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1. Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality

Author

Yun Soo Hong, Stephanie L. Battle, Wen Shi, Daniela Puiu, Vamsee Pillalamarri, Jiaqi Xie, Nathan Pankratz, Nicole J. Lake, Monkol Lek, Jerome I. Rotter, Stephen S. Rich, Charles Kooperberg, Alex P. Reiner, Paul L. Auer, Nancy Heard-Costa, Chunyu Liu, Meng Lai, Joanne M. Murabito, Daniel Levy, Megan L. Grove, Alvaro Alonso, Richard Gibbs, Shannon Dugan-Perez, Lukasz P. Gondek, Eliseo Guallar, and Dan E. Arking

Subjects
Science
Abstract

Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.

Published
2023
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3. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author

Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner

Subjects
EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Published
2023
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4. The genetic basis of thoracic aortic disease: The future of aneurysm classification?

Author

M Yousuf Salmasi, Shehani Alwis, Shabnam Cyclewala, Omar A. Jarral, Heba Mohamed, David Mozalbat, Christoph A. Nienaber, Thanos Athanasiou, Deborah Morris-Rosendahl, James Moore Jr, Yun Xu, John Pepper, Declan O'Regan, Jan-Lukas Robertus, Aung Oo, Sumesh Sasidharan, Selene Pirola, Michael Sabetai, Richard Gibbs, and Rakesh Uppal

Subjects
Thoracic aortic aneurysms (TAA), aortic dissection, genotype, syndromic, polymorphisms, hereditary aortic aneurysms and dissection, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

The expansion in the repertoire of genes linked to thoracic aortic aneurysms (TAA) has revolutionised our understanding of the disease process. The clinical benefits of such progress are numerous, particularly helping our understanding of non-syndromic hereditary causes of TAA (HTAAD) and further refinement in the subclassification of disease. Furthermore, the understanding of aortic biomechanics and mechanical homeostasis has been significantly informed by the discovery of deleterious mutations and their effect on aortic phenotype. The drawbacks in genetic testing in TAA lie with the inability to translate genotype to accurate prognostication in the risk of thoracic aortic dissection (TAD), which is a life-threatening condition. Under current guidelines, there are no metrics by which those at risk for dissection with normal aortic diameters may undergo preventive surgery. Future research lies with more advanced genetic diagnosis of HTAAD and investigation of the diverse pathways involved in its pathophysiology, which will i) serve to improve our understanding of the underlying mechanisms, ii) improve guidelines for treatment and iii) prevent complications for HTAAD and sporadic aortopathies.

Published
2023
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5. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author

Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y. Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee-Ming Chuang, Ren-Hua Chung, Joanne E. Curran, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani W. Manichaikul, Preuss Michael, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Muagututia S. Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii-Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A Viaud-Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alexander P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gina M. Peloso, and Pradeep Natarajan

Subjects
Science
Abstract

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Published
2022
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6. Carbon dioxide flushing versus saline flushing of thoracic aortic stents (INTERCEPTevar): protocol for a multicentre pilot randomised controlled trial

Author

Abhinav Singh, Bijan Modarai, Richard Gibbs, Stephen Crockett, Oliver Lyons, Richard Nicholas, Colin Bicknell, Stephen Gunning, Lydia Hanna, Mohamad Hamady, Dennis Gable, Morad Sallam, and Said Abisi

Subjects
Medicine
Abstract

Introduction Thoracic endovascular aortic repair (TEVAR) carries a 3%–6.1% stroke risk, including risk of ‘silent’ cerebral infarction (SCI). Stent-grafts are manufactured in room air and retain air. Instructions for use recommend saline flushing to ‘de-air’ the system prior to insertion, but substantial amounts of air are released when deploying them, potentially leading to downstream neuronal injury and SCI. Carbon dioxide (CO2) is more dense and more soluble in blood than air, without risk of bubble formation, so could be used in addition to saline to de-air stents. This pilot trial aims to assess the feasibility of a full-scale randomised controlled trial (RCT) investigating the neuroprotective benefit against SCI with the use of CO2-flushed aortic stent-grafts.Methods and analysis This is a multicentre pilot RCT, which is taking place in vascular centres in the UK, USA and New Zealand. Patients identified for TEVAR will be enrolled after informed written consent. 120 participants will be randomised (1:1) to TEVAR-CO2 or TEVAR-saline, stratified according to TEVAR landing zone. Participants will undergo preoperative neurocognitive tests and quality of life assessments, which will be repeated at 6 weeks, or first outpatient appointment, and 6 months. Inpatient neurological testing will be performed within 48 hours of return to level 1 care for clinical stroke or delirium. Diffusion-weighted MRI will be undertaken within 72 hours postoperatively (1–7 days) and at 6 months to look for evidence and persistence of SCI. Feasibility will be assessed via measures of recruitment and retention, informing the design of a full-scale trial.Ethics and dissemination The study coordination centre has obtained approval from the London Fulham Research Ethics Committee (19/LO/0836) and Southern Health and Disability Ethics Committee (NZ) and UK’s Health Regulator Authority (HRA). The study has received ethical approval for recruitment in the UK (Fulham REC, 19/LO/0836), New Zealand (21/STH/192) and the USA (IRB 019-264, Ref 378630). Consent for entering into the study will be taken using standardised consent forms by the local study team, led by a local PI. The results of the trial will be submitted for publication in an open access journal.Trial registration number NCT03886675

Published
2023
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8. Community‐based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability

Author

Aniko Sabo, David Murdock, Shannon Dugan, Qingchang Meng, Marie‐Claude Gingras, Jianhong Hu, Donna Muzny, and Richard Gibbs

Subjects
adults, clinical exome, intellectual disability, Genetics, QH426-470
Abstract

Abstract Background Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation. Methods Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family. Results All five families enrolled in the study opted‐in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow‐up in an appointment with a board certified clinical geneticist. Conclusion Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing‐based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID.

Published
2020
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9. Integrated Molecular Characterization of Testicular Germ Cell Tumors

Author

Hui Shen, Juliann Shih, Daniel P. Hollern, Linghua Wang, Reanne Bowlby, Satish K. Tickoo, Vésteinn Thorsson, Andrew J. Mungall, Yulia Newton, Apurva M. Hegde, Joshua Armenia, Francisco Sánchez-Vega, John Pluta, Louise C. Pyle, Rohit Mehra, Victor E. Reuter, Guilherme Godoy, Jeffrey Jones, Carl S. Shelley, Darren R. Feldman, Daniel O. Vidal, Davor Lessel, Tomislav Kulis, Flavio M. Cárcano, Kristen M. Leraas, Tara M. Lichtenberg, Denise Brooks, Andrew D. Cherniack, Juok Cho, David I. Heiman, Katayoon Kasaian, Minwei Liu, Michael S. Noble, Liu Xi, Hailei Zhang, Wanding Zhou, Jean C. ZenKlusen, Carolyn M. Hutter, Ina Felau, Jiashan Zhang, Nikolaus Schultz, Gad Getz, Matthew Meyerson, Joshua M. Stuart, Rehan Akbani, David A. Wheeler, Peter W. Laird, Katherine L. Nathanson, Victoria K. Cortessis, Katherine A. Hoadley, David Wheeler, Daniel Hughes, Kyle Covington, Joy C. Jayaseelan, Viktoriya Korchina, Lora Lewis, Jianhong Hu, HarshaVardhan Doddapaneni, Donna Muzny, Richard Gibbs, Daniel Hollern, Benjamin G. Vincent, Shengjie Chai, Christof C. Smith, J. Todd Auman, Yan Shi, Shaowu Meng, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Piotr A. Mieczkowski, Corbin D. Jones, Matthew D. Wilkerson, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Lisle E. Mose, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Gordon Saksena, Carrie Cibulskis, Steven E. Schumacher, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Dorothy Cheung, Eric Chuah, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Yussanne Ma, Michael Mayo, Richard A. Moore, A. Gordon Robertson, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Marco A. Marra, Daniel J. Weisenberger, David J. Van Den Berg, Phillip H. Lai, Mario Berrios, Andrea Holbrook, Moiz S. Bootwalla, Dennis T. Maglinte, Debyani Chakravarty, Jianjiong Gao, Zachary Heins, Ritika Kundra, Angelica Ochoa, Chris Sander, Marc Ladanyi, Vesteinn Thorsson, Amie J. Radenbaugh, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Jaegil Kim, Michael S. Lawrence, Sam Meier, Timothy Defreitas, Lynda Chin, John N. Weinstein, Wenbin Liu, Gordon B. Mills, Yiling Lu, Leendert Looijenga, Alan H. Bryce, André L. Carvalho, Darren Feldman, Michael Ittmann, Seth Lerner, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Sandra Cottingham, David Chesla, Charles Saller, Katherine Tarvin, Luiz Fernando Lopes, Cristovam Scapulatempo-Neto, Natália D.A. Aredes, Wolter Oosterhuis, Ad Gillis, Hans Stoop, Wil Eijkenboom, George Sandusky, Sue Ellen Martin, Manju Aron, Siamak Daneshmand, Hooman Djaladat, David Quinn, Tanya Dorff, Jochen K. Lennerz, Leigh B. Thorne, Marija Gamulin, Zeljko Kastelan, Tvrtko Hudolin, Christian Kubisch, Lori Boice, Mei Huang, Amy H. Perou, W. Kimryn Rathmell, Todd Pihl, Yunhu Wan, Qiang Sun, Rashi Naresh, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Martin L. Ferguson, Jean C. Zenklusen, Jiashan (Julia) Zhang, Margi Sheth, John A. Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer, Heidi J. Sofia, and Tanja M. Davidsen

Subjects
Biology (General), QH301-705.5
Abstract

Summary: We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance—KIT, KRAS, and NRAS—exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas. : Shen et al. identify molecular characteristics that classify testicular germ cell tumor types, including a separate subset of seminomas defined by KIT mutations. This provides a set of candidate biomarkers for risk stratification and potential therapeutic targeting. Keywords: The Cancer Genome Atlas, testicular germ cell tumors, seminoma, nonseminoma, DNA methylation, exome sequencing, KIT, copy number, miR-375

Published
2018
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10. Primary lung carcinoid metastatic to the breast

Author

Marianna Zagurovskaya, MD, Karen Tran-Harding, MD, and Richard Gibbs, MD

Subjects
Carcinoid, Neuroendocrine, DIPNECH, Breast, Lung, Metastasis, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Lung carcinoid tumors account for approximately 2% of lung cancers, with 10% of the tumors represented by the atypical type. While atypical carcinoids are metastatic to intrathoracic lymph nodes in approximately half of the cases on the initial presentation, distant metastases are seen in only 20% of the patients and are found most frequently in bones, liver, adrenal glands, and brain. We present a case of an unusual metastatic disease to the breast in 51-year-old female who developed a new breast mass 2 years after left lower lobectomy due to atypical carcinoid tumor. Atypical pulmonary carcinoid metastases to the breast are exceptionally uncommon, yet they are important considerations for appropriate management, especially with an anamnesis of this neoplasm.

Published
2017
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11. Genomic encyclopedia of bacteria and archaea: sequencing a myriad of type strains.

Author

Nikos C Kyrpides, Philip Hugenholtz, Jonathan A Eisen, Tanja Woyke, Markus Göker, Charles T Parker, Rudolf Amann, Brian J Beck, Patrick S G Chain, Jongsik Chun, Rita R Colwell, Antoine Danchin, Peter Dawyndt, Tom Dedeurwaerdere, Edward F DeLong, John C Detter, Paul De Vos, Timothy J Donohue, Xiu-Zhu Dong, Dusko S Ehrlich, Claire Fraser, Richard Gibbs, Jack Gilbert, Paul Gilna, Frank Oliver Glöckner, Janet K Jansson, Jay D Keasling, Rob Knight, David Labeda, Alla Lapidus, Jung-Sook Lee, Wen-Jun Li, Juncai Ma, Victor Markowitz, Edward R B Moore, Mark Morrison, Folker Meyer, Karen E Nelson, Moriya Ohkuma, Christos A Ouzounis, Norman Pace, Julian Parkhill, Nan Qin, Ramon Rossello-Mora, Johannes Sikorski, David Smith, Mitch Sogin, Rick Stevens, Uli Stingl, Ken-Ichiro Suzuki, Dorothea Taylor, Jim M Tiedje, Brian Tindall, Michael Wagner, George Weinstock, Jean Weissenbach, Owen White, Jun Wang, Lixin Zhang, Yu-Guang Zhou, Dawn Field, William B Whitman, George M Garrity, and Hans-Peter Klenk

Subjects
Biology (General), QH301-705.5
Abstract

Microbes hold the key to life. They hold the secrets to our past (as the descendants of the earliest forms of life) and the prospects for our future (as we mine their genes for solutions to some of the planet's most pressing problems, from global warming to antibiotic resistance). However, the piecemeal approach that has defined efforts to study microbial genetic diversity for over 20 years and in over 30,000 genome projects risks squandering that promise. These efforts have covered less than 20% of the diversity of the cultured archaeal and bacterial species, which represent just 15% of the overall known prokaryotic diversity. Here we call for the funding of a systematic effort to produce a comprehensive genomic catalog of all cultured Bacteria and Archaea by sequencing, where available, the type strain of each species with a validly published name (currently∼11,000). This effort will provide an unprecedented level of coverage of our planet's genetic diversity, allow for the large-scale discovery of novel genes and functions, and lead to an improved understanding of microbial evolution and function in the environment.

