Volume 26 Number 2 April 2013

Volume 26 Number 2 April 2013 Baylor University Medical Center Proceedings Multipatient Studies 95 Model for the cost-efficient delivery of continuous quality cancer care: a hospital and private-practice collaboration 163 166 Thermoregulatory catheter–associated inferior vena cava thrombus 168 J. L. Gierman, W. P. Shutze Sr., G. J. Pearl, M. L. Foreman, S. E. Hohmann, and W. P. Shutze Jr. 103 Impact of sham-controlled vertebroplasty trials on referral patterns at two academic medical centers High-intensity, occupation-specific training in a series of firefighters during phase II cardiac rehabilitation J. Adams, D. Cheng, and R. F. Berbarie 109 Morphological features of temporal arteritis 116 Quality of life of HIV/AIDS patients in a secondary health care facility, Ilorin, Nigeria W. C. Roberts, S. Zafar, and J. M. Ko 120 Timing and causes of death after injuries J. Sobrino and S. Shafi Volume 26, Number 2 • April 2013 Baylor University Medical Center, Dallas, Texas 124 Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease M. M. Benjamin and W. C. Roberts 137 177 179 182 185 Editorials, Tributes, and Book Reviews 194 146 Lymphoma in the breast Inflammatory breast cancer K. Y. Ha, S. B. Glass, and L. Laurie Pages 93–232 152 Plasmablastic lymphoma following transplantation 156 Recurrent acute inflammatory demyelinating polyradiculoneuropathy following R-CHOP treatment for non-Hodgkin lymphoma 159 Endolymphatic sac tumor and otalgia M. J. Van Vrancken, L. Keglovits, and J. Krause J. J. Liang, P. P. Singh, and T. E. Witzig M. Zarghouni, M. L. Kershen, L. Skaggs, A. Bhatki, S. C. Gilbert, C. E. Gomez, and M. J. Opatowsky To access Baylor’s physicians, clinical services, or educational programs, contact the Baylor Physician ConsultLine: 1-800-9BAYLOR (1-800-922-9567) 161 196 Tributes to Harold C. Urschel Jr., MD A. U. Goldstein and M. A. Ramsay 199 Tribute to Elgin W. Ware Jr., MD Steve Frost 200 Book review: Making Rounds with Oscar James Marroquin From the Editor 202 Facts and ideas from anywhere William C. Roberts Miscellany 94 158 165 167 187 192 193 212 215 Inguinal lymphadenopathy as the initial presentation of sarcoidosis J. George, R. Graves, and R. Meador Jr. Tributes to George E. Hurt Jr., MD B. Allison, C. H. Scheihing, and W. C. Roberts K. Y. Ha, J. C. Wang, and J. I. Gill 149 An underappreciated problem with auscultation Allen B. Weisse Charles Stewart Roberts Case Studies Diagnosis and management of delayed hemoperitoneum following therapeutic paracentesis M. J. Katz, M. N. Peters, J. D. Wysocki, and C. Chakraborti J. I. Ewing, C. A. Denham, C. R. Osborne, N. B. Green, J. Divers, and J. E. Pippen Jr. The debate on national health insurance . . . 80 years ago Hepatitis C and recurrent treatment-resistant acute ischemic stroke A. Saxsena, J. Tarsia, C. Dunn, A. Aysenne, B. Shah, and D. F. Moore Invited commentary 144 The calcium-alkali syndrome M. Arroyo, A. Z. Fenves, and M. Emmett 191 Thomas B. Gore Persistent giant U wave inversion with anoxic brain injury M. N. Peters, M. J. Katz, L. A. Howell, J. C. Moscona, T. A. Turnage, and P. Delafontaine Our experience as a Health Volunteers Overseas–sponsored team in Huế, Vietnam A forgotten landmark medical study from 1932 by the Committee on the Cost of Medical Care A 21-year-old pregnant woman with congenital heart disease D. Luke Glancy Historical Studies 142 Congenitally bicuspid aortic valve in brothers: coarctation of the aorta with a normally functioning aortic valve in one and no coarctation but severe aortic stenosis in the other S. Zafar and W. C. Roberts 174 S. I. Bello and I. K. Bello Review Articles Ascites with elevated protein content as the presenting sign of constrictive pericardial disease B. A. George, G. dePrisco, J. F. Trotter, A. C. Henry III, and R. C. Stoler 171 S. S. Lindsey, D. F. Kallmes, M. J. Opatowsky, E. A. Broyles, and K. F. Layton 106 Kayser-Fleischer rings of acute Wilson’s disease A. M. Mantas, J. Wells, and J. Trotter Y. M. Coyle, A. M. Miller, and R. S. Paulson 100 Levamisole-induced vasculitis R. Abdul-Karim, C. Ryan, C. Rangel, and M. Emmett 231 Clinical research studies enrolling patients Avocations: Photograph by Dr. Rosenthal Avocations: Photograph by Dr. Hoppenstein Avocations: Photograph by Dr. Khan Baylor news Reader comments In memoriam Selected published abstracts of Baylor researchers 2012 publications of the Baylor Health Care System medical and scientific staff Instructions for authors www.BaylorHealth.edu/Proceedings Indexed in PubMed, with full text available through PubMed Central Baylor University Medical Center Proceedings The peer-reviewed journal of Baylor Health Care System, Dallas, Texas Volume 26, Number 2 • April 2013 Editor in Chief William C. Roberts, MD Associate Editor Michael A. E. Ramsay, MD Associate Editor Andrew Z. Fenves, MD Founding Editor George J. Race, MD, PhD Bradley R. Grimsley, MD Joseph M. Guileyardo, MD Carson Harrod, PhD H. A. Tillmann Hein, MD Daragh Heitzman, MD Priscilla A. Hollander, MD, PhD Ronald C. Jones, MD Göran B. Klintmalm, MD, PhD Sally M. Knox, MD John R. Krause, MD Joseph A. Kuhn, MD Zelig H. Lieberman, MD Jay D. Mabrey, MD Michael J. Mack, MD Gavin M. Melmed, JD, MBA, MD Robert G. Mennel, MD Dan M. Meyer, MD Michael Opatowsky, MD Joyce A. O’Shaughnessy, MD Dighton C. Packard, MD Gregory J. Pearl, MD Robert P. Perrillo, MD Daniel E. Polter, MD Irving D. Prengler, MD Chet R. Rees, MD Randall L. Rosenblatt, MD Lawrence R. Schiller, MD W. Greg Schucany, MD Jeffrey M. Schussler, MD S. Michelle Shiller, DO Craig T. Shoemaker, MD Michael J. Smerud, MD Marvin J. Stone, MD C. Allen Stringer Jr., MD William L. Sutker, MD Gary L. Tunell, MD Beverlee Warren, MA, MS Wilson Weatherford, MD Lawrence S. Weprin, MD F. David Winter Jr., MD Larry M. Wolford, DMD Scott W. Yates, MD, MBA, MS wc.roberts@BaylorHealth.edu Editorial Board Jenny Adams, PhD W. Mark Armstrong, MD Joanne L. Blum, MD, PhD C. Richard Boland Jr., MD Jennifer Clay Cather, MD Evangeline T. Cayton, MD Cristie Columbus, MD Barry Cooper, MD R. D. Dignan, MD Gregory G. Dimijian, MD Michael Emmett, MD Giovanni Filardo, PhD Adrian E. Flatt, MD Dennis R. Gable, MD D. Luke Glancy, MD L. Michael Goldstein, MD Paul A. Grayburn, MD Editorial Staff Managing Editor Cynthia D. Orticio, MA, ELS Administrative Liaison JaNeene Jones, RN, FACHE Residents/Fellows Mina Benjamin, MD Kyle Gummelt, DO Brittany D. Shoemake, MD Anumeha Tandon, MD Design and Production Aptara, Inc. Cynthia.Orticio@BaylorHealth.edu Baylor University Medical Center Proceedings (ISSN 0899-8280), a peer-reviewed journal, is published quarterly (January, April, July, and October). Proceedings is indexed in PubMed and CINAHL; the full text of articles is available both at www. BaylorHealth.edu/Proceedings and www.pubmedcentral.nih.gov. The journal’s mission is to communicate information about the research and clinical activities, continuing education, philosophy, and history of the Baylor Health Care System. Funding for the journal is provided by the following: • Baylor Health Care System Foundation • Helen Buchanan and Stanley Joseph Seeger Endowment for Surgery Funding is also provided by donations made by the medical staff and subscribers. These donations are acknowledged each year in the April or July issue. For more information on supporting Proceedings and Baylor Health Care System with charitable gifts and bequests, please call the Foundation at 214-820-3136. Donations can also be made online at http://give.baylorhealth.com/. Statements and opinions expressed in Proceedings are those of the authors and not necessarily those of Baylor Health Care System or its board of trustees. 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All rights reserved. Printed in the United States of America on acid-free paper. Press date: March 8, 2013. To access Baylor’s physicians, clinical services, or educational programs, contact the Baylor Physician ConsultLine: 1-800-9BAYLOR (1-800-922-9567). 93 Clinical research studies enrolling patients through Baylor Research Institute Currently, Baylor Research Institute is conducting more than 800 research projects. Studies open to enrollment are listed in the Table. To learn more about a study or to enroll patients, please call or e-mail the contact person listed. Table. Clinical research studies conducted through Baylor Research Institute that are enrolling patients Research area Specific disease/condition Contact information (name, phone number, and e-mail address) Asthma and pulmonary disease Chronic obstructive pulmonary disease, asthma (adult) Rose Boehm, RRT, RCP, AE-C 214-820-9772 RoseB@BaylorHealth.edu Cancer Breast, ovarian, endometrial, prostate, brain, lung, bladder, colorectal, pancreatic, and head and neck cancer; hematological malignancies, leukemia, multiple myeloma, non-Hodgkin’s lymphoma; melanoma vaccine Grace Townsend 214-818-8472 cancer.trials@BaylorHealth.edu Type 1 and type 2 diabetes, cardiovascular events Kris Chionh 214-820-3416 kristen.chionh@BaylorHealth.edu Pancreatic islet transplantation Kerri Purcell, RN 817-922-4640 kerrip@BaylorHealth.edu Diabetes (Fort Worth) Type 2 Theresa Cheyne, RN 817-922-2579 theresa.cheyne@BaylorHealth.edu Gastroenterology Crohn’s disease Dallas Clinical Trials Office 214-820-9626 jenniha@BaylorHealth.edu Heart and vascular disease (Dallas) Aortic aneurysms, coronary artery disease, hypertension, poor leg circulation, heart attack, heart disease, congestive heart failure, angina, carotid artery disease, familial hypercholesterolemia, surgical renal denerMerielle Boatman vation for hypertension, diabetes in heart disease, cholesterol disorders, heart valves, thoracotomy pain, stem cells, critical limb ischemia 214-820-2273 MeriellH@BaylorHealth.edu Heart and vascular disease (Fort Worth) Atrial fibrillation, carotid artery stenting Deborah Devlin 817-922-2575 Deborah.Devlin@BaylorHealth.edu Heart and vascular disease (Plano) Aneurysms; coronary artery disease; uncontrolled hypertension; intermittent claudication; heart attack; heart disease; heart valve repair and replacement; critical limb ischemia; repair of AAA, TAA, and dissections with endografts; thoracic surgery leak repair; atrial fibrillation; carotid artery disease; heart failure; left atrial appendage and stroke; gene profiling Natalie Settele, PA-C 469-814-4712 natalie.settele@BaylorHealth.edu Hepatology Liver disease Shalundra Conwell 214-820-1731 Shalundra.Conwell@BaylorHealth.edu HIV/AIDS Bryan King, LVN 214-823-2533 bryan.king@ntidc.org Hepatitis C, hepatitis B Shalundra Conwell 214-820-1731 Shalundra.Conwell@BaylorHealth.edu Homocysteine and kidney disease, dialysis fistulas, urine/protein disorders in cancer patients Dallas Clinical Trials Office 214-820-9626 jenniha@BaylorHealth.edu Stroke Dion Graybeal, MD 214-820-4561 Dion.Graybeal@BaylorHealth.edu Multiple sclerosis Annette Okai, MD 214-820-4655 annette.okai@BaylorHealth.edu Neurosurgery Cerebral aneurysms Kennith Layton, MD 214-827-1600 KennithL@BaylorHealth.edu Rheumatology (9900 N. Central Expressway) Rheumatoid arthritis, psoriatic arthritis, lupus, gout, ankylosing spondylitis John J. Cush, MD 214-987-1253 Kathryn Dao, MD 214-987-1249 jenniha@BaylorHealth.edu jenniha@BaylorHealth.edu Bone marrow, blood stem cells Grace Townsend 214-818-8472 Grace.Townsend@BaylorHealth.edu Solid organs Shalundra Conwell 214-820-1731 Shalundra.Conwell@BaylorHealth.edu Weight management Obesity Kris Chionh 214-820-3416 kristen.chionh@BaylorHealth.edu Women’s health (Fort Worth) Endometriosis and endometrial ablation Theresa Cheyne, RN 817-922-2579 theresa.cheyne@BaylorHealth.edu Diabetes (Dallas) Infectious disease Nephrology Neurology Transplantation Baylor Research Institute is dedicated to providing the support and tools needed for successful clinical research. To learn more about Baylor Research Institute, please contact Kristine Hughes at 214-820-7556 or Kristine.Hughes@BaylorHealth.edu. 94 Proc (Bayl Univ Med Cent) 2013;26(2):94 Model for the cost-efficient delivery of continuous quality cancer care: a hospital and private-practice collaboration Yvonne M. Coyle, MD, Alan M. Miller, MD, PhD, and R. Steven Paulson, MD, MBA Cancer care is expensive due to the high costs of treatment and preventable utilization of resources. Government, employer groups, and insurers are seeking cancer care delivery models that promote both cost-efficiency and quality care. Baylor University Medical Center at Dallas (BUMC), a large tertiary care hospital, in collaboration with Texas Oncology, a large private oncology practice, established two independent centers that function cooperatively within the Baylor Charles A. Sammons Cancer Center, the Oncology Evaluation and Treatment Center (OETC) and Infusion Center, to deliver urgent care and infusions after hours to oncology patients. Quality measures based on evidence-based care and cost-efficiency measures were implemented within these centers. Ability to meet predetermined goals for these measures will be a guide for implementing continuous quality and cost-efficiency interventions. During the first two quarters of operations, 2023 patients received care in the OETC (n = 423) and Infusion Center (n = 1600). The average time spent in the OETC was 48% less than the time spent in the BUMC emergency department (ED). Eighty-nine percent of the cancer center’s patients who received urgent care at BUMC were referred to the OETC for this care, instead of the BUMC ED. The hospital admission rate in the OETC was 59% lower than it was in the BUMC ED, a high-volume level I trauma center. The addition of the OETC and Infusion Center to the cancer center holds promise for providing continuous quality cancer care that is cost-efficient. T he ideal cancer care delivery model is coordinated to provide comprehensive multidisciplinary services (1). However, this type of care can be costly, not only with respect to the high cost of treatment, but also related to the preventable use of resources. Therefore, government, employer groups, and insurers are seeking models for the delivery of quality cancer care that is cost-efficient. Oncologists in private practice are in a unique position to take the lead in defining treatment and operational standards for the delivery of cancer care that is value based, with regards to cost and quality, through collaborations with hospitals and insurers. This article describes two independent centers—the Oncology Evaluation and Treatment Center (OETC) and the Infusion Center—that serve as a model for the delivery of continuous cancer quality care to promote cost-efficiency. The centers were established within the existing Baylor Charles A. Sammons Cancer Center Proc (Bayl Univ Med Cent) 2013;26(2):95–99 through a joint collaboration of a hospital, Baylor University Medical Center at Dallas (BUMC), and Texas Oncology, a large statewide private oncology practice. HISTORY OF THE BAYLOR CHARLES A. SAMMONS CANCER CENTER The cancer center opened in 1976 and is an integral part of BUMC, a not-for-profit tertiary care hospital with 1025 beds whose medical staff is composed of physicians in private practice. The BUMC campus includes a large-volume emergency department (ED), designated as a Level I trauma center offering the most comprehensive level of service to patients. Promoting multidisciplinary interaction among physicians from Texas Oncology and other specialties housed at BUMC has been the main concept underlying the organization and development of a cancer center. The long-standing working relationship between BUMC and Texas Oncology dates back to 1972, when a small private practice called the Medical Oncology Group was developed to provide coverage and assistance with the growing number of oncology consults at BUMC (2). Currently, Texas Oncology leases space in the cancer center, further emphasizing the concept of collaboration between BUMC and Texas Oncology. Since the opening of the Sammons Cancer Center in 1976, education and clinical and basic science cancer research has been an important part of the center’s activities (3). Along with the opening of the cancer center, a medical oncology fellowship program, funded in part by Texas Oncology and by BUMC, was established at BUMC the same year. In conjunction with the training program, cancer research at the cancer center is coordinated between BUMC and Texas Oncology. Texas Oncology is a part of the US Oncology Network. McKesson Specialty Health supports the US Oncology Network to advance the science of oncology by providing the infrastructure to support innovative clinical trials and clinical care operations, as From the Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center at Dallas (Coyle, Miller); and Texas Oncology, Dallas, Texas (Coyle, Miller, Paulson). Corresponding author: Yvonne M. Coyle, MD, Baylor Charles A. Sammons Cancer Center, Medical Director, Oncology Evaluation and Treatment Center, 3410 Worth Street, Dallas, TX 75246 (e-mail: yvonne.coyle@usoncology.com). 95 well as to provide the technological solutions to improve cancer clinical outcomes. The US Oncology Network is one of the nation’s largest networks of community-based oncology physicians, serving more than 850,000 cancer patients annually. The new facility for outpatient services at the cancer center opened in 2011. BUMC opened the Baylor T. Boone Pickens Cancer Hospital in January 2012. Recognizing the need to further integrate oncology patient care at the cancer center to provide continuous quality care that promotes cost-efficiency, BUMC, in collaboration with Texas Oncology, opened the OETC and the Infusion Center in March 2012. Table 1. Oncology Evaluation and Treatment Center quality measures Adult cancer supportive care Outcome measure Chemotherapy-related breakthrough nausea and vomiting Treat with an additional antiemetic agent from a different drug class Palliative care consult Hospital admissions for Obtain palliative care consult if intractable pain pain is resistant to conventional interventions or if there is a high risk for poor pain control related to one or more of the following: • Neuropathic pain • Incident or breakthrough pain • Associated psychological and family distress • Rapid escalation of opioid dosage • History of drug or alcohol abuse • Impaired cognitive function ONCOLOGY EVALUATION AND TREATMENT CENTER AND INFUSION CENTER MODEL The OETC and the Infusion Center have Febrile neutropenia a cooperative working relationship and are housed side by side in an outpatient facility located on the first floor of the cancer hospital. The OETC provides urgent care after office hours as well as scheduled procedures during office hours to adult oncology patients of all oncology physicians at BUMC, including Texas Oncology physicians. The procedures scheduled are diagnostic and therapeutic, such as thoracenteses, paracenteses, and lumbar punctures for the administration of intrathecal chemotherapy, as well as to maintain adherence to prescheduled clinical research testing, which may occur outside of normal office hours. All acute care can be provided at the OETC, with the exception of care required by patients who are transported by emergency medical services or care for patients with acute myocardial infarctions, cerebral vascular accidents, or trauma. Therefore, if necessary, OETC patients may be transferred to the BUMC ED, which is located in close proximity to the cancer hospital and is accessible by an indoor connector. The Infusion Center is open 24 hours a day 7 days a week to provide oncology patients access to blood product transfusions, as well as hydrating, chemotherapy, and biological therapy infusions. Thus, interruptions in cancer care can be prevented by administering infusions that are due on weekends and holidays in the Infusion Center, when private practice offices at the Sammons Cancer Center are closed. The OETC and Infusion Center are staffed with a medical director under contract with BUMC, who is also a Texas Oncology physician, and a nurse manager employed by BUMC. BUMC owns and operates the OETC and the Infusion Center and owns the equipment therein, as well as employing the nursing staff within these two centers. Accordingly, BUMC bills facility and technical fees. Providers that evaluate and treat the patients in the OETC include Texas Oncology physicians and internal medicine physicians, all of whom have BUMC medical staff membership and admitting privileges, and these providers 96 Quality measure Hospital admissions for intractable nausea and vomiting • High risk: within 1 hour treat with • Hospital admissions for febrile neutropenia a broad-spectrum, antipseudomonal, bactericidal, antibiotic • Hospital 30-day, all-cause, regimen as initial empiric therapy risk standardization mortality rate following • Low risk: treat with ciprofloxacin febrile neutropenia + amoxicillin or ciprofloxacin + hospitalization clindamycin for penicillin-allergic patients bill for the related professional fees. Patients are referred to the OETC by their oncology physicians. Patients in the OETC may be transferred for services provided in the Infusion Center 24 hours a day, and patients in the Infusion Center can be evaluated and treated after normal office hours by an OETC provider, if necessary. To promote efficient patient care, providers staffing the OETC are able to access the Texas Oncology electronic medical record, iKnowMed, developed by the US Oncology Network, in addition to the BUMC electronic medical record, Eclipsys. Evidence-based medicine is used as a guide to deliver quality cancer supportive care in the OETC. The most prevalent patient clinical problems evaluated and treated in the OETC are used to periodically select quality measures derived from the National Comprehensive Cancer Network Guidelines for Cancer Supportive Care (4). Adherence to clinical outcome-based quality of care measures for the OETC is measured on a quarterly basis (Table 1) (5–7). As an indirect measure of quality of care in the OETC, Press Ganey patient satisfaction scores will be collected and analyzed quarterly (8). The cost-efficiency measures were selected based on commonly accepted business practices, as well as a review of the literature (9, 10). These measures focus on health care utilization, staff, facility, and ancillary service costs required to evaluate and treat patients in the OETC, as well as the time that patients spend in the OETC. Adherence to these measures will be reported quarterly. Table 2 includes the current cost-efficiency measures for the OETC. The cost-efficiency measure, mean cost per visit, Baylor University Medical Center Proceedings Volume 26, Number 2 Table 2. Oncology Evaluation and Treatment Center cost-efficiency measures • • • • • • Time spent in the OETC OETC hospital admission rate BUMC admission rate for oncology patients BUMC Emergency Department admission rate for oncology patients Average length of stay for oncology patients at BUMC Mean cost per visit in the OETC OETC indicates Oncology Evaluation and Treatment Center; BUMC, Baylor University Medical Center at Dallas. will be determined primarily based on nursing staff and provider hourly wages, drug and supply costs, and ancillary service costs, such as laboratory and radiology services. The cost per visit will be adjusted for severity of illness. Quality improvement and cost-efficiency interventions will be based on predetermined goals for adherence to the quality and cost measures listed in Tables 1 and 2. Together, the OETC and Infusion Center provide patients with continuous supportive cancer care to 1) promote favorable clinical outcomes, 2) support the successful completion of clinical cancer research studies, and 3) reduce health care costs by decreasing preventable and expensive health care utilization. Within the OETC, health services research studies are being conducted to further advance our knowledge of the most costefficient ways to deliver quality cancer care (11). The Figure presents the model for the delivery of quality continuous cancer care to promote cost-efficiency that we developed by incorporating the OETC and Infusion Center within our existing cancer center infrastructure. INITIAL UTILIZATION RESULTS Between April and December 2012, the first two quarters of operations of the OETC and Infusion Centers, a total of 2023 oncology patients received care: 423 in the OETC and 1600 in the Infusion Center. During the first quarter, we identified visits to the BUMC ED if at least one cancer International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code was assigned for the care that was received during one of these visits (12). Health care delivery data for the first quarter of the OETC and Infusion Center operations are as follows. The average time spent in the OETC (3 hours and 48 minutes) was 48% lower than it was for the time spent for oncology patients in the BUMC ED (7 hours and 17 minutes). Ninety percent of the cancer center’s patients who received urgent care at BUMC were referred to the OETC for this care, instead of the BUMC ED. The hospital admission rate in the OETC was 34%, compared with 83% for the BUMC ED. DISCUSSION Comprehensive and coordinated oncology care is necessary to promote favorable clinical outcomes for oncology patients, but it is costly. In a recent study, it was projected that the total cost of cancer care would be $173 billion by 2020, which April 2013 Figure. Model for the cost-efficient delivery of continuous quality cancer care. The Baylor Charles A. Sammons Cancer Center at Baylor University Medical Center (BUMC) includes cancer center outpatient services, the Baylor T. Boone Pickens Cancer Hospital, and the Oncology Evaluation and Treatment Center (OETC) and Infusion Center. represents a 39% increase from 2010 (13). As a result, costcontainment efforts by insurers have become commonplace. These cost-containment efforts have resulted in lower reimbursement for drugs, as well as for evaluation and management services, which is occurring in the face of rising costs for the new technologies required for the treatment of cancer. Coinciding with the decline in cancer care reimbursement from insurers over the last decade, the delivery of cancer care in the community setting decreased from 85% to 65% in 2012, correlating with a number of community-based oncologists entering into employment or management arrangements with institutionally based programs in 2011 (14). Thus, it is important for oncologists in community-based settings to be engaged in developing models that promote the cost-efficient delivery of quality cancer care due to the current trends in health care economics. To provide direction for addressing this issue, the Institute of Medicine recently convened a workshop where its participants determined that the medical home concept should be considered when redesigning models of care in oncology (15). Because cancer is increasingly being viewed as a chronic disease, the concept of the patient-centered medical home (PCMH), a model that has been used mainly in the primary care setting, is a viable option for use in the delivery of costefficient and quality cancer care. In the medical home model, care is provided by a dedicated team of providers, and they are reimbursed with an upfront fee and higher reimbursement for episodes of care (15). An episode of care is a managed care concept in which a single payment for health care services is provided for a specific illness during a set time period (16). The National Committee for Quality Assurance (NCQA) developed the standards for the primary care PCMH program (17). The NCQA’s standards for the PCMH program require a physician-led care team to direct disease management and care coordination, to standardize care which is evidence-based, and to promote patient disease management education (17). Results Model for the cost-efficient delivery of continuous quality cancer care: a hospital and private-practice collaboration 97 indicate that the use of the PCMH model has a positive effect on quality and cost, as well as satisfaction of the patient and the clinical team (17). In 2010, Consultants in Medical Oncology and Hematology (CMOH), a community-based single-specialty practice in Philadelphia, became the first oncology practice recognized by the NCQA as a level three PCMH program (18). Achievement at this level requires the highest level of expertise related to patient communication, data tracking, care management, self-management support, electronic prescribing, test tracking, referral tracking, advanced electronic patient communications, and performance metrics reporting and improvement (18). As the result of CMOH implementing the PCMH model, ED visits decreased by 68%, chemotherapy-related hospital admissions decreased by 51%, and length of hospital stay decreased by 21% (14, 18). In addition, CMOH outpatient visits and chemotherapy outpatient visits per patient per year decreased