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1. Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies

Author

Pennells, L. (Lisa), Kaptoge, S. (Stephen), Wood, A., Sweeting, M, Zhao, X.H., White, I., Kavousi, M. (Maryam), Pavlovic, J., Ibanez, AM, Geleijnse, JM, Pennells, L. (Lisa), Kaptoge, S. (Stephen), Wood, A., Sweeting, M, Zhao, X.H., White, I., Kavousi, M. (Maryam), Pavlovic, J., Ibanez, AM, and Geleijnse, JM

Abstract

Aims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms. Conclusion Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Published
2019
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4. The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases

Author

Danesh, J, Erqou, S, Walker, M, Thompson, Sg, Tipping, R, Ford, C, Pressel, S, Walldius, G, Jungner, I, Folsom, Ar, Chambless, Le, Knuiman, M, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Willeit, J, Kiechl, S, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, Edoardo, Tikhonoff, Valerie, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, Rp, Tybjaerg Hansen, A, Nordestgaard, Bg, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, S, Vanuzzo, D, Pilotto, L, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Smith, Fb, Taylor, J, Guralnik, J, Phillips, C, Wallace, R, Blazer, D, Khaw, Kt, Jansson, Jh, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, Rs, Pencina, Mj, Bladbjerg, Em, Jorgensen, T, Moller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Bjorkelund, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, T, Rodriguez, B, Bouter, Lm, Heine, Rj, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, J, Sato, S, Iso, H, Kitamura, A, Noda, H, Goldbourt, U, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, D, Poppelaars, Jl, Meade, T, Cooper, J, Hedblad, B, Berglund, G, Engstrom, G, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Kuller, L, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, J, De Stavola, B, Knottenbelt, C, Cooper, Ja, Bauer, Ka, Rosenberg, Rd, Naito, Y, Holme, I, Nakagawa, H, Miura, H, Ducimetiere, P, Jouven, X, Crespo, C, Garcia Palmieri, M, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, C, Sattar, N, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, D, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Ben Shlomo, Y, Howard, Bv, Zhang, Y, Best, L, Umans, J, Onat, A, Meade, Tw, Njolstad, I, Mathiesen, E, Lochen, Ml, Wilsgaard, T, Gaziano, Jm, Stampfer, M, Ridker, P, Ulmer, H, Diem, G, Concin, H, Rodeghiero, F, Tosetto, A, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Ford, I, Robertson, M, He, Y, Ibanez, Am, Feskens, Ej, Kromhout, D, Collins, R, Di Angelantonio, E, Kaptoge, S, Lewington, S, Orfei, L, Pennells, L, Perry, P, Ray, K, Sarwar, N, Scherman, M, Thompson, A, Watson, S, Wensley, F, White, Ir, Wood, Am, Emerging Risk Factors Collaboration, Interne Geneeskunde, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: CARIM School for Cardiovascular Diseases, Movement Behavior, Executive board Vrije Universiteit, Clinical Child and Family Studies, Sociology and Social Gerontology, Earth and Climate, Environmental Policy Analysis, Developmental Genetics, Danesh, J, Erqou, S, Walker, M, Thompson, Sg, Tipping, R, Ford, C, Pressel, S, Walldius, G, Jungner, I, Folsom, Ar, Chambless, Le, Knuiman, M, Whincup, Ph, Wannamethee, Sg, Morris, Rw, Willeit, J, Kiechl, S, Santer, P, Mayr, A, Wald, N, Ebrahim, S, Lawlor, Da, Yarnell, Jw, Gallacher, J, Casiglia, E, Tikhonoff, V, Nietert, Pj, Sutherland, Se, Bachman, Dl, Keil, Je, Cushman, M, Psaty, Bm, Tracy, Rp, Tybjaerg Hansen, A, Nordestgaard, Bg, Frikke Schmidt, R, Giampaoli, S, Palmieri, L, Panico, Salvatore, Vanuzzo, D, Pilotto, L, Simons, L, Mccallum, J, Friedlander, Y, Fowkes, Fg, Lee, Aj, Smith, Fb, Taylor, J, Guralnik, J, Phillips, C, Wallace, R, Blazer, D, Khaw, Kt, Jansson, Jh, Donfrancesco, C, Salomaa, V, Harald, K, Jousilahti, P, Vartiainen, E, Woodward, M, D'Agostino, Rb, Wolf, Pa, Vasan, R, Pencina, Mj, Bladbjerg, Em, Jorgensen, T, Moller, L, Jespersen, J, Dankner, R, Chetrit, A, Lubin, F, Rosengren, A, Wilhelmsen, L, Lappas, G, Eriksson, H, Bjorkelund, C, Cremer, P, Nagel, D, Tilvis, R, Strandberg, T, Rodriguez, B, Bouter, Lm, Heine, Rj, Dekker, Jm, Nijpels, G, Stehouwer, Cd, Rimm, E, Pai, J, Sato, S, Iso, H, Kitamura, A, Noda, H, Goldbourt, U, Salonen, Jt, Nyyssönen, K, Tuomainen, Tp, Deeg, D, Poppelaars, Jl, Meade, T, Cooper, J, Hedblad, B, Berglund, G, Engstrom, G, Döring, A, Koenig, W, Meisinger, C, Mraz, W, Kuller, L, Selmer, R, Tverdal, A, Nystad, W, Gillum, R, Mussolino, M, Hankinson, S, Manson, J, De Stavola, B, Knottenbelt, C, Cooper, Ja, Bauer, Ka, Rosenberg, Rd, Naito, Y, Holme, I, Nakagawa, H, Miura, H, Ducimetiere, P, Jouven, X, Crespo, C, Garcia Palmieri, M, Amouyel, P, Arveiler, D, Evans, A, Ferrieres, J, Schulte, H, Assmann, G, Shepherd, J, Packard, C, Sattar, N, Cantin, B, Lamarche, B, Després, Jp, Dagenais, Gr, Barrett Connor, E, Wingard, D, Bettencourt, R, Gudnason, V, Aspelund, T, Sigurdsson, G, Thorsson, B, Trevisan, M, Witteman, J, Kardys, I, Breteler, M, Hofman, A, Tunstall Pedoe, H, Tavendale, R, Lowe, Gd, Ben Shlomo, Y, Howard, Bv, Zhang, Y, Best, L, Umans, J, Onat, A, Meade, Tw, Njolstad, I, Mathiesen, E, Lochen, Ml, Wilsgaard, T, Gaziano, Jm, Stampfer, M, Ridker, P, Ulmer, H, Diem, G, Concin, H, Rodeghiero, F, Tosetto, A, Brunner, E, Shipley, M, Buring, J, Cobbe, Sm, Ford, I, Robertson, M, He, Y, Ibanez, Am, Feskens, Ej, Kromhout, D, Collins, R, Di Angelantonio, E, Kaptoge, S, Lewington, S, Orfei, L, Pennells, L, Perry, P, Ray, K, Sarwar, N, Scherman, M, Thompson, A, Watson, S, Wensley, F, White, Ir, and Wood, A. M.