Published
2014
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12. CGAP-align: a high performance DNA short read alignment tool.

Author

Yaoliang Chen, Ji Hong, Wanyun Cui, Jacques Zaneveld, Wei Wang, Richard Gibbs, Yanghua Xiao, and Rui Chen

Subjects
Medicine, Science
Abstract

Next generation sequencing platforms have greatly reduced sequencing costs, leading to the production of unprecedented amounts of sequence data. BWA is one of the most popular alignment tools due to its relatively high accuracy. However, mapping reads using BWA is still the most time consuming step in sequence analysis. Increasing mapping efficiency would allow the community to better cope with ever expanding volumes of sequence data.We designed a new program, CGAP-align, that achieves a performance improvement over BWA without sacrificing recall or precision. This is accomplished through the use of Suffix Tarray, a novel data structure combining elements of Suffix Array and Suffix Tree. We also utilize a tighter lower bound estimation for the number of mismatches in a read, allowing for more effective pruning during inexact mapping. Evaluation of both simulated and real data suggests that CGAP-align consistently outperforms the current version of BWA and can achieve over twice its speed under certain conditions, all while obtaining nearly identical results.CGAP-align is a new time efficient read alignment tool that extends and improves BWA. The increase in alignment speed will be of critical assistance to all sequence-based research and medicine. CGAP-align is freely available to the academic community at http://sourceforge.net/p/cgap-align under the GNU General Public License (GPL).

Published
2013
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13. PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.

Author

Shi-He Liu, Donald D Rao, John Nemunaitis, Neil Senzer, Guisheng Zhou, David Dawson, Marie-Claude Gingras, Zhaohui Wang, Richard Gibbs, Michael Norman, Nancy S Templeton, Francesco J Demayo, Bert O'Malley, Robbi Sanchez, William E Fisher, and F Charles Brunicardi

Subjects
Medicine, Science
Abstract

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.

Published
2012
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14. High-precision, whole-genome sequencing of laboratory strains facilitates genetic studies.

Author

Anjana Srivatsan, Yi Han, Jianlan Peng, Ashley K Tehranchi, Richard Gibbs, Jue D Wang, and Rui Chen

Subjects
Genetics, QH426-470
Abstract

Whole-genome sequencing is a powerful technique for obtaining the reference sequence information of multiple organisms. Its use can be dramatically expanded to rapidly identify genomic variations, which can be linked with phenotypes to obtain biological insights. We explored these potential applications using the emerging next-generation sequencing platform Solexa Genome Analyzer, and the well-characterized model bacterium Bacillus subtilis. Combining sequencing with experimental verification, we first improved the accuracy of the published sequence of the B. subtilis reference strain 168, then obtained sequences of multiple related laboratory strains and different isolates of each strain. This provides a framework for comparing the divergence between different laboratory strains and between their individual isolates. We also demonstrated the power of Solexa sequencing by using its results to predict a defect in the citrate signal transduction pathway of a common laboratory strain, which we verified experimentally. Finally, we examined the molecular nature of spontaneously generated mutations that suppress the growth defect caused by deletion of the stringent response mediator relA. Using whole-genome sequencing, we rapidly mapped these suppressor mutations to two small homologs of relA. Interestingly, stable suppressor strains had mutations in both genes, with each mutation alone partially relieving the relA growth defect. This supports an intriguing three-locus interaction module that is not easily identifiable through traditional suppressor mapping. We conclude that whole-genome sequencing can drastically accelerate the identification of suppressor mutations and complex genetic interactions, and it can be applied as a standard tool to investigate the genetic traits of model organisms.

Published
2008
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16. Precision Neurology for Dementia (P2-6.002)

Author

Joshua Shulman, Nora Vanegas-Arroyave, Jamie Fong, Sarah Elsea, Chi-ing Lin, Hiba Saade, Fatima Chavez, Kimberly Walker, Bo Yuan, Eric Venner, Jianhong Hu, Ariel Levchenko, Hadley Smith, Jill Robinson, Belen Pascual, Donna Muzny, Richard Gibbs, Amy McGuire, and Joseph Masdeu

Published
2023

17. Type II Endoleaks and Culprit Vessels: Will 4D MRI Change the Paradigm?

Author

Lydia Hanna, Richard G.J. Gibbs, Thanos Athanasiou, James Moore, Xiao Yun Xu, Christoph Nienaber, John Pepper, Declan O'Regan, Jan-Lukas Robertus, Deborah Morris-Rosendahl, Aung Oo, Sumesh Sasidharan, Selene Pirola, M. Yousuf Salmasi, Omar Jarral, Michael Sabetai, George Asimakopoulos, Richard Gibbs, and Rakesh Uppal

Subjects
Surgery, Cardiology and Cardiovascular Medicine
Published
2023

18. Data Supplement from Squamous Cell Carcinoma of the Oral Tongue in Young Non-Smokers Is Genomically Similar to Tumors in Older Smokers

Author

Jeffrey N. Myers, Mitchell J. Frederick, Jing Wang, David A. Wheeler, John N. Weinstein, Richard Gibbs, Adel K. El-Naggar, Jennifer Drummond, Jane H. Zhou, Marcus V. Ortega Alves, C. Jillian Tsai, Alexandra Ward, Jiping Wang, Samar A. Jasser, Mei Zhao, David M. Neskey, Jiexin Zhang, and Curtis R. Pickering

Abstract

Supplementary Figure S1. Association between age, number of mutations and smoking status.

Published
2023

19. Data from Squamous Cell Carcinoma of the Oral Tongue in Young Non-Smokers Is Genomically Similar to Tumors in Older Smokers

Author

Jeffrey N. Myers, Mitchell J. Frederick, Jing Wang, David A. Wheeler, John N. Weinstein, Richard Gibbs, Adel K. El-Naggar, Jennifer Drummond, Jane H. Zhou, Marcus V. Ortega Alves, C. Jillian Tsai, Alexandra Ward, Jiping Wang, Samar A. Jasser, Mei Zhao, David M. Neskey, Jiexin Zhang, and Curtis R. Pickering

Abstract

Purpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.Experimental Design: DNA isolated from tongue tumors of young (45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.

Published
2023

20. Structural variation across 138,134 samples in the TOPMed consortium

Author

Goo Jun, Adam English, Ginger Metcalf, Jianzhi Yang, Mark Chaisson, Nathan Pankratz, Vipin Menon, William Salerno, Olga Krasheninina, Albert Smith, John Lane, Thomas Blackwell, Hyun Min Kang, Sejal Salvi, Qingchang Meng, Hua Shen, Divya Pasham, Sravya Bhamidipati, Kavya Kottapalli, Donna Arnett, Allison Ashley-Koch, Paul Auer, KAthleen Beutel, Joshua Bis, John Blangero, Donald Bowden, Jennifer Brody, Brian Cade, Yii-Der Ida Chen, Michael Cho, Joanne Curran, Myriam Fornage, Barry Frredman, Tasha Fingerlin, Bruce Gelb, Lifang Hou, Yi-Jen Hung, John P Kane, Robert Kaplan, Wonji Kim, Ruth Loos, Gregory Marcus, Rasika Mathias, Stephen McGarvey, Courtney Montgomery, Take Naseri, Seyed Nouraie, Michael Preuss, Nicholette Palmer, Patricia Peyser, Laura Raffield, Aakrosh Ratan, Susan Redline, Muagututia Reupena, Jerome Rotter, Stephen Rich, Michiel Rienstra, Ingo Ruczinski, Vijay Sankaran, David Schwartz, Christine Seidman, Jonathan Seidman, Edwin Silverman, Jennifer Smith, Adrienne Stilp, Kent Taylor, Marilyn Telen, Scott Weiss, L. Keoki Williams, Baojun Wu, Lisa Yanek, Yingze Zhang, Jessica Lasky-Su, Marie-Claude Gingras, Susan Dutcher, Evan Eichler, Stacey Gabriel, Soren Germer, Ryan Kim, Karine Martinez, Deborah Nickerson, James Luo, Alexander Reiner, Richard Gibbs, Eric Boerwinkle, Goncaol Abecasis, and Fritz Sedlazeck

Subjects
Article
Abstract

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

Published
2023

21. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022

22. xAtlas: scalable small variant calling across heterogeneous next-generation sequencing experiments

Author

Jesse Farek, Daniel Hughes, William Salerno, Yiming Zhu, Aishwarya Pisupati, Adam Mansfield, Olga Krasheninina, Adam C English, Ginger Metcalf, Eric Boerwinkle, Donna M Muzny, Richard Gibbs, Ziad Khan, and Fritz J Sedlazeck

Subjects
Health Informatics, Computer Science Applications
Abstract

Background The growing volume and heterogeneity of next-generation sequencing (NGS) data complicate the further optimization of identifying DNA variation, especially considering that curated high-confidence variant call sets frequently used to validate these methods are generally developed from the analysis of comparatively small and homogeneous sample sets. Findings We have developed xAtlas, a single-sample variant caller for single-nucleotide variants (SNVs) and small insertions and deletions (indels) in NGS data. xAtlas features rapid runtimes, support for CRAM and gVCF file formats, and retraining capabilities. xAtlas reports SNVs with 99.11% recall and 98.43% precision across a reference HG002 sample at 60× whole-genome coverage in less than 2 CPU hours. Applying xAtlas to 3,202 samples at 30× whole-genome coverage from the 1000 Genomes Project achieves an average runtime of 1.7 hours per sample and a clear separation of the individual populations in principal component analysis across called SNVs. Conclusions xAtlas is a fast, lightweight, and accurate SNV and small indel calling method. Source code for xAtlas is available under a BSD 3-clause license at https://github.com/jfarek/xatlas.

Published
2022

27. Trends in mortality from aortic dissection analyzed from the World Health Organization Mortality Database from 2000 to 2017

Author

Nour Abdallah, Christian Mouchati, Conor Crowley, Lydia Hanna, Richard Goodall, Justin Salciccioli, Dominic Marshall, Richard Gibbs, and Joseph Shalhoub

Subjects
Male, Norway, Aortic dissection, World Health Organization, United States, United Kingdom, 1117 Public Health and Health Services, Europe, WHO, Cardiovascular System & Hematology, Aneurysm, Dissecting, Humans, Female, Mortality, Cardiology and Cardiovascular Medicine, 1102 Cardiorespiratory Medicine and Haematology, Czech Republic
Abstract

Background: We assessed trends in aortic dissection (AD) death rates in 23 countries from 2000 to 2017. Methods: We extracted AD mortality data for countries with high usability data from the World Health Organization (WHO) Mortality Database and from the Center for Disease Control (CDC) WONDER Database for the United States of America (USA). Age Standardized Death Rates (ASDRs) per 100,000 population were computed. Trends were assessed by locally weighted scatter plot smoother (LOWESS) regression. Results: Between 2000 and 2017, ASDRs from AD decreased in Australia, Belgium, Croatia, Denmark, France, Italy, New Zealand, Norway, Sweden, the United Kingdom, and the USA for both sexes. Increasing AD mortality was observed in Austria, Czech Republic, Germany, Hungary, Israel, and Japan for both sexes. The largest absolute increases in ASDR were in Japan for men (+1.59) and women (+1.11). The largest percentage decreases were in Norway for men (−0.91) and in New Zealand (−0.6) for women. In 2017, the highest mortality rates were in Japan for both sexes (3.22 and 2.09, respectively). The lowest ASDR was in Kyrgyzstan for both sexes (0.16 and 0.10, respectively). ASDRs for AD in 2017 were higher for men than women in all countries included. Spain had the greatest difference between the gender's mortality rates with a 2.71-fold higher mortality average rate in men. Conclusion: We identified an overall decrease in AD mortality in most included countries, while an increase was noted in other countries including Israel and Japan.

Published
2022

28. Factors associated with infrainguinal bypass graft patency at 1-year; a retrospective analysis of a single centre experience

Author

Pasha Normahani, Ismail Yusuf Anwar, Alona Courtney, Amish Acharya, Viknesh Sounderajah, Chira Mustafa, Usman Jaffer, Joseph Shalhoub, Celia Riga, Richard Gibbs, Michael Jenkins, Colin Bicknell, Alun H Davies, David Nott, Christopher Aylwin, Nigel J Standfield, National Institute of Health Research, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
medicine.medical_specialty, Cardiac & Cardiovascular Systems, Referral, SURGERY, Infrainguinal bypass, 030204 cardiovascular system & hematology, LIMB SALVAGE, THERAPY, Lower limb, Blood Vessel Prosthesis Implantation, 03 medical and health sciences, 0302 clinical medicine, Ischemia, Risk Factors, Retrospective analysis, FAILURE, Humans, Medicine, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, AMPUTATION-FREE, ANGIOPLASTY, 1102 Cardiorespiratory Medicine and Haematology, Vascular Patency, Retrospective Studies, Advanced and Specialized Nursing, Science & Technology, Graft patency, business.industry, Graft Occlusion, Vascular, INTRAOPERATIVE DUPLEX, General Medicine, Surgery, LEG BASIL TRIAL, SEVERE ISCHEMIA, anti-thrombotic, Single centre, Treatment Outcome, Peripheral Vascular Disease, bypass revascularization, Collaborators, Cardiovascular System & Cardiology, SURVIVAL, lower limb, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine, patency, Safety Research
Abstract

Introduction: The aim of this study was to identify factors associated with primary graft patency 1 year following open lower limb revascularisation (LLR) at a tertiary referral vascular service. Methods: A retrospective analysis of patients undergoing infra-inguinal bypass surgery between January 2016 and May 2017 at a tertiary vascular centre (St Mary’s Hospital, London) was performed. Data regarding patient demographics, comorbidities, type of operation and post-operative anti-thrombotic strategy were collected. Quality of run-off score was assessed from pre-operative imaging. Results: Seventy-seven cases were included in the analysis. Overall, the primary patency rate at 1-year was 63.6% ( n = 49/77) and the secondary patency rate was 67.5% ( n = 52/77). Independent variables with statistically significant inferior patency rates at 1-year were (1) bypasses with below knee targets (p = 0.0096), (2) chronic limb threatening ischaemia indication (p = 0.038), (3) previous ipsilateral revascularisation (p Conclusion: At 1-year follow-up, previous ipsilateral revascularisation was the most significant factor in affecting patency rates. Patients in this subgroup should therefore be deemed high-risk, which should be reflected in the informed consent and peri-operative management.