by 22% and 12%, respectively (14, 18). The US Oncology network launched its program, Innovent Oncology, in 2010 to improve the clinical management of oncology patients receiving chemotherapy (19). The program is supported by the US Oncology network and is offered at all of the Texas Oncology sites. This program creates a link between physicians and insurers by using evidence-based practice guidelines for the selection of chemotherapy, along with patient support services and advance care planning to promote favorable cost metrics and health care utilization patterns. The clinical and cost outcomes included in Innovent Oncology are chemotherapy-related hospitalizations and ED visits, length of hospital stay, chemotherapy costs, end-of-life care including hospice enrollment, death in a hospital, and chemotherapy administration within 2 to 4 weeks of death. Insurers make a single payment for each patient enrolled in Innovent Oncology, and they provide Innovent Oncology staff with access to program enrollee health care utilization and financial data to calculate the program’s clinical and cost outcomes. Initial results related to implementation of the program are encouraging. Physician adherence to the evidence-based practice guidelines for the selection of chemotherapy was 72%, which increased to over 80% for the most recent quarter (J. R. Hoverman, personal communication, September 12, 2012). In addition, there was a substantial decrease in the hospitalization costs for the first 100 patients enrolled in this program (19). However, as important as CMOH and the Innovent Oncology program are in promoting the cost-efficient delivery of quality cancer care within the private oncology practice setting, we propose it is just as important to make interventions in the emergency and urgent care settings to prevent avoidable health care utilization. The need to develop interventions for reducing avoidable inpatient and outpatient visits at all points of care that are affordable, efficient, and of high quality is of further importance since it is projected that there will be a shortage of oncologists in the US by 2020 (13). This shortage in oncologists is due, in part, to the increase in the aging US population among whom the cancer incidence is higher (13). Through the combined efforts of an oncology group practice and hospital, the 98 OETC and Infusion Center was incorporated within the cancer center, creating a model for the efficient delivery of continuous quality care to help prevent the avoidable use of costly health care resources. Analysis of data from the first quarter of operations for the OETC and Infusion Center provides evidence that we are likely to achieve our goal of reducing preventable health care utilization in a cost-efficient manner. A total of 2023 oncology patients received care in the OETC and Infusion Center, and 90% of the cancer center’s patients who received urgent care at BUMC were referred to the OETC for this care, instead of the BUMC ED. The average time spent in the OETC was 48% lower than the time spent for oncology patients in the BUMC ED, as would be expected since the BUMC ED is a high-volume Level I trauma center. Moreover, the hospital admission rate in the OETC was 34%, which was more than 59% lower than it was for the BUMC ED. Similarly, the hospital admission rate in the OETC was almost 50% lower than what was recently reported for oncology patients in the ED using a statewide database in North Carolina (63.2%) (20). Furthermore, our new initiatives for conducting health service research within the OETC and Infusion Center hold promise for providing our cancer center and others with results that will assist in developing new methods for effectively organizing, managing, financing, and delivering quality cancer care. An additional benefit related to establishing new models for cancer care delivery that promote favorable cost-efficiency and clinical outcomes is that more equitable medical insurance reimbursement contracts for both the payer and payee may be negotiated for this type of center. This type of center also has an infrastructure conducive to receiving bundled payments for a defined episode of care (21). The bundled payment functions as a tool of alignment between insurers and providers, which can eliminate some of the unintended financial incentives that can lead to fractured and inefficient care. Using the episode of care model tied to bundled payments is a rapidly evolving movement by insurers to produce the best cost and clinical outcomes by decreasing unwanted variations in the delivery of health care (22). Given the growing public awareness of the need to redesign the cancer delivery system, including government, physicians and hospitals, and employer groups and insurers, a new health care environment is developing that demands accountability for the cost and quality of care. Consequently, it is critical for oncologists to continue to take the lead in defining standards of care for specific disease states and to collaborate with hospitals and insurers when possible to develop systems for the delivery of high-quality and cost-efficient cancer care. Acknowledgments We thank Kevin Croy, vice president and assistant general counsel for the Baylor Health Care System, and JaNeene Jones, chief operating officer for the Baylor Health Care System and vice president for oncology services, for their critical review of the manuscript regarding the working relationship between Baylor University Medical Center and Texas Oncology at the Baylor Charles A. Sammons Cancer Center; J. Russell Baylor University Medical Center Proceedings Volume 26, Number 2 Hoverman, MD, medical director for the US Oncology Innovent Oncology program, for his critical review of the manuscript and providing information regarding the status of Innovent Oncology; Dighton Packard, MD, chairman of the Department of Emergency Medicine at Baylor University Medical Center, for his critical review of the manuscript; Kimberly Hanna, RN, the nurse manager for the Oncology Evaluation and Treatment Center and Infusion Center, for her critical review of the manuscript; and Margaret Hinshelwood, PhD, for her critical review of the manuscript along with completing its formatting and producing the tables and figure for the manuscript. 1. 2. 3. 4. 5. 6. 7. 8. Bunnell CA, Weingart SN, Swanson S, Mamon HJ, Shulman LN. Models of multidisciplinary cancer care: physician and patient perceptions in a comprehensive cancer center. J Oncol Pract 2010;6(6):283–288. Winter FD Jr. Group practice at Baylor University Medical Center. Proc (Bayl Univ Med Cent) 2004;17(1):64–72. Stone MJ, Aronoff BE, Evans WP, Fay JW, Lieberman ZH, Matthews CM, Race GJ, Scruggs RP, Stringer CA Jr. History of the Baylor Charles A. Sammons Cancer Center. Proc (Bayl Univ Med Cent) 2003;16(1):30–58. National Comprehensive Cancer Network. NCCN guidelines for supportive care. Available at http://www.nccn.org/professionals/physician_ gls/f_guidelines.asp#supportive. National Comprehensive Cancer Network. NCCN guidelines for palliative care. Available at http://www.nccn.org/professionals/physician_gls/ pdf/palliative.pdf. National Comprehensive Cancer Network. NCCN guidelines for antiemesis. Available at http://www.nccn.org/professionals/physician_gls/pdf/ antiemesis.pdf. National Comprehensive Cancer Network. NCCN guidelines for prevention and treatment of cancer-related infections. Available at http://www. nccn.org/professionals/physician_gls/pdf/infections.pdf. Press Ganey Associates. US wait times average 4 hours 7 minutes in emergency departments in 2009. 2010 Emergency Department Pulse Report: Patient Perspectives on American Health Care. Available at http://www. pressganey.com/pressroom/10-07-22/Patients_Spent_Average_of_Four_ April 2013 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Hours_Seven_Minutes_in_U_S_Emergency_Departments_in_2009_According_to_New_Report_from_Press_Ganey.aspx. Agency for Healthcare Research and Quality. 2007 National Healthcare Quality Report. Rockville, MD: US Department of Health and Human Services, February 2008. Paul J, Seeman N, Gagliardi A, Mahindra S, Blackstien-Hirsch P, Brown AD. New Measures of Ambulatory Care Performance in Ontario: Preliminary System Snapshot, 2006. Toronto, ON: Health System Performance Research Network, 2006. Available at http://www.hsprn.ca/reports/2006/ ambulatory_2006.html. Flook EE, Sanazaro PJ. Health services research: origins and milestones. In Flook EE, Sanazaro PJ, eds. Health Services Research and R&D in Perspective. Ann Arbor, MI: Health Administration Press, 1993. ICD-9-CM: The International Classification of Diseases, 9th Revision, Clinical Modification. Washington, DC: The National Center for Health Statistics and the Centers for Medicare and Medicaid Services, 2011. Erikson C, Salsberg E, Forte G, Bruinooge S, Goldstein M. Future supply and demand for oncologists: challenges to assuring access to oncology services. J Oncol Pract 2007;3(2):79–86. Sprandio JD. Oncology patient-centered medical home. Am J Manag Care 2012;18(5 Spec No. 2):SP98-SP. Levit L, Smith AP, Benz EJ, Ferrell B. Ensuring quality cancer care through the oncology workforce. J Oncol Pract 2010;6(1):7–11. Hornbrook MC, Hurtado AV, Johnson RE. Health care episodes: definition, measurement and use. Med Care Rev 1985;42(2):163–218. National Committee for Quality Assurance. Patient-centered medical home. Available at http://www.ncqa.org/tabid/631/default.aspx. Sprandio JD. Oncology patient-centered medical home and accountable health care. Commun Oncol 2010;7(12):565–572. Hoverman JR, Klein I, Harrison D, Hayes J, Garey JS, Nelson GC, Sipala M, Houldin S, Ciaglo J, Taniguchi C, Jameson M, Abdullahpour M, McQueen J, Verrilli DK, Beveridge R. Impact of a cancer management program. J Clin Oncol 2012;30(Suppl 34):Abstract 227. Mayer DK, Travers D, Wyss A, Leak A, Waller A. Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 2011;29(19):2683–2688. Moeller DJ, Evans J. Episode-of-care payment creates clinical advantages. Manag Care 2010;19(1):42–45. Fallon JA. Cost effectiveness of integrated medicine. J Oncol Pract 2012;8(4):211. Model for the cost-efficient delivery of continuous quality cancer care: a hospital and private-practice collaboration 99 Thermoregulatory catheter–associated inferior vena cava thrombus Joshua L. Gierman, MD, William P. Shutze Sr., MD, Gregory J. Pearl, MD, Michael L. Foreman, MD, Stephen E. Hohmann, MD, and William P. Shutze Jr. The use of thermoregulatory catheters (TRCs) in critically ill patients has become increasingly popular. TRCs have been shown to be effective in regulating patient body temperature with improved outcomes. Critically ill patients, especially multitrauma patients and those with femoral catheters, are at high risk for deep vein thrombosis (DVT). Among patients for whom chemical DVT prophylaxis is not an option, inferior vena cava (IVC) filters are often placed prophylactically. The development of intravascular ultrasound (IVUS) has allowed placement of IVC filters at the bedside for patients who are too ill for transport to the operating room or cardiac catheterization lab. After encountering several patients with occult DVT of the IVC during bedside IVC filter placement, we performed a retrospective review to determine the incidence of DVT or pulmonary embolus (PE) in patients who had been treated with a TRC at Baylor University Medical Center at Dallas. Since 2008, IVC filters have been deployed at the bedside with the use of IVUS at Baylor University Medical Center. During that same time period, 83 patients had a TRC placed for either intravascular warming or cooling during their resuscitation. Forty-seven out of 83 patients who had a TRC placed survived their injuries. Ten of 47 patients (21%) were diagnosed with DVT or PE, and 6 of these 10 (60%) were found to have caval thrombus. We present this case series as evidence that undiagnosed IVC thrombus associated with TRCs may be higher than previously suspected, given that 5 out of 10 patients who had IVUS of their IVC for prophylactic IVC filter placement, as well as one patient diagnosed with PE, were found to have caval thrombus. W ithin the last 15 years, the use of thermoregulatory catheters (TRCs) has gained popularity. They have been used to induce hypothermia to improve outcomes in cases of cardiopulmonary arrest and to reverse the harmful effects of hypothermia in the trauma patient by providing a means for rapid rewarming (1–3). Over the last 3 years at our institution, the trauma service has been utilizing the Alsius catheter and Coolguard Icy thermoregulatory system to aid in resuscitation of hypothermic patients as well as in the cooling of patients with fever and traumatic brain injury. During that same period of time, the vascular surgery service has been placing bedside inferior vena cava (IVC) filters in critically ill patients using intravascular ultrasound (IVUS) (4, 5). Some of the patients who had TRCs used during their hospital course also had IVC filters placed either for prophylaxis or after a 100 diagnosis of deep venous thrombosis (DVT) or pulmonary embolus (PE). Surprisingly, caval thrombus was found in several of these patients undergoing placement of an IVC filter with IVUS. Currently, only one series has examined the risk of iliofemoral DVT (6), and only one case has been reported of vena cava thrombus associated with the use of a TRC (7). We performed a retrospective review to examine whether trauma patients who have been exposed to a TRC are at additional risk for iliocaval DVT in addition to the risk of DVT associated with femoral vein catheterization. MATERIALS AND METHODS Institutional review board approval was obtained for our study. Patient records were obtained from the trauma registry at Baylor University Medical Center at Dallas to identify patients who had TRCs placed beginning in 2008. Catheterization lab records were reviewed to identify patients receiving IVC filters during the same time period. The Student’s t test was used for statistical comparison of age and injury severity score (ISS). RESULTS Since 2008, 83 trauma patients have had a TRC placed as part of their postinjury care: 47 of those patients, with an average age of 41 years and an ISS of 20.9, survived their initial injuries, and 32 patients had no diagnosis of DVT/PE, nor were they selected for prophylactic IVC filter placement. Fifteen of the 47 were referred for IVC filter