostatic hypotension). The confirmatory factor analysis could be carried out in 9 domains and showed that 6 of them and the Non-Motor Fluctuations subscale adjusted to the model satisfactorily according to the root mean square error of approximation. Furthermore, all domains had comparative fit index values >0.95, except depression and pain (both, 0.94) and sleep and wakefulness (0.90). The Non-Motor Fluctuations subscale showed satisfactory root mean square error of approximation (0.07), but a low comparative fit index value (0.91). A 5-cluster solution, correctly classifying 96% of the cases, was found. Conclusions: Overall, most subscales of the Movement Disorder Society Non-Motor Rating Scale are unidimensional, and although each subscale is distinct in terms of content covered, factors and clusters that are of clinical relevance are discernible and contribute to our understanding of possible nonmotor subtypes in Parkinson's disease. The project was supported by a two-stage academic peer-reviewed grant from the International Parkinson’s and Movement Disorder’s Society (IPMDS) as well as Clinical Research Network (CRN), London South and London North Thames, National Institute of Health Research (for the UK sites). Sí
Published: 2020

11. The global burden of cancer attributable to risk factors, 2010–19 : A systematic analysis for the Global Burden of Disease Study 2019

Author: Khanh Bao Tran, Justin J Lang, Kelly Compton, Rixing Xu, Alistair R Acheson, Hannah Jacqueline Henrikson, Jonathan M Kocarnik, Louise Penberthy, Amirali Aali, Qamar Abbas, Behzad Abbasi, Mohsen Abbasi-Kangevari, Zeinab Abbasi-Kangevari, Hedayat Abbastabar, Michael Abdelmasseh, Sherief Abd-Elsalam, Ahmed Abdelwahab Abdelwahab, Gholamreza Abdoli, Hanan Abdulkadir Abdulkadir, Aidin Abedi, Kedir Hussein Abegaz, Hassan Abidi, Richard Gyan Aboagye, Hassan Abolhassani, Abdorrahim Absalan, Yonas Derso Abtew, Hiwa Abubaker Ali, Eman Abu-Gharbieh, Basavaprabhu Achappa, Juan Manuel Acuna, Daniel Addison, Isaac Yeboah Addo, Oyelola A Adegboye, Miracle Ayomikun Adesina, Mohammad Adnan, Qorinah Estiningtyas Sakilah Adnani, Shailesh M Advani, Sumia Afrin, Muhammad Sohail Afzal, Manik Aggarwal, Bright Opoku Ahinkorah, Araz Ramazan Ahmad, Rizwan Ahmad, Sajjad Ahmad, Sohail Ahmad, Sepideh Ahmadi, Haroon Ahmed, Luai A Ahmed, Muktar Beshir Ahmed, Tarik Ahmed Rashid, Wajeeha Aiman, Marjan Ajami, Gizachew Taddesse Akalu, Mostafa Akbarzadeh-Khiavi, Addis Aklilu, Maxwell Akonde, Chisom Joyqueenet Akunna, Hanadi Al Hamad, Fares Alahdab, Fahad Mashhour Alanezi, Turki M Alanzi, Saleh Ali Alessy, Abdelazeem M Algammal, Mohammed Khaled Al-Hanawi, Robert Kaba Alhassan, Beriwan Abdulqadir Ali, Liaqat Ali, Syed Shujait Ali, Yousef Alimohamadi, Vahid Alipour, Syed Mohamed Aljunid, Motasem Alkhayyat, Sadeq Ali Ali Al-Maweri, Sami Almustanyir, Nivaldo Alonso, Shehabaldin Alqalyoobi, Rajaa M Al-Raddadi, Rami H Hani Al-Rifai, Salman Khalifah Al-Sabah, Ala'a B Al-Tammemi, Haya Altawalah, Nelson Alvis-Guzman, Firehiwot Amare, Edward Kwabena Ameyaw, Javad Javad Aminian Dehkordi, Mohammad Hosein Amirzade-Iranaq, Hubert Amu, Ganiyu Adeniyi Amusa, Robert Ancuceanu, Jason A Anderson, Yaregal Animut Animut, Amir Anoushiravani, Ali Arash Anoushirvani, Alireza Ansari-Moghaddam, Mustafa Geleto Ansha, Benny Antony, Maxwell Hubert Antwi, Sumadi Lukman Anwar, Razique Anwer, Anayochukwu Edward Anyasodor, Jalal Arabloo, Morteza Arab-Zozani, Olatunde Aremu, Ayele Mamo Argaw, Hany Ariffin, Timur Aripov, Muhammad Arshad, Al Artaman, Judie Arulappan, Raphael Taiwo Aruleba, Armin Aryannejad, Malke Asaad, Mulusew A Asemahagn, Zatollah Asemi, Mohammad Asghari-Jafarabadi, Tahira Ashraf, Reza Assadi, Mohammad Athar, Seyyed Shamsadin Athari, Maha Moh'd Wahbi Atout, Sameh Attia, Avinash Aujayeb, Marcel Ausloos, Leticia Avila-Burgos, Atalel Fentahun Awedew, Mamaru Ayenew Awoke, Tewachew Awoke, Beatriz Paulina Ayala Quintanilla, Tegegn Mulatu Ayana, Solomon Shitu Ayen, Davood Azadi, Sina Azadnajafabad, Saber Azami-Aghdash, Melkalem Mamuye Azanaw, Mohammadreza Azangou-Khyavy, Amirhossein Azari Jafari, Hosein Azizi, Ahmed Y Y Azzam, Amirhesam Babajani, Muhammad Badar, Ashish D Badiye, Nayereh Baghcheghi, Nader Bagheri, Sara Bagherieh, Saeed Bahadory, Atif Amin Baig, Jennifer L Baker, Ahad Bakhtiari, Ravleen Kaur Bakshi, Maciej Banach, Indrajit Banerjee, Mainak Bardhan, Francesco Barone-Adesi, Fabio Barra, Amadou Barrow, Nasir Z Bashir, Azadeh Bashiri, Saurav Basu, Abdul-Monim Mohammad Batiha, Aeysha Begum, Alehegn Bekele Bekele, Alemayehu Sayih Belay, Melaku Ashagrie Belete, Uzma Iqbal Belgaumi, Arielle Wilder Bell, Luis Belo, Habib Benzian, Alemshet Yirga Berhie, Amiel Nazer C Bermudez, Eduardo Bernabe, Akshaya Srikanth Bhagavathula, Neeraj Bhala, Bharti Bhandari Bhandari, Nikha Bhardwaj, Pankaj Bhardwaj, Krittika Bhattacharyya, Vijayalakshmi S Bhojaraja, Soumitra S Bhuyan, Sadia Bibi, Awraris Hailu Bilchut, Bagas Suryo Bintoro, Antonio Biondi, Mesfin Geremaw Birega Birega, Habitu Eshetu Birhan, Tone Bjørge, Oleg Blyuss, Belay Boda Abule Bodicha, Srinivasa Rao Bolla, Archith Boloor, Cristina Bosetti, Dejana Braithwaite, Michael Brauer, Hermann Brenner, Andrey Nikolaevich Briko, Nikolay Ivanovich Briko, Christina Maree Buchanan, Norma B Bulamu, Maria Teresa Bustamante-Teixeira, Muhammad Hammad Butt, Nadeem Shafique Butt, Zahid A Butt, Florentino Luciano Caetano dos Santos, Luis Alberto Cámera, Chao Cao, Yin Cao, Giulia Carreras, Márcia Carvalho, Francieli Cembranel, Ester Cerin, Promit Ananyo Chakraborty, Periklis Charalampous, Vijay Kumar Chattu, Odgerel Chimed-Ochir, Jesus Lorenzo Chirinos-Caceres, Daniel Youngwhan Cho, William C S Cho, Devasahayam J Christopher, Dinh-Toi Chu, Isaac Sunday Chukwu, Aaron J Cohen, Joao Conde, Sandra Cortés, Vera Marisa Costa, Natália Cruz-Martins, Garland T Culbreth, Omid Dadras, Fentaw Teshome Dagnaw, Saad M A Dahlawi, Xiaochen Dai, Lalit Dandona, Rakhi Dandona, Parnaz Daneshpajouhnejad, Anna Danielewicz, An Thi Minh Dao, Reza Darvishi Cheshmeh Soltani, Aso Mohammad Darwesh, Saswati Das, Dragos Virgil Davitoiu, Elham Davtalab Esmaeili, Fernando Pio De la Hoz, Sisay Abebe Debela, Azizallah Dehghan, Biniyam Demisse, Fitsum Wolde Demisse, Edgar Denova-Gutiérrez, Afshin Derakhshani, Meseret Derbew Molla, Diriba Dereje, Kalkidan Solomon Deribe, Rupak Desai, Markos Desalegn Desalegn, Fikadu Nugusu Dessalegn, Samuel Abebe A Dessalegni, Gashaw Dessie, Abebaw Alemayehu Desta, Syed Masudur Rahman Dewan, Samath Dhamminda Dharmaratne, Meghnath Dhimal, Mostafa Dianatinasab, Nancy Diao, Daniel Diaz, Lankamo Ena Digesa, Shilpi Gupta Dixit, Saeid Doaei, Linh Phuong Doan, Paul Narh Doku, Deepa Dongarwar, Wendel Mombaque dos Santos, Tim Robert Driscoll, Haneil Larson Dsouza, Oyewole Christopher Durojaiye, Sareh Edalati, Fatemeh Eghbalian, Elham Ehsani-Chimeh, Ebrahim Eini, Michael Ekholuenetale, Temitope Cyrus Ekundayo, Donatus U Ekwueme, Maha El Tantawi, Mostafa Ahmed Elbahnasawy, Iffat Elbarazi, Hesham Elghazaly, Muhammed Elhadi, Waseem El-Huneidi, Mohammad Hassan Emamian, Luchuo Engelbert Bain, Daniel Berhanie Enyew, Ryenchindorj Erkhembayar, Tegegne Eshetu, Babak Eshrati, Sharareh Eskandarieh, Juan Espinosa-Montero, Farshid Etaee, Azin Etemadimanesh, Tahir Eyayu, Ifeanyi Jude Ezeonwumelu, Sayeh Ezzikouri, Adeniyi Francis Fagbamigbe, Saman Fahimi, Ildar Ravisovich Fakhradiyev, Emerito Jose A Faraon, Jawad Fares, Abbas Farmany, Umar Farooque, Hossein Farrokhpour, Abidemi Omolara Fasanmi, Ali Fatehizadeh, Wafa Fatima, Hamed Fattahi, Ginenus Fekadu, Berhanu Elfu Feleke, Allegra Allegra Ferrari, Simone Ferrero, Lorenzo Ferro Desideri, Irina Filip, Florian Fischer, Roham Foroumadi, Masoud Foroutan, Takeshi Fukumoto, Peter Andras Gaal, Mohamed M Gad, Muktar A Gadanya, Abduzhappar Gaipov, Nasrin Galehdar, Silvano Gallus, Tushar Garg, Mariana Gaspar Fonseca, Yosef Haile Gebremariam, Teferi Gebru Gebremeskel, Mathewos Alemu Gebremichael, Yohannes Fikadu Geda, Yibeltal Yismaw Gela, Belete Negese Belete Gemeda, Melaku Getachew, Motuma Erena Getachew, Kazem Ghaffari, Mansour Ghafourifard, Seyyed-Hadi Ghamari, Mohammad Ghasemi Nour, Fariba Ghassemi, Ajnish Ghimire, Nermin Ghith, Maryam Gholamalizadeh, Jamshid Gholizadeh Navashenaq, Sherief Ghozy, Syed Amir Gilani, Paramjit Singh Gill, Themba G Ginindza, Abraham Tamirat T Gizaw, James C Glasbey, Justyna Godos, Amit Goel, Mahaveer Golechha, Pouya Goleij, Davide Golinelli, Mohamad Golitaleb, Giuseppe Gorini, Bárbara Niegia Garcia Goulart, Giuseppe Grosso, Habtamu Alganeh Guadie, Mohammed Ibrahim Mohialdeen Gubari, Temesgen Worku Gudayu, Maximiliano Ribeiro Guerra, Damitha Asanga Gunawardane, Bhawna Gupta, Sapna Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Mekdes Kondale Gurara, Alemu Guta, Parham Habibzadeh, Atlas Haddadi Avval, Nima Hafezi-Nejad, Adel Hajj Ali, Arvin Haj-Mirzaian, Esam S Halboub, Aram Halimi, Rabih Halwani, Randah R Hamadeh, Sajid Hameed, Samer Hamidi, Asif Hanif, Sanam Hariri, Netanja I Harlianto, Josep Maria Haro, Risky Kusuma Hartono, Ahmed I Hasaballah, S M Mahmudul Hasan, Hamidreza Hasani, Seyedeh Melika Hashemi, Abbas M Hassan, Soheil Hassanipour, Khezar Hayat, Golnaz Heidari, Mohammad Heidari, Zahra Heidarymeybodi, Brenda Yuliana Herrera-Serna, Claudiu Herteliu, Kamal Hezam, Yuta Hiraike, Mbuzeleni Mbuzeleni Hlongwa, Ramesh Holla, Marianne Holm, Nobuyuki Horita, Mohammad Hoseini, Md Mahbub Hossain, Mohammad Bellal Hossain Hossain, Mohammad-Salar Hosseini, Ali Hosseinzadeh, Mehdi Hosseinzadeh, Mihaela Hostiuc, Sorin Hostiuc, Mowafa Househ, Junjie Huang, Fernando N Hugo, Ayesha Humayun, Salman Hussain, Nawfal R Hussein, Bing-Fang Hwang, Segun Emmanuel Ibitoye, Pulwasha Maria Iftikhar, Kevin S Ikuta, Olayinka Stephen Ilesanmi, Irena M Ilic, Milena D Ilic, Mustapha Immurana, Kaire Innos, Pooya Iranpour, Lalu Muhammad Irham, Md Shariful Islam, Rakibul M Islam, Farhad Islami, Nahlah Elkudssiah Ismail, Gaetano Isola, Masao Iwagami, Linda Merin J, Abhishek Jaiswal, Mihajlo Jakovljevic, Mahsa Jalili, Shahram Jalilian, Elham Jamshidi, Sung-In Jang, Chinmay T Jani, Tahereh Javaheri, Umesh Umesh Jayarajah, Shubha Jayaram, Seyed Behzad Jazayeri, Rime Jebai, Bedru Jemal, Wonjeong Jeong, Ravi Prakash Jha, Har Ashish Jindal, Yetunde O John-Akinola, Jost B Jonas, Tamas Joo, Nitin Joseph, Farahnaz Joukar, Jacek Jerzy Jozwiak, Mikk Jürisson, Ali Kabir, Salah Eddine Oussama Kacimi, Vidya Kadashetti, Farima Kahe, Pradnya Vishal Kakodkar, Laleh R Kalankesh, Leila R Kalankesh, Rohollah Kalhor, Vineet Kumar Kamal, Farin Kamangar, Ashwin Kamath, Tanuj Kanchan, Eswar Kandaswamy, Himal Kandel, HyeJung Kang, Girum Gebremeskel Kanno, Neeti Kapoor, Sitanshu Sekhar Kar, Shama D Karanth, Ibraheem M Karaye, André Karch, Amirali Karimi, Bekalu Getnet Kassa, Patrick DMC Katoto, Joonas H Kauppila, Harkiran Kaur, Abinet Gebremickael Kebede, Leila Keikavoosi-Arani, Gemechu Gemechu Kejela, Phillip M Kemp Bohan, Maryam Keramati, Mohammad Keykhaei, Himanshu Khajuria, Abbas Khan, Abdul Aziz Khan Khan, Ejaz Ahmad Khan, Gulfaraz Khan, Md Nuruzzaman Khan, Moien AB Khan, Javad Khanali, Khaled Khatab, Moawiah Mohammad Khatatbeh, Mahalaqua Nazli Khatib, Maryam Khayamzadeh, Hamid Reza Khayat Kashani, Mohammad Amin Khazeei Tabari, Mehdi Khezeli, Mahmoud Khodadost, Min Seo Kim, Yun Jin Kim, Adnan Kisa, Sezer Kisa, Miloslav Klugar, Jitka Klugarová, Ali-Asghar Kolahi, Pavel Kolkhir, Farzad Kompani, Parvaiz A Koul, Sindhura Lakshmi Koulmane Laxminarayana, Ai Koyanagi, Kewal Krishan, Yuvaraj Krishnamoorthy, Burcu Kucuk Bicer, Nuworza Kugbey, Mukhtar Kulimbet, Akshay Kumar, G Anil Kumar, Narinder Kumar, Om P Kurmi, Ambily Kuttikkattu, Carlo La Vecchia, Arista Lahiri, Dharmesh Kumar Lal, Judit Lám, Qing Lan, Iván Landires, Bagher Larijani, Savita Lasrado, Jerrald Lau, Paolo Lauriola, Caterina Ledda, Sang-woong Lee, Shaun Wen Huey Lee, Wei-Chen Lee, Yeong Yeh Lee, Yo Han Lee, Samson Mideksa Legesse, James Leigh, Elvynna Leong, Ming-Chieh Li, Stephen S Lim, Gang Liu, Jue Liu, Chun-Han Lo, Ayush Lohiya, Platon D Lopukhov, László Lorenzovici, Mojgan Lotfi, Joana A Loureiro, Raimundas Lunevicius, Farzan Madadizadeh, Ahmad R Mafi, Sameh Magdeldin, Soleiman Mahjoub, Ata Mahmoodpoor, Morteza Mahmoudi, Marzieh Mahmoudimanesh, Rashidul Alam Mahumud, Azeem Majeed, Jamal Majidpoor, Alaa Makki, Konstantinos Christos Makris, Elaheh Malakan Rad, Mohammad-Reza Malekpour, Reza Malekzadeh, Ahmad Azam Malik, Tauqeer Hussain Mallhi, Sneha Deepak Mallya, Mohammed A Mamun, Ana Laura Manda, Fariborz Mansour-Ghanaei, Borhan Mansouri, Mohammad Ali Mansournia, Lorenzo Giovanni Mantovani, Santi Martini, Miquel Martorell, Sahar Masoudi, Seyedeh Zahra Masoumi, Clara N Matei, Elezebeth Mathews, Manu Raj Mathur, Vasundhara Mathur, Martin McKee, Jitendra Kumar Meena, Khalid Mehmood, Entezar Mehrabi Nasab, Ravi Mehrotra, Addisu Melese, Walter Mendoza, Ritesh G Menezes, SIsay Derso Mengesha, Laverne G Mensah, Alexios-Fotios A Mentis, Andry Yasmid Mera Mera-Mamián, Tuomo J Meretoja, Mehari Woldemariam Merid, Amanual Getnet Mersha, Belsity Temesgen Meselu, Mahboobeh Meshkat, Tomislav Mestrovic, Junmei Miao Jonasson, Tomasz Miazgowski, Irmina Maria Michalek, Gelana Fekadu Worku Mijena, Ted R Miller, Shabir Ahmad Mir, Seyed Kazem Mirinezhad, Seyyedmohammadsadeq Mirmoeeni, Mohammad Mirza-Aghazadeh-Attari, Hamed Mirzaei, Hamid Reza Mirzaei, Abay Sisay Misganaw, Sanjeev Misra, Karzan Abdulmuhsin Mohammad, Esmaeil Mohammadi, Mokhtar Mohammadi, Abdollah Mohammadian-Hafshejani, Reza Mohammadpourhodki, Arif Mohammed, Shafiu Mohammed, Syam Mohan, Mohammad Mohseni, Nagabhishek Moka, Ali H Mokdad, Alex Molassiotis, Mariam Molokhia, Kaveh Momenzadeh, Sara Momtazmanesh, Lorenzo Monasta, Ute Mons, Ahmed Al Montasir, Fateme Montazeri, Arnulfo Montero, Mohammad Amin Moosavi, Abdolvahab Moradi, Yousef Moradi, Mostafa Moradi Sarabi, Paula Moraga, Lidia Morawska, Shane Douglas Morrison, Jakub Morze, Abbas Mosapour, Ebrahim Mostafavi, Seyyed Meysam Mousavi, Haleh Mousavi Isfahani, Amin Mousavi Khaneghah, Christine Mpundu-Kaambwa, Sumaira Mubarik, Francesk Mulita, Daniel Munblit, Sandra B Munro, Efrén Murillo-Zamora, Jonah Musa, Ashraf F Nabhan, Ahamarshan Jayaraman Nagarajan, Shankar Prasad Nagaraju, Gabriele Nagel, Mohammadreza Naghipour, Mukhammad