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1. Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Author

Ghorbani, Peyman, Kim, Sang, Smith, Tyler, Minarrieta, Lucía, Robert-Gostlin, Victoria, Kilgour, Marisa, Ilijevska, Maja, Alecu, Irina, Snider, Shayne, Margison, Kaitlyn, Nunes, Julia, Woo, Daniel, Pember, Ciara, ODwyer, Conor, Ouellette, Julie, Kotchetkov, Pavel, St-Pierre, Julie, Bennett, Steffany, Lacoste, Baptiste, Blais, Alexandre, Fullerton, Morgan, and Nair, Meera

Abstract

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Published
2023

2. Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments: A Case Study.

Author

Stanton, Robert, Robinson, David, Aziz, Yasmin, Sucharew, Heidi, Khatri, Pooja, Broderick, Joseph, Janis, L, Kemp, Stephanie, Mlynash, Michael, Lansberg, Maarten, Albers, Gregory, Flaherty, Matthew, Adeoye, Opeolu, Woo, Daniel, Ferioli, Simona, Kissela, Brett, Kleindorfer, Dawn, and Saver, Jeffrey

Subjects
clinical trial, epidemiologists, feasibility studies, ischemic stroke, prospective studies, Humans, Treatment Outcome, Prospective Studies, Feasibility Studies, Stroke, Ischemic Stroke, Thrombectomy, Endovascular Procedures, Brain Ischemia
Abstract

BACKGROUND: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. METHODS: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. RESULTS: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to

Published
2023

3. Projections of Endovascular Therapy–Eligible Patients With Stroke for the US Population

Author

Mistry, Eva A., Khoury, Jane C., Kleindorfer, Dawn O., Kissela, Brett M., Alwell, Kathleen S., Jasne, Adam S., Ferioli, Simona, De Los Rios La Rosa, Felipe, Coleman, Elisheva, Demel, Stacie L., Walsh, Kyle B., Slavin, Sabreena J., Star, Michael, Haverbusch, Mary, Mackey, Jason, Woo, Daniel, Aziz, Yasmin N., Heldner, Mirjam R., Fischer, Urs, Jadhav, Ashutosh P., Jovin, Tudor G., Albers, Gregory W., Nogueira, Raul G., and Khatri, Pooja

Published
2024
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6. HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma

Author

Garrett, Matthew C., Albano, Rebecca, Carnwath, Troy, Elahi, Lubayna, Behrmann, Catherine A., Pemberton, Merissa, Woo, Daniel, O’Brien, Eric, VanCauwenbergh, Brett, Perentesis, John, Shah, Sanjit, Hagan, Matthew, Kendler, Ady, Zhao, Chuntao, Paranjpe, Aditi, Roskin, Krishna, Kornblum, Harley, Plas, David R., and Lu, Q. Richard

Published
2023
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7. Differences in peripheral immune system gene expression in frontotemporal degeneration.

Author

Sawyer, Russell P, Hill, Emily J, Yokoyama, Jennifer, Medvedovic, Mario, Ren, Yan, Zhang, Xiang, Choubey, Divaker, Shatz, Rhonna S, Miller, Bruce, and Woo, Daniel

Subjects
Leukocytes, Mononuclear, Humans, Amyotrophic Lateral Sclerosis, Neurodegenerative Diseases, Atrophy, Case-Control Studies, Gene Expression, Aged, Middle Aged, Female, Male, Frontotemporal Dementia, Transcriptome, amyotrophic lateral sclerosis, frontotemporal dementia, genetics, dementia, neurodegeneration, inflammation, transcriptomics, Genetics, Dementia, Brain Disorders, Acquired Cognitive Impairment, Neurosciences, Rare Diseases, Neurodegenerative, Prevention, Clinical Research, Frontotemporal Dementia (FTD), Aetiology, 2.1 Biological and endogenous factors
Abstract

AbstractThe peripheral immune system has a key pathophysiologic role in Frontotemporal degeneration (FTD). We sought a comprehensive transcriptome-wide evaluation of gene expression alterations unique to the peripheral immune system in FTD compared to healthy controls and amyotrophic lateral sclerosis.Nineteen subjects with FTD with 19 matched healthy controls and 9 subjects with amyotrophic lateral sclerosis underwent isolation of peripheral blood mononuclear cells (PBMCs) which then underwent bulk ribonucleic acid sequencing.There was increased expression in genes associated with CD19+ B-cells, CD4+ T-cells, and CD8+ T-cells in FTD participants compared to healthy controls. In contrast, there was decreased expression in CD33+ myeloid cells, CD14+ monocytes, BDCA4+ dendritic cells, and CD56+ natural killer cells in FTD and healthy controls. Additionally, there was decreased expression is seen in associated with 2 molecular processes: autophagy with phagosomes and lysosomes, and protein processing/export. Significantly downregulated in PBMCs of FTD subjects were genes involved in antigen processing and presentation as well as lysosomal lumen formation compared to healthy control PBMCs.Our findings that the immune signature based on gene expression in PBMCs of FTD participants favors adaptive immune cells compared to innate immune cells. And decreased expression in genes associated with phagosomes and lysosomes in PBMCs of FTD participants compared to healthy controls.