placement. Five of these 15 patients were diagnosed with either DVT or PE prior to vascular referral. Four patients received an IVC filter; of them, three underwent filter placement under fluoroscopy, and the other patient who received a filter secondary to PE had it placed with IVUS guidance. This demonstrated a caval thrombus. The fifth patient was found to have a femoral DVT and was treated with anticoagulation. Ten patients underwent prophylactic placement or attempted placement of an IVC filter at bedside with IVUS, four of whom were discovered to have IVC thrombus at the time of From the Department of Surgery (Gierman, Shutze Sr., Pearl, Foreman, Hohmann), Baylor University Medical Center at Dallas; and Texas Vascular Associates, Dallas, Texas (Shutze Jr.). Corresponding author: William P. Shutze Sr., MD, Texas Vascular Associates, 621 N. Hall Street, Suite 100, Dallas, Texas 75226 (e-mail: William.Shutze@ BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):100–102 Figure 2. Intravascular ultrasound image depicting inferior vena cava thrombus. Figure 1. Diagnosis of DVT in patients receiving a thermoregulatory catheter. DVT indicates deep vein thrombosis; IVC, inferior vena cava; IVUS, intravascular ultrasound; PE, pulmonary embolus. filter placement. A fifth patient was diagnosed with caval thrombus by IVUS, but had too extensive a thrombus to allow for IVC filter placement. He was treated with anticoagulation. The remaining five patients did not have caval thrombus detected by IVUS (Figure 1). The average age for patients with DVT, PE, or vena cava thrombus was 28 years. This was less than the average age of the overall group (41) but was not statistically different (P > 0.05). The ISS of the patients in the DVT, PE, or vena cava thrombus subgroup was 33. This was much higher than in the overall group (ISS = 21) treated with TRCs who survived their initial injuries, and this difference reached statistical significance (P = 0.039). DISCUSSION TRCs have been shown to be an effective clinical tool, whether to improve outcomes when used for corporal cooling after cardiac arrest or to efficiently reverse hypothermia (1–3). However, there is little reported evidence addressing potential complications. Specifically, the potential to form venous thromboembolism (VTE) has only been reported in one study (6) and in a single case report (7). The patient population examined in this study was at high risk for DVT/VTE. Because of their associated injuries, most of these patients could not receive chemical DVT prophylaxis. Critical illness with contraindications to chemoprophylaxis carries a 7% DVT risk (8). DVT/VTE associated with femoral vein catheters ranges from 10% to 25% (9, 10). In looking at our April 2013 institutional experience with TRCs by the trauma service, we found that the overall rate of DVT/VTE formation was 21% (10/47). This is at the high end of the spectrum, but not out of line with what has been previously published. A previous study of DVT formation in patients with TRCs showed a 50% rate of DVT formation (6). We found occult caval thrombus in 60% of patients ultimately diagnosed with DVT. Given the high incidence of occult caval DVT discovered at the time of prophylactic filter placement, we feel that the 21.3% rate of DVT (specifically caval DVT) in this study may be an underestimation. Only 10 of 47 patients underwent cavography or IVUS. The status of the IVC was not evaluated in 32 of the 47 patients in this series, and a significant number of caval DVT cases could have gone undetected. We did find a higher ISS in patients with DVT/PE (33 vs. 21, P = 0.039) compared to the overall group. This could indicate that injury severity contributes to DVT formation. However, we feel that this possibly represents a selection bias, as the more critically ill patients are typically selected to receive prophylactic IVC filters. Only by studying every patient receiving a TRC can the true rate of DVT and caval DVT be determined and the effect of age and ISS be honestly assessed. There are two points of concern regarding the DVT/VTE associated with these catheters. The first is the fact that half of the caval DVTs were found in asymptomatic patients. Therefore, the actual rate of DVT formation could be as high as 50% in our studied patient population (similar to the experience of Simosa et al). Since 60% of patients having prophylactic IVC filters placed were found to have IVC DVT, the use of TRCs may increase the incidence of DVT significantly higher than the baseline rates for critically ill patients who typically develop DVT in the lower extremity veins or in the femoral vein if a catheter has been placed there. The second point of concern is Thermoregulatory catheter–associated inferior vena cava thrombus 101 that these proximal DVTs are much more dangerous, as they are associated with a higher mortality rate when compared with more distal DVTs (11). They are also less likely to be detected by surveillance, symptoms, or noninvasive imaging. The increased incidence of caval DVT with TRCs identified by our study is therefore quite worrisome. Although there has not been a comparison of IVUS and venography for thrombotic occlusion, IVUS has been shown to be more sensitive than venography in detecting nonthrombotic lesions (12, 13). This increased sensitivity may translate to the diagnosis of thrombotic lesions as well. Caval DVT in patients from TRCs can be nonocclusive and attached to the wall of the IVC and may not be obvious on venography. However, IVUS readily identifies these clots (Figure 2). Notably, the three patients in our series who had fluoroscopy only when having their IVC filters placed could have had missed caval thrombus. We believe that the use of IVUS during the placement of IVC filters increased the sensitivity in identifying occult caval DVTs in asymptomatic patients. Therefore, we recommend the use of IVUS to detect occult DVT in patients with a history of femoral TRCs. 3. 4. 5. 6. 7. 8. 9. 10. 11. 1. 2. 102 Taylor EE, Carroll JP, Lovitt MA, Petrey LB, Gray PE, Mastropieri CJ, Foreman ML. Active intravascular rewarming for hypothermia associated with traumatic injury: early experience with a new technique. Proc (Bayl Univ Med Cent) 2008;21(2):120–126. Diringer MN; Neurocritical Care Fever Reduction Trial Group. Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Crit Care Med 2004;32(2):559–564. 12. 13. Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive Care Med 2004;30(4):556–575. Garrett JV, Passman MA, Guzman RJ, Dattilo JB, Naslund TC. Expanding options for bedside placement of inferior vena cava filters with intravascular ultrasound when transabdominal duplex ultrasound imaging is inadequate. Ann Vasc Surg 2004;18(3):329–334. Ebaugh JL, Chiou AC, Morasch MD, Matsumura JS, Pearce WH. Bedside vena cava filter placement guided with intravascular ultrasound. J Vasc Surg 2001;34(1):21–26. Simosa HF, Petersen DJ, Agarwal SK, Burke PA, Hirsch EF. Increased risk of deep venous thrombosis with endovascular cooling in patients with traumatic head injury. Am Surg 2007;73(5):461–464. Lau E, Bajzer C, Menon V. Inferior vena cava thrombus associated with intravascular cooling catheter. Resuscitation 2010; 81(11):1457–1458. Malinoski D, Ewing T, Patel MS, Jafari F, Sloane B, Nguyen B, Barrios C, Kong A, Cinat M, Dolich M, Lekawa M, Hoyt DB. Risk factors for venous thromboembolism in critically ill trauma patients who cannot receive chemical prophylaxis. Injury 2011;10(1):1–6. Joynt GM, Kew J, Gomersall CD, Leung VY, Liu EK. Deep venous thrombosis caused by femoral venous catheters in critically ill adult patients. Chest 2000;117(1):178–183. Trottier SJ, Veremakis C, O’Brien J, Auer AI. Femoral deep vein thrombosis associated with central venous catheterization: results from a prospective, randomized trial. Crit Care Med 1995;23(1):52–59. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125(1):1–7. Neglén P, Raju S. Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 2002;35(4):694–700. Raju S, Neglen P. High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 2006;44(1):136–143. Baylor University Medical Center Proceedings Volume 26, Number 2 Impact of sham-controlled vertebroplasty trials on referral patterns at two academic medical centers Sara S. Lindsey, MD, David F. Kallmes, MD, Michael J. Opatowsky, MD, Elizabeth A. Broyles, RN, and Kennith F. Layton, MD Debate persists regarding the merit of vertebroplasty following publication of blinded vertebroplasty trials in 2009, one of which was the Investigational Vertebroplasty Efficacy and Safety Trial (INVEST). This study was performed to determine whether referring physicians at two academic medical centers were aware of the trial results and to assess if this awareness prompted a change in their treatment of osteoporotic fractures. E-mail surveys were distributed to physicians within the Mayo Clinic and Baylor Health Care System (BHCS). Of 1390 surveys sent, 194 (14%) were returned. Results showed that 92 of 158 respondents (58%) reported familiarity with INVEST; 66 of 92 (72%) agreed that INVEST changed their understanding of vertebroplasty efficacy; and 64 of 92 (70%) agreed that INVEST diminished their enthusiasm to refer patients for vertebroplasty. However, 105 of 159 respondents (66%) felt vertebroplasty was an effective procedure in appropriate patients. Mayo physicians were more likely than BHCS physicians to be aware of INVEST (73% vs 67%, P < .0001), respond that INVEST changed their understanding of the appropriate treatment for osteoporotic compression fractures (79% vs 57%, P = 0.026), view vertebroplasty less favorably (45% vs 21%, P = 0.005), and treat osteoporotic compression fractures with medical therapy/pain management alone (73% vs 48%, P = 0.003). INVEST changed referring physicians’ understanding of the role of vertebroplasty and diminished their willingness to refer osteoporotic compression fracture patients; the impact varied by location. results, whether their awareness of these results changed their understanding of the efficacy of vertebroplasty and/or their management decisions for patients suffering from painful osteoporotic fractures, and whether there were differences between the institutions regarding these research questions. METHODS Short e-mail surveys were distributed to physicians in a wide range of specialties (Table) that commonly encounter patients with osteoporotic compression fractures within the Mayo Clinic system (Rochester, MN) and the Baylor Health Care System (BHCS, Dallas–Fort Worth, TX). The survey was sent to all physicians with accessible e-mail addresses in these specialty areas, not only to individual physicians who had previously referred patients to interventional neuroradiology for vertebroplasty. Results were collected from September to November 2010 and were analyzed using Survey Monkey. Approval for this research was granted by the institutional review board of Baylor Research Institute. The survey asked participants about their familiarity with the INVEST study, their understanding of the role of vertebroplasty for treatment of osteoporotic compression fractures, if the Table. Respondents by subspecialty T he Investigational Vertebroplasty Safety and Efficacy Trial (INVEST) (1) and a concurrent Australian vertebroplasty trial (2) were published in the New England Journal of Medicine in August 2009 and demonstrated equivalent efficacy for vertebroplasty and a sham intervention for improvement in pain and function in osteoporotic compression fracture patients. Despite extensive criticism (3–8), these studies created controversy regarding the benefit and appropriateness of vertebral augmentation. Historically, the literature has shown positive outcomes associated with thousands of vertebroplasty patients (9, 10). Follow-up vertebroplasty studies have ensued (11, 12), including a study from the Mayo Clinic, which documented a statistically significant decline in referral volumes before and after publication of the August 2009 sham-controlled studies (13). This study was performed to determine whether referring physicians at two academic medical centers, one of which (Mayo Clinic) was the lead site for INVEST, were aware of the INVEST trial Proc (Bayl Univ Med Cent) 2013;26(2):103–105 Specialty n Specialty n Cardiology 4 Neurosurgery 5 Endocrinology 13 Orthopedic surgery 6 Family medicine 40 Pain management 6 Gastroenterology 7 Physical medicine and rehabilitation 20 Hematology/oncology 9 Pulmonology 9 Internal medicine 51 Rheumatology 1 Neurology 14 Transplant medicine 5 From the Department of Radiology, Baylor University Medical Center at Dallas (Lindsey, Opatowsky, Broyles, Layton); and the Mayo Clinic, Rochester, MN (Kallmes). Corresponding author: Sara Lindsey, MD, Department of Radiology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: Sara.Lindsey@BaylorHealth.edu). 103 INVEST results changed their understanding of the treatment for osteoporotic compression fractures or changed their referral patterns for vertebroplasty, and how they were currently treating patients with painful osteoporotic compression fractures. In addition to collecting information on respondents’ specialty, it asked whether they had seen at least one patient during the last 18 months with an osteoporotic vertebral compression fracture. Statistical analysis of the data was performed with chi-square tests. Physicians were allowed to skip questions. Referring physicians were not queried regarding the Buchbinder et al trial (2) or any of the other vertebral augmentation trials in our survey. No incentives were offered for participation. RESULTS Surveys were distributed to 1390 clinicians with a collective response rate of 14% (194 participants). Overall, 92 of 158 respondents (58%) reported being familiar with INVEST (36 respondents did not answer this question), and 53 of these 92 respondents (58%) agreed and 13 (14%) strongly agreed that the results of INVEST had changed their understanding of the efficacy of vertebroplasty (Figure 1); 51 (55%) agreed and 13 (14%) strongly agreed that the study had diminished their enthusiasm to refer patients for vertebroplasty (Figure 2). Cumulatively, 105 respondents (66%) felt that vertebroplasty was an effective procedure in appropriate patients, 52 respondents (33%) felt that vertebroplasty was of limited efficacy, and 2 respondents (1.3%) felt that the potential benefits of vertebroplasty were outweighed by the risks of the procedure (Figure 3). There was a statistically significant difference in the responses between clinicians in the two geographic locations, with Mayo physicians being more aware of the INVEST study (63 of 86 [73%] at Mayo vs 29 of 43 [67%] at BHCS; chi-square DF 1, P < 0.001) and responding that INVEST had changed their understanding of the appropriate treatment for osteoporotic compression fractures (Figure 1; 49 of 62 [79%] at Mayo vs 17 of Figure 2. Respondents indicating that INVEST diminished their enthusiasm to refer patients for vertebroplasty. Difference between Mayo and Baylor respondents: ␹2 (1, n = 92) = 0.82, P = 0.3662. Figure 3. Respondents’ current view of vertebroplasty for treatment of osteoporotic compression fractures. Difference between Mayo and Baylor respondents: ␹2 (2, n = 159) = 10.76, P = 0.0046. Figure 1. Respondents indicating that INVEST changed their understanding of the role of vertebroplasty for treatment of osteoporotic compression fractures. Difference between Mayo and Baylor respondents: ␹2 (1, n = 92) = 4.99, P = 0.0255. 