Published
2021

29. Abstract P5-02-36: Proteogenomic profiling of fresh frozen core biopsies from CALGB 40601

Author

Eric J. Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi Vashist, Matthew V. Holt, LaTerrica Williams, Jonathan Lei, Beom-Jun Kim, Yongchao Dou, Viktoriya Korchina, Richard Gibbs, Donna Muzny, Harshavardhan Doddapaneni, Henry Rodriguez, Ana Robles, Tara Hiltke, DR Mani, Michael Gillette, Terry Hyslop, Yujia Wen, Linda McCart, George Miles, Steven Carr, Bing Zhang, Shankha Satpathy, Matthew Ellis, and Meenakshi Anurag

Subjects
Cancer Research, Oncology
Abstract

Background: Targeted therapy for HER2+ breast cancer has significantly improved outcomes for this aggressive subtype. However, a subset of patients do not achieve pathological complete response (pCR). In CALGB 40601, a randomized Phase III Trial for neoadjuvant treatment of HER2+ primary breast cancer with Paclitaxel (T: taxane) combined with HER2 antibody therapy (H: Herceptin/Trastuzumab), the small molecule inhibitor Lapatinib (L), or the antibody-inhibitor combination, pCR frequency was 56% for the combination (THL arm), 46% for Trastuzumab (TH arm), and 32% for Lapatinib (TL arm, closed early because of lower efficacy) (PMID: 26527775). While a recent publication reports relapse-free survival (RFS), overall survival (OS), and RNA-based gene expression signatures that can predict pCR (PMID: 33095682), understanding the proteogenomic landscape of treatment response should facilitate identification of alternative and therapeutically tractable protein targets for treatment-resistant tumors. Methods: Microscaled proteogenomic profiling (PMID: 31988290) was performed on treatment-naïve, flash-frozen core needle biopsies from the CALGB 40601 trial obtained from the Alliance for Clinical Trials in Oncology tissue bank. Multi-omics profiling included whole-exome sequencing (WES), RNA-sequencing, and mass spectroscopy-based proteomics and phosphoproteomics from one or two cores from each patient. Results: Eighty baseline core biopsies from 54 patients, including 22 patients from the THL arm, 24 from the TH arm, and 8 from the TL arm, from the CALGB 40601 tissue archive were of sufficient quality to yield genomics, transcriptomics, and/or proteomics profiling data. The frequency of pCR for profiled samples was representative of the overall trial cohort. Linear models were employed to identify baseline determinants of pCR for each arm and to assess differences in genes associated with response between the TH and THL arms. Pathways associated with RNA processing, translation, and the proteasome were elevated in pCR tumors in TH and THL arms, while cell cycle, DNA replication and repair pathways were higher in pCR only in the THL arm. While enrichment of similar pathways was observed in pCR in the transcriptome, the proteome specifically showed enrichment of pathways associated with extracellular matrix and EMT in non-pCR in the THL but not the TH arm. In particular, “EMT”, “ECM-receptor interaction”, and “extracellular structure organization” constituted the most enriched pathways and GO terms that were higher in non-pCR than in pCR tumors from the combination arm (THL) in the proteomics data despite showing no enrichment in the transcriptomics data. Driving this pathway enrichment were several collagens and matrix metalloproteinases that were significantly elevated in non-pCR tumors at the protein but not the RNA level. Finally, kinase target enrichment of differential phosphorylation sites suggested that the activity of PAK1, a regulator of cytoskeletal remodeling, is elevated in non-pCR tumors from the THL arm (p=0.006), but not the TH arm (p=0.69). Conclusion: Proteogenomic analysis of archival HER2+ breast cancer core biopsies provides opportunities for identifying proteins and phosphorylation sites in treatment-naive tumors that are associated with pCR to neoadjuvant Paclitaxel/anti-HER2 therapy. Notably, proteomic but not transcriptomic data showed that ECM and EMT pathways were elevated in non-pCR tumors; thus, signatures encompassing these pathways may serve as biomarkers for aggressive HER2+ breast cancer that is more likely to evade treatment. Non-pCR tumors in the THL arm were also marked by elevated levels of PAK1 target phosphorylation sites, suggesting that this kinase may be a potential therapeutic target in HER2+ breast cancer that is refractory to combination anti-HER2 therapy. Citation Format: Eric J. Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi Vashist, Matthew V. Holt, LaTerrica Williams, Jonathan Lei, Beom-Jun Kim, Yongchao Dou, Viktoriya Korchina, Richard Gibbs, Donna Muzny, Harshavardhan Doddapaneni, Henry Rodriguez, Ana Robles, Tara Hiltke, DR Mani, Michael Gillette, Terry Hyslop, Yujia Wen, Linda McCart, George Miles, Steven Carr, Bing Zhang, Shankha Satpathy, Matthew Ellis, Meenakshi Anurag. Proteogenomic profiling of fresh frozen core biopsies from CALGB 40601 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-36.

Published
2023

31. Truvari: Refined Structural Variant Comparison Preserves Allelic Diversity

Author

Adam C. English, Vipin K. Menon, Richard Gibbs, Ginger A. Metcalf, and Fritz J. Sedlazeck

Subjects
Benchmarking, Gene Frequency, Genome, Human, Genomic Structural Variation, Humans, High-Throughput Nucleotide Sequencing, Algorithms, Alleles
Abstract

For multi-sample structural variant analyses like merging, benchmarking, and annotation, the fundamental operation is to identify when two SVs are the same. Commonly applied approaches for comparing SVs were developed alongside technologies which produce ill-defined boundaries. As SV detection becomes more exact, algorithms to preserve this refined signal are needed. Here we present Truvari - a SV comparison, annotation and analysis toolkit - and demonstrate the effect of SV comparison choices by building population-level VCFs from 36 haplotype-resolved long-read assemblies. We observe over-merging from other SV merging approaches which causes up to a 2.2x inflation of allele frequency relative to Truvari.

Published
2022

32. Brain Protection in the Endo-Management of Proximal Aortic Aneurysms

Author

Richard Gibbs and Lydia Hanna

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Cerebral arteries, Magnetic resonance imaging, Brain protection, 030204 cardiovascular system & hematology, medicine.disease, Neuroprotection, Transcranial Doppler, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine.artery, medicine, Cardiology, Thoracic aorta, 030212 general & internal medicine, business, Complication, Stroke
Abstract

Neurological brain injury (NBI) remains the most feared complication following thoracic endovascular aortic repair (TEVAR), and can manifest as clinically overt stroke and/or more covert injury, detected only on explicit neuropsychological testing. Microembolic signals (MES) detected on transcranial Doppler (TCD) monitoring of the cerebral arteries during TEVAR and the high prevalence and incidence of new ischaemic infarcts on diffusion-weighted magnetic resonance imaging (DW-MRI) suggests procedure-related solid and gaseous cerebral microembolisation to be an important cause of NBI. Any intervention that can reduce the embolic burden during TEVAR may, therefore, help mitigate the risk of stroke and the covert impact of ischaemic infarcts to the function of the brain. This perspective article provides an understanding of the mechanism of stroke and reviews the available evidence regarding potential neuroprotective strategies that target high-risk procedural steps of TEVAR to reduce periprocedural cerebral embolisation.

Published
2020

33. Location of Reentry Tears Affects False Lumen Thrombosis in Aortic Dissection Following TEVAR

Author

Richard Gibbs, Kristijonas Milinis, Claudia Menichini, Chlöe Harriet Armour, Xiao Yun Xu, and Imperial College Healthcare Charity

Subjects
reentry tear, Patient-Specific Modeling, IMPACT, Computed Tomography Angiography, False lumen, endovascular procedures, patient-specific geometrical models, false lumen, Risk Factors, aortic dissection, PREDICTORS, Aortic dissection, RISK, Models, Cardiovascular, Reentry, Thrombosis, MEDICAL-TREATMENT, Treatment Outcome, Physiological flow, cardiovascular system, Stents, Radiology, Thoracic and Thoracoabdominal Aortic Interventions, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, medicine.medical_specialty, computational fluid dynamics, Vascular Remodeling, Prosthesis Design, Aortography, thoracic endovascular aortic repair, Blood Vessel Prosthesis Implantation, medicine.artery, medicine, MANAGEMENT, Humans, Radiology, Nuclear Medicine and imaging, Thrombus, thrombosis, stent-graft, Aorta, Science & Technology, Aortic Aneurysm, Thoracic, business.industry, Hemodynamics, ENDOVASCULAR REPAIR, 1103 Clinical Sciences, medicine.disease, Blood Vessel Prosthesis, Peripheral Vascular Disease, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Tears, Surgery, business
Abstract

Purpose: To report a study that assesses the influence of the distance between the distal end of a thoracic stent-graft and the first reentry tear (SG-FRT) on the progression of false lumen (FL) thrombosis in patients who underwent thoracic endovascular aortic repair (TEVAR). Materials and Methods: Three patient-specific geometrical models were reconstructed from postoperative computed tomography scans. Two additional models were created by artificially changing the SG-FRT distance in patients 1 and 2. In all 5 models, computational fluid dynamics simulations coupled with thrombus formation modeling were performed at physiological flow conditions. Predicted FL thrombosis was compared to follow-up scans. Results: There was reduced false lumen flow and low time-averaged wall shear stress (TAWSS) in patients with large SG-FRT distances. Predicted thrombus formation and growth were consistent with follow-up scans for all patients. Reducing the SG-FRT distance by 30 mm in patient 1 increased the flow and time-averaged wall shear stress in the upper abdominal FL, reducing the thrombus volume by 9.6%. Increasing the SG-FRT distance in patient 2 resulted in faster thoracic thrombosis and increased total thrombus volume. Conclusion: The location of reentry tears can influence the progression of FL thrombosis following TEVAR. The more distal the reentry tear in the aorta the more likely it is that FL thrombosis will occur. Hence, the distal landing zone of the stent-graft should be chosen carefully to ensure a sufficient SG-FRT distance.

Published
2020

35. Whole genome sequence analysis of blood lipid levels in66,000 individuals

Author

Margaret Sunitha, Selvaraj, Xihao, Li, Zilin, Li, Akhil, Pampana, David Y, Zhang, Joseph, Park, Stella, Aslibekyan, Joshua C, Bis, Jennifer A, Brody, Brian E, Cade, Lee-Ming, Chuang, Ren-Hua, Chung, Joanne E, Curran, Lisa, de Las Fuentes, Paul S, de Vries, Ravindranath, Duggirala, Barry I, Freedman, Mariaelisa, Graff, Xiuqing, Guo, Nancy, Heard-Costa, Bertha, Hidalgo, Chii-Min, Hwu, Marguerite R, Irvin, Tanika N, Kelly, Brian G, Kral, Leslie, Lange, Xiaohui, Li, Martin, Lisa, Steven A, Lubitz, Ani W, Manichaikul, Preuss, Michael, May E, Montasser, Alanna C, Morrison, Take, Naseri, Jeffrey R, O'Connell, Nicholette D, Palmer, Patricia A, Peyser, Muagututia S, Reupena, Jennifer A, Smith, Xiao, Sun, Kent D, Taylor, Russell P, Tracy, Michael Y, Tsai, Zhe, Wang, Yuxuan, Wang, Wei, Bao, John T, Wilkins, Lisa R, Yanek, Wei, Zhao, Donna K, Arnett, John, Blangero, Eric, Boerwinkle, Donald W, Bowden, Yii-Der Ida, Chen, Adolfo, Correa, L Adrienne, Cupples, Susan K, Dutcher, Patrick T, Ellinor, Myriam, Fornage, Stacey, Gabriel, Soren, Germer, Richard, Gibbs, Jiang, He, Robert C, Kaplan, Sharon L R, Kardia, Ryan, Kim, Charles, Kooperberg, Ruth J F, Loos, Karine A, Viaud-Martinez, Rasika A, Mathias, Stephen T, McGarvey, Braxton D, Mitchell, Deborah, Nickerson, Kari E, North, Bruce M, Psaty, Susan, Redline, Alexander P, Reiner, Ramachandran S, Vasan, Stephen S, Rich, Cristen, Willer, Jerome I, Rotter, Daniel J, Rader, Xihong, Lin, Gina M, Peloso, and Sebastian, Zoellner