Published
2022

9. Brain volume: An important determinant of functional outcome after acute ischemic stroke

Author

Schirmer, Markus D., Donahue, Kathleen L., Nardin, Marco J., Dalca, Adrian V., Giese, Anne-Katrin, Etherton, Mark R., Mocking, Steven J. T., McIntosh, Elissa C., Cole, John W., Holmegaard, Lukas, Jood, Katarina, Jimenez-Conde, Jordi, Kittner, Steven J., Lemmens, Robin, Meschia, James F., Rosand, Jonathan, Roquer, Jaume, Rundek, Tatjana, MD, Ralph L. Sacco, Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Stanne, Tara M., Vagal, Achala, Wasselius, Johan, Woo, Daniel, Bevan, Stephen, Heitsch, Laura, Phuah, Chia-Ling, MD, Daniel Strbian, Tatlisumak, Turgut, Levi, Christopher R., Attia, John, McArdle, Patrick F., Worrall, Bradford B., Wu, Ona, Jern, Christina, Lindgren, Arne, Maguire, Jane, Thijs, Vincent, and Rost, Natalia S.

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). Methods: We analyzed cross-sectional data of the multi-site, international hospital-based MRI-GENetics Interface Exploration (MRI-GENIE) study (July 1, 2014- March 16, 2019) with clinical brain magnetic resonance imaging (MRI) obtained on admission for index stroke and functional outcome assessment. Post-stroke outcome was determined using the modified Rankin Scale (mRS) score (0-6; 0: asymptomatic; 6 death) recorded between 60-190 days after stroke. Demographics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke) were recorded during index admission. Results: Utilizing the data from 912 acute ischemic stroke (AIS) patients (65+/-15 years of age, 58% male, 57% history of smoking, and 65% hypertensive) in a generalized linear model, brain volume (per 155.1cm^3 ) was associated with age (beta -0.3 (per 14.4 years)), male sex (beta 1.0) and prior stroke (beta -0.2). In the multivariable outcome model, brain volume was an independent predictor of mRS (beta -0.233), with reduced odds of worse long-term functional outcomes (OR: 0.8, 95% CI 0.7-0.9) in those with larger brain volumes. Conclusions: Larger brain volume quantified on clinical MRI of AIS patients at time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of mechanisms of post-stroke recovery.

Published
2020
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10. Differential impact of acute fine particulate matter exposure on risk of stroke by stroke subtype, age, sex, and race: a case-crossover study

Author

Bhuiyan, Mohammad Alfrad Nobel, Brokamp, Cole, Madsen, Tracy E., Khoury, Jane C., Sucharew, Heidi, Alwell, Kathleen, Moomaw, Charles J., Hossain, Monir, Flaherty, Matthew L., Woo, Daniel, Mackey, Jason, La Rosa, Felipe De Los Rios, Martini, Sharyl, Ferioli, Simona, Adeoye, Opeolu, Kissela, Brett M., and Kleindorfer, Dawn

Subjects
Statistics - Applications
Abstract

Objective: Association between acute ambient fine particulate matter (PM2.5, aerodynamic diameter less than 2.5 and cardiovascular events are well documented. However, it remains unclear whether acute exposure to PM2.5 acts as a trigger for hemorrhagic (intracerebral or subarachnoid hemorrhage) or non-hemorrhagic (infarct or transient ischemic attack) stroke onset. We, therefore, examined the association between ambient PM2.5 and stroke onset, and whether this relationship differs by stroke subtype, age, sex, and race. Methods: We used a time-stratified case-crossover design to examine the association between exposure to PM2.5 and stroke onset for the calendar year 2010. Data were collected from the Greater Cincinnati Northern Kentucky Stroke Study. We included patients 20 years and older, initially ascertained through hospital ICD-9 discharge codes. Daily ambient concentrations of PM2.5 were estimated from the patient's residential addresses using a spatiotemporal model. Conclusion: Our findings suggest that short-term PM2.5 exposure, particularly at three days before the event, is associated with stroke onset but varies according to stroke subtype, age, sex, and race., Comment: One coauthor didnt want to submit the paper on the arxiv

Published
2019

11. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author

Bakker, Mark K, van der Spek, Rick AA, van Rheenen, Wouter, Morel, Sandrine, Bourcier, Romain, Hostettler, Isabel C, Alg, Varinder S, van Eijk, Kristel R, Koido, Masaru, Akiyama, Masato, Terao, Chikashi, Matsuda, Koichi, Walters, Robin G, Lin, Kuang, Li, Liming, Millwood, Iona Y, Chen, Zhengming, Rouleau, Guy A, Zhou, Sirui, Rannikmäe, Kristiina, Sudlow, Cathie LM, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, WM Monique, Friedrich, Christoph M, Hirsch, Sven, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan RI, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina JM, Malik, Rainer, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel JE, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Veldink, Jan H, and Ruigrok, Ynte M