104 30 [57%] at BHCS, chi-square DF 1, P = 0.026). There was also a statistically significant difference between clinicians in the two locales in response to descriptions of their current understanding of vertebroplasty for treatment of osteoporotic compression fractures, with Mayo clinicians viewing vertebroplasty less favorably than BHCS physicians (Figure 3; 39 of 87 [45%] at Mayo vs 15 of 72 [21%] at BHCS, chi-square DF 2, P = 0.005). A majority of respondents from both clinician groups indicated that the INVEST results had diminished their willingness to refer patients for vertebroplasty, although the difference between the two respondent groups was not statistically significant for this question (Figure 2; 45 of 62 [73%] at Mayo vs 19 of 30 [63%] at BHCS, chi-square DF 1, P = 0.366). Mayo clinicians were also statistically significantly more likely than BHCS clinicians Baylor University Medical Center Proceedings Volume 26, Number 2 considering all of the subsequent and ongoing clinical trials investigating the efficacy of vertebroplasty. Further research is needed to address the suggested flaws and confounding factors and to clarify the appropriate treatment of patients with osteoporotic compression fractures. The current ambiguity surrounding vertebroplasty should prompt physicians to enroll as many patients as possible into well-designed trials to help generate data. Acknowledgments The authors thank Sunni Barnes, PhD, director of survey research and clinical trials at BHCS. 1. Figure 4. Respondents’ approach to treating most of their patients with painful osteoporotic compression fractures. Difference between Mayo and Baylor respondents: ␹2 (1, n = 136) = 8.73, P = 0.0031. to treat osteoporotic compression fracture patients with medical therapy and pain management alone, rather than in combination with vertebroplasty (Figure 4; 57 of 78 [73%] at Mayo vs 28 of 58 [48%] at BHCS, chi-square DF 1, P = 0.003). 2. 3. 4. 5. DISCUSSION This survey suggests that INVEST negatively influenced clinicians’ perceptions of and referral patterns for vertebroplasty for treatment of painful osteoporotic compression fractures, similar to the findings reported by Luetmer and Kallmes (13). It also unveiled interesting geographic distinctions, as the survey results varied significantly by location. Though a percentage of physicians at both sites viewed vertebroplasty as an effective procedure in appropriate patients (55% at Mayo vs 79% at BHCS), the referral/utilization rates of vertebral augmentation were notably lower (27% at Mayo vs 52% at BHCS); the reason for this discrepancy is likely multifaceted but was not determined by this survey. This study sampled a relatively small population of physicians and included inherent bias by limiting the survey to two predefined groups of physicians. The response rate was within the previously published range for e-mail–based surveys, which has been as low as 6% (14). Subgroup analysis by medical subspecialty was not performed due to the relatively small sample size. The Mayo Clinic physicians were likely more aware of the INVEST results since Mayo was the lead site in the original multicenter trial. Peer-to-peer education and interactive discussions were proactively performed at the Baylor University Medical Center campus to educate referring physicians about the INVEST data and to encourage continued patient referrals to interventional neuroradiology. Generalization of these two groups’ responses to the wider medical community may not be entirely representative. Additionally, extrapolation of this information to predict future trends in clinician demand and referral patterns for vertebroplasty is shortsighted without April 2013 6. 7. 8. 9. 10. 11. 12. 13. 14. Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH, Edwards R, Gray LA, Stout L, Owen S, Hollingworth W, Ghdoke B, Annesley-Williams DJ, Ralston SH, Jarvik JG. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med 2009;361(6):569–579. Buchbinder R, Osborne RH, Ebeling PR, Wark JD, Mitchell P, Wriedt C, Graves S, Staples MP, Murphy B. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med 2009;361(6):557–568. Baerlocher MO, Munk PL, Liu DM, Tomlinson G, Badii M, Kee ST, Loh CT, Hardy BW, Murphy KJ. Clinical utility of vertebroplasty: need for better evidence. Radiology 2010;255(3):669–674. Buchbinder R, Kallmes DF. Vertebroplasty: when randomized placebo-controlled trial results clash with common belief. Spine J 2010;10(3):241–243. Buchbinder R, Osborne RH, Kallmes D. Invited editorial presents an accurate summary of the results of two randomised placebo-controlled trials of vertebroplasty. Med J Aust 2010;192(6):338–341. Clark WA, Diamond TH, McNeil HP, Gonski PN, Schlaphoff GP, Rouse JC. Vertebroplasty for painful acute osteoporotic vertebral fractures: recent Medical Journal of Australia editorial is not relevant to the patient group that we treat with vertebroplasty. Med J Aust 2010;192(6):334–337. Kallmes D, Buchbinder R, Jarvik J, Heagerty P, Comstock B, Turner J, Osborne R. Response to “Randomized vertebroplasty trials: bad news or sham news?” AJNR Am J Neuroradiol 2009;30(10):1809–1810. Kallmes DF, Jarvik JG, Osborne RH, Comstock BA, Staples MP, Heagerty PJ, Turner JA, Buchbinder R. Clinical utility of vertebroplasty: elevating the evidence. Radiology 2010;255(3):675–680. Layton KF, Thielen KR, Koch CA, Luetmer PH, Lane JI, Wald JT, Kallmes DF. Vertebroplasty, first 1000 levels of a single center: evaluation of the outcomes and complications. AJNR Am J Neuroradiol 2007;28(4):683–689. McGirt MJ, Parker SL, Wolinsky JP, Witham TF, Bydon A, Gokaslan ZL. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J 2009;9(6):501–508. Brinjikji W, Comstock BA, Gray L, Kallmes DF. Local Anesthesia with Bupivacaine and Lidocaine for Vertebral Fracture trial (LABEL): a report of outcomes and comparison with the Investigational Vertebroplasty Efficacy and Safety Trial (INVEST). AJNR Am J Neuroradiol 2010;31(9):1631–1634. Klazen CA, Lohle PN, de Vries J, Jansen FH, Tielbeek AV, Blonk MC, Venmans A, van Rooij WJ, Schoemaker MC, Juttmann JR, Lo TH, Verhaar HJ, van der Graaf Y, van Everdingen KJ, Muller AF, Elgersma OE, Halkema DR, Fransen H, Janssens X, Buskens E, Mali WP. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial. Lancet 2010;376(9746):1085– 1092. Luetmer MT, Kallmes DF. Have referral patterns for vertebroplasty changed since publication of the placebo-controlled trials? AJNR Am J Neuroradiol 2011;32(4):647–648. Sheehan KB, McMillan SJ. Response variation in e-mail surveys: an exploration. J Advert Res 1999;39(4):45–54. Impact of sham-controlled vertebroplasty trials on referral patterns at two academic medical centers 105 High-intensity, occupation-specific training in a series of firefighters during phase II cardiac rehabilitation Jenny Adams, PhD, Dunlei Cheng, PhD, and Rafic F. Berbarie, MD Six male firefighters who were referred to phase II cardiac rehabilitation after coronary revascularization participated in a specialized regimen of high-intensity, occupation-specific training (HIOST) that simulated firefighting tasks. During each session, the electrocardiogram, heart rate, and blood pressure were monitored, and the patients were observed for adverse symptoms. No patient had to discontinue HIOST because of adverse arrhythmias or symptoms. For physicians who must make decisions about return to work, the information collected over multiple HIOST sessions might be more thorough and conclusive than the information gained during a single treadmill exercise stress test (the recommended evaluation method). F irefighting is arduous and has one of the highest occupational fatality rates in the United States (1). Surprisingly, coronary heart disease (CHD), not injury, is the number one cause of on-duty deaths among firefighters (2). However, the vast majority of these firefighters were not previously diagnosed with CHD and had uncontrolled risk factors (3). Current recommendations state that firefighters with CHD should be restricted from performing strenuous emergency duties (4). To our knowledge, there are no data regarding firefighters’ exercise tolerance following successful revascularization of their CHD and hence no assessment of whether they are then able to perform simulated firefighting tasks. The National Fire Protection Agency, which promotes codes and standards for fire safety worldwide, has proposed guidelines for veteran firefighters who may want to return to work in the presence of CHD. These guidelines include seven criteria, four of which are clinical observations that can be obtained from a patient history: 1) no angina, 2) no major coronary artery stenosis (>70% of lumen), 3) normal left ventricular ejection fraction, and 4) no persistent modifiable risk factor for plaque rupture (i.e., tobacco use, hypertension, total cholesterol >180 mg/dL, low-density lipoprotein cholesterol >100 mg/dL, or glycated hemoglobin >7%). The other three criteria involve observations made during an exercise stress test: 5) exercise tolerance >12 metabolic equivalents (METs), 6) no exerciseinduced angina, and 7) no ischemia or ventricular arrhythmia during exercise (with imaging) (5). However, treadmill exercise stress tests are not always reliable predictors of performance in 106 activities that require both strength and endurance (6), such as firefighting. Deciding whether a firefighter should return to work on the basis of the results from a single treadmill exercise stress test might be inadequate considering the unique specificity and intensity of the job. In a prior study of the exercise tolerance of firefighters, we collected metabolic data on healthy subjects as they performed simulated firefighting tasks on an obstacle course (7). We then translated the study’s tasks, which required a mean level of 12 METs, into a telemetry-monitored program of high-intensity, occupation-specific training (HIOST) within the cardiac rehabilitation (CR) program at our institution. Our goal was to evaluate the firefighter-patient’s tolerance for performing strenuous occupational tasks in repeated sessions, with the resulting information assisting the physician’s decision about the patient’s physical potential for returning to work. Here, we report data from the first six patients with CHD to undergo this training. PATIENT TRAINING From June 2008 through May 2012, six male firefighters were referred to outpatient phase II CR in Dallas, Texas, following revascularization of CHD, and they consented to participate in CR 3 days per week. CR staff gave them the option of participating in HIOST or conventional CR; all selected the HIOST option. The hospital’s institutional review board approved the reporting of their data. The patients’ demographic and clinical information is summarized in the Table. At enrollment, all six patients were on an antiplatelet regimen and were taking lipid-lowering drugs and beta-blockers. In addition, one was taking a nitrate and diuretic; another was taking ranolazine for angina. From the Cardiac Rehabilitation Department, Baylor Jack and Jane Hamilton Heart and Vascular Hospital (Adams, Berbarie), the Institute for Health Care Research and Improvement, Baylor Health Care System (Cheng), and the Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center at Dallas and Baylor Hamilton Heart and Vascular Hospital (Berbarie). Dr. Cheng is now with the Division of Biostatistics, The University of Texas School of Public Health Dallas Regional Campus. Corresponding author: Jenny Adams, PhD, Cardiac Rehabilitation Department, Baylor Heart and Vascular Hospital, 411 N. Washington, Suite 3100, Dallas, TX 75246 (e-mail: jennya@BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):106–108 Table. Clinical characteristics of six male firefighters and the data from their high-intensity, occupation-specific training (HIOST) sessions after coronary revascularization Peak values during HIOST (mean ± SD)† Pt. no. (age, y) EF (%) BMI (kg/m2) Additional cardiac risk factors* 1 (61) 65 32.4 DM, FHx, PI, STR 2 (54) 50 35.1 PI, SM, STR – CABG 34 26 147 ± 5 143 ± 12 68 ± 10 21,220 ± 1844 3 (48) 50 28.2 – + PCI 28 20 142 ± 13 168 ± 28 83 ± 14 24,160 ± 4879 4 (58) 55 26.3 FHx, PI, STR + PCI, CABG 24 20 141 ± 9 163 ± 31 69 ± 8 22,767 ± 4793 5 (51) 50 25.3 FHx – PCI, CABG 25 15 139 ± 8 167 ± 24 85 ± 8 23,494 ± 4368 6 (52) NA 31.1 – – PCI 18 15 149 ± 9 202 ± 12 88 ± 10 29,958 ± 2744 MI Type of revasc. – PCI No. of sessions Total HIOST HR (bpm) SBP (mm Hg) DBP (mm Hg) RPP‡ 24 21 140 ± 13 174 ±17 84 ± 9 23,432 ± 3515 *Other than hypertension and hyperlipidemia (present in all six patients) and obesity (see BMI). †Peak heart rate recorded every session; peak blood pressure recorded a total of 73 times. ‡Calculated for sessions during which peak heart rate and blood pressure were recorded. BMI indicates body mass index; CABG, coronary artery bypass graft surgery; DBP, diastolic blood pressure; DM, diabetes mellitus; EF, ejection fraction; FHx, family history; HR, heart rate; MI, myocardial infarction; NA, not available (pending follow-up); PCI, percutaneous coronary intervention; PI, physical inactivity; RPP, rate-pressure product (heart rate × systolic blood pressure); SBP, systolic blood pressure; SM, smoking; STR, stress. The patients were monitored by telemetry during exercise training. Resting heart rate and blood pressure measurements