Subjects
Multidisciplinary, Whole Genome Sequencing, General Physics and Astronomy, Humans, General Chemistry, Cholesterol, LDL, Lipids, General Biochemistry, Genetics and Molecular Biology, Alleles, Genome-Wide Association Study
Abstract

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Published
2021

36. 595 Penetrating Pelvic Trauma from a Crossbow Bolt: An Unusual Choice of Weapon

Author

A Ting, Richard Gibbs, C Barnetson, and A Joegi

Subjects
Pelvic trauma, medicine.medical_specialty, business.industry, medicine, Surgery, business, Crossbow
Abstract

Introduction The crossbow was a popular weapon in medieval times due to their relative ease of use and accuracy but was superseded by firearms around the 16th century. Today, it is legal for adults in the UK to own a crossbow without a licence. Case Report A young adult male victim was brought to a Major Trauma Centre with a single lower left quadrant penetrating wound caused a crossbow bolt that was self-removed immediately after the injury. A 2.5cm entry wound was present with no exit wound. The patient was haemodynamically unstable on arrival and was transferred to theatre without imaging within 16 minutes of arrival. The main operative findings were multiple small bowel serosal tears, a full thickness small bowel injury with no contamination and a left external iliac artery injury with active bleeding which were all repaired primarily. The post-operative recovery course included occlusive left cephalic and antecubital vein thrombi and an extensive non-occlusive left common femoral vein thrombus treated with anticoagulant therapy but was otherwise unremarkable. He was discharged 10 days later with no lasting sequelae at 6-week follow up. Discussion This case highlights a rare but important and likely underreported modality of penetrating injury. Crossbow bolts have low kinetic energy compared to bullets but high penetrative force, thus little energy is transferred to surrounding tissues. Hence the main injuries caused by crossbow bolts are due to direct damage to structures they come into contact with. Although rare, trauma surgeons should be aware of the pattern of injury caused by crossbows.

Published
2021

37. Drowning in data, thirsty for information and starved for understanding: A biodiversity information hub for cooperative environmental monitoring in South Africa

Author

Sandra MacFadyen, Nicky Allsopp, Res Altwegg, Sally Archibald, Judith Botha, Karen Bradshaw, Jane Carruthers, Helen De Klerk, Alta de Vos, Greg Distiller, Stefan Foord, Stefanie Freitag-Ronaldson, Richard Gibbs, Michelle Hamer, Pietro Landi, Duncan MacFadyen, Jeffrey Manuel, Guy Midgley, Glenn Moncrieff, Zahn Munch, Onisimo Mutanga, null Sershen, Rendani Nenguda, Mzabalazo Ngwenya, Daniel Parker, Mike Peel, John Power, Joachim Pretorius, Syd Ramdhani, Mark Robertson, Ian Rushworth, Andrew Skowno, Jasper Slingsby, Andrew Turner, Vernon Visser, Gerhard Van Wageningen, and Cang Hui

Subjects
Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation
Published
2022

38. The All of Us Research Program: Data quality, utility, and diversity

Author

Andrea H. Ramirez, Lina Sulieman, David J. Schlueter, Alese Halvorson, Jun Qian, Francis Ratsimbazafy, Roxana Loperena, Kelsey Mayo, Melissa Basford, Nicole Deflaux, Karthik N. Muthuraman, Karthik Natarajan, Abel Kho, Hua Xu, Consuelo Wilkins, Hoda Anton-Culver, Eric Boerwinkle, Mine Cicek, Cheryl R. Clark, Elizabeth Cohn, Lucila Ohno-Machado, Sheri D. Schully, Brian K. Ahmedani, Maria Argos, Robert M. Cronin, Christopher O’Donnell, Mona Fouad, David B. Goldstein, Philip Greenland, Scott J. Hebbring, Elizabeth W. Karlson, Parinda Khatri, Bruce Korf, Jordan W. Smoller, Stephen Sodeke, John Wilbanks, Justin Hentges, Stephen Mockrin, Christopher Lunt, Stephanie A. Devaney, Kelly Gebo, Joshua C. Denny, Robert J. Carroll, David Glazer, Paul A. Harris, George Hripcsak, Anthony Philippakis, Dan M. Roden, Brian Ahmedani, Christine D. Cole Johnson, Habib Ahsan, Donna Antoine-LaVigne, Glendora Singleton, Eric Topol, Katie Baca-Motes, Steven Steinhubl, James Wade, Mark Begale, Praduman Jain, Scott Sutherland, Beth Lewis, Melissa Behringer, Ali G. Gharavi, Louise Bier, Murray H. Brilliant, Narayana Murali, Scott Joseph Hebbring, Dorothy Farrar-Edwards, Elizabeth Burnside, Marc K. Drezner, Amy Taylor, Veena Channamsetty, Wanda Montalvo, Yashoda Sharma, Carmen Chinea, Nancy Jenks, Steve Thibodeau, Beverly Wilson Holmes, Eric Schlueter, Ever Collier, Joyce Winkler, John Corcoran, Nick D’Addezio, Martha Daviglus, Robert Winn, Dan Roden, Joshua Denny, Kim Doheny, Debbie Nickerson, Evan Eichler, Gail Jarvik, Gretchen Funk, Heidi Rehm, Niall Lennon, Sekar Kathiresan, Stacey Gabriel, Richard Gibbs, Edgar M. Gil Rico, Joannie Grand, Paul Harris, Elizabeth Shenkman, William R. Hogan, Priscilla Igho-Pemu, Cliff Pollan, Milena Jorge, Sally Okun, Jordan Smoller, Shawn N. Murphy, Margaret Elizabeth Ross, Rainu Kaushal, Eboni Winford, Febe Wallace, Vik Kheterpal, Akinlolu Ojo, Francisco A. Moreno, Irving Kron, Rachele Peterson, Usha Menon, Patricia Watkins Lattimore, Noga Leviner, Juno Obedin-Maliver, Mitchell Lunn, Lynda Malik-Gagnon, Lara Mangravite, Adria Marallo, Oscar Marroquin, Shyam Visweswaran, Steven Reis, Gailen Marshall, Patrick McGovern, Deb Mignucci, John Moore, Fatima Munoz, Gregory Talavera, George T. O'Connor, Christopher O'Donnell, Greg Orr, Fornessa Randal, Andreas A. Theodorou, Eric Reiman, Mercedita Roxas-Murray, Louisa Stark, Ronnie Tepp, Alicia Zhou, Scott Topper, Rhonda Trousdale, Phil Tsao, Lisa Weidman, Scott T. Weiss, David Wellis, Jeffrey Whittle, Amanda Wilson, Stephan Zuchner, and Michael E. Zwick

