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Charles S Fuchs, Toshihiko Doi, Raymond W Jang, Kei Muro, Taroh Satoh, Manuela Machado, Weijing Sun, Shadia I Jalal, Manish A Shah, Jean-Phillipe Metges, Marcelo Garrido, Talia Golan, Mario Mandala, Zev A Wainberg, Daniel V Catenacci, Atsushi Ohtsu, Kohei Shitara, Ravit Geva, Jonathan Bleeker, Andrew H Ko, Geoffrey Ku, Philip Philip, Peter C Enzinger, Yung-Jue Bang, Diane Levitan, Jiangdian Wang, Minori Rosales, Rita P Dalal, Harry H Yoon
Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016...
March 15, 2018: JAMA Oncology
Fenglong Xie, Lisandro D Colantonio, Jeffrey R Curtis, Meredith L Kilgore, Emily B Levitan, Keri L Monda, Monika M Safford, Ben Taylor, Mark Woodward, Paul Muntner
BACKGROUND: Cause of death is often not available in administrative claims data. OBJECTIVE: To develop claims-based algorithms to identify deaths due to fatal cardiovascular disease (CVD; ie, fatal coronary heart disease [CHD] or stroke), CHD, and stroke. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) study data were linked with Medicare claims to develop the algorithms. Events adjudicated by REGARDS study investigators were used as the gold standard...
March 14, 2018: Pharmacoepidemiology and Drug Safety
Philip Carter, Costi Alifrangis, Biancastella Cereser, Pramodh Chandrasinghe, Lisa Del Bel Belluz, Thomas Herzog, Joel Levitan, Nina Moderau, Lee Schwartzberg, Neha Tabassum, Jinrui Wen, Jonathan Krell, Justin Stebbing
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers. Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not...
February 6, 2018: Oncotarget
Adam S Barnett, Derek D Cyr, Shaun G Goodman, Bennett S Levitan, Zhong Yuan, Graeme J Hankey, Daniel E Singer, Richard C Becker, Günter Breithardt, Scott D Berkowitz, Jonathan L Halperin, Werner Hacke, Kenneth W Mahaffey, Christopher C Nessel, Keith A A Fox, Manesh R Patel, Jonathan P Piccini
AIMS: The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation. METHODS: This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1...
April 15, 2018: International Journal of Cardiology
Ibra S Fancher, Sang Joon Ahn, Crystal Adamos, Catherine Osborn, Myung-Jin Oh, Yun Fang, Catherine A Reardon, Godfrey S Getz, Shane A Phillips, Irena Levitan
BACKGROUND: Hypercholesterolemia-induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+ (Kir) channels and that Kir2.1 is an upstream mediator of flow-induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia-induced inhibition of flow-induced NO production and flow-induced vasodilation (FIV)...
March 3, 2018: Journal of the American Heart Association
Manuela Aseye Ayele Ayee, Elizabeth LeMaster, Tao Teng, James Lee, Irena Levitan
Regulation of cell volume is a fundamental property of all mammalian cells. Multiple signaling pathways are known to be activated by cell swelling and to contribute to cell volume homeostasis. Although cell mechanics and membrane tension have been proposed to couple cell swelling to signaling pathways, the impact of swelling on cellular biomechanics and membrane tension have yet to be fully elucidated. In this study, we use atomic force microscopy under isotonic and hypotonic conditions to measure mechanical properties of endothelial membranes including membrane stiffness, which reflects the stiffness of the submembrane cytoskeleton complex, and the force required for membrane tether formation, reflecting membrane tension and membrane-cytoskeleton attachment...
February 27, 2018: Biophysical Journal
Philip S Wells, Anthonie W A Lensing, Lloyd Haskell, Bennett Levitan, François Laliberté, Michael Durkin, Veronica Ashton, Yongling Xiao, Concetta Crivera, Dominique Lejeune, Jeff Schein, Patrick Lefebvre
AIMS: The EINSTEIN-Extension trial (EINSTEIN-EXT) found that continued treatment with rivaroxaban for an additional 6 or 12 months (versus placebo) after 6-12 months of initial anticoagulation significantly reduced the risk of recurrent venous thromboembolism (VTE) with a small non-significant increased risk of major bleeding (none fatal or in critical site). This study aimed to compare total healthcare cost between rivaroxaban and placebo based on the EINSTEIN-EXT event rates. METHODS: Total healthcare cost was calculated as sum of treatment and clinical event costs from a US managed care perspective...