Subjects
Databases, Factual, Nutrition and Disease, Epidemiology, Inflammatory markers, middle-aged men, Disease, Leukocyte Count, c-reactive protein, Risk Factors, Voeding en Ziekte, adult-treatment-panel, Prospective Studies, Myocardial infarction, Prospective cohort study, education.field_of_study, biology, plasma-fibrinogen, Asia, Eastern, Confounding, density-lipoprotein cholesterol, Cardiovascular disease, Lipids, myocardial-infarction, Coronary heart disease, Cardiovascular Diseases, Meta-analysis, Lipoproteins, HDL, high blood cholesterol, medicine.medical_specialty, low-dose aspirin, Population, 10-year follow-up, SDG 3 - Good Health and Well-being, Albumins, medicine, Humans, education, Triglycerides, VLAG, Inflammation, Estimation, business.industry, C-reactive protein, medicine.disease, Surgery, Emergency medicine, biology.protein, business, coronary-heart-disease, Biomarkers
Abstract

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age-and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily,with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Published
2007
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5. Transcriptome and metabolome analysis of citrus fruit to elucidate puffing disorder

Author

Abhaya M. Dandekar, David M. Rocke, Mario A. Tinoco, My L. Phu, Anna Vo, Russell L. Reagan, Ying Chen, Ana M. Ibáñez, Sandra L. Uratsu, Federico Martinelli, Ibanez, AM, Martinelli, F, Uratsu, SL, Vo, A, Tinoco, MA, Phu, ML, Chen, Y, Rocke, DM, and Dandekar, AM