Subjects
General Decision Sciences
Published
2022

39. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author

Alison Halliday, Richard Bulbulia, Leo H Bonati, Johanna Chester, Andrea Cradduck-Bamford, Richard Peto, Hongchao Pan, John Potter, Hans Henning Eckstein, Barbara Farrell, Marcus Flather, Averil Mansfield, Boby Mihaylova, Kazim Rahimi, David Simpson, Dafydd Thomas, Peter Sandercock, Richard Gray, Andrew Molyneux, Cliff P Shearman, Peter Rothwell, Anna Belli, Will Herrington, Parminder Judge, Peter Leopold, Marion Mafham, Michael Gough, Piergiorgio Cao, Sumaira MacDonald, Vasha Bari, Clive Berry, S Bradshaw, Wojciech Brudlo, Alison Clarke, Robin Cox, Susan Fathers, Kamran Gaba, Mo Gray, Elizabeth Hayter, Constance Holliday, Rijo Kurien, Michael Lay, Steffi le Conte, Jessica McManus, Zahra Madgwick, Dylan Morris, Andrew Munday, Sandra Pickworth, Wiktor Ostasz, Michiel Poorthuis, Sue Richards, Louisa Teixeira, Sergey Tochlin, Lynda Tully, Carol Wallis, Monique Willet, Alan Young, Renato Casana, Chiara Malloggi, Andrea Odero Jr, Vincenzo Silani, Gianfranco Parati, Giuseppe Malchiodi, Giovanni Malferrari, Francesco Strozzi, Nicola Tusini, Enrico Vecchiati, Gioacchino Coppi, Antonio Lauricella, Roberto Moratto, Roberto Silingardi, Jessica Veronesi, Andrea Zini, Emanuele Ferrero, Michelangelo Ferri, Andrea Gaggiano, Carmelo Labate, Franco Nessi, Daniele Psacharopulo, Andrea Viazzo, Giovanni Malacrida, Daniela Mazzaccaro, Giovanni Meola, Alfredo Modafferi, Giovanni Nano, Maria Teresa Occhiuto, Paolo Righini, Silvia Stegher, Stefano Chiarandini, Filippo Griselli, Sandro Lepidi, Fabio Pozzi Mucelli, Marcello Naccarato, Mario D'Oria, Barbara Ziani, Andrea Stella, Mortalla Dieng, Gianluca Faggioli, Mauro Gargiulo, Sergio Palermo, Rodolfo Pini, Giovanni Maria Puddu, Andrea Vacirca, Domenico Angiletta, Claudio Desantis, Davide Marinazzo, Giovanni Mastrangelo, Guido Regina, Raffaele Pulli, Paolo Bianchi, Lea Cireni, Elisabetta Coppi, Rocco Pizzirusso, Filippo Scalise, Giovanni Sorropago, Valerio Tolva, Valeria Caso, Enrico Cieri, Paola DeRango, Luca Farchioni, Giacomo Isernia, Massimo Lenti, Gian Battista Parlani, Guglielmo Pupo, Grazia Pula, Gioele Simonte, Fabio Verzini, Federico Carimati, Maria Luisa Delodovici, Federico Fontana, Gabriele Piffaretti, Matteo Tozzi, Efrem Civilini, Giorgio Poletto, Bernhard Reimers, Barbara Praquin, Sonia Ronchey, Laura Capoccia, Wassim Mansour, Enrico Sbarigia, Francesco Speziale, Pasqualino Sirignano, Danilo Toni, Roberto Galeotti, Vincenzo Gasbarro, Francesco Mascoli, Tiberio Rocca, Elpiniki Tsolaki, Giulia Bernardini, Ester DeMarco, Alessia Giaquinta, Francesco Patti, Massimiliano Veroux, Pierfrancesco Veroux, Carla Virgilio, Nicola Mangialardi, Matteo Orrico, Vincenzo Di Lazzaro, Nunzio Montelione, Francesco Spinelli, Francesco Stilo, Carlo Cernetti, Sandro Irsara, Giuseppe Maccarrone, Diego Tonello, Adriana Visonà, Beniamino Zalunardo, Emiliano Chisci, Stefano Michelagnoli, Nicola Troisi, Maela Masato, Massimo Dei Negri, Andrea Pacchioni, Salvatore Saccà, Giovanni Amatucci, Alfredo Cannizzaro, Federico Accrocca, Cesare Ambrogi, Renzo Barbazza, Giustino Marcucci, Andrea Siani, Guido Bajardi, Giovanni Savettieri, Angelo Argentieri, Riccardo Corbetta, Attilio Odero, Pietro Quaretti, Federico Z Thyrion, Alessandro Cappelli, Domenico Benevento, Gianmarco De Donato, Maria Agnese Mele, Giancarlo Palasciano, Daniela Pieragalli, Alessandro Rossi, Carlo Setacci, Francesco Setacci, Domenico Palombo, Maria Cecilia Perfumo, Edoardo Martelli, Aldo Paolucci, Santi Trimarchi, Viviana Grassi, Luigi Grimaldi, Giuliana La Rosa, Domenico Mirabella, Matteo Scialabba, Leonildo Sichel, Costantino L D'Angelo, Gian Franco Fadda, Holta Kasemi, Mario Marino, Francesco Burzotta, Francesco Alberto Codispoti, Angela Ferrante, Giovanni Tinelli, Yamume Tshomba, Claudio Vincenzoni, Deborah Amis, Dawn Anderson, Martin Catterson, Mike Clarke, Michelle Davis, Anand Dixit, Alexander Dyker, Gary Ford, Ralph Jackson, Sreevalsan Kappadath, David Lambert, Tim Lees, Stephen Louw, James McCaslin, Noala Parr, Rebecca Robson, Gerard Stansby, Lucy Wales, Vera Wealleans, Lesley Wilson, Michael Wyatt, Hardeep Baht, Ibrahim Balogun, Ilse Burger, Tracy Cosier, Linda Cowie, Gunaratnam Gunathilagan, David Hargroves, Robert Insall, Sally Jones, Hannah Rudenko, Natasha Schumacher, Jawaharlal Senaratne, George Thomas, Audrey Thomson, Tom Webb, Ellen Brown, Bernard Esisi, Ali Mehrzad, Shane MacSweeney, Norman McConachie, Alison Southam, Wayne Sunman, Ahmed Abdul-Hamiq, Jenny Bryce, Ian Chetter, Duncan Ettles, Raghuram Lakshminarayan, Kim Mitchelson, Christopher Rhymes, Graham Robinson, Paul Scott, Alison Vickers, Ray Ashleigh, Stephen Butterfield, Ed Gamble, Jonathan Ghosh, Charles N McCollum, Mark Welch, Sarah Welsh, Leszek Wolowczyk, Mary Donnelly, Stephen D'Souza, Anselm A Egun, Bindu Gregary, Thomas Joseph, Christine Kelly, Shuja Punekar, M Asad Rahi, Sonia Raj, Dare Seriki, George Thomson, James Brown, Ragunath Durairajan, Iris Grunwald, Paul Guyler, Paula Harman, Matthew Jakeways, Christopher Khuoge, Ashish Kundu, Thayalini Loganathan, Nisha Menon, Raji O Prabakaran, Devesh Sinha, Vicky Thompson, Sharon Tysoe, Dennis Briley, Chris Darby, Linda Hands, Dominic Howard, Wilhelm Kuker, Ursula Schulz, Rachel Teal, David Barer, Andrew Brown, Susan Crawford, Paul Dunlop, Ramesh Krishnamurthy, Nikhil Majmudar, Duncan Mitchell, Min P Myint, Richard O'Brien, Janice O'Connell, Naweed Sattar, Shanmugam Vetrivel, Jonathan Beard, Trevor Cleveland, Peter Gaines, John Humphreys, Alison Jenkins, Craig King, Daniel Kusuma, Ralph Lindert, Robbie Lonsdale, Raj Nair, Shah Nawaz, Faith Okhuoya, Douglas Turner, Graham Venables, Paul Dorman, Andrea Hughes, Deborah Jones, David Mendelow, Helen Rodgers, Aidas Raudoniitis, Peter Enevoldson, Hans Nahser, Imelda O'Brien, Francesco Torella, Dave Watling, Richard White, Pauline Brown, Dipankar Dutta, Lorraine Emerson, Paula Hilltout, Sachin Kulkarni, Jackie Morrison, Keith Poskitt, Fiona Slim, Sarah Smith, Amanda Tyler, Joanne Waldron, Mark Whyman, Milda Bajoriene, Lucy Baker, Amanda Colston, Bekky Eliot-Jones, Gita Gramizadeh, Catherine Lewis-Clarke, Laura McCafferty, Deborah Oliver, Debbie Palmer, Abhijeet Patil, Suzannah Pegler, Gopi Ramadurai, Aisling Roberts, Tracey Sargent, Shivaprasad Siddegowda, Ravi Singh-Ranger, Akintunde Williams, Lucy Williams, Steve Windebank, Tadas Zuromskis, Lanka Alwis, Jane Angus, Asaipillai Asokanathan, Caroline Fornolles, Diana Hardy, Sophy Hunte, Frances Justin, Duke Phiri, Marie Mitabouana-Kibou, Lakshmanan Sekaran, Sakthivel Sethuraman, Margaret L Tate, Joyce Akyea-Mensah, Stephen Ball, Angela Chrisopoulou, Elizabeth Keene, Alison Phair, Steven Rogers, John V Smyth, Colin Bicknell, Jeremy Chataway, Nicholas Cheshire, Andrew Clifton, Caroline Eley, Richard Gibbs, Mohammad Hamady, Beth Hazel, Alex James, Michael Jenkins, Nyma Khanom, Austin Lacey, Maz Mireskandari, Joanna O'Reilly, Antony Pereira, Tina Sachs, John Wolfe, Philip Davey, Gill Rogers, Gemma Smith, Gareth Tervit, Ian Nichol, Andrew Parry, Gavin Young, Simon Ashley, James Barwell, Francis Dix, Azlisham M Nor, Chris Parry, Angela Birt, Paul Davies, Jim George, Anne Graham, Leon Jonker, Nicci Kelsall, Caroline Potts, Toni Wilson, Jamie Crinnion, Larissa Cuenoud, Nikola Aleksic, Srdan Babic, Nenad Ilijevski, Đorde Radak, Dragan Sagic, Slobodan Tanaskovic, Momcilo Colic, Vladimir Cvetic, Lazar Davidovic, Dejana R Jovanovic, Igor Koncar, Perica Mutavdžic, Miloš Sladojevic, Ivan Tomic, Eike S Debus, Ulrich Grzyska, Dagmar Otto, Götz Thomalla, Jessica Barlinn, Johannes Gerber, Kathrin Haase, Christian Hartmann, Stefan Ludwig, Volker Pütz, Christian Reeps, Christine Schmidt, Norbert Weiss, Sebastian Werth, Simon Winzer, Janine Gemper, Albrecht Günther, Bianka Heiling, Elisabeth Jochmann, Panagiota Karvouniari, Carsten Klingner, Thomas Mayer, Julia Schubert, Friederike Schulze-Hartung, Jürgen Zanow, Yvonne Bausback, Franka Borger, Spiridon Botsios, Daniela Branzan, Sven Bräunlich, Henryk Hölzer, Janin Lenzer, Christopher Piorkowski, Nadine Richter, Johannes Schuster, Dierk Scheinert, Andrej Schmidt, Holger Staab, Matthias Ulrich, Martin Werner, Hermann Berger, Gábor Biró, Hans-Henning Eckstein, Michael Kallmayer, Kornelia Kreiser, Alexander Zimmermann, Bärbel Berekoven, Klaus Frerker, Vera Gordon, Giovanni Torsello, Sebastian Arnold, Cora Dienel, Martin Storck, Bernhard Biermaier, Hans Martin Gissler, Christof Klötzsch, Tomas Pfeiffer, Ralph Schneider, Leander Söhl, Michael Wennrich, Angelika Alonso, Michael Keese, Christoph Groden, Andreas Cöster, Andreas Engelhardt, Christoph-Maria Ratusinski, Bengt Berg, Martin Delle, Johan Formgren, Peter Gillgren, Lotta Jarl, Torbjörn B Kall, Peter Konrad, Niklas Nyman, Claes Skiöldebrand, Johnny Steuer, Rabbe Takolander, Jonas Malmstedt, Stefan Acosta, Katarina Björses, Kerstin Brandt, Nuno Dias, Anders Gottsäter, Jan Holst, Thorarinn Kristmundsson, Tobias Kühme, Tilo Kölbel, Bengt Lindblad, Mats Lindh, Martin Malina, Tomas Ohrlander, Tim Resch, Viola Rönnle, Björn Sonesson, Margareta Warvsten, Zbigniew Zdanowski, Erik Campbell, Per Kjellin, Hans Lindgren, Johan Nyberg, Björn Petersen, Gunnar Plate, Håkan Pärsson, Peter Qvarfordt, Pavel Ignatenko, Andrey Karpenko, Vladimir Starodubtsev, Mikhail A Chernyavsky, Maria S Golovkova, Boris B Komakha, Nikolay N Zherdev, Andrey Belyasnik, Pavel Chechulov, Dmitry Kandyba, Igor Stepanishchev, Csaba Csobay-Novák, Edit Dósa, László Entz, Balázs Nemes, Zoltán Szeberin, Pál Barzó, Mihaly Bodosi, Eniko Fákó, Béla Fülöp, Tamás Németh, Szilárd Pazdernyik, Krisztina Skoba, Erika Vörös, Eleni Chatzinikou, Athanasios Giannoukas, Christos Karathanos, Stylianos Koutsias, Georgios Kouvelos, Miltiadis Matsagkas, Styliani Ralli, Christos Rountas, Nikolaos Rousas, Konstantinos Spanos, Elias Brountzos, John D Kakisis, Andreas Lazaris, Konstantinos G Moulakakis, Leonidas Stefanis, Georgios Tsivgoulis, Spyros Vasdekis, Constantine N Antonopoulos, Ion Bellenis, Dimitrios Maras, Antonios Polydorou, Victoria Polydorou, Antonios Tavernarakis, Nikolaos Ioannou, Maria Terzoudi, Miltos Lazarides, Michalis Mantatzis, Kostas Vadikolias, Lukasz Dzieciuchowicz, Marcin Gabriel, Zbigniew Krasinski, Grzegorz Oszkinis, Fryderyk Pukacki, Maciej Slowinski, Michal-Goran Stanišic, Ryszard Staniszewski, Jolanta Tomczak, Maciej Zielinski, Piotr Myrcha, Dorota Rózanski, Stanislaw Drelichowski, Wojciech Iwanowski, Katarzyna Koncewicz, Pawel Bialek, Zbigniew Biejat, Wojciech Czepel, Anna Czlonkowska, Anatol Dowzenko, Julia Jedrzejewska, Adam Kobayashi, Jerzy Leszczynski, Andrzej Malek, Jerzy Polanski, Robert Proczka, Maciej Skorski, Mieczyslaw Szostek, Piotr Andziak, Maciej Dratwicki, Robert Gil, Miroslaw Nowicki, Jaroslaw Pniewski, Jaroslaw Rzezak, Piotr Seweryniak, Pawel Dabek, Michal Juszynski, Grzegorz Madycki, Bartosz Pacewski, Witold Raciborski, Piotr Slowinski, Walerian Staszkiewicz, Martin Bombic, Vladimír Chlouba, Jirí Fiedler, Karel Hes, Petr Koštál, Jindrich Sova, Zdenek Kríž, Mojmír Prívara, Michal Reif, Robert Staffa, Robert Vlachovský, Bohuslav Vojtíšek, Tomáš Hrbác, Martin Kuliha, Václav Procházka, Martin Roubec, David Školoudík, David Netuka, Anna Šteklácová, Vladimír Beneš III, Pavel Buchvald, Ladislav Endrych, Miroslav Šercl, Walter Campos Jr, Ivan B Casella, Nelson de Luccia, André E V Estenssoro, Calógero Presti, Pedro Puech-Leão, Celso R B Neves, Erasmo S da Silva, Cid J Sitrângulo Jr, José A T Monteiro, Gisela Tinone, Marcelo Bellini Dalio, Edwaldo E Joviliano, Octávio M Pontes Neto, Mauricio Serra Ribeiro, Patrick Cras, Jeroen M H Hendriks, Mieke Hoppenbrouwers, Patrick Lauwers, Caroline Loos, Laetitia Yperzeele, Mia Geenens, Dimitri Hemelsoet, Isabelle van Herzeele, Frank Vermassen, Parla Astarci, Frank Hammer, Valérie Lacroix, André Peeters, Robert Verhelst, Silvana Cirelli, Pol Dormal, Annelies Grimonprez, Bart Lambrecht, Philipe Lerut, Eddy Thues, Guy De Koster, Quentin Desiron, Alain Maertens de Noordhout, Danielle Malmendier, Mireille Massoz, Georges Saad, Marc Bosiers, Joren Callaert, Koen Deloose, Estrella Blanco Cañibano, Beatriz García Fresnillo, Mercedes Guerra Requena, Pilar C Morata Barrado, Miguel Muela Méndez, Antonio Yusta Izquierdo, Fernando Aparici Robles, Paula Blanes Orti, Luis García Dominguez, Rafael Martínez López, Manuel Miralles Hernández, José I Tembl Ferrairo, Ángel Chamorro, Juan Macho, Víctor Obach, Vincent Riambau, Luis San Román, Frank J Ahlhelm, Kristine Blackham, Stefan Engelter, Thomas Eugster, Henrik Gensicke, Lorenz Gürke, Philippe Lyrer, Luigi Mariani, Marina Maurer, Edin Mujagic, Mandy Müller, Marios Psychogios, Peter Stierli, Christoph Stippich, Christopher Traenka, Thomas Wolff, Benjamin Wagner, Martina M Wiegert, Sandra Clarke, Michael Diepers, Ernst Gröchenig, Philipp