Subjects
Genetics, Brain Disorders, Human Genome, Clinical Research, Prevention, Stroke, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Asian People, Blood Pressure, Case-Control Studies, Endothelial Cells, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Intracranial Aneurysm, Polymorphism, Single Nucleotide, Risk Factors, Smoking, Subarachnoid Hemorrhage, White People, HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, International Stroke Genetics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Published
2020

12. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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13. Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Author

Cudkowicz, Merit, Chase, Marianne, Coffey, Christopher, Ecklund, Dixie, Thornell, Brenda, Lungu, Codrin, Mahoney, Katy, Gutmann, Laurie, Shefner, Jeremy, Staley, Kevin, Bosch, Michael, Foster, Eric, Long, Jeffrey, Bayman, Emine, Torner, James, Yankey, Jon, Peters, Richard, Huff, Trevis, Conwit, Robin, Shinnar, Shlomo, Patch, Donna, Darras, Basil, Ellis, Audrey, Packer, Roger, Marder, Karen, Chiriboga, Claudia, Moran, Joyce, Nikolov, Blagovest, Factor, Stewart, Seeley, Carole, Greenberg, Steven, Amato, Anthony, DeGregorio, Sara, Simuni, Tanya, Ward, Tina, Kissel, John, Kolb, Stephen, Bartlett, Amy, Quinn, Joseph, Keith, Kellie, Levine, Steven, Gilles, Nadege, Coyle, Patricia, Lamb, Jessica, Wolfe, Gil, Crumlish, Annemarie, Mejico, Luis, Iqbal, Muhammad, Bowen, James, Tongco, Caryl, Nabors, Louis, Bashir, Khurram, Benge, Melanie, Canamar, Catherine, Glauser, Tracy, Woo, Daniel, Molloy, Angela, Clark, Peggy, Vollmer, Timothy, Stein, Alexander, Barohn, Richard, Dimachkie, Mazen, Le Pichon, Jean-Baptiste, Benatar, Michael, Steele, Julie, Wechsler, Lawrence, Clemens, Paula, Amity, Christine, Holloway, Robert, Annis, Christine, Goldberg, Mark, Andersen, Mariam, Iannaccone, Susan, Smith, A, Singleton, J, Doudova, Mariana, Haley, E, Quigg, Mark, Lowenhaupt, Stephanie, Malow, Beth, Adkins, Karen, Clifford, David, Teshome, Mengesha, Connolly, Noreen, Oskarsson, Björn, Dobkin, Bruce, McDonald, Craig, Henricson, Erik, and Henchcliffe, Claire

Subjects
Clinical Trials as Topic, Humans, National Institute of Neurological Disorders and Stroke (U.S.), Nervous System Diseases, Neurology, Neurosciences, United States
Abstract

IMPORTANCE: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. OBSERVATIONS: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. CONCLUSIONS AND RELEVANCE: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Published
2020

16. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, Kraft, Peter, Hansen, John‐Bjarne, Heit, John A, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Pulit, Sara L, Rannikmäe, Kristiina, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Rost, Natalia S, Rothwell, Peter M, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2022
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19. Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke

Author

Bretzner, Martin, Bonkhoff, Anna K, Schirmer, Markus D., Hong, Sungmin, Dalca, Adrian, Donahue, Kathleen, Giese, Anne-Katrin, Etherton, Mark R, Rist, Pamela M, Nardin, Marco, Regenhardt, Robert W, Leclerc, Xavier, Lopes, Renaud, Gautherot, Morgan, Wang, Clinton, Benavente, Oscar R, Cole, John W., Donatti, Amanda, Griessenauer, Christoph, Heitsch, Laura, Holmegaard, Lukas, Jood, Katarina, Jimenez-Conde, Jordi, Kittner, Steven J, Lemmens, Robin, Levi, Christopher R, McArdle, Patrick F, McDonough, Caitrin W., Meschia, James F, Phuah, Chia-Ling, Rolfs, Arndt, Ropele, Stefan, Rosand, Jonathan, Roquer, Jaume, Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Sousa, Alessandro, Stanne, Tara M, Strbian, Daniel, Tatlisumak, Turgut, Thijs, Vincent, Vagal, Achala, Wasselius, Johan, Woo, Daniel, Wu, Ona, Zand, Ramin, Worrall, Bradford B, Maguire, Jane, Lindgren, Arne G, Jern, Christina, Golland, Polina, Kuchcinski, Grégory, and Rost, Natalia S

Published
2022
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20. Premorbid Blood Pressure Control Modifies Risk of DWI Lesions With Acute Blood Pressure Reduction in Intracerebral Hemorrhage.