David Naimzada, Tapas Sadasivan Nair, Atta Abbas Naqvi, Sreenivas Narasimha Swamy, Aparna Ichalangod Narayana, Hasan Nassereldine, Zuhair S Natto, Biswa Prakash Nayak, Rawlance Ndejjo, Sabina Onyinye Nduaguba, Wogene Wogene Negash, Seyed Aria Nejadghaderi, Kazem Nejati, Sandhya Neupane Kandel, Huy Van Nguyen Nguyen, Robina Khan Niazi, Nurulamin M Noor, Maryam Noori, Nafise Noroozi, Hasti Nouraei, Ali Nowroozi, Virginia Nuñez-Samudio, Chimezie Igwegbe Nzoputam, Ogochukwu Janet Nzoputam, Bogdan Oancea, Oluwakemi Ololade Odukoya, Onome Bright Oghenetega, Ropo Ebenezer Ogunsakin, Ayodipupo Sikiru Oguntade, In-Hwan Oh, Hassan Okati-Aliabad, Akinkunmi Paul Okekunle, Andrew T Olagunju, Tinuke O Olagunju, Babayemi Oluwaseun Olakunde, Isaac Iyinoluwa Olufadewa, Emad Omer, Abidemi E Emmanuel Omonisi, Sokking Ong, Obinna E Onwujekwe, Hans Orru, Stanislav S Otstavnov, Abderrahim Oulhaj, Bilcha Oumer, Oluwatomi Funbi Owopetu, Babatunji Emmanuel Oyinloye, Mahesh P A, Alicia Padron-Monedero, Jagadish Rao Padubidri, Babak Pakbin, Keyvan Pakshir, Reza Pakzad, Tamás Palicz, Adrian Pana, Anamika Pandey, Ashok Pandey, Suman Pant, Shahina Pardhan, Eun-Cheol Park, Eun-Kee Park, Seoyeon Park, Jay Patel, Siddhartha Pati, Rajan Paudel, Uttam Paudel, Mihaela Paun, Hamidreza Pazoki Toroudi, Minjin Peng, Jeevan Pereira, Renato B Pereira, Simone Perna, Navaraj Perumalsamy, Richard G Pestell, Raffaele Pezzani, Cristiano Piccinelli, Julian David Pillay, Zahra Zahid Piracha, Tobias Pischon, Maarten J Postma, Ashkan Pourabhari Langroudi, Akram Pourshams, Naeimeh Pourtaheri, Akila Prashant, Mirza Muhammad Fahd Qadir, Zahiruddin Quazi Syed, Mohammad Rabiee, Navid Rabiee, Amir Radfar, Raghu Anekal Radhakrishnan, Venkatraman Radhakrishnan, Mojtaba Raeisi, Ata Rafiee, Alireza Rafiei, Nasiru Raheem, Fakher Rahim, Md Obaidur Rahman, Mosiur Rahman, Muhammad Aziz Rahman, Amir Masoud Rahmani, Shayan Rahmani, Vahid Rahmanian, Nazanin Rajai, Aashish Rajesh, Pradhum Ram, Kiana Ramezanzadeh, Juwel Rana, Kamal Ranabhat, Priyanga Ranasinghe, Chythra R Rao, Sowmya J Rao, Sina Rashedi, Amirfarzan Rashidi, Mahsa Rashidi, Mohammad-Mahdi Rashidi, Zubair Ahmed Ratan, David Laith Rawaf, Salman Rawaf, Lal Rawal, Reza Rawassizadeh, Mohammad Sadegh Razeghinia, Ashfaq Ur Rehman, Inayat ur Rehman, Marissa B Reitsma, Andre M N Renzaho, Maryam Rezaei, Nazila Rezaei, Negar Rezaei, Nima Rezaei, Saeid Rezaei, Mohsen Rezaeian, Aziz Rezapour, Abanoub Riad, Reza Rikhtegar, Maria Rios-Blancas, Thomas J Roberts, Peter Rohloff, Esperanza Romero-Rodríguez, Gholamreza Roshandel, Godfrey M Rwegerera, Manjula S, Maha Mohamed Saber-Ayad, Bahar Saberzadeh-Ardestani, Siamak Sabour, Basema Saddik, Erfan Sadeghi, Mohammad Reza Saeb, Umar Saeed, Mohsen Safaei, Azam Safary, Maryam Sahebazzamani, Amirhossein Sahebkar, Harihar Sahoo, Mirza Rizwan Sajid, Hedayat Salari, Sana Salehi, Marwa Rashad Salem, Hamideh Salimzadeh, Yoseph Leonardo Samodra, Abdallah M Samy, Juan Sanabria, Senthilkumar Sankararaman, Francesco Sanmarchi, Milena M Santric-Milicevic, Muhammad Arif Nadeem Saqib, Arash Sarveazad, Fatemeh Sarvi, Brijesh Sathian, Maheswar Satpathy, Nicolas Sayegh, Ione Jayce Ceola Schneider, Michaël Schwarzinger, Mario Šekerija, Subramanian Senthilkumaran, Sadaf G Sepanlou, Allen Seylani, Kenbon Seyoum, Feng Sha, Omid Shafaat, Pritik A Shah, Saeed Shahabi, Izza Shahid, Mohammad Amin Shahrbaf, Hamid R Shahsavari, Masood Ali Shaikh, Mohammed Feyisso Shaka, Elaheh Shaker, Mohammed Shannawaz, Mequannent Melaku Sharew Sharew, Azam Sharifi, Javad Sharifi-Rad, Purva Sharma, Bereket Beyene Shashamo, Aziz Sheikh, Mahdi Sheikh, Sara Sheikhbahaei, Rahim Ali Sheikhi, Ali Sheikhy, Peter Robin Shepherd, Adithi Shetty, Jeevan K Shetty, Ranjitha S Shetty, Kenji Shibuya, Reza Shirkoohi, Hesamaddin Shirzad-Aski, K M Shivakumar, Siddharudha Shivalli, Velizar Shivarov, Parnian Shobeiri, Zahra Shokri Varniab, Seyed Afshin Shorofi, Sunil Shrestha, Migbar Mekonnen Sibhat, Sudeep K Siddappa Malleshappa, Negussie Boti Sidemo, Diego Augusto Santos Silva, Luís Manuel Lopes Rodrigues Silva, Guilherme Silva Julian, Nicola Silvestris, Wudneh Simegn, Achintya Dinesh Singh, Ambrish Singh, Garima Singh, Harpreet 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Melinda Gates Foundation, Kuwait University (Kuwait), Ministry of Higher Education (Malasia), Lega Italiana per la Lotta ai Tumori, Health Effects Institute (Estados Unidos), Unión Europea. Comisión Europea. European Research Council (ERC), Unión Europea. Comisión Europea. H2020, Fundação para a Ciência e Tecnologia (Portugal), African-German Network of Excellence in Science (AGNES), Federal Ministry of Education & Research (Alemania), Alexander von Humboldt Foundation, Novo Nordisk Foundation, National Institute for Health Research (Reino Unido), National Health and Medical Research Council (Australia), Romanian National Authority for Scientific Research and Innovation, Romanian Ministry of Research Innovation and Digitalization, Ministry of Education, Science and Technological Development (Serbia), Sigrid Jusélius Foundation, Finnish Cancer Foundation, Datta Meghe Institute of Medical Sciences (India), Xiamen University (Malasia), Manipal Academy of Higher Education (India), Panjab University (India), Sistema Nacional de Investigación (Panamá), Secretaría Nacional de Ciencia, Tecnología e Innovación (Panamá), Ministry of Science and Technology (Taiwan), Lung Foundation Australia, National Natural Science Foundation of China, Wellcome Trust, UNSW Sydney (Australia), ICMR - National Institute of Epidemiology (India), University of Tasmania (Australia), National Council for Scientific and Technological Development (Brasil), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (Brasil), Institute for Advanced Studies in Basic Sciences (Irán), Ain Shams University (Egipto), International Center of Medical Sciences Research (Islamabad), National Institutes of Health (Estados Unidos), University of Oxford (Reino Unido), National Institute of Genetic Engineering and Biotechnology (Irán), Marga und Walter Boll - Stiftung, Ministero della Salute (Italia), IRCCS Materno Infantile Burlo Garofolo (Italia), King College London, Wellcome Trust/DBT India Alliance (India), Public Health, University of St Andrews. School of Medicine, and University of St Andrews. Population and Behavioural Science Division
Subjects: Male, DEATHS, DALY, cancer, risk factors, Medizin, systematic analysis, Global Health, Risk Assessment, Cancer prevention, Global Burden of Disease, RC0254, Risk-attributable cancer deaths, SDG 3 - Good Health and Well-being, RA0421, Risk Factors, RA0421 Public health. Hygiene. Preventive Medicine, Quality-Adjusted Life Year, Neoplasms, cancer, Humans, Global Burden of Disease Study, UK, Medicine(all), MCC, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Risk Factor, Smoking, COVID-19, 3rd-DAS, General Medicine, Disability-adjusted life-years, SOCIAL DETERMINANTS, Risk assessments, risk factor, Cardiovascular and Metabolic Diseases, 3121 General medicine, internal medicine and other clinical medicine, OBESITY, Cancer burden, Neoplasm, Female, LIFE-STYLE, Quality-Adjusted Life Years, HEALTH, RA, Human, RC
Abstract: Background: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01-4·94) deaths and 105 million (95·0-116) DALYs for both sexes combined, representing 44·4% (41·3-48·4) of all cancer deaths and 42·0% (39·1-45·6) of all DALYs. There were 2·88 million (2·60-3·18) risk-attributable cancer deaths in males (50·6% [47·8-54·1] of all male cancer deaths) and 1·58 million (1·36-1·84) risk-attributable cancer deaths in females (36·3% [32·5-41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6-28·4) and DALYs by 16·8% (8·8-25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9-42·8] and 33·3% [25·8-42·0]). Interpretation: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. We are grateful to the surveillance systems, including cancer registries, that generated and shared observed cancer burden data. S M Aljunid acknowledges the Department of Health Policy and Management, College of Public Health, Kuwait University for the approval and support to participate in this research project. H Ariffin acknowledges support from the Ministry of Higher Education, Malaysia (grant FRGS/1/2021/SKK0/UM/01/1). F Barra acknowledges support from Lega Italiana per la Lotta contro i Tumori - LILT - Bando 5 x 1000 anno 2019. L Belo and M Carvalho acknowledge the 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. A J Cohen was supported by the Health Effects Institute, Boston, MA, USA. J Conde acknowledges financial support from the European Research Council - ERC Starting Grant 848325. 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. T C Ekundayo was supported by the African-German Network of Excellence in Science (AGNES), the Federal Ministry of Education and Research (BMBF) and the Alexander von Humboldt Foundation (AvH). N Ghith acknowledges support from a grant from Novo Nordisk Foundation (NNF16OC0021856). J C Glasbey is support by a Doctoral Research Fellowship from the National Institute of Health Research (NIHR300175). V K Gupta and V B Gupta acknowledge funding support from National Health and Medical Research Council (NHMRC), Australia. C Herteliu, A Pana, and M Ausloos 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 is also partially supported by a grant of the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. S Hussain was supported from Operational Programme Research, Development and Education–Project, Postdoc2MUNI (number CZ.02.2. 69/0.0/0.0/18_053/0016952). M Jakovljevic acknowledges partial support through the grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. J H Kauppila acknowledges research grants from Sigrid Jusélius Foundation and the Finnish Cancer Foundation. M N Khatib acknowledges support from Datta Meghe Institute of Medical Sciences (deemed-to-be-university). Y J Kim was supported by the Research Management Centre, Xiamen University Malaysia [XMUMRF/2020-C6/ITCM/0004]. S L Koulmane Laxminarayana acknowledges institutional assistance by Manipal Academy of Higher Education, Manipal. K Krishan is supported by the UGC Centre of Advanced Study (Phase II), awarded to the Department of Anthropology, Panjab University, Chandigarh, India. I Landires is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). M-C Li was supported by the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-003-001). G Liu acknowledges support from the CREATE Hope scientific fellowship from Lung Foundation Australia. J Liu acknowledges support from the National Natural Science Foundation (72122001). J A Loureiro was supported by Scientific Employment Stimulus (FCT; CEECINST/00049/2018). E Mathews is supported by a Clinical and Public Health Early Career Fellowship (grant number IA/CPHE/17/1/503345) from the DBT India Alliance/Wellcome Trust Department of Biotechnology, India Alliance (2018–2023). T J Meretoja was supported by an unrestricted grant from Cancer Foundation Finland sr. S Mohammed acknowledges a fellowship grant from Alexander von Humboldt Foundation, outside the submitted work. M Molokhia is supported 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 received support from the Italian Ministry of Health at the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste - Italy (RC 34/2017). U Mons is supported by the Marga and Walter Boll Foundation, Kerpen, Germany. M A Moosavi acknowledges the financial support of National Institute of Genetics Engineering and Biotechnology (NIGEB). J Musa acknowledges support from the NIH/FICK43TW011416 for research-protected time for cervical cancer research and career development at University of Jos. V Nuñez-Samudio is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). O O Odukoya acknowledges support by the Fogarty International Center of the National Institutes of Health under the award number K43TW010704 for research-protected time. The content is solely the responsibility of all the authors and does not necessarily represent the official views of the National Institutes of Health. A S Oguntade acknowledges funding by a doctoral scholarship from the Nuffield Department of Population Health, University of Oxford (Oxford Population Health). J R Padubidri acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for their constant support in research collaborations. R G Pestell acknowledges support from NIH grant W81XWH1810605 Breast Cancer Research, Breakthrough Grant R21 CA235139-01. Z Z Piracha acknowledges the International Center of Medical Sciences Research (ICMSR), Islamabad (44000), Pakistan. R A Radhakrishnan acknowledges support from Wellcome Trust/DBT India Alliance - IA/CPHI/18/1/503927. U Saeed acknowledges the International Center of Medical Sciences Research (ICMSR), Islamabad, Pakistan. A M Samy acknowledges the support from Ain Shams University and the Egyptian Fulbright Mission Program. F Sha was supported by the Shenzhen Science and Technology Program (grant number KQTD20190929172835662). H R Shahsavari acknowledges the Institute for Advanced Studies in Basic Sciences (IASBS) Research Council. A Shetty acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for all the academic support. D A S Silva acknowledges financing in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001 and D A S Silva is supported in part by CNPq-Brazil (309589/2021-5). L M L R Silva was supported by project CENTRO-04-3559-FSE-000162, Fundo Social Europeu (FSE). Am Singh is supported by the International Graduate Research Scholarship, University of Tasmania. R Suliankatchi Abdulkader acknowledges support from ICMR—National Institute of Epidemiology. B Unnikrishnan acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal. H Xiao acknowledges support from the Public Health Sciences Division of the Fred Hutchinson Cancer Research Center. X Xu is supported by the University of New South Wales (Australia) Scientia Program. C Yu was supported by the National Natural Science Foundation of China (grant number 82173626) and Wuhan Medical Research Program of Joint Fund of Hubei Health Committee (grant number WJ2019H304). Sí
Published: 2022

