Browsing by Author "Adams, Robert J"

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    End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain.
    (Blood advances, 2019-12) Farrell, Ann T; Panepinto, Julie; Carroll, C Patrick; Darbari, Deepika S; Desai, Ankit A; King, Allison A; Adams, Robert J; Barber, Tabitha D; Brandow, Amanda M; DeBaun, Michael R; Donahue, Manus J; Gupta, Kalpna; Hankins, Jane S; Kameka, Michelle; Kirkham, Fenella J; Luksenburg, Harvey; Miller, Shirley; Oneal, Patricia Ann; Rees, David C; Setse, Rosanna; Sheehan, Vivien A; Strouse, John; Stucky, Cheryl L; Werner, Ellen M; Wood, John C; Zempsky, William T
    To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
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    Executive Summary: Heart Disease and Stroke Statistics—2011 Update
    (Circulation, 2011-02) Roger, Véronique L; Go, Alan S; Lloyd-Jones, Donald M; Adams, Robert J; Berry, Jarett D; Brown, Todd M; Carnethon, Mercedes R; Dai, Shifan; de Simone, Giovanni; Ford, Earl S; Fox, Caroline S; Fullerton, Heather J; Gillespie, Cathleen; Greenlund, Kurt J; Hailpern, Susan M; Heit, John A; Michael Ho, P; Howard, Virginia J; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Makuc, Diane M; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McDermott, Mary M; Meigs, James B; Moy, Claudia S; Mozaffarian, Dariush; Mussolino, Michael E; Nichol, Graham; Paynter, Nina P; Rosamond, Wayne D; Sorlie, Paul D; Stafford, Randall S; Turan, Tanya N; Turner, Melanie B; Wong, Nathan D; Wylie-Rosett, Judith
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    Fibroblast growth factor23 is associated with axonal integrity and neural network architecture in the human frontal lobes.
    (PloS one, 2018-01) Marebwa, Barbara K; Adams, Robert J; Magwood, Gayenell S; Kindy, Mark; Wilmskoetter, Janina; Wolf, Myles; Bonilha, Leonardo
    Elevated levels of FGF23 in individuals with chronic kidney disease (CKD) are associated with adverse health outcomes, such as increased mortality, large vessel disease, and reduced white matter volume, cardiovascular and cerebrovascular events. Apart from the well-known link between cardiovascular (CV) risk factors, especially diabetes and hypertension, and cerebrovascular damage, elevated FGF23 is also postulated to be associated with cerebrovascular damage independently of CKD. Elevated FGF23 predisposes to vascular calcification and is associated with vascular stiffness and endothelial dysfunction in the general population with normal renal function. These factors may lead to microangiopathic changes in the brain, cumulative ischemia, and eventually to the loss of white matter fibers. The relationship between FGF23 and brain integrity in individuals without CKD has hitherto not been investigated. In this study, we aimed to determine the association between FGF23, and white matter integrity in a cohort of 50 participants with varying degrees of CV risk burden, using high resolution structural human brain connectomes constructed from MRI diffusion images. We observed that increased FGF23 was associated with axonal loss in the frontal lobe, leading to a fragmentation of white matter network organization. This study provides the first description of the relationship between elevated levels of FGF23, white matter integrity, and brain health. We suggest a synergistic interaction of CV risk factors and FGF23 as a potentially novel determinant of brain health.
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    Heart disease and stroke statistics--2011 update: a report from the American Heart Association.
    (Circulation, 2011-02) Roger, Véronique L; Go, Alan S; Lloyd-Jones, Donald M; Adams, Robert J; Berry, Jarett D; Brown, Todd M; Carnethon, Mercedes R; Dai, Shifan; de Simone, Giovanni; Ford, Earl S; Fox, Caroline S; Fullerton, Heather J; Gillespie, Cathleen; Greenlund, Kurt J; Hailpern, Susan M; Heit, John A; Ho, P Michael; Howard, Virginia J; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Makuc, Diane M; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McDermott, Mary M; Meigs, James B; Moy, Claudia S; Mozaffarian, Dariush; Mussolino, Michael E; Nichol, Graham; Paynter, Nina P; Rosamond, Wayne D; Sorlie, Paul D; Stafford, Randall S; Turan, Tanya N; Turner, Melanie B; Wong, Nathan D; Wylie-Rosett, Judith; American Heart Association Statistics Committee and Stroke Statistics Subcommittee
    Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 1999, the Statistical Update has been cited more than 8700 times in the literature (including citations of all annual versions). In 2009 alone, the various Statistical Updates were cited 1600 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas. For this year's edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year and added a new chapter detailing how family history and genetics play a role in cardiovascular disease (CVD) risk. Also, the 2011 Statistical Update is a major source for monitoring both cardiovascular health and disease in the population, with a focus on progress toward achievement of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update. Copyright © 2011 American Heart Association. All rights reserved.
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    Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
    (Lancet, 2016-02-13) Ware, Russell E; Davis, Barry R; Schultz, William H; Brown, R Clark; Aygun, Banu; Sarnaik, Sharada; Odame, Isaac; Fuh, Beng; George, Alex; Owen, William; Luchtman-Jones, Lori; Rogers, Zora R; Hilliard, Lee; Gauger, Cynthia; Piccone, Connie; Lee, Margaret T; Kwiatkowski, Janet L; Jackson, Sherron; Miller, Scott T; Roberts, Carla; Heeney, Matthew M; Kalfa, Theodosia A; Nelson, Stephen; Imran, Hamayun; Nottage, Kerri; Alvarez, Ofelia; Rhodes, Melissa; Thompson, Alexis A; Rothman, Jennifer A; Helton, Kathleen J; Roberts, Donna; Coleman, Jamie; Bonner, Melanie J; Kutlar, Abdullah; Patel, Niren; Wood, John; Piller, Linda; Wei, Peng; Luden, Judy; Mortier, Nicole A; Stuber, Susan E; Luban, Naomi LC; Cohen, Alan R; Pressel, Sara; Adams, Robert J
    BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.