Author

Ridha, Mohamed, Hannawi, Yousef, Murthy, Santosh, Carvalho Poyraz, Fernanda, Kumar, Aditya, Park, Soojin, Roh, David, Sekar, Padmini, Woo, Daniel, and Burke, James

Abstract

BACKGROUND: Hypoperfusion due to blood pressure (BP) reduction is a potential mechanism of cerebral ischemia after intracerebral hemorrhage. However, prior evaluations of the relationship between BP reduction and ischemia have been conflicting. Untreated chronic hypertension is common in intracerebral hemorrhage and alters cerebral autoregulation. We hypothesized that the risk of diffusion-weighted imaging (DWI) hyperintensities from acute BP reduction is modified by premorbid BP control. METHODS: Individuals enrolled in the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) from 2010 to 2015 were categorized as untreated, treated, or nonhypertensive based on preintracerebral hemorrhage diagnosis and antihypertensive medication use. The percent reduction of systolic BP (SBP) was calculated between presentation and 24 hours from admission. The primary outcome was the presence of DWI lesions. Using logistic regression, we tested the association between chronic hypertension status, SBP reduction, and their interaction with DWI lesion presence. RESULTS: From 3000 participants, 877 with available magnetic resonance imaging met inclusion (mean age, 60.5±13.3 years; 42.5% women). DWI lesions were detected in 25.9%. Untreated, treated, and no hypertension accounted for 32.6%, 47.9%, and 19.5% of cases, respectively. SBP reduction was not directly associated with DWI lesions; however, an interaction effect was observed between SBP reduction and chronic hypertension status (P=0.036). Nonhypertensive subjects demonstrated a linear risk of DWI lesion presence with greater SBP reduction, whereas untreated hypertension demonstrated a stable risk across a wide range of SBP reduction (P=0.023). CONCLUSIONS: Premorbid BP control, especially untreated hypertension, may influence the relationship between DWI lesions and acute BP reduction after intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Temporal Trends and Racial Disparities in Long-Term Survival After Stroke.

Author

Robinson, David J., Lili Ding, Howard, George, Stanton, Robert J., Khoury, Jane, Sucharew, Heidi, Haverbusch, Mary, Nobel, Lisa, Khatri, Pooja, Adeoye, Opeolu, Broderick, Joseph P., Ferioli, Simona, Mackey, Jason, Woo, Daniel, De Los Rios La Rosa, Felipa, Flaherty, Matthew, Slavin, Sabreena, Star, Michael, Martini, Sharyl R., and Demel, Stacie

Published
2024
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26. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author

Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J.E., Veldink, Jan H., Ruigrok, Ynte M., Hege Aamodt, Anne, Heidi Skogholt, Anne, Brumpton, Ben M, Willer, Cristen J, Sandset, Else C, Kristoffersen, Espen S, Ellekjær, Hanne, Heuch, Ingrid, Nielsen, Jonas B, Hagen, Knut, Hveem, Kristian, Fritsche, Lars G, Thomas, Laurent F, Pedersen, Linda M, Gabrielsen, Maiken E, Holmen, Oddgeir L, Børte, Sigrid, Zhou, Wei, Abboud, Shérine, Pandolfo, Massimo, Thijs, Vincent, Leys, Didier, Bodenant, Marie, Louillet, Fabien, Touzé, Emmanuel, Mas, Jean-Louis, Samson, Yves, Leder, Sara, Léger, Anne, Deltour, Sandrine, Crozier, Sophie, Méresse, Isabelle, Canaple, Sandrine, Godefroy, Olivier, Giroud, Maurice, Béjot, Yannick, Decavel, Pierre, Medeiros, Elizabeth, Montiel, Paola, Moulin, Thierry, Vuillier, Fabrice, Dallongeville, Jean, Metso, Antti J, Metso, Tiina, Tatlisumak, Turgut, Grond-Ginsbach, Caspar, Lichy, Christoph, Kloss, Manja, Werner, Inge, Arnold, Marie-Luise, Dos Santos, Michael, Grau, Armin, Dichgans, Martin, Thomas-Feles, Constanze, Weber, Ralf, Brandt, Tobias, Pezzini, Alessandro, De Giuli, Valeria, Caria, Filomena, Poli, Loris, Padovani, Alessandro, Bersano, Anna, Lanfranconi, Silvia, Beretta, Simone, Ferrarese, Carlo, Giacolone, Giacomo, Paolucci, Stefano, Lyrer, Philippe, Engelter, Stefan, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Bonati, Leo, Gensicke, Henrik, Amort, Margareth, Markus, Hugh, Majersik, Jennifer, Worrall, Bradford, Southerland, Andrew, Cole, John, Kittner, Steven, Evangelou, Evangelos, Warren, Helen R, Gao, He, Ntritsos, Georgios, Dimou, Niki, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian’an, Mangino, Massimo, Oldmeadow, Christopher, Peter Prins, Bram, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Connell, John, de Mutsert, Renée, Doney, Alex SF, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Francis, Cordell, Heather J, Davies, Gail, de Borst, Martin H, de Geus, Eco J, Deary, Ian J, Deelen, Joris, Del Greco M, Fabiola, Yusuf Demirkale, Cumhur, Dörr, Marcus, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Mesut Erzurumluoglu, A, Ferreira, Teresa, Frånberg, Mattias, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Wouter Jukema, J, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Maris, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David CM, Lin, Li, Lind, Lars, Lindgren, Cecilia M, Liu, YongMei, Loos, Ruth JF, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O’Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, WJH Penninx, Brenda, Perola, Markus, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Tri Nguyen, Quang, Raitakari, Olli T, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna MM, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin NA, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andres, Psaty, Bruce M., Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Gormley, Padhraig, Anttila, Verneri, Palta, Priit, Esko, Tonu, Pers, Tune H, Farh, Kai-How, Cuenca-Leon, Ester, Muona, Mikko, Furlotte, Nicholas A, Kurth, Tobias, Ingason, Andres, McMahon, George, Ligthart, Lannie, Terwindt, Gisela M, Kallela, Mikko, Freilinger, Tobias M, Ran, Caroline, Gordon, Scott G, Stam, Anine H, Steinberg, Stacy, Borck, Guntram, Koiranen, Markku, Quaye, Lydia, Adams, Hieab H H, Lehtimäki, Terho, Sarin, Antti-Pekka, Wedenoja, Juho, Hinds, David A, Buring, Julie E, Schürks, Markus, Ridker, Paul M, Gudlaug Hrafnsdottir, Maria, Stefansson, Hreinn, Ring, Susan M, Hottenga, Jouke-Jan, Penninx, Brenda W J H, Färkkilä, Markus, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Malik, Rainer, Heath, Andrew C, Madden, Pamela A F, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Kals, Mart, Mägi, Reedik, Pärn, Kalle, Hämäläinen, Eija, Huang, Hailiang, Byrnes, Andrea E, Franke, Lude, Huang, Jie, Stergiakouli, Evie, Lee, Phil H, Sandor, Cynthia, Webber, Caleb, Cader, Zameel, Muller-Myhsok, Bertram, Schreiber, Stefan, Meitinger, Thomas, Eriksson, Johan G, Salomaa, Veikko, Heikkilä, Kauko, Loehrer, Elizabeth, Uitterlinden, Andre G, Hofman, Albert, van Duijn, Cornelia M, Cherkas, Lynn, Pedersen, Linda M, Stubhaug, Audun, Nielsen, Christopher S, Männikkö, Minna, Mihailov, Evelin, Milani, Lili, Göbel, Hartmut, Esserlind, Ann-Louise, Francke Christensen, Anne, Folkmann Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Aromaa, Arpo J, Raitakari, Olli, Arfan Ikram, M, Spector, Tim, Järvelin, Marjo-Riitta, Metspalu, Andres, Kubisch, Christian, Strachan, David P, Ferrari, Michel D, Belin, Andrea C, Dichgans, Martin, Wessman, Maija, van den Maagdenberg, Arn M J M, Boomsma, Dorret I, Davey Smith, George, Stefansson, Kari, Eriksson, Nicholas, Daly, Mark J, Neale, Benjamin M, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Palotie, Aarno, Akiyama, Masato, Alg, Varinder S., Børte, Sigrid, Broderick, Joseph P., Brumpton, Ben M., Dauvillier, Jérôme, Desal, Hubert, Dina, Christian, Friedrich, Christoph M., Gaál-Paavola, Emília I., Gentric, Jean-Christophe, Hirsch, Sven, Hostettler, Isabel C., Houlden, Henry, Hveem, Kristian, Jääskeläinen, Juha E., Johnsen, Marianne Bakke, Li, Liming, Lin, Kuang, Lindgren, Antti, Martin, Olivier, Matsuda, Koichi, Millwood, Iona Y., Naggara, Olivier, Niemelä, Mika, Pera, Joanna, Redon, Richard, Rouleau, Guy A., Sandvei, Marie Søfteland, Schilling, Sabine, Shotar, Eimad, Slowik, Agnieszka, Terao, Chikashi, Verschuren, W. M. Monique, Walters, Robin G., Werring, David J., Willer, Cristen J., Woo, Daniel, Worrall, Bradford B., and Zhou, Sirui

Published
2023
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27. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author