12. Statins for primary prevention among elderly men and women

Author: Maria Bergami, Edina Cenko, Jinsung Yoon, Guiomar Mendieta, Sasko Kedev, Marija Zdravkovic, Zorana Vasiljevic, Davor Miličić, Olivia Manfrini, Mihaela van der Schaar, Chris P Gale, Lina Badimon, Raffaele Bugiardini, Bergami, M, Cenko, E, Yoon, J, Mendieta, G, Kedev, S, Zdravkovic, M, Vasiljevic, Z, Milicic, D, Manfrini, O, Van der Schaar, M, Gale, CP, Badimon, L, Bugiardini, R, Bergami, Maria, Cenko, Edina, Yoon, Jinsung, Mendieta, Guiomar, Kedev, Sasko, Zdravkovic, Marija, Vasiljevic, Zorana, Miličić, Davor, Manfrini, Olivia, van der Schaar, Mihaela, Gale, Chris P, Badimon, Lina, Bugiardini, Raffaele, National Institute for Health Research (Reino Unido), and British Heart Foundation
Subjects: Male, Physiology, 30-day mortality, Hypercholesterolemia, acute coronary syndromes, sex differences, age, Statins, Hyperlipidemias, Statin therapy, 30 day mortality, statins, Cohort Studies, Primary Prevention, Myocardial infarction, myocardial infarction, prevention, Physiology (medical), Prevention therapy, Humans, ST Elevation Myocardial Infarction, Original Article, Female, cardiovascular diseases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, Aged
Abstract: Background The debate about statins in primary prevention of cardiovascular (CV) disease is still alive, especially in old and very old adults. Purpose We undertook a propensity match-weighted cohort study to investigate whether statin treatment recommendations translate into improved cardiovascular (CV) outcomes in the current routine clinical care of the elderly. Methods We included in our analysis 5,619 people aged 65 years or older from the ISACS (International Survey of Acute Coronary Syndrome) Archives (NCT04008173) who presented to hospital with a first manifestation of CV disease. Participants were stratified as statin users versus nonusers and as old (65 to 75 years) versus very old (76 years or over) adults. We estimated the effects of statins on the most severe clinical manifestation of CV disease, namely ST segment elevation myocardial infarction (STEMI), using inverse probability of treatment weighting models. Estimates were compared by test of interaction on the log scale. Results The risk of STEMI was much lower in statin users than in nonusers in both patients aged 65 to 75 years (14.7% absolute risk reduction; relative risk [RR] ratio: 0.55, 95% CI 0.45 to 0.66) and those aged 76 years and older (13.3% absolute risk reduction; RR ratio: 0.58, 95% CI 0.46 to 0.72). Estimates were similar in patients with and without history of hypercholesterolemia (interaction test; p value= 0.2408). Proportional reductions in STEMI diminished with female sex in the old (p for interaction=0.002), but not in the very old age (p for interaction=0.26). We also observed a remarkable reduction in the risk of 30- day mortality from STEMI with statin therapy in both age groups (10.2% absolute risk reduction; RR ratio: 0.39; 95% CI 0.23 – 0.68 for patients aged 76 or over and 3.8% absolute risk reduction; RR ratio 0.37; 95% CI 0.17 – 0.82 for patients aged 65 to 75 years old; interaction test, p value=0.4570). Conclusion Preventive statin therapy in the elderly reduces the risk of STEMI with benefits in mortality from STEMI, irrespective of the presence of a history of hypercholesterolemia. This effect persists after the age of 76 years. Benefits are less pronounced in women. Funding Acknowledgement Type of funding sources: None.
Published: 2022

13. 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

14. 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

15. The Movement Disorder Society Nonmotor Rating Scale: Initial Validation Study

Author: Chaudhuri, K Ray, Schrag, Anette, Weintraub, Daniel, Rizos, Alexandra, Rodriguez-Blazquez, Carmen, Mamikonyan, Eugenia, Martinez-Martin, Pablo, Chaudhuri, K. Ray, Rodriguez‐Blazquez, Carmen, Martinez‐Martin, Pablo, International Parkinson and Movement Disorder Society, United Kingdom Clinical Research Collaboration, National Institute for Health Research (Reino Unido), and University of Pennsylvania (Estados Unidos)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Nonmotor symptoms, Movement disorders, Parkinson's disease, Intraclass correlation, Scales, Severity of Illness Index, Article, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cronbach's alpha, Rating scale, Interquartile range, Activities of Daily Living, medicine, Humans, Aged, business.industry, Reproducibility of Results, Parkinson Disease, Middle Aged, medicine.disease, Nonmotor fluctuations, body regions, Inter-rater reliability, Cross-Sectional Studies, 030104 developmental biology, Standard error, Neurology, Parkinson’s disease, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Erratum to: “The Movement Disorder Society Nonmotor Rating Scale: Initial Validation Study”, by Ray Chaudhuri et al. (Mov Disord 2020; 35: 116-133). Mov Disord. 2020 Jan;35(10):116-133. https://doi.org/10.1002/mds.28266 Background: The Movement Disorder Society-sponsored Nonmotor Rating Scale is an update of the existing Parkinson's disease Nonmotor Symptoms Scale modified to address some limitations in Nonmotor Symptoms Scale scoring, structure, and symptom coverage. Methods: PD patients were recruited from movement disorder centers in an international, multicenter study. The Movement Disorder Society Nonmotor Rating Scale, consisting of 13 domains plus a subscale for nonmotor fluctuations, was rater administered, along with the Nonmotor Symptoms Scale and other clinical assessments. Standard reliability and validity testing were conducted. Results: Four hundred and two PD patients were recruited (mean age ± standard deviation, 67.42 ± 9.96 years; mean age at PD onset ± standard deviation, 59.27 ± 10.67 years; median Hoehn and Yahr stage 2 (interquartile range 2-3). Data quality was satisfactory for all Movement Disorder Society Nonmotor Rating Scale domains except sexual (6.7% missing data). There were no floor or ceiling effects for the Movement Disorder Society Nonmotor Rating Scale and nonmotor fluctuations total score; domains had no ceiling effects, but some floor effects (13.5%-83.5%). The Movement Disorder Society Nonmotor Rating Scale and nonmotor fluctuations total score internal consistency were acceptable (average Cronbach's alpha, 0.66 and 0.84, respectively); interrater reliability was excellent (intraclass correlation coefficient, >0.95); for test-retest reliability, the intraclass correlation coefficient was 0.84 for the Movement Disorder Society Nonmotor Rating Scale and 0.70 for Movement Disorder Society nonmotor fluctuations total score, and precision was excellent for the Movement Disorder Society Nonmotor Rating Scale (standard error of measurement, 25.30) and fair for nonmotor fluctuations (standard error of measurement, 7.06). Correlations between Movement Disorder Society Nonmotor Rating Scale score and the corresponding Nonmotor Symptoms Scale and Movement Disorder Society UPDRS scores were high. There were no significant sex or age effects. The Movement Disorder Society Nonmotor Rating Scale score increased with increasing PD duration, disease severity, and PD medication dose (all P
Published: 2019

16. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Bertrand, Ophélie, Caputo, Sandrine, Dupré, Anaïs, le Mentec, Marine, Belotti, Muriel, Birot, Anne-Marie, Buecher, Bruno, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Houdayer, Claude, Moncoutier, Virginie, de Pauw, Antoine, Saule, Claire, Sinilnikova, Olga, Mazoyer, Sylvie, Damiola, Francesca, Barjhoux, Laure, Verny-Pierre, Carole, Léone, M. lanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Caron, Olivier, Guillaud-Bataille, Marine, Bressac-de-Paillerets, Brigitte, Bignon, Yves- Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Noguchi, Tetsuro, Popovici, Cornel, Sobol, Hagay, Bourdon, Violaine, Remenieras, Audrey, Noguès, Catherine, Coupier, Isabelle, Pujol, Pascal, Dumont, Aurélie, Révillion, Françoise, Adenis, Claude, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Leroux, Dominique, Dreyfus, H. lène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Mari, V. ronique, Vénat-Bouvet, Laurence, Delnatte, Capucine, Bézieau, Stéphane, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Sokolowska, Johanna, Bronner, Myriam, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Ong, Kai-ren, Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brewer, Carole, Davidson, Rosemarie, Izatt, Louise, Brady, Angela, Barwell, Julian, Adlard, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Eeles, Rosalind A., Cook, Jackie, Snape, Katie, Eccles, Diana, Murray, Alex, McCann, Emma, Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Fox, Stephen, Campbell, Ian, Spurdle, Amanda, Webb, Penny, de Fazio, Anna, Tassell, Margaret, Kirk, Judy, Lindeman, Geoff, Price, Melanie, Southey, Melissa, Milne, Roger, Deb, Sid, Bowtell, David, van der Hout, Annemieke H., van den Ouweland, Ans M. W., Mensenkamp, Arjen R., van Deurzen, Carolien H. M., Kets, Carolien M., Seynaeve, Caroline, van Asperen, Christi J., Aalfs, Cora M., Gómez Garcia, Encarna B., van Leeuwen, Flora E., de Bock, G. H., Meijers-Heijboer, Hanne E. J., Obdeijn, Inge M., Gille, J. J. P., Oosterwijk, Jan C., Wijnen, Juul T., van der Kolk, Lizet E., Hooning, Maartje J., Ausems, Margreet G. E. M., Mourits, Marian J. E., Blok, Marinus J., Rookus, Matti A., van der Luijt, Rob B., van Cronenburg, T. C. T. E. F., van der Pol, Carmen C., Russell, Nicola S., Siesling, Sabine, Overbeek, Lucy, Wijnands, R., de Lange, Judith L., Clarke, Christine, Graham, Dinny, Sachchithananthan, Mythily, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, H. kan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, Antoniou, Antonis C., German Cancer Research Center, National Health and Medical Research Council (Australia), United States of Department of Health & Human Services, National Institute for Health Research (Reino Unido), French National Cancer Institute, Ligue Nationale Contre le Cancer (Francia), Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea, Canadian Institutes of Health Research, Cancer Council New South Wales (Australia), KWF Kankerbestrijding, Instituto de Salud Carlos III, Xunta de Galicia (España), Ministerio de Sanidad, Política Social e Igualdad (España), Helmholtz Association, California Breast Cancer Research Program, Federal Ministry of Education & Research (Alemania), Government of Netherlands, Russian Foundation for Basic Research, O’Mara, Tracy A. [0000-0002-5436-3232], Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P. [0000-0003-3724-4757], Barnes, Daniel R. [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Ahearn, Thomas [0000-0003-0771-7752], Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Barrowdale, Daniel [0000-0003-1661-3939], Becher, Heko [0000-0002-8808-6667], Bernstein, Leslie [0000-0002-7692-6518], Bojesen, Stig E. [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Chanock, Stephen J. [0000-0002-2324-3393], Chung, Wendy K. [0000-0003-3438-5685], Claes, Kathleen B. M. [0000-0003-0841-7372], Collée, J. Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Eliassen, A. Heather [0000-0002-3961-6609], Fritschi, Lin [0000-0002-7692-3560], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Gayther, Simon A. [0000-0001-7937-5443], Giles, Graham G. [0000-0003-4946-9099], Greene, Mark H. [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Hart, Steven N. [0000-0001-7714-2734], He, Wei [0000-0003-0161-3274], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J. [0000-0001-8397-4078], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A. [0000-0002-4361-4657], Jensen, Uffe Birk [0000-0002-6205-6355], Jones, Michael E. [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Kurian, Allison W. [0000-0002-6175-9470], Lambrechts, Diether [0000-0002-3429-302X], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John W. M. [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Milne, Roger L. [0000-0001-5764-7268], Nathanson, Katherine L. [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I. [0000-0002-9936-1599], Olson, Janet E. [0000-0003-4944-7789], Ottini, Laura [0000-0001-8030-0449], Parsons, Michael T. [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Pharoah, Paul D. P. [0000-0001-8494-732X], Punie, Kevin [0000-0002-1162-7963], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Sandler, Dale P. [0000-0002-6776-0018], Schmidt, Marjanka K. [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Toland, Amanda E. [0000-0002-0271-1792], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M. [0000-0002-1962-9322], Vega, Ana [0000-0002-7416-5137], Vijai, Joseph [0000-0002-7933-151X], Weitzel, Jeffrey N. [0000-0001-6714-092X], Wolk, Alicja [0000-0001-7387-6845], Yadav, Siddhartha [0000-0003-4630-9903], Yannoukakos, Drakoulis [0000-0001-7509-3510], Ziogas, Argyrios [0000-0003-4529-3727], Zorn, Kristin K. [0000-0003-2143-8979], Park, Sue K. [0000-0001-5002-9707], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Becher, Heiko [0000-0002-8808-6667], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, German Cancer Research Center (DKFZ), National Health and Medical Research Council of Australia, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, National Institute for Health Research (NIHR), Institut National du Cancer (INCA) France, Ligue nationale contre le cancer, Cancer Research UK, European Commision, Canadian Institutes of Health Research (CIHR), Cancer Council New South Wales, Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud, Xunta de Galicia, Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain, Fondo de Investigacion Sanitario, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Netherlands Government, Russian Foundation for Basic Research (RFBR), O'Mara, Tracy A [0000-0002-5436-3232], Tyrer, Jonathan P [0000-0003-3724-4757], Barnes, Daniel R [0000-0002-3781-7570], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Dunning, Alison M [0000-0001-6651-7166], Eliassen, A Heather [0000-0002-3961-6609], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Hart, Steven N [0000-0001-7714-2734], Hulick, Peter J [0000-0001-8397-4078], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kurian, Allison W [0000-0002-6175-9470], Martens, John WM [0000-0002-3428-3366], Milne, Roger L [0000-0001-5764-7268], Nathanson, Katherine L [0000-0002-6740-0901], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Janet E [0000-0003-4944-7789], Parsons, Michael T [0000-0003-3242-8477], Pharoah, Paul DP [0000-0001-8494-732X], Sandler, Dale P [0000-0002-6776-0018], Schmidt, Marjanka K [0000-0002-2228-429X], Toland, Amanda E [0000-0002-0271-1792], Vachon, Celine M [0000-0002-1962-9322], Weitzel, Jeffrey N [0000-0001-6714-092X], Zorn, Kristin K [0000-0003-2143-8979], Park, Sue K [0000-0001-5002-9707], Easton, Douglas F [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Coignard J] Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France. Institut Curie Paris, Paris, France. Mines ParisTech Fontainebleau, Paris, France. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. PSL University Paris, Paris, France. Paris Sud University, Orsay, France. [Lush M, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Beesley J, O'Mara TA] Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Lopez-Fernández A] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, Pathology, and Radiology & Nuclear Medicine
Subjects: 0301 basic medicine, Linkage disequilibrium, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], 45/43, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, Breast cancer, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, Genotype, breast neoplasms, Medicine and Health Sciences, 631/208/68, skin and connective tissue diseases, Cancer genetics, adult, alleles, BRCA1 protein, BRCA2 protein, female, genetic predisposition to disease, genome-wide association study, genotype, humans, linkage disequilibrium, middle aged, mutation, quantitative trait loci, risk factors, polymorphism, single nucleotide, HEBON Investigators, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], BRCA1 Protein, Genetic Predisposition to Disease/genetics, article, Single Nucleotide, Middle Aged, BRCA2 Protein/genetics, 3. Good health, Mama - Càncer - Factors de risc, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Genome-Wide Association Study/methods, Medical genetics, Female, Medical Genetics, 692/499, Adult, medicine.medical_specialty, 45/61, Science, 3122 Cancers, Population, Quantitative Trait Loci, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], ABCTB Investigators, 631/67/2324, Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, EMBRACE Collaborators, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Alleles, Medicinsk genetik, BRCA2 Protein, Mutació (Biologia), General Chemistry, 631/67/1347, Genotype frequency, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, BRCA1 Protein/genetics, 3111 Biomedicine, KConFab Investigators, Quantitative Trait Loci/genetics, Genètica, Genome-Wide Association Study
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021

17. Telomerase as a Therapeutic Target in Cardiovascular Disease

Author: Ioakim Spyridopoulos, Gavin D. Richardson, Judith Haendeler, Jedrzej Hoffmann, Joachim Altschmied, Vicente Andrés, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Progeria Research Foundation, British Heart Foundation, National Institute for Health Research (Reino Unido), Newcastle Biomedical Research Centre, Tyne Hospitals NHS Foundation Trust, Deutsche Forschungsgemeinschaft (Alemania), and Telomerase Activator to Reverse Immunosenescence in Acute Coronary Syndrome
Subjects: Telomerase, Disease, Bioinformatics, medicine.disease_cause, Coronary artery disease, Telomerase RNA component, Mice, medicine, Leukocytes, Animals, Humans, Telomerase reverse transcriptase, Exercise, Telomere Shortening, Mutation, Clinical Trials as Topic, business.industry, Models, Cardiovascular, Telomere Homeostasis, medicine.disease, Phenotype, Telomere, Cardiovascular Diseases, RNA, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, Biomarkers, Drugs, Chinese Herbal, Genome-Wide Association Study
Abstract: Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article. Work in the VA laboratory is supported by the Spanish Ministerio de Ciencia e Innovación (MCIN) (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC17/00067) with co-funding from the European Regional Development Fund (ERDF, “Una manera de hacer Europa”), and the Progeria Research Foundation (Award PRF 2019–77). The CNIC is supported by the ISCIII, the MCIN, and the Pro CNIC Foundation. I. Spyridopoulos is funded by the British Heart Foundation (PG/18/25/33587) and National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work of J. Haendeler and J. Altschmied is in part supported by the Deutsche Forschungsgemeinschaft (DFG) SFB1116, A04 (J. Haendeler and J. Altschmied), HA2868/14-1 (J. Haendeler) and AL288/5-1 (J. Altschmied). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health’. I. Spyridopoulos also receives a grant from TA-Science for the TACTIC trial (Telomerase Activator to Reverse Immunosenescence in Acute Coronary Syndrome). Sí
Published: 2021