Gruber, Andrej Isaak, Timo Kahles, Regula Marti, Krassen Nedeltchev, Luca Remonda, Nadir Tissira, Martina Valença Falcão, Gert J de Borst, Rob H Lo, Frans L Moll, Raechel Toorop, Bart H van der Worp, Evert J Vonken, Jaap L Kappelle, Ommid Jahrome, Floris Vos, Wouter Schuiling, Hendrik van Overhagen, Rudolf W M Keunen, Bob Knippenberg, Jan J Wever, Jan W Lardenoije, Michel Reijnen, Luuk Smeets, Steven van Sterkenburg, Gustav Fraedrich, Elke Gizewski, Ingrid Gruber, Michael Knoflach, Stefan Kiechl, Barbara Rantner, Timur Abdulamit, Patrice Bergeron, Raymond Padovani, Jean-Christophe Trastour, Jean-Marie Cardon, Anne Le Gallou-Wittenberg, Eric Allaire, Jean-Pierre Becquemin, Frédéric Cochennec-Paliwoda, Pascal Desgranges, Hassan Hosseini, Hicham Kobeiter, Jean Marzelle, Mohammed A Almekhlafi, Simerpreet Bal, Phillip A Barber, Shelagh B Coutts, Andrew M Demchuk, Muneer Eesa, Michelle Gillies, Mayank Goyal, Michael D Hill, Mark E Hudon, Anitha Jambula, Carol Kenney, Gary Klein, Marie McClelland, Alim Mitha, Bijoy K Menon, William F Morrish, Steven Peters, Karla J Ryckborst, Greg Samis, Supriya Save, Eric E Smith, Peter Stys, Suresh Subramaniam, Garnette R Sutherland, Tim Watson, John H Wong, L Zimmel, Vojko Flis, Jože Matela, Kazimir Miksic, Franko Milotic, Božidar Mrdja, Barbara Stirn, Erih Tetickovic, Mladen Gasparini, Anton Grad, Ingrid Kompara, Zoren Miloševic, Veronika Palmiste, Toomas Toomsoo, Balzhan Aidashova, Nursultan Kospanov, Roman Lyssenko, Daulet Mussagaliev, Rafi Beyar, Aaron Hoffman, Tony Karram, Arthur Kerner, Eugenia Nikolsky, Samy Nitecki, Silva Andonova, Chavdar Bachvarov, Vesko Petrov, Ivan Cvjetko, Vinko Vidjak, Damir Halužan, Mladen Petrunic, Bao Liu, Chang-Wei Liu, Daniel Bartko, Peter Beno, František Rusnák, Kamil Zelenák, Masayuki Ezura, Takashi Inoue, Naoto Kimura, Ryushi Kondo, Yasushi Matsumoto, Hiroaki Shimizu, Hidenori Endo, Eisuke Furui, Søren Bakke, Kristen Krohg-Sørensen, Terje Nome, Mona Skjelland, Bjørn Tennøe, João Albuquerque e Castro, Gonçalo Alves, Frederico Bastos Gonçalves, José de Aragão Morais, Ana C Garcia, Hugo Valentim, Leonor Vasconcelos, Fernando Belcastro, Fernando Cura, Patricio Zaefferer, Foad Abd-Allah, Mohamed H Eldessoki, Hussein Heshmat Kassem, Haytham Soliman Gharieb, Mary P Colgan, Syed N Haider, Joe Harbison, Prakash Madhavan, Dermot Moore, Gregor Shanik, Viviane Kazan, Munier Nazzal, Vicki Ramsey-Williams, ACST-2 Collaborative Group, Group, ACST-2 Collaborative, Halliday A., Bulbulia R., Bonati L.H., Chester J., Cradduck-Bamford A., Peto R., Pan H., Potter J., Henning Eckstein H., Farrell B., Flather M., Mansfield A., Mihaylova B., Rahimi K., Simpson D., Thomas D., Sandercock P., Gray R., Molyneux A., Shearman C.P., Rothwell P., Belli A., Herrington W., Judge P., Leopold P., Mafham M., Gough M., Cao P., MacDonald S., Bari V., Berry C., Bradshaw S., Brudlo W., Clarke A., Cox R., Fathers S., Gaba K., Gray M., Hayter E., Holliday C., Kurien R., Lay M., le Conte S., McManus J., Madgwick Z., Morris D., Munday A., Pickworth S., Ostasz W., Poorthuis M., Richards S., Teixeira L., Tochlin S., Tully L., Wallis C., Willet M., Young A., Casana R., Malloggi C., Odero A., Silani V., Parati G., Malchiodi G., Malferrari G., Strozzi F., Tusini N., Vecchiati E., Coppi G., Lauricella A., Moratto R., Silingardi R., Veronesi J., Zini A., Ferrero E., Ferri M., Gaggiano A., Labate C., Nessi F., Psacharopulo D., Viazzo A., Malacrida G., Mazzaccaro D., Meola G., Modafferi A., Nano G., Occhiuto M.T., Righini P., Stegher S., Chiarandini S., Griselli F., Lepidi S., Pozzi Mucelli F., Naccarato M., D'Oria M., Ziani B., Stella A., Dieng M., Faggioli G., Gargiulo M., Palermo S., Pini R., Puddu G.M., Vacirca A., Angiletta D., Desantis C., Marinazzo D., Mastrangelo G., Regina G., Pulli R., Bianchi P., Cireni L., Coppi E., Pizzirusso R., Scalise F., Sorropago G., Tolva V., Caso V., Cieri E., DeRango P., Farchioni L., Isernia G., Lenti M., Parlani G.B., Pupo G., Pula G., Simonte G., Verzini F., Carimati F., Delodovici M.L., Fontana F., Piffaretti G., Tozzi M., Civilini E., Poletto G., Reimers B., Praquin B., Ronchey S., Capoccia L., Mansour W., Sbarigia E., Speziale F., Sirignano P., Toni D., Galeotti R., Gasbarro V., Mascoli F., Rocca T., Tsolaki 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S., Lambert D., Lees T., Louw S., McCaslin J., Parr N., Robson R., Stansby G., Wales L., Wealleans V., Wilson L., Wyatt M., Baht H., Balogun I., Burger I., Cosier T., Cowie L., Gunathilagan G., Hargroves D., Insall R., Jones S., Rudenko H., Schumacher N., Senaratne J., Thomas G., Thomson A., Webb T., Brown E., Esisi B., Mehrzad A., MacSweeney S., McConachie N., Southam A., Sunman W., Abdul-Hamiq A., Bryce J., Chetter I., Ettles D., Lakshminarayan R., Mitchelson K., Rhymes C., Robinson G., Scott P., Vickers A., Ashleigh R., Butterfield S., Gamble E., Ghosh J., McCollum C.N., Welch M., Welsh S., Wolowczyk L., Donnelly M., D'Souza S., Egun A.A., Gregary B., Joseph T., Kelly C., Punekar S., Rahi M.A., Raj S., Seriki D., Thomson G., Brown J., Durairajan R., Grunwald I., Guyler P., Harman P., Jakeways M., Khuoge C., Kundu A., Loganathan T., Menon N., Prabakaran R.O., Sinha D., Thompson V., Tysoe S., Briley D., Darby C., Hands L., Howard D., Kuker W., Schulz U., Teal R., Barer D., Brown A., Crawford S., Dunlop P., Krishnamurthy R., Majmudar N., Mitchell D., Myint M.P., O'Brien R., O'Connell J., Sattar N., Vetrivel S., Beard J., Cleveland T., Gaines P., Humphreys J., Jenkins A., King C., Kusuma D., Lindert R., Lonsdale R., Nair R., Nawaz S., Okhuoya F., Turner D., Venables G., Dorman P., Hughes A., Jones D., Mendelow D., Rodgers H., Raudoniitis A., Enevoldson P., Nahser H., O'Brien I., Torella F., Watling D., White R., Brown P., Dutta D., Emerson L., Hilltout P., Kulkarni S., Morrison J., Poskitt K., Slim F., Smith S., Tyler A., Waldron J., Whyman M., Bajoriene M., Baker L., Colston A., Eliot-Jones B., Gramizadeh G., Lewis-Clarke C., McCafferty L., Oliver D., Palmer D., Patil A., Pegler S., Ramadurai G., Roberts A., Sargent T., Siddegowda S., Singh-Ranger R., Williams A., Williams L., Windebank S., Zuromskis T., Alwis L., Angus J., Asokanathan A., Fornolles C., Hardy D., Hunte S., Justin F., Phiri D., Mitabouana-Kibou M., Sekaran L., Sethuraman S., Tate M.L., Akyea-Mensah J., Ball S., Chrisopoulou A., Keene E., Phair A., Rogers S., Smyth J.V., Bicknell C., Chataway J., Cheshire N., Clifton A., Eley C., Gibbs R., Hamady M., Hazel B., James A., Jenkins M., Khanom N., Lacey A., Mireskandari M., O'Reilly J., Pereira A., Sachs T., Wolfe J., Davey P., Rogers G., Smith G., Tervit G., Nichol I., Parry A., Young G., Ashley S., Barwell J., Dix F., Nor A.M., Parry C., Birt A., Davies P., George J., Graham A., Jonker L., Kelsall N., Potts C., Wilson T., Crinnion J., Cuenoud L., Aleksic N., Babic S., Ilijevski N., Radak, Sagic D., Tanaskovic S., Colic M., Cvetic V., Davidovic L., Jovanovic D.R., Koncar I., Mutavdzic P., Sladojevic M., Tomic I., Debus E.S., Grzyska U., Otto D., Thomalla G., Barlinn J., Gerber J., Haase K., Hartmann C., Ludwig S., Putz V., Reeps C., Schmidt C., Weiss N., Werth S., Winzer S., Gemper J., Gunther A., Heiling B., Jochmann E., Karvouniari P., Klingner C., Mayer T., Schubert J., Schulze-Hartung F., Zanow J., Bausback Y., Borger F., Botsios S., Branzan D., Braunlich S., Holzer H., Lenzer J., Piorkowski C., Richter N., Schuster J., Scheinert D., Schmidt A., Staab H., Ulrich M., Werner M., Berger H., Biro G., Eckstein H.-H., Kallmayer M., Kreiser K., Zimmermann A., Berekoven B., Frerker K., Gordon V., Torsello G., Arnold S., Dienel C., Storck M., Biermaier B., Gissler H.M., Klotzsch C., Pfeiffer T., Schneider R., Sohl L., Wennrich M., Alonso A., Keese M., Groden C., Coster A., Engelhardt A., Ratusinski C.-M., Berg B., Delle M., Formgren J., Gillgren P., Jarl L., Kall T.B., Konrad P., Nyman N., Skioldebrand C., Steuer J., Takolander R., Malmstedt J., Acosta S., Bjorses K., Brandt K., Dias N., Gottsater A., Holst J., Kristmundsson T., Kuhme T., Kolbel T., Lindblad B., Lindh M., Malina M., Ohrlander T., Resch T., Ronnle V., Sonesson B., Warvsten M., Zdanowski Z., Campbell E., Kjellin P., Lindgren H., Nyberg J., Petersen B., Plate G., Parsson H., Qvarfordt P., Ignatenko P., Karpenko A., Starodubtsev V., Chernyavsky M.A., Golovkova M.S., Komakha B.B., Zherdev N.N., Belyasnik A., Chechulov P., Kandyba D., Stepanishchev I., Csobay-Novak C., Dosa E., Entz L., Nemes B., Szeberin Z., Barzo P., Bodosi M., Fako E., Fulop B., Nemeth T., Pazdernyik S., Skoba K., Voros E., Chatzinikou E., Giannoukas A., Karathanos C., Koutsias S., Kouvelos G., Matsagkas M., Ralli S., Rountas C., Rousas N., Spanos K., Brountzos E., Kakisis J.D., Lazaris A., Moulakakis K.G., Stefanis L., Tsivgoulis G., Vasdekis S., Antonopoulos C.N., Bellenis I., Maras D., Polydorou A., Polydorou V., Tavernarakis A., Ioannou N., Terzoudi M., Lazarides M., Mantatzis M., Vadikolias K., Dzieciuchowicz L., Gabriel M., Krasinski Z., Oszkinis G., Pukacki F., Slowinski M., Stanisic M.-G., Staniszewski R., Tomczak J., Zielinski M., Myrcha P., Rozanski D., Drelichowski S., Iwanowski W., Koncewicz K., Bialek P., Biejat Z., Czepel W., Czlonkowska A., Dowzenko A., Jedrzejewska J., Kobayashi A., Leszczynski J., Malek A., Polanski J., Proczka R., Skorski M., Szostek M., Andziak P., Dratwicki M., Gil R., Nowicki M., Pniewski J., Rzezak J., Seweryniak P., Dabek P., Juszynski M., Madycki G., Pacewski B., Raciborski W., Slowinski P., Staszkiewicz W., Bombic M., Chlouba V., Fiedler J., Hes K., Kostal P., Sova J., Kriz Z., Privara M., Reif M., Staffa R., Vlachovsky R., Vojtisek B., Hrbac T., Kuliha M., Prochazka V., Roubec M., Skoloudik D., Netuka D., Steklacova A., Benes III V., Buchvald P., Endrych L., Sercl M., Campos W., Casella I.B., de Luccia N., Estenssoro A.E.V., Presti C., Puech-Leao P., Neves C.R.B., da Silva E.S., Sitrangulo C.J., Monteiro J.A.T., Tinone G., Bellini Dalio M., Joviliano E.E., Pontes Neto O.M., Serra Ribeiro M., Cras P., Hendriks J.M.H., Hoppenbrouwers M., Lauwers P., Loos C., Yperzeele L., Geenens M., Hemelsoet D., van Herzeele I., Vermassen F., Astarci P., Hammer F., Lacroix V., Peeters A., Verhelst R., Cirelli S., Dormal P., Grimonprez A., Lambrecht B., Lerut P., Thues E., De Koster G., Desiron Q., Maertens de Noordhout A., Malmendier D., Massoz M., Saad G., Bosiers M., Callaert J., Deloose K., Blanco Canibano E., Garcia Fresnillo B., Guerra Requena M., Morata Barrado P.C., Muela Mendez M., Yusta Izquierdo A., Aparici Robles F., Blanes Orti P., Garcia Dominguez L., Martinez Lopez R., Miralles Hernandez M., Tembl Ferrairo J.I., Chamorro A., Macho J., Obach V., Riambau V., San Roman L., Ahlhelm F.J., Blackham K., Engelter S., Eugster T., Gensicke H., Gurke L., Lyrer P., Mariani L., Maurer M., Mujagic E., Muller M., Psychogios M., Stierli P., Stippich C., Traenka C., Wolff T., Wagner B., Wiegert M.M., Clarke S., Diepers M., Grochenig E., Gruber P., Isaak A., Kahles T., Marti R., Nedeltchev K., Remonda L., Tissira N., Valenca Falcao M., de Borst G.J., Lo R.H., Moll F.L., Toorop R., van der Worp B.H., Vonken E.J., Kappelle J.L., Jahrome O., Vos F., Schuiling W., van Overhagen H., Keunen R.W.M., Knippenberg B., Wever J.J., Lardenoije J.W., Reijnen M., Smeets L., van Sterkenburg S., Fraedrich G., Gizewski E., Gruber I., Knoflach M., Kiechl S., Rantner B., Abdulamit T., Bergeron P., Padovani R., Trastour J.-C., Cardon J.-M., Le Gallou-Wittenberg A., Allaire E., Becquemin J.-P., Cochennec-Paliwoda F., Desgranges P., Hosseini H., Kobeiter H., Marzelle J., Almekhlafi M.A., Bal S., Barber P.A., Coutts S.B., Demchuk A.M., Eesa M., Gillies M., Goyal M., Hill M.D., Hudon M.E., Jambula A., Kenney C., Klein G., McClelland M., Mitha A., Menon B.K., Morrish W.F., Peters S., Ryckborst K.J., Samis G., Save S., Smith E.E., Stys P., Subramaniam S., Sutherland G.R., Watson T., Wong J.H., Zimmel L., Flis V., Matela J., Miksic K., Milotic F., Mrdja B., Stirn B., Tetickovic E., Gasparini M., Grad A., Kompara I., Milosevic Z., Palmiste V., Toomsoo T., Aidashova B., Kospanov N., Lyssenko R., Mussagaliev D., Beyar R., Hoffman A., Karram T., Kerner A., Nikolsky E., Nitecki S., Andonova S., Bachvarov C., Petrov V., Cvjetko I., Vidjak V., Haluzan D., Petrunic M., Liu B., Liu C.-W., Bartko D., Beno P., Rusnak F., Zelenak K., Ezura M., Inoue T., Kimura N., Kondo R., Matsumoto Y., Shimizu H., Endo H., Furui E., Bakke S., Krohg-Sorensen K., Nome T., Skjelland M., Tennoe B., Albuquerque e Castro J., Alves G., Bastos Goncalves F., de Aragao Morais J., Garcia A.C., Valentim H., Vasconcelos L., Belcastro F., Cura F., Zaefferer P., Abd-Allah F., Eldessoki M.H., Heshmat Kassem H., Soliman Gharieb H., Colgan M.P., Haider S.N., Harbison J., Madhavan P., Moore D., Shanik G., Kazan V., Nazzal M., Ramsey-Williams V., and Gargiulo M