Jaworek, Thomas, Xu, Huichun, Gaynor, Brady J, Cole, John W., Rannikmae, Kristiina, Stanne, Tara M, Tomppo, Liisa, Abedi, Vida, Amouyel, Philippe, Armstrong, Nicole D, Attia, John, Bell, Steven, Benavente, Oscar R, Boncoraglio, Giorgio B, Butterworth, Adam, Carcel-Marquez, Jara, Chen, Zhengming, Chong, Michael, Cruchaga, Carlos, Cushman, Mary, Danesh, John, Debette, Stephanie, Duggan, David J, Durda, Jon Peter, Engstrom, Gunnar, Enzinger, Chris, Faul, Jessica D, Fecteau, Natalie S, Fernandez-Cadenas, Israel, Gieger, Christian, Giese, Anne-Katrin, Grewal, Raji P, Grittner, Ulrike, Havulinna, Aki S, Heitsch, Laura, Hochberg, Marc C, Holliday, Elizabeth, Hu, Jie, Ilinca, Andreea, Irvin, Marguerite R, Jackson, Rebecca D, Jacob, Mina A., Janssen, Raquel Rabionet, Jimenez-Conde, Jordi, Johnson, Julie A, Kamatani, Yoichiro, Kardia, Sharon L, Koido, Masaru, Kubo, Michiaki, Lange, Leslie, Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher R, Li, Jiang, Li, Liming, Lin, Kuang, Lopez, Haley, Luke, Sothear, Maguire, Jane, McArdle, Patrick F, McDonough, Caitrin W., Meschia, James F, Metso, Tiina, Muller-Nurasyid, Martina, OʼConnor, Timothy D, OʼDonnell, Martin, Peddareddygari, Leema R, Pera, Joanna, Perry, James A, Peters, Annette, Putaala, Jukka, Ray, Debashree, Rexrode, Kathryn, Ribases, Marta, Rosand, Jonathan, Rothwell, Peter M, Rundek, Tatjana, Ryan, Kathleen A, Sacco, Ralph L., Salomaa, Veikko, Sanchez-Mora, Cristina, Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Smith, Jennifer A, Smith, Nicholas L, Wassertheil-Smoller, Sylvia, Soederholm, Martin, Stine, O. C, Strbian, Daniel, Sudlow, Cathie L, Tatlisumak, Turgut, Terao, Chikashi, Thijs, Vincent, Torres-Aguila, Nuria P, Tregouet, David-Alexandre, Tuladhar, Anil M., Veldink, Jan H, Walters, Robin G, Weir, David R, Woo, Daniel, Worrall, Bradford B, Hong, Charles C, Ross, Owen, Zand, Ramin, Leeuw, Frank-Erik de, Lindgren, Arne G, Pare, Guillaume, Anderson, Christopher D., Markus, Hugh S, Jern, Christina, Malik, Rainer, Dichgans, Martin, Mitchell, Braxton D, and Kittner, Steven J

Published
2022
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29. Trends in Stroke Incidence by Neighborhood Socioeconomic Status in the Greater Cincinnati/Northern Kentucky Region (P2-4.008)

Author

Becker, Christopher, primary, Sucharew, Heidi, additional, Robinson, David, additional, Stamm, Brian, additional, Royan, Regina, additional, Nobel, Lisa, additional, Kissela, Brett, additional, Stanton, Robert, additional, Alwell, Kathleen, additional, Woo, Daniel, additional, De Los Rios La Rosa, Felipe, additional, Mackey, Jason, additional, Ferioli, Simona, additional, Mistry, Eva, additional, Demel, Stacie, additional, Haverbusch, Mary, additional, Coleman, Elisheva, additional, Jasne, Adam, additional, Slavin, Sabreena, additional, Walsh, Kyle B., additional, Star, Michael, additional, Martini, Sharyl, additional, Flaherty, Matthew, additional, Adeoye, Opeolu, additional, Khatri, Pooja, additional, Broderick, Joseph, additional, and Kleindorfer, Dawn, additional

Published
2024
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31. Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study

Author

Madsen, Tracy E., primary, Ding, Lili, additional, Khoury, Jane C., additional, Haverbusch, Mary, additional, Woo, Daniel, additional, Ferioli, Simona, additional, De Los Rios La Rosa, Felipe, additional, Martini, Sharyl R., additional, Adeoye, Opeolu, additional, Khatri, Pooja, additional, Flaherty, Matthew L., additional, Mackey, Jason, additional, Mistry, Eva A., additional, Demel, Stacie, additional, Coleman, Elisheva, additional, Jasne, Adam, additional, Slavin, Sabreena, additional, Walsh, Kyle B., additional, Star, Michael, additional, Broderick, Joseph P., additional, Kissela, Brett, additional, and Kleindorfer, Dawn O., additional

Published
2024
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32. Abstract TMP104: Timing of Recurrence After Ischemic Stroke by Subtype: A Population-Based Study

Author

Cortes, Juan C, primary, Aziz, Yasmin N, additional, Robinson, David J, additional, Stanton, Robert J, additional, Sucharew, Heidi, additional, Jasne, Adam S, additional, Ferioli, Simona, additional, Demel, Stacie, additional, Mistry, Eva, additional, Walsh, Kyle, additional, Haverbusch, Mary, additional, Alwell, Kathleen S, additional, Star, Michael, additional, De Los Rios La Rosa, Felipe, additional, Mackey, Jason, additional, Coleman, Elisheva, additional, Slavin, Sabreena J, additional, Woo, Daniel, additional, Kleindorfer, Dawn O, additional, and Kissela, Brett M, additional

Published
2024
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33. Abstract WMP42: Trends of In-Hospital Strokes Over Time: Results From the Greater Cincinnati and Northern Kentucky Stroke Study

Author

Nobel, Lisa, primary, Chulluncy Rivas, Roberto, additional, Robinson, David, additional, Stanton, Robert J, additional, Kissela, Brett M, additional, Ferioli, Simona, additional, Alwell, Kathleen, additional, Sucharew, Heidi, additional, Khatri, Pooja, additional, Adeoye, Opeolu M, additional, Broderick, Joseph P, additional, Mackey, Jason, additional, Woo, Daniel, additional, Flaherty, Matthew, additional, Martini, Sharyl, additional, DeLosRiosLa Rosa, Felipe, additional, Demel, Stacie, additional, Madsen, Tracy, additional, Star, Michael, additional, Coleman, Elisheva R, additional, Walsh, Kyle, additional, Slavin, Sabreena, additional, Jasne, Adam S, additional, Mistry, Eva, additional, Haverbusch, Mary, additional, and Kleindorfer, Dawn O, additional