18. Sarcoma classification by DNA methylation profiling

Author: Damian Stichel, Laura Romero-Pérez, Till Milde, Stefan Fröhling, Matija Snuderl, Florian Selt, Dominik Sturm, Kenneth Tou En Chang, Francisco Fernández-Klett, Sharon Yin Yee Low, Iben Lyskjaer, Marcel Kool, Wolfgang Hartmann, Adrian Cuevas-Bourdier, Simon Kreutzfeldt, Cristina R. Antonescu, Christoph Heining, Jürgen Hench, Adrienne M. Flanagan, Rolf Buslei, Gunhild Mechtersheimer, Jonas Ecker, Daniel Schrimpf, Amir Abdollahi, David Capper, Thomas Mentzel, Uta Flucke, Olaf Witt, Matthias Schick, Mark Kriegsmann, Christian Thomas, Felix Sahm, Andreas von Deimling, Jaume Mora, Pieter Wesseling, Eva Wardelmann, Sebastian Stark, Annika K. Wefers, Christian Koelsche, Marc Ladanyi, Benedikt Brors, Manfred Gessler, Winand N.M. Dinjens, David T.W. Jones, Jonathan Serrano, Jamal Benhamida, Jens Schittenhelm, Azadeh Ebrahimi, Christian Vokuhl, Thomas G. P. Grunewald, Hanno Glimm, Annekathrin Reinhardt, Manel Esteller, Juan Díaz Martín, Peter Schirmacher, Belen Casalini, Iver Petersen, Abigail K. Suwala, Jürgen Debus, Javier Alonso, Stephan Frank, Martin Sill, Martin Mynarek, Miguel Angel Idoate Gastearena, Michael Platten, Matthias Uhl, Michel Mittelbronn, Sebastian Moran, Stefan M. Pfister, Christian Hartmann, Daniel Baumhoer, Melanie Bewerunge-Hudler, Reinhard Büttner, Volker Hovestadt, Pascal Johann, Oscar M. Tirado, Philipp Sievers, Burkhard Lehner, Elke Paff, Werner Paulus, Albrecht Stenzinger, Andrey Korshunov, Marije E. Weidema, Enrique de Álava, V. F. Mautner, Andreas Unterberg, Kristian W. Pajtler, Klaus G. Griewank, Xavier Garcia del Muro, Wolfgang Wick, David E. Reuss, Thomas Klingebiel, Andreas E. Kulozik, Sebastian Brandner, Ori Staszewski, Yvonne M.H. Versleijen-Jonkers, Mirjam Blattner, Christoph E. Heilig, Stefan Rutkowski, Barbara C. Worst, Thomas Kirchner, Katja Beck, Peter Horak, Ulrich Schüller, Zane Jaunmuktane, Peter Hohenberger, Marco Prinz, Uta Dirksen, Miguel Sáinz-Jaspeado, Felix K. F. Kommoss, Martin Hasselblatt, Pathology, CCA - Imaging and biomarkers, German Cancer Aid, National Institute for Health Research (Reino Unido), NIHR - UCL Biomedical Research Centre (Reino Unido), Luxembourg National Research Fund, National Center for Tumor Diseases (Germany), National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Medical Research Council (UK), Brain Archive Information Network (UK), Brain Tumour Research, Friedberg Charitable Foundation, Fonds National de la Recherche Luxembourg, Projekt DEAL, Deutsche Krebshilfe, National Institute for Health Research (United Kingdom), and UCLH Biomedical research centre
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Soft Tissue Neoplasm, DNA Copy Number Variations, Classification and taxonomy, Science, ADN, Medizin, General Physics and Astronomy, Bone Neoplasms, Soft Tissue Neoplasms, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Bone Sarcoma, Biology, Sensitivity and Specificity, Article, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Machine Learning, Databases, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, medicine, Humans, Internet, Multidisciplinary, Soft tissue, Reproducibility of Results, Sarcoma, General Chemistry, Methylation, DNA, DNA Methylation, medicine.disease, Computational biology and bioinformatics, Dna methylation profiling, 030104 developmental biology, 030220 oncology & carcinogenesis, DNA methylation, Classifier (UML), Algorithms
Abstract: Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications., This work was funded by Deutsche Krebshilfe grant 70112499, the NCT Heidelberg and an Illumina Medical Research Grant. Part of this work was funded by the National Institute of Health Research (to S.B. and Z.J.) and to UCLH Biomedical research centre (BRC399/NS/RB/101410). Human tissues were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 18/004) which is funded by the Medical Research Council and Brain Tumour Research UK. The methylation profiling at NYU is supported by a grant from the Friedberg Charitable Foundation (to M.Sn.). M.Mi. would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant). Open Access funding enabled and organized by Projekt DEAL.
Published: 2021

19. 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

20. Adaptation and Evaluation of the Nutrition Environment Measures Survey in Stores to Assess Mediterranean Food Environments (NEMS-S-MED)

Author: Alba Martínez-García, Manuel Franco, Eva María Trescastro-López, Carles Ariza, Pamela Pereyra-Zamora, Julia Díez, Carlos Fernández-Escobar, Usama Bilal, Universidad de Alicante. Departamento de Enfermería Comunitaria, Medicina Preventiva y Salud Pública e Historia de la Ciencia, Grupo Balmis de Investigación en Salud Comunitaria e Historia de la Ciencia, National Institute for Health Research (United Kingdom), Universidad de Alicante, 7º Programa Marco - Comisión Europea, National Institute for Health Research (Reino Unido), University of Alicante (España), and Unión Europea. Comisión Europea. 7 Programa Marco
Subjects: Mediterranean climate, Nutrition Environment Measures Surveys, Health, Toxicology and Mutagenesis, Psychological intervention, lcsh:Medicine, 030209 endocrinology & metabolism, Audit, Environment, Article, Food Supply, 03 medical and health sciences, 0302 clinical medicine, Cohen's kappa, Environmental health, Surveys and Questionnaires, Humans, 030212 general & internal medicine, food environment, Adaptation (computer science), 2. Zero hunger, Measurement, lcsh:R, Public Health, Environmental and Occupational Health, Commerce, Food Services, Construct validity, Reproducibility of Results, Census, Nutrition Surveys, Food environment, Geography, Food retail, Spain, food retail, Enfermería, measurement
Abstract: The Nutrition Environment Measures Surveys are valid and reliable measures of community and consumer food environments. This article describes the adaptation and evaluation of the Nutrition Environment Measures Survey in Stores (NEMS-S) for Mediterranean urban contexts (NEMS-S-MED). Trained raters used the adapted NEMS-S-MED tool to observe and rate food outlets in 21 census tracts and 43 food stores across the city of Madrid, Spain. We evaluated inter-rater and intra-rater reliabilities, construct validity, and the tool&rsquo, s ability to discriminate between store types and between stores by area-level Socio-Economic Status (SES). Overall, the mean NEMS-S-MED score was 20.7 (SD = 9.8), which ranged from 7 to 43. Most food items displayed substantial or almost perfect inter-rater and intra-rater agreements, the percentage agreement across availability items was almost perfect and kappa statistics were also very high (median &kappa, = 1.00 for inter-rater, &kappa, = 0.92 for intra-rater). Furthermore, the NEMS-S-MED tool was able to discriminate between store types and census tracts of different SES. The adapted NEMS-S-MED instrument is a reliable and valid audit tool to assess the consumer food environment in Mediterranean urban contexts. Well-constructed measurement tools, such as the NEMS-S-MED, may facilitate the development of effective policy interventions to increase healthy food access and affordability.
Published: 2020

21. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Escala-Garcia, Maria, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Ashworth, Alan, Auer, Paul L, Auvinen, Päivi, Beckmann, Matthias W, Beesley, Jonathan, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Dwek, Miriam, Earl, Helena M, Eccles, Diana M, Eliassen, A Heather, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Guo, Qi, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Harrington, Patricia A, Hiller, Louise, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Chiun-Sheng, Huang, Guanmengqian, Hunter, David J, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Kitahara, Cari M, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orr, Nick, Peterlongo, Paolo, Petridis, Christos, Prentice, Ross L, Presneau, Nadege, Punie, Kevin, Ramachandran, Dhanya, Rennert, Gad, Romero, Atocha, Sachchithananthan, Mythily, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schwentner, Lukas, Scott, Christopher, Simard, Jacques, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Terry, Mary Beth, Thorne, Heather, Tollenaar, Rob A E M, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Turnbull, Clare, Vachon, Celine M, van der Kolk, Lizet E, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Ziogas, Argyrios, Pharoah, Paul D P, Hall, Per, Wessels, Lodewyk F A, Chenevix-Trench, Georgia, Bader, Gary D, Dörk, Thilo, Easton, Douglas F, Canisius, Sander, Schmidt, Marjanka K, Gonzalez Neira, Anna, Andrulis, Irene L., Auer, Paul L., Beckmann, Matthias W., Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Brucker, Sara Y., Chanock, Stephen J., Clarke, Christine L., Couch, Fergus J., Cross, Simon S., Daly, Mary B., Dunn, Janet A., Dunning, Alison M., Earl, Helena M., Eccles, Diana M., Eliassen, A. Heather, Evans, D. Gareth, Fasching, Peter A., Gapstur, Susan M., García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Goldgar, David E., Haiman, Christopher A., Harrington, Patricia A., Hooning, Maartje J., Hopper, John L., Hunter, David J., John, Esther M., Kitahara, Cari M., Milne, Roger L., Neuhausen, Susan L., Newman, William G., Olshan, Andrew F., Olson, Janet E., Prentice, Ross L., Sawyer, Elinor J., Schmutzler, Rita K., Southey, Melissa C., Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Tollenaar, Rob A. E. M., Troester, Melissa A., Vachon, Celine M., van der Kolk, Lizet E., Yang, Xiaohong R., Pharoah, Paul D. P., Wessels, Lodewyk F. A., Bader, Gary D., Easton, Douglas F., Schmidt, Marjanka K., HUS Comprehensive Cancer Center, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, National Institute for Health Research (Reino Unido), German Cancer Research Center, United States of Department of Health & Human Services, Cancer Research UK (Reino Unido), European Commission, Canadian Institutes of Health Research, Ministere de l'Economie, Science et Innovation du Quebec (Canadá), Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Deutsche Krebshilfe, Russian Foundation for Basic Research, Swedish Research Council, Breast Cancer Now (Reino Unido), Medical Oncology, Surgery, National Institute for Health Research (NIHR), German Cancer Research Center (DKFZ, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Cancer Research UK, Canadian Institutes of Health Research (CIHR), Ministere de l'Economie, Science et Innovation du Quebec- CANADA, KWF Kankerbestrijding, Asociacion Espanola Contra el Cancer (AECC), Russian Foundation for Basic Research (RFBR), Breast Cancer Now, London, Unión Europea. Comisión Europea, Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Bojesen, Stig E. [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Caldas, Carlos [0000-0003-3547-1489], Canzian, Federico [0000-0002-4261-4583], Chanock, Stephen J. [0000-0002-2324-3393], Chin, Suet-Feung [0000-0001-5697-1082], Dennis, Joe [0000-0003-4591-1214], Devilee, Peter [0000-0002-8023-2009], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A. [0000-0003-4885-8471], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Giles, Graham G. [0000-0003-4946-9099], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Lambrechts, Diether [0000-0002-3429-302X], Milne, Roger L. [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G. [0000-0002-6382-4678], Olson, Janet E. [0000-0003-4944-7789], Orr, Nick [0000-0003-2866-942X], Peterlongo, Paolo [0000-0001-6951-6855], Punie, Kevin [0000-0002-1162-7963], Ramachandran, Dhanya [0000-0001-8139-7799], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Simard, Jacques [0000-0001-6906-3390], Teixeira, Manuel R. [0000-0002-4896-5982], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Winqvist, Robert [0000-0003-0932-9104], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul D. P. [0000-0001-8494-732X], Bader, Gary D. [0000-0003-0185-8861], Dörk, Thilo [0000-0002-9458-0282], Easton, Douglas F. [0000-0003-2444-3247], Canisius, Sander [0000-0003-3888-8829], Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Andrulis, Irene L [0000-0002-4226-6435], Blomqvist, Carl [0000-0003-3041-1938], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Dunning, Alison M [0000-0001-6651-7166], Earl, Helena M [0000-0003-1549-8094], Fasching, Peter A [0000-0003-4885-8471], García-Sáenz, José A [0000-0001-6880-0301], Giles, Graham G [0000-0003-4946-9099], Howell, Anthony [0000-0002-6233-719X], Milne, Roger L [0000-0001-5764-7268], Newman, William G [0000-0002-6382-4678], Olson, Janet E [0000-0003-4944-7789], Olsson, Håkan [0000-0002-8794-9635], Teixeira, Manuel R [0000-0002-4896-5982], Pharoah, Paul D P [0000-0001-8494-732X], Bader, Gary D [0000-0003-0185-8861], Easton, Douglas F [0000-0003-2444-3247], Schmidt, Marjanka K [0000-0002-2228-429X], and Pharoah, Paul DP [0000-0001-8494-732X]
Subjects: 0301 basic medicine, PTEN, GTP-Binding Protein alpha Subunits, Gq-G11/genetics, 45/43, Gene regulatory network, General Physics and Astronomy, Estrogen receptor, Genome-wide association study, Apoptosis, Disease, CIRCADIAN CLOCK, VARIANTS, Bioinformatics, Genome-wide association studies, Germline, Metastasis, PATHWAY, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Gene Regulatory Networks, lcsh:Science, Multidisciplinary, TUMOR-GROWTH, Receptors, Estrogen/genetics, Prognosis, GTP-Binding Protein alpha Subunits, 3. Good health, Multidisciplinary Sciences, Receptors, Estrogen, 030220 oncology & carcinogenesis, Medical genetics, Science & Technology - Other Topics, Female, Medical Genetics, Signal Transduction, medicine.medical_specialty, Genotype, Science, 3122 Cancers, 631/208/205/2138, Breast Neoplasms, Biology, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, PROTEIN-COUPLED RECEPTORS, SDG 3 - Good Health and Well-being, Circadian Clocks, medicine, Humans, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Science & Technology, 45, Genetic Variation, Computational Biology, General Chemistry, medicine.disease, GENE, Computational biology and bioinformatics, 030104 developmental biology, Germ Cells, GTP-Binding Protein alpha Subunits/genetics, METASTASIS, GTP-Binding Protein alpha Subunits, Gq-G11, 692/4028/67/1347, lcsh:Q, CELL-GROWTH, 631/114, Genome-Wide Association Study
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis., In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
Published: 2020

22. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N., Antoniou, A.C., Mooij, T.M., Hooning, M.J., Heemskerk-Gerritsen, B.A., Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J.P., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T.D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J.M., Maugard, C., Bignon, Y.J., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Barrowdale, D., Frost, D., Evans, D.G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., Hogervorst, F.B.L., Collee, J.M., Asperen, C.J. van, Mensenkamp, A.R., Ausems, M.G.E.M., Meijers-Heijboer, H.E.J., Engelen, K. van, Blok, M.J., Oosterwijk, J.C., Verloop, J., Broek, E. van den, Mourits, M.J.E., Koppert, L.B., Hopper, J.L., John, E.M., Chung, W.K., Andrulis, I.L., Daly, M.B., Buys, S.S., Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C.F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A.M., Roos-Blom, M.J., Leeuwen, F.E. van, Arver, B., Olsson, H., Schmutzler, R.K., Engel, C., Kast, K., Phillips, K.A., Terry, M.B., Milne, R.L., Goldgar, D.E., Rookus, M.A., Andrieu, N., Easton, D.F., GENEPSO, EMBRACE, HEBON, kConFab Investigators, IBCCS, kConFab, BCFR, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Erasmus MC Cancer Institute, Rotterdam, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie [Paris], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Catherine-de-Sienne [Nantes] (CCS), Manchester University NHS Foundation Trust (MFT), Guy's & St Thomas' NHS Foundation Trust, Chapel Allerton Hospital, University of Leeds, Royal Marsden NHS Foundation Trust, Royal Devon & Exeter Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Wessex clinical genetics service, Vrije Universiteit Amsterdam [Amsterdam] (VU), University Medical Center Groningen [Groningen] (UMCG), Department of Medical Genetics, University Medical Center [Utrecht], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Department of Epidemiology, Cancer Prevention Institute of California, Columbia University [New York], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Division of Population Science, Fox Chase Cancer Center, Department of Internal Medicine, Huntsman Cancer Institute, Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Medizinische Universität Wien = Medical University of Vienna, National Institute of Oncology, Masaryk Memorial Cancer Institute (MMCI), Masaryk University [Brno] (MUNI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, The Netherlands Cancer Institute [Amsterdam, The Netherlands], Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Cancer Epidemiology Centre, Cancer Council Victoria, International Agency for Cancer Research (IACR), Netherlands Cancer Institute, 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), Université Paris sciences et lettres (PSL), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Andrieu, Nadine, Human genetics, Epidemiology and Data Science, Mavaddat, Nasim [0000-0003-0307-055X], Eeles, Ros [0000-0002-3698-6241], Engel, Christoph [0000-0002-7247-282X], Apollo - University of Cambridge Repository, Pomeranian Medical University-International Hereditary Cancer Centre, Masaryk Memorial Cancer Institute (RECAMO), Columbia Mailman School of Public Health-Columbia University [New York], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Antoniou, Antonis [0000-0001-9223-3116], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Medical Oncology, Surgery, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), United States Department of Health and Human Services, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea. European Research Council (ERC), Norwegian EEA Financial Mechanism, Hungarian Scientific Research Fund (Hungría), Ministry of Education, Youth and Sports (República Checa), MH CZ -DRO (MMCI), National Health and Medical Research Council (Australia), Australian National Breast Cancer Foundation, Cancer Australia, ERA-NET TRANSAN JTC 2012 Cancer, Transcan grant, Biotechnology and Biological Sciences Research Council (Reino Unido), Pink Ribbons Project, Netherlands Organisation of Scientific Research, Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Deutsche Krebshilfe, National Institute for Health Research (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Ministry of Economic Development, Innovation and Export Trade-grant, Canadian Institutes of Health Research, Cancer Research UK, NIH National Cancer Institute (NCI), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Ministerio de Economia y Competividad (MINECO), European Research Council (ERC), Hungarian Research Grants, MEYS -NPS I, National Health and Medical Research Council of Australia, BBMRI grant, Pink Ribbon grants, Netherlands Organisation of Scientific Research grant, KWF Kankerbestrijding, Instituto de Salud Carlos III - ISCIII, National Institute for Health Research (NIHR), European Union Seventh Framework Program (2007-2013), Canadian Institutes of Health Research (CIHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), United States of Department of Health & Human Services, European Research Council, APH - Quality of Care, APH - Methodology, Graduate School, ARD - Amsterdam Reproduction and Development, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: endocrine system diseases, SURGERY, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, BRCA2 Mutation, Breast cancer, Surgical oncology, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Salpingo-oophorectomy/methods, 0303 health sciences, Natural menopause, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics, BRCA1 Protein, Breast Neoplasms/epidemiology, Incidence (epidemiology), Incidence, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, OVARIAN, BRCA2 Protein/genetics, 3. Good health, Menopause, Risk-reducing salpingo-oophorectomy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SURVIVAL, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Salpingo-oophorectomy, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:RC254-282, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, METAANALYSIS, 030304 developmental biology, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, CONSORTIUM, risk-reducing salpingo-oophorectomy, International Agencies, medicine.disease, BRCA1, BRCA2, KCONFAB, REDUCTION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, LINK, Mutation, BRCA1 Protein/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Risk Reduction Behavior
Abstract: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. The BCFR 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 centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by 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 PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is 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 the 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. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation 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. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí
Published: 2020