Subjects
Male, medicine.medical_specialty, Time Factors, Time Factor, medicine.medical_treatment, Carotid Stenosi, MEDLINE, Carotid endarterectomy, Rate ratio, Risk Assessment, Asymptomatic, law.invention, Randomized controlled trial, law, Risk Factors, carotid artery stenting (CAS), carotid endarterectomy (CEA), Stent, medicine, Humans, Carotid Stenosis, Stroke, Endarterectomy, Aged, Endarterectomy, Carotid, business.industry, carotid artery, Risk Factor, Articles, General Medicine, trial, medicine.disease, Settore MED/22 - CHIRURGIA VASCOLARE, Surgery, Stenosis, Treatment Outcome, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Female, Stents, Human medicine, medicine.symptom, business, Human
Abstract

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Published
2021

40. Coverage of the Coeliac Artery During Thoracic Endovascular Aortic Repair: A Systematic Review and Meta-Analysis

Author

Lydia Hanna, Kyle Lam, Anita E. Agbeko, Joachim K. Amoako, Hutan Ashrafian, Viknesh Sounderajah, Ammar Abdullah, and Richard Gibbs

Subjects
Male, Aortic Aneurysm, Thoracic, Endoleak, Spinal Cord Ischemia, Endovascular Procedures, Aorta, Thoracic, Middle Aged, Blood Vessel Prosthesis Implantation, Treatment Outcome, Celiac Artery, Ischemia, Risk Factors, Humans, Surgery, Stents, Cardiology and Cardiovascular Medicine, Aged, Retrospective Studies
Abstract

To investigate the clinical impact of coeliac artery (CA) coverage during thoracic endovascular aortic repair (TEVAR).This systematic review and meta-analysis was conducted according to the PRISMA guidelines. Electronic databases were searched from 1989 to 2020 for studies reporting visceral ischaemia, spinal cord ischaemia (SCI), 30 day/in hospital mortality, endoleaks, re-intervention, and caudal stent graft migration following CA coverage in patients undergoing TEVAR. Meta-analysis was conducted using random effects modelling. The quality of the evidence was graded using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.Fifteen observational studies with 236 patients (108 male, age range 61.3 - 79 years) were included. The pooled visceral ischaemia rate was 13% with significant heterogeneity between studies (95% confidence intervals [CI] 4 - 24; ICA coverage during TEVAR is associated with high rates of visceral ischaemia, spinal cord ischaemia, 30 day/in hospital mortality, endoleaks, and re-intervention. Although the literature is of poor quality and questions remain over effects estimates, there is evidence that CA coverage should be avoided if at all possible, during TEVAR.PROSPERO registration number 244084.

Published
2021

41. Abstract CT026: The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial

Author

Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, and Lisa A. Carey

Subjects
Cancer Research, Oncology
Abstract

Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P= Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026.

Published
2022

42. Cerebral embolic protection in thoracic endovascular aortic repair

Author

A.H. Perera, Christen D. Barras, Gagandeep Grover, Nung Rudarakanchana, Abhinav Singh, Alun H. Davies, Richard Gibbs, and Mohamad Hamady

Subjects
Male, Aortography, Ultrasonography, Doppler, Transcranial, medicine.medical_treatment, Aorta, Thoracic, Pilot Projects, 030204 cardiovascular system & hematology, Prosthesis Design, Embolic Protection Devices, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Interquartile range, medicine.artery, medicine, Embolism, Air, Humans, Thoracic aorta, Prospective Studies, 030212 general & internal medicine, Embolization, Stroke, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Cerebral infarction, Endovascular Procedures, Magnetic resonance imaging, Middle Aged, medicine.disease, Diffusion Magnetic Resonance Imaging, Treatment Outcome, Intracranial Embolism, Dose area product, Feasibility Studies, Female, Surgery, Cardiology and Cardiovascular Medicine, Nuclear medicine, business
Abstract

Background Stroke occurs in 3% to 8% and silent cerebral infarction in >60% of patients undergoing thoracic endovascular aortic repair (TEVAR). We investigated the utility of a filter cerebral embolic protection device (CEPD) to reduce diffusion-weighted magnetic resonance imaging (DW-MRI) detected cerebral injury and gaseous and solid embolization during TEVAR. Methods Patients anatomically suitable underwent TEVAR with CEPD, together with intraoperative transcranial Doppler to detect gaseous and solid high-intensity transient signals (HITSs), pre- and postoperative DW-MRI, and clinical neurologic assessment ≤6 months after the procedure. Results Ten patients (mean age, 68 years) underwent TEVAR with a CEPD. No strokes or device-related complications developed. The CEPD added a median of 7 minutes (interquartile range [IQR], 5-16 minutes) to the procedure, increased the fluoroscopy time by 3.3 minutes (IQR, 2.4-3.9 minutes), and increased the total procedural radiation by 2.2%. The dose area product for CEPD was 1824 mGy·cm2 (IQR, 1235-3392 mGy·cm2). The average contrast volume used increased by 23 mL (IQR, 24-35 mL). New DW-MRI lesions, mostly in the hindbrain, were identified in seven of nine patients (78%). The median number was 1 (IQR, 1-3), with a median surface area of 6 mm2 (IQR, 3-16 mm2). A total of 2835 HITSs were detected in seven patients: 91% gaseous and 9% solid. The maximum number of HITSs were detected during CEPD manipulation: 142 (IQR, 59-146; 95% gaseous and 5% solid). The maximum number of HITSs during TEVAR occurred during stent deployment: 82 (IQR, 73-142; 81% gas and 11% solid). Solid HITSs were associated with an increase in surface area of new DW-MRI lesions (rs = 0.928; P = .01). Increased gaseous HITSs were associated with new DW-MRI lesions (rs = 0.912; P = .01), which were smaller ( Conclusions The use of a CEPD with TEVAR appeared to be safe and feasible in this first pilot study and could serve as a useful adjunct to reduce cerebral injury. The significance of gaseous embolization and its role in cerebral injury in TEVAR warrants further investigation.

Published
2018

43. Wearable Sensor Technology Efficacy in Peripheral Vascular Disease (wSTEP)

Author

Ara Darzi, Nicholas J.W. Cheshire, Richard M. Kwasnicki, Colin Bicknell, Michael Jenkins, Pasha Normahani, Richard Gibbs, Louise Allen, Celia Riga, NIHR Imperial Biomedical Research Centre, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
Adult, Male, medicine.medical_specialty, Treatment outcome, Wearable computer, Pilot Projects, 030204 cardiovascular system & hematology, 030230 surgery, law.invention, Wearable Electronic Devices, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Surveys and Questionnaires, Humans, Medicine, In patient, Aged, Aged, 80 and over, business.industry, Vascular disease, 11 Medical And Health Sciences, Intermittent Claudication, Middle Aged, medicine.disease, Alternative treatment, Intermittent claudication, Exercise Therapy, Peripheral, Treatment Outcome, Quality of Life, Physical therapy, Female, Surgery, medicine.symptom, business
Abstract

OBJECTIVE: To evaluate the effect of using wearable activity monitors (WAMs) in patients with intermittent claudication (IC) within a single-center randomized controlled trial. BACKGROUND: WAMs allow users to set daily activity targets and monitor their progress. They may offer an alternative treatment to supervised exercise programs (SEPs) for patients with IC. METHODS: Thirty-seven patients with IC were recruited and randomized into intervention or control group. The intervention consisted of a feedback-enabled, wrist-worn activity monitor (WAM) in addition to access to SEP. The control group was given access to SEP only. The outcome measures were maximum walking distance (MWD), claudication distance (CD), and quality of life as measured by the VascuQol questionnaire. Participants were assessed upon recruitment, and at 3, 6, and 12 months. RESULTS: Patients in the WAM group showed significant improvement in MWD at 3 and 6 months (80-112 m, to 178 m; P < 0.001), which was sustained at 12 months. The WAM group also increased CD (40 vs 110 m; P < 0.001) and VascuQol score (4.7 vs 5.8; P = 0.004). The control group saw a temporary increase in VascuQol score at 6 months (4.5 vs 4.7; P = 0.028), but no other improvements in MWD or CD were observed. Significantly higher improvements in MWD were seen in the WAM group compared with that in the control group at 6 months (82 vs -5 m; P = 0.009, r = 0.47) and 12 months (69 vs 7.5 m; P = 0.011, r = 0.52). CONCLUSIONS: The study demonstrates the significant, sustained benefit of WAM-led technologies for patients with IC. This potentially resource-sparing intervention is likely to provide a valuable adjunct or alternative to SEP.

Published
2018

44. Technical Note: Left Subclavian Artery Scallop Endografts to Facilitate a Proximal Landing Zone and Upper Extremity Access for Branched Endovascular Aortic Repair of Type II Thoracoabdominal Aortic Aneurysms

Author

Ammar Abdullah, Lydia Hanna, M. Hamady, Richard Gibbs, and Michael Jenkins

Subjects
medicine.medical_specialty, medicine.medical_treatment, Left subclavian artery, Subclavian Artery, 030204 cardiovascular system & hematology, Thoracoabdominal Aortic Aneurysms, Aortic repair, Prosthesis Design, 030218 nuclear medicine & medical imaging, Upper Extremity, 03 medical and health sciences, Blood Vessel Prosthesis Implantation, 0302 clinical medicine, stomatognathic system, Technical Note, Medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular diseases, Retrospective Studies, Aortic Aneurysm, Thoracic, business.industry, Endovascular Procedures, Scallop thoracic endovascular aortic repair, Stent, Technical note, Surgery, Blood Vessel Prosthesis, Pectinidae, Treatment Outcome, Landing zone, Spinal cord ischaemia, Scallop, Stents, Cardiology and Cardiovascular Medicine, business, Branched endovascular aortic repair, Upper limb access
Abstract

Purpose To describe the dual purpose of left subclavian artery (LSA) scallop endografts to create the proximal landing zone (PLZ) and facilitate antegrade left-sided upper extremity access for branched endovascular aortic repair (BEVAR) of Type II thoracoabdominal aneurysms (TAAA) with a short PLZ. Technique Three patients with an inadequate ( Conclusion LSA scallop endografts are a feasible and useful adjunct to create the PLZ and to provide antegrade access for visceral stenting of branches and target vessels through the LSA scallop in branched endovascular repair of Type II TAAA with short PLZ.