were taken before and after each session, and the patients performed warm-up and cool-down routines. A physician was in the room and approved the exercise regimen. The patients participated in supervised endurance training (treadmill walking) during several early sessions (the number varied per individual) until their vital signs were found to respond appropriately to exercise. At that juncture, the patients began the subsequent HIOST sessions, which were specifically designed to mirror the occupational tasks included in our prior study of healthy firefighters (7). During HIOST, no calculated target heart rate range was used to restrict exercise intensity. Training was symptomlimited; patients were monitored for hypertension (blood pressure >240/110 mm Hg), hypotension (systolic blood pressure decrease of ≥10 mm Hg), elevated rate-pressure product (≥36,000), ventricular arrhythmias, ST depression, angina, dizziness, pain, shortness of breath, and perceived exertion. The HIOST workouts were customized by incrementally increasing cardiovascular intensity and weight loads over the course of the CR program exercise sessions. The patients wore weighted vests (10 to 55 pounds) as they completed the following occupation-specific tasks (Figure): • Carrying a weighted box ranging from 11.5 to 50 pounds (simulates carrying equipment) • Climbing stairs carrying a 15- or 30-pound hose (simulates carrying a high-rise hose pack to an upper-story location) • Dragging a 50-, 95-, or 165-pound dummy (simulates removing a victim from a fire scene) • Using a stair-climbing machine (simulates walking up stairs) • Pulling a 30- or 60-pound fire hose (simulates advancing a hose) April 2013 • Raising a pike pole weighing 5.5 to 15.4 pounds (simulates removing debris from a ceiling) • Hitting a tire for 20 to 60 seconds with a 9-pound sledgehammer (simulates forcible entry) The six patients participated in a total of 153 sessions; 36 consisted of supervised endurance training and 117 were HIOST. During each session, the peak exercise heart rate was determined from the electrocardiogram. Peak blood pressure was recorded a total of 73 times during HIOST, and the resulting rate-pressure product values were calculated (see the Table). None of the patients had to stop training because of adverse arrhythmias or symptoms. Peak heart rates were likely blunted by beta-blocker therapy, but all six patients were able to perform firefighting tasks that mirrored the 12-MET activities from the prior study. During exercise, their peak blood pressures remained well below 240/110 mm Hg, the limit recommended by established guidelines (8), and their rate-pressure product values were below the 36,000 threshold (9). DISCUSSION The American College of Sports Medicine endorses using specificity of training for cardiac patients who desire to return to manual labor occupations (10). To our knowledge, this is the first report of firefighters’ ability to perform occupation-specific tasks following successful coronary revascularization. The HIOST program has limitations. Because the CR setting lacks the danger and stress of actual fire suppression activities, the patients’ physiological responses during training may not reflect their responses on the job at a fire scene. In addition, the program cannot simulate many of the hazardous work conditions that firefighters must face, including exposure to smoke, carbon monoxide, fumes, and other chemicals (11); heat stress (12); and high noise levels (13). High-intensity, occupation-specific training in a series of firefighters during phase II cardiac rehabilitation 107 a b Acknowledgments Grant support was provided by the Harry S. Moss Heart Trust and the Baylor Health Care System Foundation, Dallas, Texas, through the Cardiovascular Research Review Committee and in cooperation with the Baylor Heart and Vascular Institute. The authors thank the committee for their continued support of cardiovascular rehabilitation research projects. Beverly Peters, MA, ELS, a freelance medical editor, assisted with manuscript development and preparation. 1. Fabio A, Ta M, Strotmeyer S, Li W, Schmidt E. Incidentlevel risk factors for firefighter injuries at structural fires. J Occup Environ Med 2002;44(11):1059–1063. 2. Kales SN, Soteriades ES, Christophi CA, Christiani DC. Emergency duties and deaths from heart disease among firefighters in the United States. N Engl J Med 2007;356(12):1207–1215. 3. Kales SN, Soteriades ES, Christoudias SG, Christiani DC. Firefighters and on-duty deaths from coronary c d heart disease: a case control study. Environ Health 2003;2(1):14. 4. Soteriades ES, Smith DL, Tsismenakis AJ, Baur DM, Kales SN. Cardiovascular disease in US firefighters: a systematic review. Cardiol Rev 2011;19(4):202–215. 5. Hales T. Practical application of the NFPA 1582 Standard [presentation]. Quoted by Mittelman J. How to reduce cardiovascular mortality in your fire department. New England College of Occupational and Environmental Medicine (NECOEM) Reporter 2008;2(24):1–2, 5. Available at http://www.necoem.org/newsletter_archive2.html; accessed January 11, 2013. 6. Åstrand P-O, Rodahl K, Dahl HA, Strømme SB. Textbook of Work Physiology: Physiological Bases of Exercise, 4th ed. Champaign, IL: Human Kinetics, 2003:346. 7. Adams J, Roberts J, Simms K, Cheng D, Hartman J, Bartlett C. Measurement of functional capacity requirements to aid in development of an occupation-specific rehabilitation training program to help firefighters with cardiac disease safely return to work. Am J Cardiol 2009;103(6):762–765. Figure. Four of the occupation-specific activities performed by firefighters while wearing a weighted 8. American Association of Cardiovascular and Pulmonary vest: (a) after climbing stairs with a hose pack, (b) dragging a dummy, (c) using a stair-climbing Rehabilitation. Guidelines for Cardiac Rehabilitation and machine, and (d) hitting a tire with a sledgehammer. Secondary Prevention Programs, 4th ed. Champaign, IL: Human Kinetics, 2004:115. 9. Adams J, Cline MJ, Hubbard M, McCullough T, Hartman J. A new Despite these limitations, HIOST allows patients to perparadigm for post-cardiac event resistance exercise guidelines. Am J Cardiol form simulated firefighting tasks while their electrocardiogram, 2006;97(2):281–286. 10. American College of Sports Medicine. ACSM’s Guidelines for Exercise blood pressure, and heart rate are monitored in a clinical setting, Testing and Prescription, 8th ed. Philadelphia: Lippincott Williams & providing information about exercise-induced angina, ischemia, Wilkins, 2010:222. and arrhythmias over multiple sessions. For physicians who 11. Carey MG, Thevenin BJ. High-resolution 12-lead electrocardiograms of must make decisions about return to work, these findings might on-duty professional firefighters: a pilot feasibility study. J Cardiovasc Nurs be more thorough and conclusive than the information gained 2009;24(4):261–267. 12. Rossi R. Fire fighting and its influence on the body. Ergonomics during a single treadmill exercise stress test. 2003;46(10):1017–1033. 13. Tubbs RL. Noise and hearing loss in firefighting. Occup Med 1995;10(4):843–856. 108 Baylor University Medical Center Proceedings Volume 26, Number 2 Morphological features of temporal arteritis William C. Roberts, MD, Saleha Zafar, MD, and Jo Mi Ko, BA Although it varies from center to center, the frequency of temporal artery biopsy in patients suspected of having temporal arteritis (TA) is relatively small. Most commonly, patients suspected of having TA are placed on prednisone for varying periods of time, and if symptoms disappear or lessen the diagnosis is made. During a recent 13-year period at Baylor University Medical Center at Dallas, 15 patients with TA had the diagnosis of TA confirmed by histological examination of a biopsy of one temporal artery. The length of the biopsied artery varied from 0.7 to 5.5 cm (mean 2.7). The 15 patients ranged in age from 68 to 94 years (mean 82, median 85), and 11 (73%) were women. In 13 of the 15 patients (87%), the lumen of the temporal artery was narrowed >95% in cross-sectional area by the panarteritis, and the temporal artery was associated with giant cells in 11 patients (73%). Large collections of erythrocytes were present in the inflamed arterial walls in 5 patients (33%). All 15 patients were treated with varying doses of prednisone with favorable response in each. Eight patients (53%) died from 1 to 105 months (mean 52, median 57) after biopsy of the temporal artery. We have neither positive nor negative evidence that the TA played a role in the patients’ death. Despite the present study and numerous others in the last 70 years, the cause of TA remains a mystery. I n 1932 and in 1934, Bayard T. Horton, a vascular specialist at the Mayo Clinic, and others (1, 2) reported two patients with headache, scalp tenderness, weight loss, fever, and night sweats, and histologic examination of one biopsied temporal artery disclosed granulomatous panarteritis. Thereafter, the condition was called temporal arteritis (TA) by some and Horton’s disease by others. In 1937, Horton and Magath (3) described visual loss, jaw claudication, and elevated erythrocyte sedimentation rates in several additional patients with the disease. According to Boes (4), Horton in 1942 was the first to give a patient with TA Kendall’s adrenocorticoid extract (nonpure), but apparently it had no effect on the patient’s disease. Shick and colleagues (5), in 1950, also at the Mayo Clinic, reported clinical improvement in two patients with TA using a pure form of cortisone. The present study summarizes findings in 15 patients with TA seen at Baylor University Medical Center at Dallas (BUMC) in the last 13 years and describes in detail the various histological features in the temporal artery in these patients. Proc (Bayl Univ Med Cent) 2013;26(2):109–115 METHODS Cases coded as TA by the surgical pathology division of the Department of Pathology of BUMC from 1997 through 2012 were retrieved. Fifteen such cases having biopsy of one temporal artery were found. The paraffin blocks of the temporal artery in each patient were retrieved and recut. The resulting 6-micron-thick sections were stained by both the hematoxylineosin method and by the Movat method, and the sections were examined. The clinical records in each patient were retrieved and examined in the BUMC record room, and pertinent findings were tabulated in each patient. Finally, the Social Security Death Index was searched to determine how many of the 15 patients had died. RESULTS Pertinent findings in the 15 patients are summarized in Tables 1 and 2. The 15 patients ranged in age from 68 to 94 years (mean 82) at the time of the temporal artery biopsy; 11 were women and 4 were men. The age at biopsy in all 15 patients corresponded to the age at which symptoms and/or signs of TA appeared. The symptoms at the time of temporal artery biopsy are displayed for each patient in Table 1: headache in 12, visual disturbance in 10, mastication pain in 7, and temporal artery tenderness in 6. At the time of biopsy, the indirect systemic arterial pressure was ≥140 mm Hg systolic and/or ≥90 mm Hg diastolic in 11 patients (73%). The body mass index was >25 kg/m2 in 8 of the 15 patients, but in none was it ≥30 kg/m2. Anemia (hematocrit <35%) was present in 8 (57%) of the 14 patients in which the result of this test was available. The platelet count was >250 mm3 in 9 of the 11 patients in whom it was performed. The erythrocyte sedimentation rates were elevated (>20 mm/hour) in all 10 patients where the results were available. The serum C-reactive protein was elevated in all 5 patients in which it was done. One patient (#2) had an aortic aneurysm, and one patient (#8) had had a stroke a few months before From the Baylor Heart and Vascular Institute (Roberts, Zafar, Ko) and the Departments of Pathology and Internal Medicine (Division of Cardiology) (Roberts), Baylor University Medical Center at Dallas. Corresponding author: William C. Roberts, MD, Baylor Heart and Vascular Institute, 621 North Hall Street, Dallas, TX 75226 (e-mail: wc.roberts@ BaylorHealth.edu). 109 BMI indicates body mass index; BP, blood pressure; CRP, C-reactive protein; CS, cigarette smokers; ESR, erythrocyte sedimentation rate; H, headache; HCT, hematocrit; Hgb, hemoglobin; LC, leg claudication; MP, mastication pain; PR, polymyalgia rheumatica; S/D, peak systole/end diastole; VD, visual disturbance; –, not done, not applicable, or no information. 