23. Left ventricular functional recovery of infarcted and remote myocardium after STsegment elevation myocardial infarction (METOCARD-CNIC randomized clinical trial substudy)

Author: Valentin Fuster, Nina Ajmone Marsan, José M. Montero-Cabezas, Chiara Bucciarelli-Ducci, Jeroen J. Bax, Javier Sánchez-González, Tomaž Podlesnikar, Borja Ibanez, Zlatko Fras, Nina Greif, Rodrigo Fernández-Jiménez, Victoria Delgado, Gonzalo Pizarro, Centro Nacional de Investigaciones Cardiovasculares Carlos III (España), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación ProCNIC, Ministerio de Ciencia, Innovación y Universidades (España), National Institute for Health Research (Reino Unido), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III - ISCIII, European Regional Development Fund (ERDF/FEDER), and National Institute of Health Reseach (Reino Unido)
Subjects: Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Time Factors, Infarto del miocardio con elevación del ST, medicine.medical_treatment, Enfermedad cardiovascular, 030204 cardiovascular system & hematology, Ventricular Function, Left, 030218 nuclear medicine & medical imaging, law.invention, Tratamiento médico, 0302 clinical medicine, Randomized controlled trial, law, ST segment, Myocardial infarction, Metoprolol, education.field_of_study, Ventricular Remodeling, Radiological and Ultrasound Technology, medicine.diagnostic_test, Middle Aged, Microvascular obstruction, Adrenergic beta-1 Receptor Antagonists, Treatment Outcome, Intramyocardial hemorrhage, Cardiology, Administration, Intravenous, Female, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Population, Magnetic Resonance Imaging, Cine, 03 medical and health sciences, Percutaneous Coronary Intervention, Medicina preventiva, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular diseases, Intravenous metoprolol, education, Anterior Wall Myocardial Infarction, Aged, Angiology, Feature-tracking cardiovascular magnetic resonance, business.industry, Myocardium, Research, Left ventricular remodeling, Percutaneous coronary intervention, Magnetic resonance imaging, Recovery of Function, medicine.disease, ST-segment elevation myocardial infarction, lcsh:RC666-701, ST Elevation Myocardial Infarction, business
Abstract: We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (- 8.6 ± 9.0% to - 14.5 ± 8.0%; P
Published: 2020

24. 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

25. Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan

Author: Miguel Calero, Tammaryn Lashley, Tamas Revesz, Agueda Rostagno, Jorge Ghiso, Janice L. Holton, Fundación Centro De Investigación De Enfermedades Neurológicas, National Institutes of Health (Estados Unidos), Ministerio de Ciencia (España), Fundación Reina Sofía, Alzheimer's Research UK, National Institute for Health Research (Reino Unido), University College London Hospitals NHS Foundation Trust, Imperial College London (Reino Unido), and CBD Solutions
Subjects: Amyloid, Protein Folding, Programmed cell death, Apolipoprotein B, Neurosciences. Biological psychiatry. Neuropsychiatry, Plaque, Amyloid, Article, Mice, chemistry.chemical_compound, Western blot, medicine, Animals, Humans, Amino Acid Sequence, Familial British dementia, Peptide sequence, Adaptor Proteins, Signal Transducing, biology, medicine.diagnostic_test, Clusterin, Chemistry, Chromosome 13 dementias, Brain, Neurofibrillary Tangles, Alzheimer's disease, Ligand (biochemistry), eye diseases, Cell biology, Neurology, Apolipoprotein J, Familial Danish dementia, Apo J, biology.protein, Dementia, Thioflavin, sense organs, RC321-571
Abstract: Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms. This work was supported by grants from the National Institutes of Health NS051715 (to AR) and AG030539, AG051266, AG059695, and AG065651 (to JG) and from CIBERNED and the Spanish Ministry of Science (SAF2016-78603-R and PID2019-110401RB-I00) and Institutional grants from the Queen Sofia Foundation, CIEN Foundation and the Carlos III Institutes of Health (to MC). TL is supported by an Alzheimer's Research UK senior fellowship. TR is supported by a grant from the Karin & Sten Mortstedt CBD Solutions AB, Stockholm, Sweden and by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). The views expressed are those of the authors and not necessarily those of the NIH, NHS, the NIHR or the Department of Health. Sí
Published: 2021

26. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI):a single-blind randomised controlled trial

Author: Derek J Hausenloy, Rajesh K Kharbanda, Ulla Kristine Møller, Manish Ramlall, Jens Aarøe, Robert Butler, Heerajnarain Bulluck, Tim Clayton, Ali Dana, Matthew Dodd, Thomas Engstrom, Richard Evans, Jens Flensted Lassen, Erika Frischknecht Christensen, José Manuel Garcia-Ruiz, Diana A Gorog, Jakob Hjort, Richard F Houghton, Borja Ibanez, Rosemary Knight, Freddy K Lippert, Jacob T Lønborg, Michael Maeng, Dejan Milasinovic, Ranjit More, Jennifer M Nicholas, Lisette Okkels Jensen, Alexander Perkins, Nebojsa Radovanovic, Roby D Rakhit, Jan Ravkilde, Alisdair D Ryding, Michael R Schmidt, Ingunn Skogstad Riddervold, Henrik Toft Sørensen, Goran Stankovic, Madhusudhan Varma, Ian Webb, Christian Juhl Terkelsen, John P Greenwood, Derek M Yellon, Hans Erik Bøtker, Anders Junker, Anne Kaltoft, Morten Madsen, Evald Høj Christiansen, Lars Jakobsen, Steen Carstensen, Steen Dalby Kristensen, Troels Thim, Karin Møller Pedersen, Mette Tidemand Korsgaard, Allan Iversen, Erik Jørgensen, Francis Joshi, Frants Pedersen, Hans Henrik Tilsted, Karam Alzuhairi, Kari Saunamäki, Lene Holmvang, Ole Ahlehof, Rikke Sørensen, Steffen Helqvist, Bettina Løjmand Mark, Anton Boel Villadsen, Bent Raungaard, Leif Thuesen, Martin Kirk Christiansen, Philip Freeman, Svend Eggert Jensen, Charlotte Schmidt Skov, Ahmed Aziz, Henrik Steen Hansen, Julia Ellert, Karsten Veien, Knud Erik Pedersen, Knud Nørregård Hansen, Ole Ahlehoff, Helle Cappelen, Daniel Wittrock, Poul Anders Hansen, Jens Peter Ankersen, Kim Witting Hedegaard, John Kempel, Henning Kaus, Dennis Erntgaard, Danny Mejsner Pedersen, Matthias Giebner, Troels Martin Hansen Hansen, Mina Radosavljevic-Radovanovic, Maja Prodanovic, Lidija Savic, Marijana Pejic, Dragan Matic, Ana Uscumlic, Ida Subotic, Ratko Lasica, Vladan Vukcevic, Alfonso Suárez, Beatriz Samaniego, César Morís, Eduardo Segovia, Ernesto Hernández, Iñigo Lozano, Isaac Pascual, Jose M. Vegas-Valle, José Rozado, Juan Rondán, Pablo Avanzas, Raquel del Valle, Remigio Padrón, Alfonso García-Castro, Amalia Arango, Ana B. Medina-Cameán, Ana I. Fente, Ana Muriel-Velasco, Ángeles Pomar-Amillo, César L. Roza, César M. Martínez-Fernández, Covadonga Buelga-Díaz, David Fernández-Gonzalo, Elena Fernández, Eloy Díaz-González, Eugenio Martinez-González, Fernando Iglesias-Llaca, Fernando M. Viribay, Francisco J. Fernández-Mallo, Francisco J. Hermosa, Ginés Martínez-Bastida, Javier Goitia-Martín, José L. Vega-Fernández, Jose M. Tresguerres, Juan A. Rodil-Díaz, Lara Villar-Fernández, Lucía Alberdi, Luis Abella-Ovalle, Manuel de la Roz, Marcos Fernández-Carral Fernández-Carral, María C. Naves, María C. Peláez, María D. Fuentes, María García-Alonso, María J. Villanueva, María S. Vinagrero, María Vázquez-Suárez, Marta Martínez-Valle, Marta Nonide, Mónica Pozo-López, Pablo Bernardo-Alba, Pablo Galván-Núñez, Polácido J. Martínez-Pérez, Rafael Castro, Raquel Suárez-Coto, Raquel Suárez-Noriega, Rocío Guinea, Rosa B. Quintana, Sara de Cima, Segundo A. Hedrera, Sonia I. Laca, Susana Llorente-Álvarez, Susana Pascual, Teodorna Cimas, Anthony Mathur, Eleanor McFarlane-Henry, Gerry Leonard, Jessry Veerapen, Mark Westwood, Martina Colicchia, Mary Prossora, Mervyn Andiapen, Saidi Mohiddin, Valentina Lenzi, Jun Chong, Rohin Francis, Amy Pine, Caroline Jamieson-Leadbitter, Debbie Neal, J. Din, Jane McLeod, Josh Roberts, Karin Polokova, Kristel Longman, Lucy Penney, Nicki Lakeman, Nicki Wells, Oliver Hopper, Paul Coward, Peter O'Kane, Ruth Harkins, Samantha Guyatt, Sarah Kennard, Sarah Orr, Stephanie Horler, Steve Morris, Tom Walvin, Tom Snow, Michael Cunnington, Amanda Burd, Anne Gowing, Arvindra Krishnamurthy, Charlotte Harland, Derek Norfolk, Donna Johnstone, Hannah Newman, Helen Reed, James O'Neill, John Greenwood, Josephine Cuxton, Julie Corrigan, Kathryn Somers, Michelle Anderson, Natalie Burtonwood, Petra Bijsterveld, Richard Brogan, Tony Ryan, Vivek Kodoth, Arif Khan, Deepti Sebastian, Diana Gorog, Georgina Boyle, Lucy Shepherd, Mahmood Hamid, Mohamed Farag, Nicholas Spinthakis, Paulina Waitrak, Phillipa De Sousa, Rishma Bhatti, Victoria Oliver, Siobhan Walshe, Toral Odedra, Ying Gue, Rahim Kanji, Alisdair Ryding, Amanda Ratcliffe, Angela Merrick, Carol Horwood, Charlotte Sarti, Clint Maart, Donna Moore, Francesca Dockerty, Karen Baucutt, Louise Pitcher, Mary Ilsley, Millie Clarke, Rachel Germon, Sara Gomes, Thomas Clare, Sunil Nair, Jocasta Staines, Susan Nicholson, Oliver Watkinson, Ian Gallagher, Faye Nelthorpe, Janine Musselwhite, Konrad Grosser, Leah Stimson, Michelle Eaton, Richard Heppell, Sharon Turney, Victoria Horner, Natasha Schumacher, Angela Moon, Paula Mota, Joshua O'Donnell, Abeesh Sadasiva Panicker, Anntoniette Musa, Luke Tapp, Suresh Krishnamoorthy, Valerie Ansell, Danish Ali, Samantha Hyndman, Prithwish Banerjee, Martin Been, Ailie Mackenzie, Andrew McGregor, David Hildick-Smith, Felicity Champney, Fiona Ingoldby, Kirstie Keate, Lorraine Bennett, Nicola Skipper, Sally Gregory, Scott Harfield, Alexandra Mudd, Christopher Wragg, David Barmby, Ever Grech, Ian Hall, Janet Middle, Joann Barker, Joyce Fofie, Julian Gunn, Kay Housley, Laura Cockayne, Louise Weatherlley, Nana Theodorou, Nigel Wheeldon, Pene Fati, Robert F. Storey, James Richardson, Javid Iqbal, Zul Adam, Sarah Brett, Michael Agyemang, Cecilia Tawiah, Kai Hogrefe, Prashanth Raju, Christine Braybrook, Jay Gracey, Molly Waldron, Rachael Holloway, Senem Burunsuzoglu, Sian Sidgwick, Simon Hetherington, Charmaine Beirnes, Olga Fernandez, Nicoleta Lazar, Abigail Knighton, Amrit Rai, Amy Hoare, Jonathan Breeze, Katherine Martin, Michelle Andrews, Sheetal Patale, Amy Bennett, Andrew Smallwood, Elizabeth Radford, James Cotton, Joe Martins, Lauren Wallace, Sarah Milgate, Shahzad Munir, Stella Metherell, Victoria Cottam, Ian Massey, Jane Copestick, Jane Delaney, Jill Wain, Kully Sandhu, Lisa Emery, Charlotte Hall, Chiara Bucciarelli-Ducci, Rissa Besana, Jodie Hussein, Sheila Bell, Abby Gill, Emily Bales, Gary Polwarth, Clare East, Ian Smith, Joana Oliveira, Saji Victor, Sarah Woods, Stephen Hoole, Angelo Ramos, Annaliza Sevillano, Anne Nicholson, Ashley Solieri, Emily Redman, Jean Byrne, Joan Joyce, Joanne Riches, John Davies, Kezia Allen, Louie Saclot, Madelaine Ocampo, Mark Vertue, Natasha Christmas, Raiji Koothoor, Reto Gamma, Wilson Alvares, Stacey Pepper, Barbara Kobson, Christy Reeve, Iqbal Malik, Emma Chester, Heidi Saunders, Idah Mojela, Joanna Smee, Justin Davies, Nina Davies, Piers Clifford, Priyanthi Dias, Ramandeep Kaur, Silvia Moreira, Yousif Ahmad, Lucy Tomlinson, Clare Pengelley, Amanda Bidle, Sharon Spence, Rasha Al-Lamee, Urmila Phuyal, Hakam Abbass, Tuhina Bose, Rebecca Elliott, Aboo Foundun, Alan Chung, Beth Freestone, Dr Kaeng Lee, Dr Mohamed Elshiekh, George Pulikal, Gurbir Bhatre, James Douglas, Lee Kaeng, Mike Pitt, Richard Watkins, Simrat Gill, Amy Hartley, Andrew Lucking, Berni Moreby, Damaris Darby, Ellie Corps, Georgina Parsons, Gianluigi De Mance, Gregor Fahrai, Jenny Turner, Jeremy Langrish, Lisa Gaughran, Mathias Wolyrum, Mohammed Azkhalil, Rachel Bates, Rachel Given, Rajesh Kharbanda, Rebecca Douthwaite, Steph Lloyd, Stephen Neubauer, Deborah Barker, Anne Suttling, Charlotte Turner, Clare Smith, Colin Longbottom, David Ross, Denise Cunliffe, Emily Cox, Helena Whitehead, Karen Hudson, Leslie Jones, Martin Drew, Nicholas Chant, Peter Haworth, Robert Capel, Rosalynn Austin, Serena Howe, Trevor Smith, Alex Hobson, Philip Strike, Huw Griffiths, Brijesh Anantharam, Pearse Jack, Emma Thornton, Adrian Hodgson, Alan Jennison, Anna McSkeane, Bethany Smith, Caroline Shaw, Chris Leathers, Elissa Armstrong, Gayle Carruthers, Holly Simpson, Jan Smith, Jeremy Hodierne, Julie Kelly, Justin Barclay, Kerry Scott, Lisa Gregson, Louise Buchanan, Louise McCormick, Nicci Kelsall, Rachel Mcarthy, Rebecca Taylor, Rebecca Thompson, Rhidian Shelton, Roger Moore, Sharon Tomlinson, Sunil Thambi, Theresa Cooper, Trevor Oakes, Zakhira Deen, Chris Relph, Scott prentice, Lorna Hall, Angela Dillon, Deborah Meadows, Emma Frank, Helene Markham-Jones, Isobel Thomas, Joanne Gale, Joanne Denman, John O'Connor, Julia Hindle, Karen Jackson-Lawrence, Karen Warner, Kelvin Lee, Robert Upton, Ruth Elston, Sandra Lee, Vinod Venugopal, Amanda Finch, Catherine Fleming, Charlene Whiteside, Chris Pemberton, Conor Wilkinson, Deepa Sebastian, Ella Riedel, Gaia Giuffrida, Gillian Burnett, Helen Spickett, James Glen, Janette Brown, Lauren Thornborough, Lauren Pedley, Maureen Morgan, Natalia Waddington, Oliver Brennan, Rebecca Brady, Stephen Preston, Chris Loder, Ionela Vlad, Julia Laurence, Angelique Smit, Kirsty Dimond, Michelle Hayes, Loveth Paddy, Jacolene Crause, Nadifa Amed, Priya Kaur-Babooa, Roby Rakhit, Tushar Kotecha, Hossam Fayed, Antonis Pavlidis, Bernard Prendergast, Brian Clapp, Divaka Perara, Emma Atkinson, Howard Ellis, Karen Wilson, Kirsty Gibson, Megan Smith, Muhammed Zeeshan Khawaja, Ruth Sanchez-Vidal, Simon Redwood, Sophie Jones, Aoife Tipping, Anu Oommen, Cara Hendry, DR Fazin Fath-Orboubadi, Hannah Phillips, Laurel Kolakaluri, Martin Sherwood, Sarah Mackie, Shilpa Aleti, Thabitha Charles, Liby Roy, Rob Henderson, Rod Stables, Michael Marber, Alan Berry, Andrew Redington, Kristian Thygesen, Henning Rud Andersen, Colin Berry, Andrew Copas, Tom Meade, Henning Kelbæk, Hector Bueno, Paul von Weitzel-Mudersbach, Grethe Andersen, Andrew Ludman, Nick Cruden, Dragan Topic, Zlatko Mehmedbegovic, Jesus Maria de la Hera Galarza, Steven Robertson, Laura Van Dyck, Rebecca Chu, Josenir Astarci, Zahra Jamal, Daniel Hetherington, Lucy Collier, British Heart Foundation, University College London Hospitals NHS Foundation Trust, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden, National Institute for Health Research (Reino Unido), Singapore Ministry of Health, Ministry of Education (Singapur), and Unión Europea. European Cooperation in Science and Technology (COST)
Subjects: Male, Death, Sudden, Cardiac/prevention & control, medicine.medical_treatment, Myocardial Infarction, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Medicine, ST-SEGMENT ELEVATION, Single-Blind Method, 030212 general & internal medicine, Myocardial infarction, Prospective Studies, Prospective cohort study, Heart Failure/etiology, 11 Medical and Health Sciences, Myocardial Infarction/complications, General Medicine, Middle Aged, RC666, Combined Modality Therapy, LIMB, 3. Good health, Intention to Treat Analysis, Hospitalization, Treatment Outcome, Ischemic Preconditioning, Myocardial, Female, Life Sciences & Biomedicine, Ischemic Preconditioning, Myocardial/methods, medicine.medical_specialty, CONDI-2/ERIC-PPCI Investigators, ISCHEMIA/REPERFUSION INJURY, 03 medical and health sciences, CARDIOPROTECTION, Medicine, General & Internal, Percutaneous Coronary Intervention, General & Internal Medicine, Humans, In patient, Aged, Heart Failure, Intention-to-treat analysis, Science & Technology, ADJUNCT, business.industry, Percutaneous coronary intervention, medicine.disease, United Kingdom, SIZE, Death, Sudden, Cardiac, Emergency medicine, Myocardial infarction complications, Single blind, business, TASK-FORCE
Abstract: BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden. The ERIC-PPCI trial was funded by a British Heart Foundation clinical study grant (grant number CS/14/3/31002) and a University College London Hospitals/University College London Biomedical Research Centre clinical research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants (grant numbers 11-108354 and 11-115818), Novo Nordisk Foundation (grant number NNF13OC0007447), and TrygFonden (grant number 109624). DJH was supported by the British Heart Foundation (grant number FS/10/039/28270), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the Duke-National University Singapore Medical School, the Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (grant number NMRC/CSA-SI/0011/2017) and its Collaborative Centre Grant scheme (grant number NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (grant number MOE2016-T2-2-021). HEB was supported by the Novo Nordisk Foundation (grant numbers NNF14OC0013337, NNF15OC0016674). RKK is supported by the Oxford NIHR Biomedical Centre. The research was also supported by the NIHR infrastructure at Leeds. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This article is based on the work of COST Action EU-CARDIOPROTECTION (CA16225) and supported by COST (European Cooperation in Science and Technology). We thank all study personnel for their invaluable assistance. Sí
Published: 2019