Subjects
Citrus, Plant Science, Biology, Transcriptome, chemistry.chemical_compound, Metabolomics, Plant Growth Regulators, Arabidopsis, Genetics, Metabolome, Brassinosteroid, Protein Interaction Maps, Abscisic acid, Oligonucleotide Array Sequence Analysis, Plant Diseases, Albedo breakdown, Citrus, Fruit disorder, Metabolomics, Puffing, Transcriptomics, Gene Expression Profiling, food and beverages, General Medicine, biology.organism_classification, chemistry, Biochemistry, Fruit, Gibberellin, Citric acid, Agronomy and Crop Science, Signal Transduction, Transcription Factors
Abstract

a b s t r a c t A systems-level analysis reveals details of molecular mechanisms underlying puffing disorder in Citrus fruit. Flavedo, albedo and juice sac tissues of normal fruits and fruits displaying symptoms of puffing disorder were studied using metabolomics at three developmental stages. Microarrays were used to compare normal and puffed fruits for each of the three tissues. A protein-protein interaction network inferred from previous work on Arabidopsis identified hub proteins whose transcripts show significant changes in expression. Glycolysis, the backbone of primary metabolism, appeared to be severely affected by the disorder, based on both transcriptomic and metabolomic results. Significantly less citric acid was observed consistently in puffed fruits. Gene set enrichment analysis suggested that glycolysis and carbo- hydrate metabolism were significantly altered in puffed samples in both albedo and flavedo. Expression of invertases and genes for sucrose export, amylose-starch and starch-maltose conversion was higher in puffed fruits. These changes may significantly alter source-sink communications. Genes associated with gibberellin and cytokinin signaling were downregulated in symptomatic albedo tissues, suggesting that these hormones play key roles in the disorder. Findings may be applied toward the development of early diagnostic methods based on host response genes and metabolites (i.e. citric acid), and toward therapeutics based on hormones.

Published
2013

6. Advancements in dementia research, diagnostics, and care in Latin America: Highlights from the 2023 Alzheimer's Association International conference satellite symposium in Mexico City.

Author

Sosa AL, Brucki SM, Crivelli L, Lopera FJ, Acosta DM, Acosta-Uribe J, Aguilar D, Aguilar-Navarro SG, Allegri RF, Bertolucci PH, Calandri IL, Carrillo MC, Mendez PAC, Cornejo-Olivas M, Custodio N, Damian A, de Souza LC, Duran-Aniotz C, García AM, García-Peña C, Gonzales MM, Grinberg LT, Ibanez AM, Illanes-Manrique MZ, Jack CR Jr, Leon-Salas JM, Llibre-Guerra JJ, Luna-Muñoz J, Matallana D, Miller BL, Naci L, Parra MA, Pericak-Vance M, Piña-Escudero SD, França Resende EP, Ringman JM, Sevlever G, Slachevsky A, Suemoto CK, Valcour V, Villegas-Lanau A, Yassuda MS, Mahinrad S, and Sexton C

Subjects
Humans, Latin America epidemiology, Mexico epidemiology, Alzheimer Disease therapy, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Biomedical Research, Congresses as Topic, Dementia therapy, Dementia diagnosis, Dementia genetics, Dementia epidemiology
Abstract

Introduction: While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care., Methods: In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm., Results: Significant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted., Discussion: The myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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7. Behavioural insights (BI) for childhood development and effective public policies in Latin America: a survey and a randomised controlled trial.