Published
2024
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34. Abstract TP1: Changing Trends in the Epidemiology of Subarachnoid Hemorrhage: A Population-Based Study

Author

Robinson, David, primary, Stanton, Robert J, additional, Mistry, Eva, additional, Broderick, Joe, additional, Ding, Lili, additional, Mackey, Jason, additional, Flaherty, Matthew, additional, Haverbusch, Mary, additional, Adeoye, Opeolu M, additional, Prestigiacomo, Charles J, additional, Star, Michael, additional, DeLosRiosLa Rosa, Felipe, additional, Martini, Sharyl, additional, Slavin, Sabreena, additional, Demel, Stacie, additional, Ferioli, Simona, additional, Aziz, Yasmin, additional, Walsh, Kyle B, additional, Jasne, Adam S, additional, Khatri, Pooja, additional, Woo, Daniel, additional, Kleindorfer, Dawn O, additional, and Kissela, Brett M, additional

Published
2024
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35. Abstract WMP98: Elevated Troponin With and Without Myocardial Infarction in Acute Ischemic Stroke

Author

Menzies, Lauren E, primary, Robinson, David, additional, Sucharew, Heidi, additional, Kissela, Brett M, additional, Stanton, Robert J, additional, DeLosRiosLa Rosa, Felipe, additional, Mackey, Jason, additional, Demel, Stacie, additional, Ferioli, Simona, additional, Woo, Daniel, additional, Mistry, Eva, additional, Haverbusch, Mary, additional, Coleman, Elisheva R, additional, Jasne, Adam S, additional, Slavin, Sabreena, additional, Walsh, Kyle, additional, Star, Michael, additional, Rothenberg, Florence, additional, and Kleindorfer, Dawn O, additional

Published
2024
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36. Abstract WMP47: Neighborhood Socio-Economic Status as a Predictor of All-Cause Long-Term Post-Stroke Mortality

Author

Nobel, Lisa, primary, Robinson, David, additional, Stanton, Robert J, additional, Becker, Christopher, additional, Kleindorfer, Dawn O, additional, Alwell, Kathleen, additional, Ding, Lili, additional, Khatri, Pooja, additional, Adeoye, Opeolu M, additional, Ferioli, Simona, additional, Mackey, Jason, additional, Woo, Daniel, additional, Martini, Sharyl, additional, DeLosRiosLa Rosa, Felipe, additional, Demel, Stacie, additional, Madsen, Tracy, additional, Star, Michael, additional, Coleman, Elisheva R, additional, Walsh, Kyle, additional, Slavin, Sabreena, additional, Jasne, Adam S, additional, Mistry, Eva, additional, Haverbusch, Mary, additional, and Kissela, Brett M, additional

Published
2024
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37. Abstract TMP82: How Well Do Prehospital Stroke Triage Scores Identify Patients With Intracerebral Hemorrhage?

Author

Wechsler, Paul M, primary, Robinson, David, additional, Sucharew, Heidi, additional, Stanton, Robert J, additional, Demel, Stacie, additional, Mistry, Eva, additional, Ferioli, Simona, additional, Khatri, Pooja, additional, Walsh, Kyle B, additional, Flaherty, Matthew L, additional, Jasne, Adam S, additional, Haverbusch, Mary, additional, Slavin, Sabreena, additional, Mackey, Jason, additional, Star, Michael, additional, Coleman, Elisheva R, additional, Martini, Sharyl R, additional, DeLosRiosLa Rosa, Felipe, additional, Alwell, Kathleen, additional, Adeoye, Opeolu M, additional, Woo, Daniel, additional, Kleindorfer, Dawn O, additional, and Kissela, Brett M, additional

Published
2024
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38. Abstract 147: Novel Inflammatory and Pro-Thrombotic mRNA Pathways Associated With Worse 3-month Outcome After Intracerebral Hemorrhage

Author

Wright, W. S, primary, Langefeld, Carl D., additional, Comeau, Mary, additional, Hawkins, Greg, additional, Flaherty, Matthew, additional, Gilkerson, Lee, additional, Howard, Tim D., additional, James, Michael L, additional, Kittner, Steven J, additional, Mehndiratta, Prachi, additional, Roh, David, additional, Vahidy, Farhaan, additional, Testai, Fernando, additional, Bagga, Ranjit, additional, Thornton, James B., additional, Cortes, Juan Camilo, additional, Menzies, Lauren, additional, Nobel, Lisa, additional, Wechsler, Paul, additional, Xia, Christina, additional, Woo, Daniel, additional, and Demel, Stacie, additional

Published
2024
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41. Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome

Author

Bonkhoff, Anna K, Hong, Sungmin, Bretzner, Martin, Schirmer, Markus D., Regenhardt, Robert W, Arsava, E. Murat, Donahue, Kathleen, Nardin, Marco, Dalca, Adrian, Giese, Anne-Katrin, Etherton, Mark R, Hancock, Brandon L., Mocking, Steven J.T., McIntosh, Elissa, Attia, John, Benavente, Oscar, Cole, John W., Donatti, Amanda, Griessenauer, Christoph, Heitsch, Laura, Holmegaard, Lukas, Jood, Katarina, Jimenez-Conde, Jordi, Kittner, Steven, Lemmens, Robin, Levi, Christopher, McDonough, Caitrin W., Meschia, James, Phuah, Chia-Ling, Rolfs, Arndt, Ropele, Stefan, Rosand, Jonathan, Roquer, Jaume, Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Soederholm, Martin, Sousa, Alessandro, Stanne, Tara M, Strbian, Daniel, Tatlisumak, Turgut, Thijs, Vincent, Vagal, Achala, Wasselius, Johan, Woo, Daniel, Zand, Ramin, McArdle, Patrick, Worrall, Bradford B, Jern, Christina, Lindgren, Arne G, Maguire, Jane, Golland, Polina, Bzdok, Danilo, Wu, Ona, and Rost, Natalia S

Published
2022
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42. Substance Use and Performance of Toxicology Screens in the Greater Cincinnati Northern Kentucky Stroke Study

Author

Madsen, Tracy E., Cummings, Olivia W., De Los Rios La Rosa, Felipe, Khoury, Jane C., Alwell, Kathleen, Woo, Daniel, Ferioli, Simona, Martini, Sharyl, Adeoye, Opeolu, Khatri, Pooja, Flaherty, Matthew L., Mackey, Jason, Mistry, Eva A., Demel, Stacie L., Coleman, Elisheva, Jasne, Adam S., Slavin, Sabreena J., Walsh, Kyle, Star, Michael, Broderick, Joseph P., Kissela, Brett M., and Kleindorfer, Dawn O.

Published
2022
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43. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author

Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O’Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t’Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, Woo, Daniel, and Rosand, Jonathan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis, Telomeres Mendelian Randomization Collaboration, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

44. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Author

Telomeres Mendelian Randomization Collaboration, Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t'Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, and Woo, Daniel

Subjects
Telomeres Mendelian Randomization Collaboration, Telomere, Humans, Neoplasms, Cardiovascular Diseases, Genetic Predisposition to Disease, Risk Assessment, Germ-Line Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Mendelian Randomization Analysis, Telomere Homeostasis, Polymorphism, Single Nucleotide, and over, Prevention, Clinical Research, Cancer, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

45. Biomarker‐driven phenotyping in Parkinson's disease: A translational missing link in disease‐modifying clinical trials

Author

Espay, Alberto J, Schwarzschild, Michael A, Tanner, Caroline M, Fernandez, Hubert H, Simon, David K, Leverenz, James B, Merola, Aristide, Chen‐Plotkin, Alice, Brundin, Patrik, Kauffman, Marcelo A, Erro, Roberto, Kieburtz, Karl, Woo, Daniel, Macklin, Eric A, Standaert, David G, and Lang, Anthony E

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Parkinson's Disease, Neurodegenerative, Prevention, Brain Disorders, Aging, Neurological, Good Health and Well Being, Biomarkers, Clinical Trials as Topic, Humans, Parkinson Disease, Parkinson's disease, biomarkers, neuroprotection, systems biology, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

46. Impact of Poverty on Stroke Recurrence: A Population-Based Study.

Author

Becker, Christopher J., Sucharew, Heidi, Robinson, David, Stamm, Brian, Royan, Regina, Nobel, Lisa, Stanton, Robert J., Jasne, Adam S., Woo, Daniel, De Los Rios La Rosa, Felipe, Mackey, Jason, Ferioli, Simona, Mistry, Eva A., Demel, Stacie, Haverbusch, Mary, Coleman, Elisheva, Slavin, Sabreena, Walsh, Kyle B., Star, Michael, and Flaherty, Matthew L.

Published
2024
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47. Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns

Author

Baker, Anna D., Schwamm, Lee H., Sanborn, Danita Y., Furie, Karen, Stretz, Christoph, Mac Grory, Brian, Yaghi, Shadi, Kleindorfer, Dawn, Sucharew, Heidi, Mackey, Jason, Walsh, Kyle, Flaherty, Matt, Kissela, Brett, Alwell, Kathleen, Khoury, Jane, Khatri, Pooja, Adeoye, Opeolu, Ferioli, Simona, Woo, Daniel, Martini, Sharyl, De Los Rios La Rosa, Felipe, Demel, Stacie L., Madsen, Tracy, Star, Michael, Coleman, Elisheva, Slavin, Sabreena, Jasne, Adam, Mistry, Eva A., Haverbusch, Mary, Merkler, Alexander E., Kamel, Hooman, Schindler, Joseph, Sansing, Lauren H., Faridi, Kamil F., Sugeng, Lissa, Sheth, Kevin N., and Sharma, Richa

Published
2022
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48. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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