27. 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

28. Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week

Author: Davidson, Sean M, Ferdinandy, Péter, Andreadou, Ioanna, Bøtker, Hans Erik, Heusch, Gerd, Ibanez, Borja, Ovize, Michel, Schulz, Rainer, Yellon, Derek M, Hausenloy, Derek J, Garcia-Dorado, David, Unión Europea. European Cooperation in Science and Technology (COST), National Institute for Health Research (Reino Unido), Danish Council for Strategic Research, Novo Nordisk Foundation, Ministry of Human Capacities (Hungria), Deutsche Forschungsgemeinschaft (Alemania), British Heart Foundation, Ministry of Health (Singapore), Ministry of Education Academic Research (Singapur), Instituto de Salud Carlos III, and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Subjects: Myocardial infarction, Ischemia, Reperfusion, Cardioprotection
Abstract: Many treatments have been identified that confer robust cardioprotection in experimental animal models of acute ischemia and reperfusion injury. However, translation of these cardioprotective therapies into the clinical setting of acute myocardial infarction (AMI) for patient benefit has been disappointing. One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells. Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities. In this regard, emerging data suggest that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This review will present an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of cardioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies. This paper emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225. This paper is based upon work FROM COST ACTION EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). Dr. Davidson was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Dr. Ferdinandy has been supported by the the National Research, Development and Innovation Office of Hungary (NVKP_16-1-2016-0017; OTKA KH 125570; and OTKA 115378) and by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic programme of the Semmelweis University. Dr. Bøtker was supported by The Danish Council for Strategic Research (11-108354), Novo Nordisk Foundation (Conditioning Based Intervention Strategies–ConBis), and Trygfonden. Dr. Heusch was supported by the German Research Foundation (SFB 1116, B 08). Dr. Ovize has been supported by the OPeRa (ANR-10-IBHU-0004 OPeRa) and the RHU MARVELOUS (ANR-16-RHUS-0009) programs. Dr. Schulz was funded by the German Research Foundation SFB/CRC 1213/B05. Dr. Hausenloy was supported by the British Heart Foundation (FS/10/039/28270), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-021). Dr. Garcia-Dorado was supported by the Instituto de Salud Carlos III, CIBERCV-Instituto de Salud Carlos III, Spain (grant CB16/11/00479 to DGD, cofunded with European Regional Development Fund-FEDER contribution), and grants PIE/2013-00047 and PI 17/1397 Sí
Published: 2019

29. 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

30. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

Author: Klaus-Dieter Schlüter, Soni Deshwal, Hans Erik Bøtker, Michael Rahbek-Schmidt, Derek J. Hausenloy, Zoltán Giricz, Péter Ferdinandy, Moises Di Sante, David Garcia-Dorado, Fabio Di Lisa, Kerstin Boengler, Nina Kaludercic, Pasquale Pagliaro, Marisol Ruiz-Meana, Andreas Skyschally, Sean M. Davidson, Borja Ibanez, Gerd Heusch, Michel Ovize, Ioanna Andreadou, Efstathios K. Iliodromitis, Catherine D. E. Wilder, Panagiotis Efentakis, Salvatore Antonucci, Markus Neuhäuser, Petra Kleinbongard, Rainer Schulz, Saveria Femminò, Derek M. Yellon, Yvan Devaux, CarMeN, laboratoire, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), ESA Scientific Support Office, European Space Agency (ESA), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Danish Council for Strategic Research, Novo Nordisk Foundation, TrygFonden, British Heart Foundation, National Institute for Health Research (Reino Unido), Duke National University Singapore, National Medical Research Council (Singapur), Ministry of Education (Singapur), Hungarian National Research, Development, and Innovation Office, Hungarian Academy of Sciences, and Deutsche Forschungsgemeinschaft (Alemania)
Subjects: 0301 basic medicine, Biomedical Research, Data Interpretation, Physiology, [SDV]Life Sciences [q-bio], Medizin, Drug Evaluation, Preclinical, Myocardial Infarction, isolated rabbit cardiomyocytes, Infarction, ISCHEMIA-REPERFUSION INJURY, ISOLATED RAT-HEART, cardiology working group, Clinical endpoint, acute myocardial-infarction, Myocardial infarction, Ischemic Preconditioning, bypass, Cardioprotection, isolated rat-heart, BYPASS GRAFT-SURGERY, Statistical, MALATE-ASPARTATE SHUTTLE, Preclinical, 3. Good health, Data Accuracy, [SDV] Life Sciences [q-bio], Research Design, Data Interpretation, Statistical, Ischemic Preconditioning, Myocardial, Cardiology and Cardiovascular Medicine, graft-surgery, position paper, mitochondrial permeability transition, HEART POSITION PAPER, medicine.medical_specialty, ACUTE MYOCARDIAL-INFARCTION, CORONARY-ARTERY OCCLUSION, Animals, Cardiology, Cardiovascular Agents, Disease Models, Animal, Humans, Myocardial Reperfusion Injury, Reproducibility of Results, ischemia-reperfusion injury, Context (language use), heart, CARDIOLOGY WORKING GROUP, 03 medical and health sciences, Physiology (medical), medicine, Myocardial, Intensive care medicine, Practical Guideline, business.industry, Animal, coronary-artery occlusion, Guideline, medicine.disease, Clinical trial, MITOCHONDRIAL PERMEABILITY TRANSITION, 030104 developmental biology, malate-aspartate shuttle, Disease Models, Cardiovascular System & Cardiology, Ischemic preconditioning, Drug Evaluation, ISOLATED RABBIT CARDIOMYOCYTES, business
Abstract: The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment.
Published: 2018

31. Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms

Author: Jesús de Pedro-Cuesta, Pablo Martinez-Martin, Kallol Ray Chaudhuri, Concha Bielza, Jesse Mu, Pedro Larrañaga, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Unión Europea. Comisión Europea. H2020, National Institute for Health Research (Reino Unido), and École Polytechnique Fédérale de Lausanne
Subjects: 0301 basic medicine, Aging, Longitudinal study, medicine.medical_specialty, Motor symptoms, Parkinson's disease, Matemáticas, Cognitive Neuroscience, Non-motor symptoms, Disease, lcsh:RC321-571, 03 medical and health sciences, Cluster analysis, 0302 clinical medicine, Physical medicine and rehabilitation, Text mining, medicine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, Informática, Subtypes, business.industry, subtypes, motor symptoms, medicine.disease, non-motor symptoms, 3. Good health, 030104 developmental biology, Cohort, Physical therapy, Non motor, Psychology, business, 030217 neurology & neurosurgery, Neuroscience, cluster analysis, Cohort study
Abstract: Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages. This study was funded by the Spanish Ministry of Economy and Competitiveness through the Cajal Blue Brain (C080020-09; the Spanish partner of the Blue Brain initiative from École Polytechnique Fédérale de Lausanne) and TIN2016-79684-P projects, the Regional Government of Madrid through the S2013/ICE-2845-CASI-CAM-CM project, the European Union's Horizon 2020 research and innovation programme under grant agreement No. 720270, and the National Institute of Health Research in the UK (UKCRN No: 10084). Sí
Published: 2017

32. Distribution and impact on quality of life of the pain modalities assessed by the King's Parkinson's disease pain scale

Author: Martinez-Martin, Pablo, Manuel Rojo-Abuin, Jose, Rizos, Alexandra, Rodriguez-Blazquez, Carmen, Trenkwalder, Claudia, Perkins, Lauren, Sauerbier, Anna, Odin, Per, Antonini, Angelo, Chaudhuri, Kallol Ray, International Parkinson's Disease Non-Motor Group (PDNMG), EUROPAR Study Group, King's Parkinson's Disease Pain Scale (KPPS), Parkinson's UK, National Institute for Health Research (Reino Unido), NIHR - Mental Health Biomedical Research Centre (Reino Unido), South London and Maudsley NHS Foundation Trust (Reino Unido), Imperial College London (Reino Unido), NIHR - Mental Health Biomedical Research Centre, NHS - Foundation Trust, and King ’s College London
Subjects: 0301 basic medicine, Quality of life, medicine.medical_specialty, Parkinson's disease, Neurology, Disease, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Physical medicine and rehabilitation, medicine, RC346-429, Pain modalities, Modalities, business.industry, Pain scale, Burning mouth syndrome, medicine.disease, 030104 developmental biology, Physical therapy, Pain catastrophizing, Neurology (clinical), Neurology. Diseases of the nervous system, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: In Parkinson’s disease, pain is a prevalent and complex symptom of diverse origin. King’s Parkinson’s disease pain scale, assesses different pain syndromes, thus allowing exploration of its differential prevalence and influence on the health-related quality of life of patients. Post hoc study 178 patients and 83 matched controls participating in the King’s Parkinson’s disease pain scale validation study were used. For determining the respective distribution, King’s Parkinson’s disease pain scale items and domains scores = 0 meant absence and ≥1 presence of the symptom. The regular scores were used for the other analyses. Health-related quality of lifewas evaluated with EQ-5D-3L and PDQ-8 questionnaires. Parkinson’s disease patients experienced more pain modalities than controls. In patients, Pain around joints (King’s Parkinson’s disease pain scale item 1) and Pain while turning in bed (item 8) were the most prevalent types of pain, whereas Burning mouth syndrome (item 11) and Pain due to grinding teeth (item 10) showed the lowest frequency. The total number of experienced pain modalities closely correlated with the PDQ-8 index, but not with other variables. For all pain types except Pain around joints (item 1) and pain related to Periodic leg movements/RLS (item 7), patients with pain had significantly worse health-related quality of life. The influence of pain, as a whole, on the health-related quality of life was not remarkable after adjustment by other variables. When the particular types of pain were considered, adjusted by sex, age, and Parkinson’s disease duration, pain determinants were different for EQ-5D-3L and PDQ-8. King’s Parkinson’s disease pain scale allows exploring the distribution of the diverse syndromic pain occurring in Parkinson’s disease and its association with health-related quality of life., Pain: Under-appreciated impact on quality of life Researchers confirm that the pain experienced by patients with Parkinson disease (PD) is a key determinant of health-related quality of life. Pain is a common non-motor symptom that is often underacknowledged and undertreated. Using data from the recently validated pain scale for PD, Pablo Martinez-Martin (Carlos III Institute of Health in Madrid, Spain) and colleagues explored the impact of specific pain modalities on patients’ quality of life. They found that patients with PD reported experiencing twice as many types of pain than controls, with pain around the joints and pain while moving in bed being the most prevalent. Furthermore, there was a close correlation between the number of experienced pain modalities and quality of life as evaluated with the PD questionnaire PDQ-8. Understanding the different types of pain in PD will aid the provision of effective pain relief and greatly improve patients’wellbeing.
Published: 2017

33. 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

34. Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

Author: Alfonso Valencia, Enrique Carrillo-de Santa Pau, David Juan, Nikos Sidiropoulos, Dirk S. Paul, Tomi Pastinen, Kate Downes, Daniel Rico, Stephen Watt, Alice L. Mann, Nicolas Rapin, José M. Fernández, Mattia Frontini, Nicole Soranzo, Taco W. Kuijpers, Oliver Stegle, Francesco Paolo Casale, Henk Stunnenberg, Stephan Beck, Vera Pancaldi, Lu Chen, Frederik Otzen Bagger, Simone Ecker, Angelika Merkel, Apollo - University of Cambridge Repository, Fundación La Caixa, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), National Institute for Health Research (Reino Unido), Medical Research Council (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Wellcome Trust, Royal Society Wolfson Research Merit Award, Frontini, Mattia [0000-0001-8074-6299], Downes, Kate [0000-0003-0366-1579], Soranzo, Nicole [0000-0003-1095-3852], Paul, Dirk [0000-0002-8230-0116], AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, AII - Amsterdam institute for Infection and Immunity, and Other departments
Subjects: Male, Cell type, Transcription, Genetic, Neutrophils, CD14, T cells, Phenotypic plasticity, Biology, Monocytes, Epigenesis, Genetic, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Immune system, Cluster Analysis, Humans, Gene Regulatory Networks, ddc:576.5, Epigenetics, Gene, 030304 developmental biology, 0303 health sciences, DNA methylation, Gene Expression Profiling, Research, Immune cells, Genetic Variation, Differential variability, Environmental exposure, 3. Good health, Chromatin, Cell biology, Gene Expression Regulation, Organ Specificity, Immune System, 030220 oncology & carcinogenesis, CpG Islands, Female, Gene expression, Heterogeneity, Genome-Wide Association Study
Abstract: BACKGROUND: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. RESULTS: We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16- monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers. CONCLUSIONS: Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability . We would like to thank K. Pearce and M. Kristiansen (UCL Genomics) for processing the Illumina Infinium HumanMethylation450 BeadChips; D. Balzereit, S. Dökel, A. Kovacsovics, and M. Linser (Max Planck Institute for Molecular Genetics) for help with generating the RNA-seq data; B. Phipson (Murdoch Childrens Research Institute), H.C. Bravo (University of Maryland), and P. Guilhamon (UCL Cancer Institute) for advice on statistical analyses; C. Bock (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) for useful discussions; A. Orozco (University of Costa Rica) for technical support; V. Naranbhai, B. Fairfax, and J. Knight (University of Oxford) for providing access to the neutrophil gene expression data set for replication; and L. Phipps for proofreading the manuscript. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers, and thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the NIHR Cambridge Biomedical Research Centre (BRC) for funding. BLUEPRINT Consortium: Cornelis A. Albers (Radboud University), Vyacheslav Amstislavskiy (Max Planck Institute for Molecular Genetics), Sofie Ashford (University of Cambridge), Lorenzo Bomba (Wellcome Trust Sanger Institute), David Bujold (McGill University), Frances Burden (University of Cambridge), Stephan Busche (McGill University), Maxime Caron (McGill University), Shu-Huang Chen (McGill University), Warren A. Cheung (McGill University), Laura Clarke (European Bioinformatics Institute), Irina Colgiu (Wellcome Trust Sanger Institute), Avik Datta (European Bioinformatics Institute), Oliver Delaneau (University of Geneva), Heather Elding (Wellcome Trust Sanger Institute), Samantha Farrow (University of Cambridge), Diego Garrido-Martín (Centre for Genomic Regulation), Bing Ge (McGill University), Roderic Guigo (Centre for Genomic Regulation), Valentina Iotchkova (European Bioinformatics Institute), Kousik Kundu (Wellcome Trust Sanger Institute), Tony Kwan (McGill University), John J. Lambourne (University of Cambridge), Ernesto Lowy (European Bioinformatics Institute), Daniel Mead (Wellcome Trust Sanger Institute), Farzin Pourfarzad (Sanquin Research and Landsteiner Laboratory), Adriana Redensek (McGill University), Karola Rehnstrom (University of Cambridge), Augusto Rendon (University of Cambridge), David Richardson (European Bioinformatics Institute), Thomas Risch (Max Planck Institute for Molecular Genetics), Sophia Rowlston (University of Cambridge), Xiaojian Shao (McGill University), Marie-Michelle Simon (McGill University), Marc Sultan (Max Planck Institute for Molecular Genetics), Klaudia Walter (Wellcome Trust Sanger Institute), Steven P. Wilder (European Bioinformatics Institute), Ying Yan (Wellcome Trust Sanger Institute), Stylianos E. Antonarakis (University of Geneva), Guillaume Bourque (McGill University), Emmanouil T. Dermitzakis (University of Geneva), Paul Flicek (European Bioinformatics Institute), Hans Lehrach (Max Planck Institute for Molecular Genetics), Joost H. A. Martens (Radboud University), Marie-Laure Yaspo (Max Planck Institute for Molecular Genetics), Willem H. Ouwehand (University of Cambridge). Sí
Published: 2017