February 22, 2018: Journal of Medical Economics
Matthew Shane Loop, Leslie A McClure, Emily B Levitan, Mohammad Z Al-Hamdan, William L Crosson, Monika M Safford
Chronic exposure to fine particulate matter (PM2.5 ) is accepted as a causal risk factor for coronary heart disease (CHD). However, most of the evidence for this hypothesis is based upon cohort studies in whites, comprised of either only males or females who live in urban areas. It is possible that many estimates of the effect of chronic exposure to PM2.5 on risk for CHD do not generalize to more diverse samples. METHODS: Therefore, we estimated the relationship between chronic exposure to PM2...
March 2018: American Heart Journal
John P Donnelly, Sindhu Lakkur, Suzanne E Judd, Emily B Levitan, Russell Griffin, George Howard, Monika M Safford, Henry E Wang
Background: Prior studies suggest disparities in sepsis risk and outcomes based on place of residence. We sought to examine the association between neighborhood socioeconomic status (nSES) and hospitalization for infection and sepsis. Methods: We conducted a prospective cohort study using data from 30239 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. nSES was defined using a score derived from census data and classified into quartiles...
February 12, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Teresa N Harrison, Jin-Wen Y Hsu, Robert S Rosenson, Emily B Levitan, Paul Muntner, T Craig Cheetham, Rong Wei, Ronald D Scott, Kristi Reynolds
PURPOSE: A substantial percentage of patients report intolerance or side effects of statin treatment leading to treatment changes or discontinuation. The purpose of this study was to examine statin therapy changes and subsequent effects on low-density lipoprotein cholesterol (LDL-C) among patients with statin intolerance (SI). METHODS: We identified 45,037 adults from Kaiser Permanente Southern California with SI documented between 2006 and 2012. Changes in statin therapy in the year before and after the SI index date were examined...
February 2018: Cardiovascular Drugs and Therapy
Jeffrey R Curtis, Shuo Yang, Jasvinder A Singh, Fenglong Xie, Lang Chen, Huifeng Yun, Paul Muntner, Shia T Kent, Emily B Levitan, Monika M Safford, Kenneth G Saag, Jie Zhang
BACKGROUND/PURPOSE: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol treatment guidelines recommend statins for patients with diabetes aged 40-75 years due to their elevated cardiovascular disease (CVD) risk. We compared the incidence of hospitalized acute myocardial infarction (MI), stroke, and coronary revascularization according to whether patients had diabetes, rheumatoid arthritis (RA), both or neither. METHODS: Using 2006 to 2010 private and public health plan claims, we identified 4 mutually exclusive retrospective cohorts age>40: patients with 1) RA and diabetes; 2) RA only; 3) diabetes only; 4) neither condition...
February 6, 2018: Arthritis Care & Research
Dinara Bulgari, Anupma Jha, David L Deitcher, Edwin S Levitan
Neurotransmission is mediated by synaptic exocytosis of neuropeptide-containing dense-core vesicles (DCVs) and small-molecule transmitter-containing small synaptic vesicles (SSVs). Exocytosis of both vesicle types depends on Ca2+ and shared secretory proteins. Here, we show that increasing or decreasing expression of Myopic (mop, HD-PTP, PTPN23), a Bro1 domain-containing pseudophosphatase implicated in neuronal development and neuropeptide gene expression, increases synaptic neuropeptide stores at the Drosophila neuromuscular junction (NMJ)...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Thao Lan Le, Robert D Levitan, Robert E Mann, Robert G Maunder
BACKGROUND: Harmful alcohol use is associated with disease and mortality. Identifying new determinants of harmful drinking may aid the 16.3 million adults who have alcohol use disorders. Childhood adversity is associated with alcohol use, but is not amenable to change. Attachment insecurity (anxiety and avoidance) may be associated with alcohol use and may be a target for modification or used to personalize interventions. OBJECTIVES: This study aims to (a) identify the association between attachment insecurity and harmful drinking, (b) determine if attachment insecurity may mediate between childhood adversity and harmful drinking, and (c) test sex as a moderator between attachment insecurity and harmful drinking in the mediation relationship...