Author

Tomio AA, Dottori M, Hesse E, Torrente F, Flichtentrei D, and Ibanez AM

Subjects
Government, Humans, Latin America, Surveys and Questionnaires, Health Behavior, Public Policy
Abstract

Objectives: We developed (a) a survey to investigate the knowledge of childhood health experts on public policies and behavioural insights (BI), as well as its use in Latin American and the Caribbean countries (LACs), and (b) an intervention (randomised controlled trial) to test the influence of nudges on the effect of a simulated public health programme communication., Participants and Settings: A total of 2003 LACs childhood health professionals participated in the study through a Hispanic online platform., Primary and Secondary Outcomes: We used regression models analysing expertise-related information, individual differences and location. We extracted several outcome variables related to (a) 'Public Policy Knowledge Index' based on the participants' degree of knowledge on childhood health public policies and (b) BI knowledge, perceived effectiveness and usefulness of a simulated public programme communication. We also analysed a 'Behavioural Insights Knowledge Index' (BIKI) based on participants' performance in BI questions., Results: In general, health professionals showed low BI knowledge (knowledge of the term BI: χ 2 =210.29, df=1 and p<0.001; BIKI: χ 2 =160.5, df=1 and p<0.001), and results were modulated by different factors (age, academic formation, public policy knowledge and location). The use of BI principles for the communication of the public programme revealed higher impact and clarity ratings from professionals than control messages., Conclusions: Our findings provide relevant knowledge about BI in health professionals to inform governmental and non-governmental organisations' decision-making processes related with childhood public policies and BI designs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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8. Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics.

Author

Gonzalez-Ibanez AM, Ruiz LM, Jensen E, Echeverria CA, Romero V, Stiles L, Shirihai OS, and Elorza AA

Abstract

Erythropoiesis is the most robust cellular differentiation and proliferation system, with a production of ∼2 × 10 11 cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) are expected to be a key regulatory point that has not been described previously. We described that a specific MtDy pattern occurs in human erythropoiesis from EPO-induced human CD34 + cells, characterized predominantly by mitochondrial fusion at early stages followed by fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondrial morphology, low mitochondrial membrane potential, a drop in the expression of the respiratory complexes II and IV and increased ROS. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor, cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work reveal MtDy as a hot spot in the control of erythroid differentiation, which might signal downstream for metabolic reprogramming through regulation of the mPTP., (Copyright © 2020 Gonzalez-Ibanez, Ruiz, Jensen, Echeverria, Romero, Stiles, Shirihai and Elorza.)

Published
2020
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9. Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells.

Author

Jensen EL, Gonzalez-Ibanez AM, Mendoza P, Ruiz LM, Riedel CA, Simon F, Schuringa JJ, and Elorza AA

Subjects
Animals, Blotting, Western, Cell Proliferation genetics, Cells, Cultured, Copper metabolism, Erythropoiesis genetics, Erythropoiesis physiology, Flow Cytometry, Humans, Mice, Mice, Inbred BALB C, Microscopy, Confocal, Mitochondria metabolism, Mitochondrial Proteins metabolism, Cell Proliferation physiology, Leukocytes, Mononuclear metabolism
Abstract

The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine - a copper chelator - showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.

Published
2019
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10. Non-cytotoxic copper overload boosts mitochondrial energy metabolism to modulate cell proliferation and differentiation in the human erythroleukemic cell line K562.

Author

Ruiz LM, Jensen EL, Rossel Y, Puas GI, Gonzalez-Ibanez AM, Bustos RI, Ferrick DA, and Elorza AA

Subjects
Humans, K562 Cells, Cell Differentiation, Cell Proliferation, Copper metabolism, Energy Metabolism drug effects, Mitochondria drug effects
Abstract

Copper is integral to the mitochondrial respiratory complex IV and contributes to proliferation and differentiation, metabolic reprogramming and mitochondrial function. The K562 cell line was exposed to a non-cytotoxic copper overload to evaluate mitochondrial dynamics, function and cell fate. This induced higher rates of mitochondrial turnover given by an increase in mitochondrial fusion and fission events and in the autophagic flux. The appearance of smaller and condensed mitochondria was also observed. Bioenergetics activity included more respiratory complexes, higher oxygen consumption rate, superoxide production and ATP synthesis, with no decrease in membrane potential. Increased cell proliferation and inhibited differentiation also occurred. Non-cytotoxic copper levels can modify mitochondrial metabolism and cell fate, which could be used in cancer biology and regenerative medicine., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Published
2016
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11. Platelet neutral mucoprotein and plasma fibrinogen.

Author

Morelli AC, Pedace E, Ibanez AM, and Niemetz M

Subjects
Chromatography, Gel, Humans, Methods, Staining and Labeling, Blood Platelet Disorders blood, Blood Platelets, Fibrinogen isolation & purification, Mucoproteins blood
Published
1972

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