35. The Neutrophil Life Cycle

Author: Andrés Hidalgo, Charlotte Summers, Leo Koenderman, Edwin R. Chilvers, Medical Research Council (Reino Unido), Wellcome Trust, GlaxoSmithKline, National Institute for Health Research (Reino Unido), Ministerio de Ciencia, Innovación y Universidades (España), Fundación ProCNIC, Netherlands Organization for Scientific Research, Chilvers, Edwin [0000-0002-4230-9677], Summers, Charlotte [0000-0002-7269-2873], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, SYSTEMIC INFLAMMATION, BLOOD, Neutrophils, BONE-MARROW, ved/biology.organism_classification_rank.species, Immunology, Bone Marrow Cells, Spleen, Review, Biology, G-CSF, GRANULOCYTES, Systemic inflammation, MOUSE, Granulopoiesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Journal Article, Animals, Homeostasis, Humans, IMMUNE-RESPONSE, Immunology and Allergy, Model organism, KINETICS, Progenitor, Innate immune system, Science & Technology, ved/biology, GRANULOPOIESIS, Cell Differentiation, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Organ Specificity, 1107 Immunology, SURVIVAL, Disease Susceptibility, Bone marrow, medicine.symptom, Life Sciences & Biomedicine, Biomarkers, 030215 immunology
Abstract: Neutrophils are recognized as an essential part of the innate immune response, but an active debate still exists regarding the life cycle of these cells. Neutrophils first differentiate in the bone marrow through progenitor intermediaries before entering the blood, in a process that gauges the extramedullary pool size. Once believed to be directly eliminated in the marrow, liver, and spleen, neutrophils, after circulating for less than 1 day, are now known to redistribute into multiple tissues with poorly understood kinetics. In this review, we provide an update on the dynamic distribution of neutrophils across tissues in health and disease, and emphasize differences between humans and model organisms. We further highlight issues to be addressed to exploit the unique features of neutrophils in the clinic. The work in the authors laboratories is funded by (ERC) Medical Research Council, Wellcome Trust, GlaxoSmithKline, MedImmune, the NIHR Cambridge Biomedical Research Centre, British Heart Foundation, National Institute for Health, Cambridge NIHR Biomedical Research Centre, the MCIU (Ministerio de Ciencia, Innovación y Universidades), the Pro-CNIC Foundation, the Dutch Science Agenda (NWA) and the Netherlands Organization for Scientific Research (NWO). The CNIC is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505). Sí
Published: 2019

36. Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients:Discovery and validation studies

Author: Sonia Gatius, Petronela Buiga, Robert C. Klein, Ruoyan Xu, Christopher Yau, Samar Elorbany, Jean-Baptiste Cazier, Javier Benitez, Rick Tearle, Alba Mota, Gil McVean, Bassim Hassan, Robert C. Bast, Leticia Campo, María Josefa Mosteiro García, Stefano Lise, Fabrizio Miranda, Maria D. Lozano, Kevin Dunne, Daniel M. Hayden, Mohammad KaramiNejadRanjbar, Brock A. Peters, Alex Laios, Karin Hellner, Lorna Witty, Gema Moreno-Bueno, Xavier Matias-Guiu, Sunanda Dhar, Donatien Fotso Chedom, Stephen Kennedy, Tatjana Sauka-Spengler, Rebecca Yu Zhang, Sandra Herrero-Gonzalez, Simon J. Leedham, Maria Ruiz-Miró, K Gaitskell, Ruth M. Williams, Mara Artibani, Ahmed Ashour Ahmed, Radoje Drmanac, Kevin A. Myers, Ian Tomlinson, Karim Ahmed, Medical Research Council (UK), University of Oxford, National Institute for Health Research (UK), Ministerio de Sanidad y Consumo (España), Wellcome Trust, Instituto de Salud Carlos III, Ovarian Cancer Action (Reino Unido), NIHR - Oxford Biomedical Research Centre (Reino Unido), National Institute for Health Research (Reino Unido), Experimental Cancer Medicine Centres, Medical Research Council (Reino Unido), and Cancer Research UK (Reino Unido)
Subjects: 0301 basic medicine, Pathology, Cellular differentiation, Genes, BRCA2, Genes, BRCA1, SOX2, Gene Expression, lcsh:Medicine, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Regulatory Sequences, Nucleic Acid, medicine.disease_cause, Ovarian Neoplasms, lcsh:R5-920, Mutation, education.field_of_study, High-Throughput Nucleotide Sequencing, Cell Differentiation, General Medicine, Middle Aged, 3. Good health, Precancer, medicine.anatomical_structure, Neoplastic Stem Cells, Screening, Female, lcsh:Medicine (General), Research Paper, Adult, Image-Guided Biopsy, medicine.medical_specialty, Population, Antineoplastic Agents, Biology, Fallopian tube, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Deep sequencing, 03 medical and health sciences, Ovarian cancer, Cell Line, Tumor, Biomarkers, Tumor, medicine, Humans, education, Fallopian Tubes, Aged, Neoplasm Staging, SOXB1 Transcription Factors, lcsh:R, Cancer, medicine.disease, BRCA mutations, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, Laparoscopy, Precancerous Conditions
Abstract: Open Access funded by Medical Research Council. Under a Creative Commons license.-- et al., Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p, This work is funded by the Medical Research Council (H8RSRS00), Ovarian Cancer Action (HER00070), the Oxford Biomedical Research Centre, the National Institute for Health Research (HJRWAC05) and the Experimental Cancer Medicine Centre. MJG is recipient of a research contract from the Instituto de Salud Carlos III of the Ministerio Español de Sanidad y Consumo (Miguel Servet tipo II Program, CPII 13-00047). C.Y. acknowledges the support of an MRC New Investigator Research Grant (Ref No. MR-L001411-1) and the Wellcome Trust Core Award Grant Number 090532-Z-09-Z.
Published: 2016

37. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction:trials and tribulations

Author: Gerd Heusch, David Garcia-Dorado, Derek M. Yellon, Robert A. Kloner, David Erlinge, Michel Ovize, Derek J. Hausenloy, Thomas Engstrøm, Hans Erik Bøtker, Borja Ibanez, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School [Singapore], Hatter Cardiovascular Institute, Institute Cardiovascular Science, University College London (UCL), Biomedical Research Center, National Institute Health Research, University College London Hospitals (UCLH), Department of Cardiology, Gentofte University Hospital, Medical School, Institute for Pathophysiology, West-German Heart and VascularCenter, Essen University Hospital, Spanish National Centre for Cardiovascular Research, IIS Hospital Universitario Fundación Jiménez Díaz, Huntington Medical Research Institute, School Medicine Department Medicine, Division Cardiovascular Medicine, University of Southern California (USC), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Biomedical Research Centertr, National Institute Health research, British Heart Foundation, Rosetrees Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Cardiovascular Research Network of the Spanish Institute of Health Instituto de Salud Carlos III (ISCiii RETICS-RIC) RD12/0042/0021, German Research Foundation He 1320/18-3 SFB 1116 B8, Carlos III Institute of Health, European Regional Development Fund (ERDF/FEDER)PI13/01979, ISCiii Cardiovascular Research Network RD12/0042/0054, Red de Investigacion Cardiovascular del Instituto de Salud Carlos III, grupo Hospital Universitari Vall d'Hebron RETICS 2012 RD12/0042/0021, Duke NUS Medical School, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), National Institute for Health Research (Reino Unido), Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares), Deutsche Forschungsgemeinschaft (Alemania), Instituto de Salud Carlos III, and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Subjects: 0301 basic medicine, Adenosine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Vasodilator Agents, Medizin, 030204 cardiovascular system & hematology, Mitochondrial Membrane Transport Proteins, 0302 clinical medicine, Hypothermia, Induced, Oximes, Medicine, Myocardial infarction, Enzyme Inhibitors, Ischemic Postconditioning, Protein Kinase C, Metoprolol, Cause of death, Cardioprotection, Clinical Trials as Topic, Cardiogenic shock, BYPASS GRAFT-SURGERY, RANDOMIZED CONTROLLED-TRIAL, NO-REFLOW PHENOMENON, Combined Modality Therapy, Coronary Vessels, 3. Good health, reperfusion, LONG-TERM BENEFIT, Current Opinion, Cardiology, cardiovascular system, Cyclosporine, Nucleotides, Cyclic, Cardiology and Cardiovascular Medicine, Oligopeptides, medicine.drug, Signal Transduction, medicine.medical_specialty, Cardiotonic Agents, CONTROLLED CLINICAL-TRIAL, wound, PERCUTANEOUS CORONARY INTERVENTION, Myocardial Reperfusion, Myocardial Reperfusion Injury, Nitric Oxide, ISCHEMIA-REPERFUSION, 03 medical and health sciences, LEFT-VENTRICULAR FUNCTION, Internal medicine, infarctus du myocarde, Journal Article, Humans, Secosteroids, cardiovascular diseases, Nitrites, PROTEIN KINASE-C, business.industry, Mitochondrial Permeability Transition Pore, Patient Selection, Percutaneous coronary intervention, medicine.disease, MITOCHONDRIAL PERMEABILITY TRANSITION, 030104 developmental biology, Heart failure, ST Elevation Myocardial Infarction, business, Reperfusion injury, blessure
Abstract: Ischaemic heart disease (IHD) remains the leading cause of death and disability in Europe and worldwide. A major cause of morbidity and mortality in IHD patients is an acute ST-segment elevation myocardial infarction (STEMI), which despite prompt reperfusion by primary percutaneous coronary intervention (PPCI) has significant mortality (7% death at 1 year) and morbidity (22% prolonged or new hospitalization for heart failure at 1 year) in patients with large infarcts.1 When high-risk STEMI patients presenting with cardiogenic shock are not excluded, mortality at 1 year is even higher, at 12% after 1 year.2 As such, there remains an urgent need to discover novel therapies which can be given prior to or at the time of PPCI to reduce myocardial infarct (MI) size in order to preserve left ventricular (LV) systolic function, prevent the onset of heart failure, and improve survival in reperfused STEMI patients. In patients presenting with STEMI, rapid access to the emergency medical services and timely reperfusion by PPCI minimize the total ischaemic time, a major determinant of MI size. Although myocardial reperfusion is essential to salvage myocardium following a STEMI, the process of restoring coronary blood flow to the ischaemic tissue can, in itself, induce myocardial injury and cardiomyocyte death, a phenomenon which is known as ‘myocardial reperfusion injury’.3,4 Crucially, there is currently no effective therapy for reducing myocardial reperfusion injury in STEMI patients, and therefore, it remains a valid target for cardioprotection. However, the search for an effective therapy capable of targeting myocardial reperfusion injury and reducing MI size has been quite challenging, with a large number of failures to translate novel cardioprotective therapies into the …
Published: 2016

38. Morphogenesis of myocardial trabeculae in the mouse embryo

Author: Robert J.M. Wilson, Gabriella Captur, Guillermo Luxán, James C. Moon, Timothy J. Mohun, Michael F Bennett, Arthur Nasis, José Luis de la Pompa, Medical Research Council (Reino Unido), Higher Education Funding Council for England, Ministerio de Economía y Competitividad (España), and National Institute for Health Research (Reino Unido)
Subjects: 0301 basic medicine, NON-COMPACTION, EXPRESSION, Histology, non‐compaction cardiomyopathy, Organogenesis, Notch signaling pathway, Morphogenesis, Cardiac embryology, Biology, Mice, 03 medical and health sciences, Developmental biology, medicine, Animals, Molecular Biology, Ecology, Evolution, Behavior and Systematics, HEART DEVELOPMENT, ARCHITECTURE, cardiac embryology, Embryonic heart, Heart development, Cardiogenesis, MUTATIONS, Myocardium, cardiogenesis, PROLIFERATION, Heart, Embryo, Original Articles, Cell Biology, Anatomy, Non-compaction cardiomyopathy, Embryonic stem cell, 030104 developmental biology, medicine.anatomical_structure, Ventricle, CONDUCTION SYSTEM, Original Article, RESOLUTION EPISCOPIC MICROSCOPY, VENTRICULAR NONCOMPACTION CARDIOMYOPATHY, Developmental Biology
Abstract: Formation of trabeculae in the embryonic heart and the remodelling that occurs prior to birth is a conspicuous, but poorly understood, feature of vertebrate cardiogenesis. Mutations disrupting trabecular development in the mouse are frequently embryonic lethal, testifying to the importance of the trabeculae, and aberrant trabecular structure is associated with several human cardiac pathologies. Here, trabecular architecture in the developing mouse embryo has been analysed using high-resolution episcopic microscopy (HREM) and three-dimensional (3D) modelling. This study shows that at all stages from mid-gestation to birth, the ventricular trabeculae comprise a complex meshwork of myocardial strands. Such an arrangement defies conventional methods of measurement, and an approach based upon fractal algorithms has been used to provide an objective measure of trabecular complexity. The extent of trabeculation as it changes along the length of left and right ventricles has been quantified, and the changes that occur from formation of the four-chambered heart until shortly before birth have been mapped. This approach not only measures qualitative features evident from visual inspection of 3D models, but also detects subtle, consistent and regionally localised differences that distinguish each ventricle and its developmental stage. Finally, the combination of HREM imaging and fractal analysis has been applied to analyse changes in embryonic heart structure in a genetic mouse model in which trabeculation is deranged. It is shown that myocardial deletion of the Notch pathway component Mib1 (Mib1(flox/flox); cTnT-cre) results in a complex array of abnormalities affecting trabeculae and other parts of the heart. This work was supported by funding to TJM from the Medical Research Council (U117562103); to JCM by the Higher Education Funding Council for England; to JLdlP and GL by grants SAF2010-17555 and SAF2013-45543-R from the Spanish Ministry of Economy and Competitiveness (MINECO); and to GC by a research fellowship at the University College London Biomedical Research Centre from the UK National Institutes of Health Research Cardiometabolic Programme. Sí
Published: 2016

39. Mortality according to CD4 count at start of combination antiretroviral therapy among HIV positive patients followed for up to 15 years after start of treatment: collaborative cohort study

Author: May, Margaret T, Vehreschild, Jorg-Janne, Trickey, Adam, Obel, Niels, Reiss, Peter, Bonnet, Fabrice, Mary-Krause, Murielle, Samji, Hasina, Cavassini, Matthias, Gill, Michael John, Shepherd, Leah C, Crane, Heidi M, d'Arminio Monforte, Antonella, Burkholder, Greer A, Johnson, Margaret M, Sobrino-Vegas, Paz, Domingo, Pere, Zangerle, Robert, Justice, Amy C, Sterling, Timothy R, Miró, José M, Sterne, Jonathan A C, Antiretroviral Therapy Cohort Collaboration (ART-CC), University of Bristol [Bristol], Universität zu Köln = University of Cologne, University of Copenhagen = Københavns Universitet (UCPH), University of Amsterdam [Amsterdam] (UvA), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, CHU Bordeaux [Bordeaux], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Université de Lausanne = University of Lausanne (UNIL), University of Calgary, UCL Medical School, University of Washington [Seattle], 'San Paolo' Hospital, University of Alabama [Tuscaloosa] (UA), Royal Free London NHS Foundation Trust, Instituto Salud Carlos III, Universitat Autònoma de Barcelona (UAB), Universität Innsbruck [Innsbruck], Yale University [New Haven], VA Connecticut Healthcare System, Vanderbilt University [Nashville], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Medical Research Council (Reino Unido), Department for International Development (Reino Unido), National Institute for Health Research (Reino Unido), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Institut National de la Santé et de la Recherche Médicale (Francia), Ministère de la Santé (Francia), Ministero della Salute (Italia), Ministerio de Sanidad (España), Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), Red de Investigación Cooperativa en Investigación en Sida (España), Stichting HIV Monitoring (Netherlands), Unión Europea, National Institutes of Health (Estados Unidos), NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), United States Department of Veterans Affairs, Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, Veterans Health Administration, Unión Europea. Comisión Europea. 7 Programa Marco, Government of Alberta (Canadá), Government of Columnia (Estados Unidos), Government of the United Kingdom, Abbott, Gilead Sciences (Spain), Tibotec-Upjohn, ViiV Healthcare, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, Roche, Boehringer Ingelheim Fonds, Merck, Sharp & Dohme, HAL UPMC, Gestionnaire, Antiretroviral Therapy Cohort Collaboration (ART-CC), Boulle, A., Stephan, C., Miro, JM., Cavassini, M., Chêne, G., Costagliola, D., Dabis, F., Monforte£££Antonella D'Arminio£££ AD., Del Amo, J., Van Sighem, A., Fätkenheuer, G., Gill, J., Guest, J., Haerry, DH., Hogg, R., Justice, A., Shepherd, L., Obel, N., Crane, H., Smith, C., Reiss, P., Saag, M., Sterling, T., Teira, R., Williams, M., Zangerle, R., Sterne, J., May, M., Ingle, S., Trickey, A., Universität zu Köln, University of Copenhagen = Københavns Universitet (KU), Université de Lausanne (UNIL), AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Global Health, and Universitat de Barcelona
Subjects: 0301 basic medicine, Male, Integrase inhibitor, HIV Infections, Kaplan-Meier Estimate, Cohort Studies, 0302 clinical medicine, Cohort collaboration, 030212 general & internal medicine, Lymphocytes, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, Reverse-transcriptase inhibitor, Relative survival, Mortality rate, Antiretrovirals, Middle Aged, 3. Good health, Antiretroviral therapy, Infectious Diseases, Anti-Retroviral Agents, Cohort, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV/AIDS, Female, medicine.drug, Cohort study, Microbiology (medical), Adult, medicine.medical_specialty, Adolescent, Population, antiretroviral therapy, CD4 count, Limfòcits, 03 medical and health sciences, Young Adult, Internal medicine, medicine, VIH (Virus), Humans, Mortality, education, Survival analysis, business.industry, HIV (Viruses), cohort collaboration, HIV, mortality, Antiretroviral agents, Surgery, CD4 Lymphocyte Count, 030104 developmental biology, Morbiditat, Morbidity, business
Abstract: The strong association of CD4 count at start of combination therapy with subsequent survival in HIV-infected patients diminished during the first 5 years of treatment. After 5 years, lower baseline CD4 counts were not associated with higher mortality., Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. Methods. We estimated mortality rates (MRs) by time since start of ART (
Published: 2016

40. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author: Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.
Subjects: 0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract: Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
Published: 2016

41. HIV testing history and access to treatment among migrants living with HIV in Europe

Author: Giota Touloumi, Tullio Prestileo, Maria Prins, Ibidun Fakoya, Julia del Amo, Fiona Burns, Andrew Copas, Katharine Ea Darling, Henrique Barros, Anne-Francoise Gennotte, Debora Alvarez-del Arco, Alain Volny-Anne, Claudia Wengenroth, Susana Monge, Unión Europea. Comisión Europea. 7 Programa Marco, National Institute for Health Research (Reino Unido), Fundación para la Investigación y la Prevención del Sida en España, Centro de Investigación Biomedica en Red - CIBER, APH - Global Health, Infectious diseases, aMASE Study Team, Aerssens, A., Aguado, M., Alimi, B., Anagnostou, O., Anderson, J., Antoniadou, A., Arando, M., Barberà, M.J., Barthélemy, A., Belda-Ibáñez, J., Bertisch, B., Bil, J., Blanco, J.R., Block, K., Boesecke, C., Boura, M., Burgos, J., Cabo, J., Calabuig, E., Campbell, L., Cardoso, O., Claudia, W., Clumeck, N., Colucci, A., Corrao, S., Cuellar, S., Cunha, J., Daikos, G., Darling, K., Del Romero, J., Dellot, P., Domingo, P., Dronda, F., Ebeling, F., Engelhardt, A., Engler, B., Farrell, J., Fehr, J., Feijó, M., Fernández, E., Fernández García, E., Fernandez, T., Fortes, A.L., Fox, J., Garcia de Olalla, P., García, F., Gargalianos-Kakolyris, P., Germano, I., Gilleran, G., Gilson, R., Goepel, S., Gogos, H.A., Gómez Sirvent, J.L., Gountas, I., Gregg, A., Gutiérrez, F., Gutierrez, M.M., Hermans, I., Iribarren, J.A., Knobel, H., Koulai, L., Kourkounti, S., La Morté, C., LeCompte, T., Ledergerber, B., Leonidou, L., Ligero, M.C., Lindergard, G., Lino, S., Lopes, M.J., Lopez Lirola, A., Louhenapessy, M., Lourida, G., Luzi, A.M., Maltez, F., Manirankunda, L., Martín-Pérez, A., Martins, L., Masía, M., Mateu, M.G., Meireles, P., Mendes, A., Metallidis, S., Mguni, S., Milinkovic, A., Miró, J.M., Mohrmann, K., Montero, M., Mouhebati, T., Moutschen, M., Müller, M., Murphy, C., Nöstlinger, C., Ocaña, I., Okumu-Fransche, S., Onwuchekwa, G., Ospina, J.E., Otiko, D., Pacheco, P., Palacios, R., Paparizos, V., Papastamopoulos, V., Paredes, V., Patel, N., Pellicer, T., Peña, A., Petrosillo, N., Pinheiro, A., Poças, J., Portillo, A., Post, F., Prestileo, F., Prins, P., Protopapas, K., Psichogiou, M., Pulido, F., Rebollo, J., Ribeirinho, A., Río, I., Robau, M., Rockstroh, J.K., Rodrigues, E., Rodríguez, M., Sajani, C., Salavert, M., Salman, R., Sanz, N., Schuettfort, G., Schüttfort, G., Schwarze-Zander, C., Serrão, R., Silva, D., Silva, V., Silverio, P., Skoutelis, A., Staehelin, C., Stephan, C., Stretton, C., Styles, F., Sutre, A.F., Taylor, S., Teixeira, B., Thierfelder, C., Tsachouridou, O., Tudor, K., Valadas, E., van Frankenhuijsen, M., Vázquez, M., Velasco Arribas, M., Vera, M., Vinciana, P., Voudouri, N., Wasmuth, J.C., Wilkins, E., Young, L., Yurdakul, S., Zafra Espinosa, T., Zuilhof, W., and Zuure, F.
Subjects: Male, 0301 basic medicine, Cross-sectional study, HIV Infections, migrants, Logistic regression, Health Services Accessibility, Sexual and Gender Minorities, 0302 clinical medicine, Pregnancy, Health care, Medicine, 030212 general & internal medicine, 10. No inequality, Research Articles, Reproductive health, Transients and Migrants, AIDS Serodiagnosis, virus diseases, 3. Good health, Europe, Infectious Diseases, Anti-Retroviral Agents, behavior and behavior mechanisms, population characteristics, Bisexuality, Female, Viral load, geographic locations, Research Article, Adult, Sexual Behavior, Migrants, primary healthcare, 03 medical and health sciences, Humans, HIV serodiagnosis, ddc:610, Heterosexuality, Anti-Retroviral Agents/therapeutic use, Cross-Sectional Studies, Europe/epidemiology, HIV Infections/diagnosis, HIV Infections/drug therapy, Logistic Models, Primary Health Care, Sexual Behavior/statistics & numerical data, HIV, health services accessibility, business.industry, Health services accessibility, Public Health, Environmental and Occupational Health, social sciences, Treatment as prevention, 030112 virology, Residence, business, Primary healthcare, Demography
Abstract: INTRODUCTION: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe. METHODS: A cross-sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV-positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign-born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men. RESULTS: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post-migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three-quarters of people on antiretrovirals had an HIV viral load
Published: 2018

42. A robust blood gene expression-based prognostic model for castration-resistant prostate cancer

Author: William Oh, Yixuan Gong, Matthias Heck, Matthew D. Galsky, Roman Nawroth, Eric E. Schadt, Johann S. de Bono, Uma Chippada-Venkata, Li Wang, Margitta Retz, Che-Kai Tsao, David Olmos, Jun Zhu, Prostate Cancer Foundation, Cancer Research UK (Reino Unido), National Institute for Health Research (Reino Unido), [Wang,L, Schadt,E, Zhu,J] Icahn Institute for Genomics and Multiscale Biology, New York, NY, United States. [Wang,L, Zhu,J] Department of Genetics and Genomic Sciences, New York, United States. [Gong,Y, Chippada-Venkata,U, Galsky,M, Tsao,CK, Zhu,J, Oh,WK] Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, United States. [Heck,MM, Retz,M, Nawroth,R] Klinikum rechts der Isar, Technische Universität München, Department of Urology, Munich, Germany. [Bono,J de] Royal Marsden Hospital, Institute for Cancer Research, Sutton, Surrey, United Kingdom. [Olmos,D] Spanish National Cancer Research Centre (CNIO), Prostate Cancer clinical research Unit, Madrid, Spain. [Olmos,D] Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Medical Oncology Deparment, CNIO-IBIMA Genitourinary Cancer Clinical Research Unit, Málaga, Spain., and The project was partially funded by Young Investigator Award from Prostate Cancer Foundation (LW), R01MH090948 (JZ), and U01AG046170 (JZ). JDB's laboratory is supported by a Cancer Research UK Centre grant, Experimental Cancer Medicine Centre funding, a Prostate Cancer UK and Movember Centre of Excellence grant, and a National Institute for Health Research Biomedical Research Center to the Royal Marsden/ICR.
Subjects: Oncology, BIOMARKER, SELECTION, Male, Myeloid, Regulación hacia abajo, Gene Expression, Prostate cancer, Gene expression, Phenomena and Processes::Biological Phenomena::Biological Processes [Medical Subject Headings], NETWORK, Neoplasm Metastasis, Masculino, Medicine(all), Marcadores biológicos, Linfocitos, MEN, General Medicine, Middle Aged, Prognosis, 3. Good health, ddc, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms, Castration-Resistant, medicine.anatomical_structure, SURVIVAL, Biomarker (medicine), Células mieloides, Research Article, PCA3, medicine.medical_specialty, Check Tags::Male [Medical Subject Headings], Anatomy::Cells::Myeloid Cells [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [Medical Subject Headings], Internal medicine, medicine, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], Biomarkers, Tumor, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes [Medical Subject Headings], Humans, RNA, Messenger, SIGNATURES, Aged, Neoplasm Staging, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings], business.industry, ARN mensajero, Neoplasias de la próstata resistentes a la castración, Gene Expression Profiling, Procesos biológicos, Cancer, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], 1ST-LINE CHEMOTHERAPY, medicine.disease, Gene expression profiling, TO-LYMPHOCYTE RATIO, Immunology, Cancer biomarkers, business
Abstract: Castration-resistant prostate cancer (CRPC) is associated with wide variations in survival. Recent studies of whole blood mRNA expression-based biomarkers strongly predicted survival but the genes used in these biomarker models were non-overlapping and their relationship was unknown. We developed a biomarker model for CRPC that is robust, but also captures underlying biological processes that drive prostate cancer lethality. Using three independent cohorts of CRPC patients, we developed an integrative genomic approach for understanding the biological processes underlying genes associated with cancer progression, constructed a novel four-gene model that captured these changes, and compared the performance of the new model with existing gene models and other clinical parameters. Our analysis revealed striking patterns of myeloid- and lymphoid-specific distribution of genes that were differentially expressed in whole blood mRNA profiles: up-regulated genes in patients with worse survival were overexpressed in myeloid cells, whereas down-regulated genes were noted in lymphocytes. A resulting novel four-gene model showed significant prognostic power independent of known clinical predictors in two independent datasets totaling 90 patients with CRPC, and was superior to the two existing gene models. Whole blood mRNA profiling provides clinically relevant information in patients with CRPC. Integrative genomic analysis revealed patterns of differential mRNA expression with changes in gene expression in immune cell components which robustly predicted the survival of CRPC patients. The next step would be validation in a cohort of suitable size to quantify the prognostic improvement by the gene score upon the standard set of clinical parameters. The project was partially funded by Young Investigator Award from Prostate Cancer Foundation (LW), R01MH090948 (JZ), and U01AG046170 (JZ). None of the aforementioned funding bodies were involved in the study design and conduct. We would like to thank our team of clinical coordinators including Teena Kochukoshy, Manpreet Brar, and Victoria Gresia for consenting patients, collecting blood, and providing database support for the study. JDB's laboratory is supported by a Cancer Research UK Centre grant, Experimental Cancer Medicine Centre funding, a Prostate Cancer UK and Movember Centre of Excellence grant, and a National Institute for Health Research Biomedical Research Center to the Royal Marsden/ICR. Sí
Published: 2015

43. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain. 10Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain. 11Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece. 13Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain. 14Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain. 15Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 16Department of Oncology, Lund University, Lund, Sweden. 17Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 18Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. 27Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America. 28Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America. 29Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia. 32Department of Epidemiology, Columbia University, New York, New York, United States of America. 33Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. 34Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD
Subjects: Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
Published: 2014

44. Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes

Author: Kenneth Walsh, Leanne E. Felkin, Kalyani D. Panse, Lucia Munoz, Nadia Rosenthal, Paul J.R. Barton, Masayuki Shimano, Kazuto Nakamura, Marina López-Olañeta, María Villalba, Enrique Lara-Pezzi, Jesús M. Gómez-Salinero, British Heart Foundation, National Institute for Health Research (Reino Unido), South London and Maudsley NHS Foundation Trust (Reino Unido), Imperial College London (Reino Unido), Unión Europea. Comisión Europea, Ministerio de Ciencia e Innovación (España), and Comunidad de Madrid (España)
Subjects: Time Factors, Cardiac fibrosis, medicine.medical_treatment, Pharmaceutical Science, Myostatin, 030204 cardiovascular system & hematology, Mice, 0302 clinical medicine, Myocyte, Myocytes, Cardiac, Genetics (clinical), Cells, Cultured, Mice, Knockout, 0303 health sciences, biology, 3. Good health, Cell biology, Molecular Medicine, Collagen, Cardiology and Cardiovascular Medicine, Signal Transduction, medicine.medical_specialty, Follistatin-Related Proteins, Paracrine Communication, Bone morphogenetic protein, 03 medical and health sciences, Paracrine signalling, Internal medicine, Genetics, medicine, Cell Adhesion, Animals, Humans, 030304 developmental biology, Cell Proliferation, Heart Failure, Growth factor, Connective Tissue Growth Factor, Proteins, Fibroblasts, medicine.disease, Fibrosis, Coculture Techniques, Rats, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Gene Expression Regulation, biology.protein, Follistatin
Abstract: Follistatins are extracellular inhibitors of the TGF-β family ligands including activin A, myostatin and bone morphogenetic proteins. Follistatin-like 3 (FSTL3) is a potent inhibitor of activin signalling and antagonises the cardioprotective role of activin A in the heart. FSTL3 expression is elevated in patients with heart failure and is upregulated in cardiomyocytes by hypertrophic stimuli, but its role in cardiac remodelling is largely unknown. Here, we show that the production of FSTL3 by cardiomyocytes contributes to the paracrine activation of cardiac fibroblasts, inducing changes in cell adhesion, promoting proliferation and increasing collagen production. We found that FSTL3 is necessary for this response and for the induction of cardiac fibrosis. However, full activation requires additional factors, and we identify connective tissue growth factor as a FSTL3 binding partner in this process. Together, our data unveil a novel mechanism of paracrine communication between cardiomyocytes and fibroblasts that may provide potential as a therapeutic target in heart remodelling. British Heart Foundation [PG/08/084/25827]; Heart Research UK; National Institute for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton; Harefield NHS Foundation Trust; Imperial College; European Union [ERG-239158, ITN-289600]; Spanish Ministry of Science and Innovation [BFU2009-10016, CP08/00144]; Regional Government of Madrid [S2010/BMD-2321 'Fibroteam'] Sí
Published: 2012

45. Effects of Streptococcus pneumoniae strain background on complement resistance

Author: Birgitta Henriques-Normark, William P. Hanage, Jose Yuste, Brian G. Spratt, Sophia Opel, Catherine Hyams, Jeremy S. Brown, Katie Bax, National Institute for Health Research (United Kingdom), and National Institute for Health Research (Reino Unido)
Subjects: Serotype, Bacterial capsule, Bacterial Diseases, Neutrophils, Complement System, lcsh:Medicine, medicine.disease_cause, MOSAIC GENES, INFECTION, Bacterial Physiology, DEPOSITION, lcsh:Science, Complement C1q, Multidisciplinary, Streptococci, Flow Cytometry, Antibodies, Bacterial, Innate Immunity, Bacterial Pathogens, Bacterial Biochemistry, Host-Pathogen Interaction, Streptococcus pneumoniae, Infectious Diseases, Medical Microbiology, Science & Technology - Other Topics, Medicine, MEDIATED IMMUNITY, CAPSULAR SEROTYPE, Protein Binding, Research Article, FACTOR-H, PHASE VARIATION, General Science & Technology, Immunology, Virulence, Enzyme-Linked Immunosorbent Assay, Biology, Microbiology, INVASIVE-DISEASE, Classical complement pathway, Streptococcal Infections, MD Multidisciplinary, medicine, Humans, Serotyping, Bacterial Capsules, Science & Technology, MULTIDISCIPLINARY SCIENCES, lcsh:R, Immunity, Bacteriology, Complement System Proteins, Complement system, HISTIDINE TRIAD PROTEINS, Immunoglobulin G, Immune System, iC3b, Bacterial Pneumonia, lcsh:Q
Abstract: BACKGROUND: Immunity to infections caused by Streptococcus pneumoniae is dependent on complement. There are wide variations in sensitivity to complement between S. pneumoniae strains that could affect their ability to cause invasive infections. Although capsular serotype is one important factor causing differences in complement resistance between strains, there is also considerable other genetic variation between S. pneumoniae strains that may affect complement-mediated immunity. We have therefore investigated whether genetically distinct S. pneumoniae strains with the same capsular serotype vary in their sensitivity to complement mediated immunity. METHODOLOGY AND PRINCIPAL FINDINGS: C3b/iC3b deposition and neutrophil association were measured using flow cytometry assays for S. pneumoniae strains with different genetic backgrounds for each of eight capsular serotypes. For some capsular serotypes there was marked variation in C3b/iC3b deposition between different strains that was independent of capsule thickness and correlated closely to susceptibility to neutrophil association. C3b/iC3b deposition results also correlated weakly with the degree of IgG binding to each strain. However, the binding of C1q (the first component of the classical pathway) correlated more closely with C3b/iC3b deposition, and large differences remained in complement sensitivity between strains with the same capsular serotype in sera in which IgG had been cleaved with IdeS. CONCLUSIONS: These data demonstrate that bacterial factors independent of the capsule and recognition by IgG have strong effects on the susceptibility of S. pneumoniae to complement, and could therefore potentially account for some of the differences in virulence between strains. This work was undertaken at University College London, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme. CH was supported by the Astor Foundation and Glaxo Smith Kline through the University College London MB PhD programme. JY was supported by the British Lung Foundation (P05/3). BHN is supported by the Ragnar and Torsten So¨ derberg foundation and the Swedish Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí
Published: 2011

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