January 15, 2018: Substance Use & Misuse
Don R Levitan
The evolution of gametic compatibility and the effectiveness of compatibility, within and across species, depend on whether sperm from different males directly compete for an egg and whether eggs ever have a choice. Direct sperm competition and egg choice depend on whether sperm from different males arrive at an egg in the brief interval between first sperm contact and fertilization. Although this process may be relevant for all sexually reproducing organisms, it is most easily examined in aquatic external fertilizers...
January 2018: American Naturalist
Emily B Levitan, Melissa K Van Dyke, Matthew Shane Loop, Ronan O'Beirne, Monika M Safford
PURPOSE: For patients with heart failure with reduced ejection fraction (HFrEF), guidelines recommend use of beta-blockers with gradual up-titration. However, many patients with HFrEF do not use beta-blockers and up-titration is rare. Our purpose was to identify and rank barriers to beta-blocker use and up-titration from the perspective of primary care physicians. METHODS: We conducted 4 moderated, structured group discussions among 19 primary care physicians using the nominal group technique; 16 participants also completed a survey...
December 2017: Cardiovascular Drugs and Therapy
Justin Graffi, Ellen Moss, Alexia Jolicoeur-Martineau, Gal Moss, Vanessa Lecompte, Katherine Pascuzzo, Vanessa Babineau, Cathryn Gordon-Green, Viara R Mileva-Seitz, Klaus Minde, Roberto Sassi, Meir Steiner, James L Kennedy, Helene Gaudreau, Robert Levitan, Michael J Meaney, Ashley Wazana
BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads...
November 14, 2017: Infant Behavior & Development
Matthew T Mefford, Robert S Rosenson, Mary Cushman, Michael E Farkouh, Leslie A McClure, Virginia G Wadley, Marguerite R Irvin, Vera A Bittner, Monika M Safford, Ransi Somaratne, Keri L Monda, Paul Muntner, Emily B Levitan
Background -Despite concerns about adverse neurocognitive events raised by prior trials, pharmacologic PCSK9 inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in life-long exposure to low LDL-C can provide information on the potential long-term effects of low LDL-C on neurocognitive impairment and decline. Methods -We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among African-American REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants with (n=241) and without (n=10,454) C697X or Y142X LOF variants...
November 16, 2017: Circulation
Johnny Kopinja, Raquel S Sevilla, Diane Levitan, David Dai, Amy Vanko, Edward Spooner, Chris Ware, Robert Forget, Kun Hu, Astrid Kral, Peter Spacciapoli, Richard Kennan, Lata Jayaraman, Vincenzo Pucci, Samanthi Perera, Weisheng Zhang, Christian Fischer, Michael H Lam
Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition...
October 23, 2017: Scientific Reports
Patrícia P Silveira, Irina Pokhvisneva, Hélène Gaudreau, Leslie Atkinson, Alison S Fleming, Marla B Sokolowski, Meir Steiner, James L Kennedy, Laurette Dubé, Robert D Levitan, Michael J Meaney
BACKGROUND: We have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods. OBJECTIVES: Our aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status...
January 1, 2018: Appetite
Elizabeth Le Master, Ru-Ting Huang, Chongxu Zhang, Yedida Bogachkov, Cassandre Coles, Tzu-Pin Shentu, Yue Sheng, Ibra S Fancher, Carlos Ng, Theodore Christoforidis, Pappasani V Subbaiah, Evgeny Berdyshev, Zhijian Qain, David T Eddington, James Lee, Michael Cho, Yun Fang, Richard D Minshall, Irena Levitan
OBJECTIVE: Disturbed flow (DF) is well-known to induce endothelial dysfunction and synergistically with plasma dyslipidemia facilitate plaque formation. Little is known, however, about the synergistic impact of DF and dyslipidemia on endothelial biomechanics. Our goal was to determine the impact of DF on endothelial stiffness and evaluate the role of dyslipidemia/oxLDL (oxidized low-density lipoprotein) in this process. APPROACH AND RESULTS: Endothelial elastic modulus of intact mouse aortas ex vivo and of human aortic endothelial cells exposed to laminar flow or DF was measured using atomic force microscopy...
October 12, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
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