Published
2021

45. OP011: Physician recommendations after germline sequencing in pediatric cancer patients: Texas KidsCanSeq study

Author

Sharon Plon, Lauren Desrosiers, Jill Robinson, Heidi Russell, Sarah Scollon, Hongzheng Dai, Robin Raesz-Martinez, Alva Recinos, Jacquelyn Reuther, Medha Naik, George Miles, Uma Ramamurthy, Donna Muzny, Angshumoy Roy, Richard Gibbs, Gail Tomlinson, Juan Carlos Bernini, Jonathan Gill, Timothy Griffin, Kelly Vallance, Amy McGuire, and D. Williams Parsons

Subjects
Genetics (clinical)
Published
2022

46. Abstract PD9-03: Pam50 intrinsic subtype and risk of recurrence score (ROR) for the prediction of endocrine (ET) sensitivity and pathologic response to chemotherapy in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) in the alternate trial (Alliance A011106)

Author

Cynthia X Ma, Meenakshi Anurag, Travis Dockter, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, A. Marilyn Leitch, Gary W Unzeitig, Anna Weiss, Eric P Winer, Kelly Hunt, Ann H Partridge, Lisa A Carey, Charles M Perou, Matthew J Ellis, and Vera Suman

Subjects
Cancer Research, Oncology
Abstract

Background: Neoadjuvant ET (NET) offers an opportunity to assess ET sensitivity for ER+ HER2- BC and potentially to tailor therapy. Ki67 >10% on biopsy after 2-4 weeks (wks) of NET identifies patients (pts) with intrinsic ET resistance; while pathologic complete response (pCR) and modified preoperative endocrine prognostic index of 0 (mPEPI 0: pT1-2N0, Ki67 ≤2.7%) at surgery indicates sensitivity to ET. However, on-NET biopsy is not always acceptable or feasible and delays the ET sensitivity determination. PAM50 ROR score and intrinsic subtypes by tumor RNA profiling are prognostic in pts with early stage ER+ HER2- BC, and predict pCR rates to neoadjuvant chemotherapy (NCT) (PMC2667820). We therefore hypothesized that PAM50 analysis on pre-NET biopsies could predict the likelihood of a) a high on-NET Ki67, b) mPEPI-0 or pCR at surgery and, c) pCR for pts triaged to NCT. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal pts with clinical stage II/III ER+ (Allred score 6-8) HER2- BC to receive neoadjuvant anastrozole, fulvestrant, or both for 6 months before surgery. Research biopsy was required at pre-NET and wk 4, then optional at wk 12. Pts with Ki67 >10% on biopsy at wk 4 or 12 discontinued NET and were offered NCT. PAM50 intrinsic subtype and ROR-P values were generated from mRNA sequencing (RNASeq) analysis on pre-NET biopsies using open-source informatics (PMC7723687) and evaluated for prediction of on-NET Ki67 >10% at wk 4 or 12, pCR or mPEPI-0 post NET, and pCR post NCT. Results: 749 of 1,297 eligible trial pts were included in the analyses, after excluding 548 pts due to insufficient pre-NET tumor for RNASeq (n=511) or PAM50 normal subtype (n=37). Similar to the entire ALTERNATE population, the rate of Ki67 >10% at wk 4 or 12 was 24.4% (95% CI: 21.4-27.7%) and the rate of mPEPI-0/pCR post NET was 19.8% (95% CI: 17.0-22.8%). There were 393 (52.5%) Lum A, 302 (40.3%) Lum B, and 54 (7.2%) non-Lum (9 Basal, 45 HER2-E) BCs. These included 196 (26.2%) ROR-P low, 354 (47.3%) ROR-P medium and 199 (26.6%) ROR-P high BCs. Both the rates of Ki67 >10% at wk 4 or 12 and mPEPI-0/pCR differed significantly with respect to PAM50 subtype or ROR-P category, such that Lum A or ROR-P low BCs were least likely to have a Ki67 >10% at wk 4 or 12 and most likely to achieve mPEPI-0/pCR (Table). 93 of 168 (55.4%) pts triaged to NCT had RNA-seq results, yielding 26 Lum A, 49 Lum B, 4 Basal and 14 HER2-E, with the pCR rates of 0%, 6.1%, 0%, and 21.4%, respectively. There were 10 ROR-P low, 39 medium, and 44 high tumors, with a pCR rate of 0%, 5.1% and 9.1%, respectively. Conclusion: These data indicate that both baseline ROR-P and intrinsic subtype are predictive of early on-NET Ki67 > 10% and mPEPI 0/pCR at surgery after NET. For pts triaged to NCT based on an early on-NET Ki67 >10%, the HER2-E group had the highest pCR rate (20%) and no pCRs were observed in Lum A. These data may be useful for directing neoadjuvant therapy in postmenopausal pts with ER+ HER2- BC. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50CA186784, P50-CA58223, U01 CA214125, U24CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. Trials.gov Identifier: NCT01953588. Table 1.Rates of Ki67 >10% and mPEPI-0/pCR post NET by PAM50 subtype and ROR-P categoryKi67 >10% at wk 4 or 12mPEPI 0/pCR post NETPAM50 SubtypenYes, n (%)PnNo, n (%)PLum A37251 (13.7%) 95% CI: 10.4-17.6% Citation Format: Cynthia X Ma, Meenakshi Anurag, Travis Dockter, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, A. Marilyn Leitch, Gary W Unzeitig, Anna Weiss, Eric P Winer, Kelly Hunt, Ann H Partridge, Lisa A Carey, Charles M Perou, Matthew J Ellis, Vera Suman. Pam50 intrinsic subtype and risk of recurrence score (ROR) for the prediction of endocrine (ET) sensitivity and pathologic response to chemotherapy in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) in the alternate trial (Alliance A011106) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-03.

Published
2022

47. Four-year results of the Bolton relay proximal scallop endograft in the management of thoracic and thoracoabdominal aortic pathology with unfavorable proximal landing zone

Author

Ammar Abdullah, Richard Gibbs, M. Hamady, Colin Bicknell, Elika Kashef, Michael Jenkins, Lydia Hanna, and Celia Riga

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Time Factors, Databases, Factual, Vertebral artery, 030204 cardiovascular system & hematology, Prosthesis Design, Risk Assessment, 03 medical and health sciences, Blood Vessel Prosthesis Implantation, 0302 clinical medicine, Aneurysm, Postoperative Complications, Risk Factors, medicine.artery, London, medicine, Thoracic aorta, Humans, 030212 general & internal medicine, Common carotid artery, Myocardial infarction, Aortic rupture, Aged, Retrospective Studies, Aortic dissection, Aged, 80 and over, Aortic Aneurysm, Thoracic, business.industry, Endovascular Procedures, Middle Aged, medicine.disease, Blood Vessel Prosthesis, medicine.anatomical_structure, Treatment Outcome, cardiovascular system, Surgery, Female, Cardiology and Cardiovascular Medicine, business, Artery
Abstract

Background Thoracic endovascular aortic repair with a scallop design (scallop-TEVAR) is a useful treatment strategy to extend the proximal landing zone (PLZ), while maintaining perfusion to one or more of the supra-aortic trunks (SATs) when treating aortic pathology with an unfavorable PLZ. The durability of this approach with the Bolton Relay scallop endograft (Terumo Aortic, Sunrise, Fla) has not been established. Methods A retrospective review of prospectively collected data on consecutive patients that received scallop-TEVAR in zones 0 to 2 at a tertiary aortic unit was undertaken. The main outcome was durability, characterized by survival estimates, freedom from reintervention to the thoracic aorta and PLZ, migration and aneurysm sac regression. Results Between 2009 and 2019, 38 patients (71% male; median age, 70 years) underwent scallop-TEVAR for thoracic aortic pathology (n = 28, 74%) or as a part of thoracoabdominal aneurysm repair (n = 10 [26%]). The use of scallop-TEVAR significantly extended the PLZ (median, 5 mm preoperative PLZ vs 26 mm extended PLZ; P = .0001). A total of 41 SATs were perfused with a scallop, including the left subclavian artery (n = 25), left common carotid artery (n = 6), neo/innominate artery (n = 4), left subclavian artery, and vertebral artery (n = 1), innominate artery, and left common carotid artery (n = 2) in conjunction with 15 extra-anatomical bypasses. The PLZ was at Ishimaru zone 0 and 1 in 6 cases (16%), respectively, and zone 2 in 26 cases (68%). Technical success was 98%. The 30-day mortality was 5% (2/38; 1 death from myocardial infarction and 1 from multiorgan failure). A minor stroke occurred in three patients (8%) and temporary spinal cord ischemia in two patients (5%). The median follow-up was 4.5 years (range, 0-10.53 years) during which two patients (5%) developed type Ia endoleak and required intervention to the PLZ (one from device-related migration and one from disease progression). All-cause and aorta-related survival were 72% and 85% and freedom from thoracic and PLZ reintervention was 92% and 97%, respectively. There were no cases of early or late thoracic aortic rupture, retrograde type A aortic dissection or SAT occlusion. Conclusions Scallop-TEVAR offers a less invasive treatment option to extend the seal zone in selected patients with an unfavorable PLZ, allowing for a durable repair in terms of overall survival and reintervention. Periprocedural stroke remains a principle concern.

Published
2020

48. COVID-19 and vascular surgery at a Central London teaching hospital

Author

G Sritharan, X Luo, J Shalhoub, Celia Riga, Usman Jaffer, D Nott, Alexander Rolls, Richard Gibbs, A Sudarsanam, Christopher Aylwin, N J Standfield, A H Davies, Colin Bicknell, and M P Jenkins

Subjects
Male, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, MEDLINE, Teaching hospital, Correspondence, London, medicine, Humans, Intensive care medicine, Hospitals, Teaching, Pandemics, 11 Medical and Health Sciences, Aged, Science & Technology, Viral Epidemiology, business.industry, COVID-19, Vascular surgery, medicine.disease, Pneumonia, Female, Surgery, business, Coronavirus Infections, Vascular Surgical Procedures, Life Sciences & Biomedicine
Published
2020

49. Exclusive dealing without territory exclusivity in multichannel systems: managing channel conflict and driving commitment

Author

Richard Gibbs and Alberto Sa Vinhas

Subjects
Marketing, Economics and Econometrics, business.industry, media_common.quotation_subject, 05 social sciences, Exclusive dealing, Sample (statistics), Competition (economics), Channel conflict, 0502 economics and business, 050211 marketing, Quality (business), Business, Reseller, Business and International Management, 050203 business & management, Downstream (petroleum industry), Communication channel, media_common
Abstract

The exclusive dealing literature suggests that manufacturers should protect exclusive dealers (ED) from intrabrand competition by assigning exclusive territories (ET). We consider ED systems without ET and investigate how manufacturers can enhance ED channel outcomes, such as the ED’s level of commitment to the relationship, by strategically managing its downstream communication efforts with ED and non-ED channels. We show that these cross-channel communication efforts (i.e., the quality of communication between the manufacturer and non-ED resellers in the ED reseller’s territory) are important drivers of relationship conflict and commitment for ED resellers, while playing a limited role for non-ED resellers. These results underscore the need for manufacturers to understand the perspectives and behaviors of each individual channel within a multichannel system and manage their different distribution channel types as an integrated system. We find support for our hypotheses in a sample of 672 observations corresponding to different ED and non-ED resellers selling a manufacturer’s product-line across several European countries.

Published
2018

50. Robotic Arch Catheter Placement Reduces Cerebral Embolization During Thoracic Endovascular Aortic Repair (TEVAR)

Author

Richard Gibbs, M. Hamady, Colin Bicknell, A.H. Perera, L. Monzon, and Celia Riga

Subjects
Aortic arch, medicine.medical_specialty, business.industry, medicine.medical_treatment, Robotic Surgical Procedures, 030204 cardiovascular system & hematology, medicine.disease, Surgery, Transcranial Doppler, 03 medical and health sciences, Catheter, 0302 clinical medicine, Embolism, medicine.artery, medicine, Thoracic aorta, Radiology, Embolization, Cardiology and Cardiovascular Medicine, business, Stroke, 030217 neurology & neurosurgery
Abstract

Objective Stroke caused by cerebral embolization constitutes a principal risk during arch manipulation and thoracic endovascular aortic repair (TEVAR). This study investigates the incidence of cerebral embolization during catheter placement in the aortic arch, and compares robotic and manual techniques. Methods Intra-operative transcranial Doppler (TCD) was performed in 11 patients undergoing TEVAR. Wire and catheter placement in the arch was performed by two experienced operators. Manual and robotic catheter placement and removal were compared for each patient; 44 manoeuvres were studied in total. A conventional 5Fr pigtail catheter was used for manual cannulation via a 5Fr access sheath. The 6Fr/9Fr co-axial Magellan endovascular robotic system was used for robotic navigation operated from a remote workstation. The number of high intensity transient signals (HITS) detected by TCD during different stages of TEVAR was recorded. Results The median procedural embolization rate was 173 (interquartile range 97–240). There were significantly fewer HITS detected during robotic catheter placement with six in total (median 0, IQR 0–1), compared with 38 HITS (median 2, IQR 1–5) during manual catheter placement ( p = .018). There were no HITS detected during robotic catheter removal by auto-retraction as per manufacturer instructions. On two occasions, however, when the robotic catheter system was removed manually without correcting for articulation, it resulted in one HIT in one case and 11 HITS in the second case. Conclusions Robotic catheter placement is feasible during TEVAR, and results in significantly less cerebral embolization compared with manual techniques. The active manoeuvrability, control, and stability of the robotic system is likely to reduce contact with an atheromatous aortic arch wall, and thereby reduce dislodgement of particulate matter and result in less embolization. The importance of adhering to manufacturer instructions during use and removal of the robotic catheter is also highlighted.

Published
2017

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