60 19 26.2 6 281 4/13/2009 15 94 M – – 94 + + + 0 + + + 160/90 14.3 40.0 41 50 3 25.4 19 369 8/22/2008 14 83 M – – 83 0 0 + 0 0 0 0 115/70 9.9 29.5 103 60 60 4 – 29.8 25.1 – – – 57 258 – 32.0 – – 11.0 110/70 155/95 + 0 + + 0 0 0 + + 0 + 0 + 0 68 81 – 68 3 – M M 13 68 9/9/2010 4/25/1998 12 81 60 24 – q 90 2/10/2000 11 F 28 92 90 + 0 0 0 0 0 0 175/80 13.6 32.4 21.8 60 60 11 14 29.1 20.8 – 28 q 269 565 33.5 9.8 220/80 140/60 + + 0 0 0 0 0 0 0 + + 0 + + 89 86 – 96 74 – F 86 9/8/2004 89 3/26/2002 9 10 F 11.2 29.9 130 60 60 0.5 0.25 26.0 q q 24.3 26 92 245 230 32.2 35.8 12.1 10.6 140/80 150/55 0 0 + 0 0 + 0 0 + + + 0 0 + 85 86 – 85 1 – F F 86 8 85 3/22/2001 11/22/2010 7 60 60 – 73 23.0 24.6 – – – 121 347 379 32.0 38.2 12.4 10.5 130/60 130/90 0 + + 0 0 + + 0 + 0 + 0 + + 80 82 90 85 65 87 F F 1/29/2002 6 82 11/21/2002 5 80 60 40 17 – 27.1 26.2 – – 40.1 – 76 470 37.0 11.5 13.3 180/90 140/80 0 0 0 0 0 0 + 0 + 0 0 0 + + 77 77 – 85 105 – F 77 6/25/1997 10/23/2001 4 2 3 8/3/2001 1 F 331 8/6/1998 Patient 77 60 70 73 26 20.0 20.8 – – – – 35.2 26.9 11.7 8.5 170/75 130/80 0 + + + 0 0 + 0 + + + + + + 75 75 – 79 50 – F Date of biopsy 75 LC PR CS VD MP H Symptoms at time of biopsy Sex F BMI (kg/m2) CRP (mg/ dL) ESR (mm/ hr) BP s/d (mm Hg) Hgb (g/dL) HCT (%) Platelet count (mm3) Age at symptom onset (yr) Age at death (yr) Age at biopsy (years) 75 Maximal dose of prednisone (mg) Minimal time on prednisone (mo) Temporal artery tenderness Interval from biopsy to death (mo) Table 1. Clinical and laboratory findings in the 15 patients with temporal arteritis confirmed by biopsy and treated with prednisone 110 Baylor University Medical Center Proceedings biopsy. The length of the temporal artery biopsied ranged from 0.7 to 5.5 cm (mean 2.7); sample images and descriptions appear in Figures 1 to 9. In 13 of the 15 patients (87%), the lumen of the temporal artery was narrowed >95% in cross-sectional area. The temporal artery was associated with giant cells in 11 patients (73%). All 15 patients received prednisone (maximal dose 40–70 mg) for 0.25 to 73 months (mean 22), and all had symptomatic improvement, including 5 with loss or virtual loss of symptoms. DISCUSSION It might seem a bit inappropriate in 2013 to report a series of only 15 patients with biopsy-proven TA when others have reported such large series of patients with biopsy-proven TA (6–35). Gonzalez-Gay and colleagues (13, 19, 20, 25, 26, 28, 31), for example, in 7 articles from 1998 to 2011 described anywhere from 161 to 255 patients with biopsy-proven TA (called “giant cell arteritis” by the authors), but none contained a photomicrograph of a temporal artery. Indeed, of the 30 studies presented in Table 3 (6–35), only two included a photomicrograph of a temporal artery, and in both only hematoxylineosin–stained sections had been used. It is not possible to demonstrate the locations of the panarteritis, i.e., how much of the process involved the intima, media, and adventitia, without an elastic tissue stain that readily identifies the internal and external elastic membranes allowing clear demonstration of media, thus separating it from the intima and adventitia. We employed the Movat stain for this purpose in our study (36). We prefer the phrase “temporal arteritis” to the phrase “giant cell arteritis” because giant cells are not seen in all TA patients having biopsies of the temporal arteries. Among our 15 patients, we found giant cells in only 11. Mahr and colleagues (37) suggested that finding giant cells in patients with TA is determined in part by the lengths of the temporal arteries examined. These authors examined surgical Volume 26, Number 2 Table 2. Morphological findings in the 15 patients with biopsy-proven temporal arteritis Cross-sectional narrowing Collection of red blood cells in intima Lymphocytes Giant cells 3 >95% 0 +++ ++ 11 2 >95% + +++ ++ 2.4 8 2 >95% 0 +++ ++ 4 2.0 8 2 >95% + +++ ++ 5 2.4 12 2 >95% + +++ ++ 6 0.7 3 2 >95% 0 + 0 7 2.6 8 2 51%–75% + + 0 8 2.2 4 2 >95% 0 +++ ++ 9 5.5 19 6 >95% 0 +++ ++ 10 3.0 8 4 >95% 0 +++ + 11 0.7 2 2 >95% 0 + + 12 1.9 4 2 >95% + +++ ++ 13 2.1 6 3 >95% 0 +++ ++ 14 3.5 7 4 >95% 0 +++ 0 15 3.0 7 3 51%–75% 0 +++ 0 Length (cm) of excised TA Number of histological cross-sections Maximal diameter (mm) of crosssections 1 4.2 8 2 4.7 3 Patient TA indicates temporal arteritis. a b c routine endeavor. A near universal observation in TA is a rapid, sometimes dramatic, diminution or loss of symptoms after corticosteroid therapy has been initiated. If there is not a quick symptomatic response, biopsy e d can then be performed. There appears to be little change in the histologic features of the TA before corticosteroid therapy and up to about 6 weeks after initiation of therapy (10). A report by Guevara et al described Figure 1. Patient 1. Various views of the temporal artery. (a) Movat-stained section (×40) showing relatively intact media (pink), very thickened intima (green) with severe luminal narrowing, and severely thickened a positive biopsy after 6 months of predfibrous tissue of the adventitia (tan). (b) Hematoxylin-eosin (H&E)–stained section showing numerous inflam- nisone treatment (38). If a patient with matory cells involving the outer intima, media, and inner adventitia (×100). (c) A close-up showing intimal suspected TA has a negative biopsy of the granulomatous-type cells adjacent to the media with penetration of the media (H&E, ×400). (d) Another temporal artery, is it useful then to biopsy view showing an inflamed nodule in brackets in the adventitia (H&E, ×40). (e) A close-up of that nodule the contralateral temporal artery? Accord(H&E, ×400). ing to a study by Boyev and colleagues (18), biopsy of one temporal artery in a patient reports of temporal artery biopsies in 223 patients with TA and with TA provides a 97% chance that the same findings would be found that 164 (74%) of the reports mentioned the presence of present in the contralateral temporal artery, so that the additional giant cells. These authors also mentioned that a temporal artery biopsy would rarely be useful diagnostically. length of at least 0.5 cm was sufficient for diagnosis of TA. Our On occasion, TA resolves without corticosteroid therapy. smallest length among the patients was 0.7 cm. Among the Horton et al, in their original two patients, described tempofour patients in whom we did not see giant cells, the lengths rary remissions with relapses (1), and they later described seven of the temporal artery biopsied were 0.7, 2.6, 3.0, and 3.5 cm; additional patients in whom remission occurred without drug the latter three lengths were among the longest in the patients therapy months after diagnosis (3). Patients have been described we studied. where headaches and local symptoms have disappeared simply Although the present study focuses on the histologic features by removal of a portion of the temporal artery for diagnostic of TA, one might reasonably ask if biopsy of this artery is a useful purposes (39, 40). April 2013 Morphological features of temporal arteritis 111 a a b c b Figure 2. Patient 2. (a) A Movat-stained section (×100) of temporal artery with severely narrowed lumen (within the green portion) of the intima with blood (red) within the intimal plaque and marked disruption of the internal elastic membrane (black). The adventitia is thickened by dense fibrous tissue (tan). (b) The same section stained by hematoxylin-eosin (×100). (c) A close up of a portion of the media showing numerous mononuclear cells (×400). Figure 4. Patient 6. Two views of Movat-stained sections of the temporal artery showing (a) virtual occlusion (×100) and (b) severe narrowing (×100). The internal elastic membrane (black) is interrupted and the quantity of fibrous tissue in the adventitia is considerably less than in previously illustrated cases. a Figure 3. Patient 4. Movat-stained section (×40) of the temporal artery showing near-total occlusion of the lumen, blood (red) within the intimal plaque, disruption of the internal elastic membrane (black), and severely thickened adventitia by dense fibrous tissue (tan). The absence of much lumen and the marked thickening of the adventitia by dense fibrous tissue makes these arteries, by external palpation, quite firm and nodular. b c Figure 5. Patient 8. (a) A Movat-stained section of the temporal artery showing near occlusion of the lumen by fibrous tissue and mucopolysaccharide material (green) and dense fibrous tissue causing considerable thickening of the adventitia. (b) Hematoxylin-eosin stain (×40) of another section of the same artery showing numerous inflammatory cells between the 8:00 and 11:00 positions. (c) Close-up (×400) of a portion of the inflammatory cells. 112 Baylor University Medical Center Proceedings Volume 26, Number 2 a b a Figure 6. Patient 9. (a) View of a hematoxylin-eosin–stained section (×20) of the temporal artery with virtual total occlusion of its lumen. The darkened area represents collections of inflammatory cells. The adventitia is thickened by fibrous tissue. (b) A close-up (×400) of a minute portion of the inflammatory infiltrates. Granulomatous-type cells and a giant cell are visible. a Figure 9. Patient 13. (a) A Movat-stained section of the temporal artery (×40) with severe luminal narrowing. The lumen in all sections in temporal arteritis tends to be in the more central portion of the artery and not on the periphery, as it is in typical atherosclerosis. (b) A close-up hematoxylin-eosin–stained section (×400) shows several giant cells in the outer intima adjacent to the media. These cells are lined up perpendicular to the smooth muscle cells in the media. 1. 2. 3. 4. 5. b 6. c 7. 8. 9. 10. Figure 7. Patient 9. (a) A Movat-stained section (×40) of three branches of a temporal artery with narrowing of each branch, marked disruption of the media in two of the branches, and dense fibrous tissue in the adventitia. (b) A close-up of a hematoxylin-eosin–stained section (×400) of a portion of the inflammatory cells in the media. (c) Another hematoxylin-eosin stained section (×400) showing giant cells among the collection of cells. 11. 12. 13. a b 14. 15. Figure 8. Patient 10. A Movat-stained section of the temporal artery showing (a) severe narrowing of the lumen (×100) and (b) less narrowing (×100). The amount of adventitial fibrous tissue is considerable. Inflammatory cells are present in the intima, media, and adventitia. The dark staining in the medial wall in part b represents calcific deposits. April 2013 b 16. Horton BT, Magath TB, Brown GE. An undescribed form of arteritis of the temporal vessels. Proc Staff Meet Mayo Clinic 1932;7:700–701. Horton BT, Magath TB, Brown GE. Arteritis of the temporal vessels: a previously undescribed form. Arch Intern Med 1934;53:400–409. Horton BT, Magath TB. Arteritis of the temporal vessels: report of seven cases. Proc Staff Meet Mayo Clinic 1937;12:548–553. Boes CJ. Bayard Horton’s clinicopathological description of giant cell (temporal) arteritis. Cephalalgia 2007;27(1):68–75. Shick RM, Baggenstoss AH, Fuller BF, Polley HF. Effects of cortisone and ACTH on periarteritis nodosa and cranial arteritis. Proc Staff Meet Mayo Clin 1950;25(17):492–494. Birkhead NC, Wagener HP, Shick RM. Treatment of temporal arteritis with adrenal corticosteroids; results in fifty-five cases in which lesion was proved at biopsy. J Am Med Assoc 1957;163(10):821–827. Huston KA, Hunder GG, Lie JT, Kennedy RH, Elveback LR. Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 1978;88(2):162–167. Graham E, Holland A, Avery A, Russell RW. Prognosis in giant-cell arteritis. Br Med J (Clin Res Ed) 1981;282(6260):269–271. Nordborg E, Bengtsson BA. Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. BMJ 1989;299(6698):549–550. Achkar AA, Lie JT, Hunder GG, O’Fallon WM, Gabriel SE. How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann Intern Med 1994;120(12):987–992. Lie JT. Aortic and extracranial large vessel giant cell arteritis: a review of 72 cases with histopathologic documentation. Semin Arthritis Rheum 1995;24(6):422–431. Salvarani C, Gabriel SE, O’Fallon WM, Hunder GG. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med 1995;123(3):192–194. González-Gay MA, Blanco R, Rodríguez-Valverde V, Martínez-Taboada VM, Delgado-Rodriguez M, Figueroa M, Uriarte E. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998;41(8):1497–1504. Cid MC, Font C, Oristrell J, de la Sierra A, Coll-Vinent B, López-Soto A, Vilaseca J, Urbano-Márquez A, Grau JM. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis Rheum 1998;41(1):26–32. Duhaut P, Pinede L, Demolombe-Rague S, Loire R, Seydoux D, Ninet J, Pasquier J; Groupe de Recherche sur l’Artérite à Cellules Géantes. Giant cell arteritis and cardiovascular risk factors: a multicenter, prospective case-control study. Arthritis Rheum 1998;41(11):1960–1965. Duhaut P, Pinède L, Bornet H, Demolombe-Ragué S, Dumontet C, Ninet J, Loire R, Pasquier J; Groupe de Recherche sur l’Artérite à Cellules Géantes. Biopsy proven and biopsy negative temporal arteritis: Morphological features of temporal arteritis 113 114 Baylor University Medical Center Proceedings Volume 26, Number 2 3001 225 Walvick, 2011 Ninan, 2011 225 459 174 26 287 30 57 255 49 240 151 74 9 147 161 161 722 74 207 207 200 239 115 67 175 284 90 38 55 62/163 – 80/94 – 132/155 10/20 28/50 116/139 0/49 110/130 36/137 – 3/8 38/109 79/82 79/82 – 16/58 50/157 118/282 59/141 106/133 22/103 21/51 190/345 – 26/64 9/33 28/27 M/F (78.2) – (74.2) – 50–80+ – (77.5) 56–89 (74.6) 55–94 (75) 50–69 (64.1) 50–80+ (74) 50–80+ – 65–90 (75) – (75) 50–80+ (75) 50–80+ (75) – 50+ (72) 50+ (74.5) 50+ (74) 57–92 (74.5) 50+ (73.5) 50–80+ 54–96 (69) 31–93 (71.7) – 55–88 56–92 (75) 60–83 Age range (mean) 14 9 14 19 27 6 18 25 9 23 50 11 – 22 18 18 28 36 6 6 16 21 42 25 3 10 10 25 6 Length of study (yr) 5.5 – 3.5 – – – – – 3 – 6.8 2 – – – – – – 36 – – – – – – 1 11 19 – Followup (yr) ESR indicates erythrocyte sedimentation rate; F, female; M, male; TA, temporal arteritis; −, no information. 207 107 Zhou, 2009 Martinez-Lado, 2011 287 240 Gonzalez-Gay, 2005 Gonzalez-Gay, 2009 173 Salvarani, 2004 30 181 Hall, 2003 78 11 Ray-Chaudhur, 2002 Makkuni, 2008 174 Liozon, 2001 Narvaez, 2007 190 Gonzalez-Gay, 2001 49 190 Gonzalez-Gay, 2000 255 756 Boyev, 1999 Gonzalez-Gay, 2007 148 Brack, 1999 Larsson, 2006 292 Duhaut, 1999 125 Salvarani, 1995 400 72 Lie, 1995 200 535 Achkar, 1994 Duhaut, 1998 284 Nordborg, 1989 Cid, 1998 90 Graham, 1981 239 42 Huston, 1978 Gonzalez-Gay, 1998 55 Patients (n) Birkhead, 1957 First author, year of publication Biopsyproven TA (n) – 12 71 0 – – – – – – – – – – – – – – – 1 – – – – – – 7 3 1 – Deaths attributed to TA – 0 – – – – – – – – – – – – – – – 38 – – – – – – 82 32 21 – Deaths (n) – 81 92.7 – – 78.5 94.4 – – 93 – – 66 90 93 93 – – 88 – 82.7 94 – 96 63 – 81 96 – Mean ESR values (mm/hr) – – 11.7 – – – 11.4 – – 11.7 – – – 11.3 11.8 11.8 – – 15.6 – 12.2 – – – – – – 11.5 – Median hemoglobin values (g/dl) – 391,000 392,000 – – – 340,000 – – 397,000 – – – 419,000 412,816 412,816 – – 424,000 – 337,000 – – – – – – – – Median platelet count (mm3) – – 36 – 138 12 16 89 – 21 – – 5 58 – 42 – 18 20 – 28 64 – – – – 55 17 21 Visual loss (n) – – 174 – – – 78 – – – – – 11 174 – – – 74 292 – – 239 – – 249 – 90 42 55 Received corticosteroids (n) Table 3. Reported studies of patients with temporal arteritis confirmed by biopsy of the temporal artery – – 44.1 – – – 1 – – – – – 1.5 – – – – – 36 – – – – – – – 84 77 15 Maximal length of treatment (mo) – – 71 – – – – – – – – – – – – – – – – – – – – – – – 18 11 – Patients that relapsed (n) 0 0 0 + 0 + 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Temporal artery photo mics – – – 26 – – – – – – – – 7 – – – – – – – – – – – – – – – – Giant cell histology (n) 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. differences in clinical spectrum at the onset of the disease. Ann Rheum Dis 1999;58(6):335–341. Brack A, Martinez-Taboada V, Stanson A, Goronzy JJ, Weyand CM. Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum 1999;42(2):311–317. Boyev LR, Miller NR, Green WR. Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 1999;128(2):211–215. González-Gay MA, García-Porrúa C, Llorca J, Hajeer AH, Brañas F, Dababneh A, González-Louzao C, Rodriguez-Gil E, Rodríguez-Ledo P, Ollier WE. Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients. Medicine (Baltimore) 2000;79(5):283–292. González-Gay MA, Garcia-Porrua C, Rivas MJ, Rodriguez-Ledo P, Llorca J. Epidemiology of biopsy proven giant cell arteritis in northwestern Spain: trend over an 18 year period. Ann Rheum Dis 2001;60(4):367–371. Liozon E, Herrmann F, Ly K, Robert PY, Loustaud V, Soria P, Vidal E. Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 2001;111(3):211–217. Ray-Chaudhuri N, Kiné DA, Tijani SO, Parums DV, Cartlidge N, Strong NP, Dayan MR. Effect of prior steroid treatment on temporal artery biopsy findings in giant cell arteritis. Br J Ophthalmol 2002;86(5):530–532. Hall JK, Volpe NJ, Galetta SL, Liu GT, Syed NA, Balcer LJ. The role of unilateral temporal artery biopsy. Ophthalmology 2003;110(3):543– 548. Salvarani C, Crowson CS, O’Fallon WM, Hunder GG, Gabriel SE. Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, over a fifty-year period. Arthritis Rheum 2004;51(2):264–268. Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S, Garcia-Porrua C, SanchezAndrade A, Paz-Carreira J, Martin J, Llorca J. Giant cell arteritis: laboratory tests at the time of diagnosis in a series of 240 patients. Medicine (Baltimore) 2005;84(5):277–290. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, Garcia-Porrua C, Sanchez-Andrade A, Llorca J. Giant cell arteritis: disease patterns of clinical presentation in a series of 240 patients. Medicine (Baltimore) 2005;84(5):269–276. Larsson K, Mellström D, Nordborg E, Odén A, Nordborg E. Early menopause, low body mass index, and smoking are independent risk factors for developing giant cell arteritis. Ann Rheum Dis 2006;65(4):529–532. Gonzalez-Gay MA, Miranda-Filloy JA, Lopez-Diaz MJ, Perez-Alvarez R, Gonzalez-Juanatey C, Sanchez-Andrade A, Martin J, Llorca J. Giant cell April 2013 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. arteritis in northwestern Spain: a 25-year epidemiologic study. Medicine (Baltimore) 2007;86(2):61–68. Narváez J, Bernad B, Roig-Vilaseca D, García-Gómez C, Gómez-Vaquero C, Juanola X, Rodriguez-Moreno J, Nolla JM, Valverde J. Influence of previous corticosteroid therapy on temporal artery biopsy yield in giant cell arteritis. Semin Arthritis Rheum 2007;37(1):13–19. Makkuni D, Bharadwaj A, Wolfe K, Payne S, Hutchings A, Dasgupta B. Is intimal hyperplasia a marker of neuro-ophthalmic complications of giant cell arteritis? Rheumatology (Oxford) 2008;47(4):488–490. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Gomez-Acebo I, PegoReigosa R, Lopez-Diaz MJ, Vazquez-Triñanes MC, Miranda-Filloy JA, Blanco R, Dierssen T, Gonzalez-Juanatey C, Llorca J. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine (Baltimore) 2009;88(4):227–235. Zhou L, Luneau K, Weyand CM, Biousse V, Newman NJ, Grossniklaus HE. Clinicopathologic correlations in giant cell arteritis: a retrospective study of 107 cases. Ophthalmology 2009;116(8):1574–1580. Martinez-Lado L, Calviño-Díaz C, Piñeiro A, Dierssen T, VazquezRodriguez TR, Miranda-Filloy JA, Lopez-Diaz MJ, Blanco R, Llorca J, Gonzalez-Gay MA. Relapses and recurrences in giant cell arteritis: a population-based study of patients with biopsy-proven disease from northwestern Spain. Medicine (Baltimore) 2011;90(3):186–193. Walvick MD, Walvick MP. Giant cell arteritis: laboratory predictors of a positive temporal artery biopsy. Ophthalmology 2011;118(6):1201–1204. Ninan J, Nguyen AM, Cole A, Rischmueller M, Dodd T, RobertsThomson P, Hill CL. Mortality in patients with biopsy-proven giant cell arteritis: a south Australian population-based study. J Rheumatol 2011;38(10):2215–2217. Movat HZ. Demonstration of all connective tissue elements in a single stain: pentochrome stains. Arch Pathol 1955;60:289–295. Mahr A, Saba M, Kambouchner M, Polivka M, Baudrimont M, Brochériou I, Coste J, Guillevin L. Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better? Ann Rheum Dis 2006;65(6):826–828. Guevara RA, Newman NJ, Grossniklaus HE. Positive temporal artery biopsy 6 months after prednisone treatment. Arch Ophthalmol 1998;116(9):1252–1253. Bowers JM. Arteritis of the temporal vessels: report of a case. Arch Intern Med 1940;66:384–392. Harrison CV. Giant-cell or temporal arteritis: a review. J Clin Pathol 1948;1:197–211. Morphological features of temporal arteritis 115 Quality of life of HIV/AIDS patients in a secondary health care facility, Ilorin, Nigeria Shakirat I. Bello, MPharm, and Ibrahim K. Bello, MPharm This study evaluated the quality of life (QoL) and associated factors for 160 HIV/AIDS patients in Sobi Specialist Hospital, Ilorin, Nigeria. The patients were assessed with the World Health Organization Quality of Life Questionnaire-Short Version. Frequency distribution, percentages, and means were employed for the statistical analysis of the results. The mean age of the HIV/AIDS patients was 38.0 years; 70% were females, 55% were literates, more than three quarters were married, and one third were businessmen/women. The overall mean scores for healthrelated QoL were 72 for the physical domain, 67 for the psychological domain, 65 for the environment domain, and 47 for the social domain. Significant differences were observed in all domains among patients who had received 12 months of antiretroviral therapy compared with those who had just begun therapy. Marital status, fewer pills, and longer duration of therapy appeared to predict better QoL in this study. The improved QoL in the physical, psychological, and environmental domains is suggestive of the interventions offered to the patients by the pharmacists in this setting. T he pandemic of HIV and AIDS has led to serious health and socioeconomic challenges for more than two decades (1). The epidemic has also facilitated the reemergence of disease conditions such as pulmonary tuberculosis, which cause physical and psychological damage and decreased quality of life (QoL) (2, 3). Based on an overall national prevalence of 4.1%, it is estimated that in 2012, 3.6 million Nigerians were living with HIV/AIDS, 2.5 million children were orphaned, and about 1000 new cases of HIV were discovered daily (4). With this alarming increase of the HIV/AIDS pandemic in developing countries and the limited accessibility and availability of highly active antiretroviral therapy (HAART), the majority of HIV/AIDS patients continue to suffer with the disease, with a serious impact on their QoL (5). Many HIV patients battle numerous social problems such as stigma and depression, which affect their QoL in terms of their physical, mental, and social health (6). QoL is an indicator of not only how well an individual functions in daily life, but also how the individual’s perceptions of health status influence his or her life (7, 8). In Nigeria, QoL has been found to be determined by education, income, family support, HIV serostatus, and patient age (9). Further, a study reported higher QoL scores in the physical, 116 psychological, and environmental domains and a relatively lower score in the social domain among HIV patients in Nigeria (10). Mweemba et al (11) suggested that periodical assessment of QoL of people living with HIV/AIDS is imperative for holistic care, thereby ameliorating the symptoms of ill health. Such assessments are useful not only in documenting patients’ perceived burden of chronic disease, but also in evaluating treatment effects (12). This study was therefore conducted to assess QoL of HIV/ AIDS patients in Sobi Specialist Hospital, Ilorin, Nigeria. METHODS The study site was the HIV/AIDS treatment center, Sobi Specialist Hospital, Ilorin, Kwara State. Sobi Specialist Hospital, Ilorin is a secondary health care facility established in April 1985 by the Kwara State Government, located in the north central part of Nigeria. The primary ethnic group of Kwara State is Yoruba, with Nupe, Bariba, and Fulani as minorities. The facility provides health services for citizens in Kogi, Niger, Osun, Oyo, and Ekiti States and other neighboring states in Nigeria. The hospital receives referrals of HIV-positive patients from surrounding private hospitals and primary health care centers. The center was funded by Friends in Global Health and supported by the Kwara State Government. As at June 2011, the clinic had registered 616 HIV/AIDS patients, of whom 554 were on HAART. This cross-sectional study involved 160 patients selected from the population of 616 HIV/AIDS-positive patients receiving services and care from Sobi Specialist Hospital, Ilorin, during the period of April to October 2011. Included in the sample were known HIV/AIDS patients who were 18 years or older and regularly refilled their prescriptions in the pharmacy unit of the center. Newly diagnosed patients and children (less than 18 years) were excluded. At the time of drug refill, an information sheet describing the significance of the study was presented to the patients. Those who showed interest in participating were asked to sign informed consent forms. Ethical approval for the From the Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin, Nigeria (S. Bello); and the Department of Pharmacy, University of Ilorin Teaching Hospital, Ilorin, Nigeria (I. Bello). Corresponding author: Shakirat I. Bello (e-mail: sibello10@yahoo.com). Proc (Bayl Univ Med Cent) 2013;26(2):116–119 study was obtained from the Ethics and Research Committee of Kwara State Ministry of Health, Ilorin. The patients were interviewed using a pretested structured questionnaire to obtain information on sociodemographic status and treatment variables. During the interview, all drug therapy problems encountered were identified, resolved, and prevented through pharmacist intervention in collaboration with other health care providers. Counseling, education, training, and information interventions on HIV/AIDS, drug adherence, good nutrition, safe drinking water, and malaria prevention were also offered to the patients on a monthly basis. The English version of the World Health Organization Quality of Life Questionnaire-Short Version (WHOQoLBREF) was used to assess the QoL of these patients. This questionnaire consists of 26 items in four domains. The physical health domain, with seven items, assesses the impact of disease on the activities of daily living, dependence on medicinal substances, fatigue, restricted mobility, presence of pain and discomfort, sleep and rest, a lack of energy and initiative, and perceived working capacity. The psychological well-being domain includes eight items that assess the patient’s thoughts about body image and appearance, positive feelings, negative feelings, self-esteem and personal beliefs, higher cognitive functions, spirituality, anxiety, suicide, and depression. The third domain, social relationships, has three items that assess personal relationships, social contacts, social support, and sexual activity. The final domain, environment, with eight items, assesses areas such as freedom, quality of home environment, physical safety and security, financial status, involvement in recreational activity, health, and social care quality and accessibility. The English version of the instrument was translated to the Yoruba language (the main language understood by most patients); the translated version was validated prior to administration to participants. The QoL of each patient was assessed monthly during drug refill at the main pharmacy of the hospital. The participants who could not read were interviewed, while literates completed the questionnaire under the supervision of the researchers. Participants selected the number on a 5-point Likert-type scale that best represented their opinion, based on their life over the previous 4 weeks. In the scale, 1 indicated low and negative perceptions, and 5 indicated high and positive perceptions, which denoted better QoL. Negatively worded items were reverse scored, and all scores were checked for appropriate range (between 1 and 5). Descriptive statistics, including frequency, means, percentages, minimum values, and maximum values, were calculated. Each item contributed equally to the domain score. To transform scores so that they were equivalent to those used for the WHOQOL-100, two steps were used. First, scores were converted to a range between 4 and 20, comparable with the WHOQOL-100. Second, these scores were multiplied by 5 so that the scores were converted to a scale of 0 to 100, where 100 is the highest health-related QoL. Student’s t test was used to analyze the differences between the mean scores of QoL. P < 0.05 was set as the level of statistical significance. April 2013 RESULTS A total of 160 eligible participants completed the questionnaires; most were married (76%) and female (70%). The mean age of the participants was 38.0 years (range 18–53 years). The modal age range was 31–40 years. Other participant demographics are shown in Table 1. Almost half of the patients were on HAART for over 12 months and employed self-reminder or alarm methods of medication-taking behavior (Table 2). A fixed-dose combination of a zidovudine-based regimen was most tolerated by the patients, and more than three quarters of the patients were taking two pills daily (Table 3). HIV-seropositive married women had the highest QoL scores in all the domains compared to those with a different marital status (Table 4). Among the patients included in the present study, however, those on two pills per day of antiretroviral drugs had the best QoL in the four domains. There was no significant difference in the QoL of patients in the various domains when compared based on pill burden (Table 5). When patients’ QoL was assessed with respect to duration of antiretroviral therapy, patients who had received treatment for over 12 months had higher QoL scores in the psychological and social domains; the difference was statistically significant for the psychological domain (Table 6). Table 7 reveals the overall QoL of the patients. The highest mean score was observed in the physical domain followed by the psychological and environmental domains, while the social domain had the lowest score. Table 1. Sociodemographic characteristics of 160 HIV/AIDS patients in Sobi Specialist Hospital, Ilorin Variables Gender Age (years) Marital status Education Occupation N (%) Females 112 (70%) Males 48 (30%) 18–30 46 (29%) 31–40 67 (42%) 41–50 38 (24%) >50 9 (5%) Single 19 (12%) Married 121 (76%) Widowed 12 (7%) Divorced 8 (5%) None 49 (31%) Primary school 50 (31%) Secondary school 38 (24%) Tertiary 23 (14%) Businessmen/women 58 (37%) Public servants 25 (16%) Self-employed 34 (20%) Students 7 (4%) Not employed 36 (23%) Quality of life of HIV/AIDS patients in a secondary health care facility, Ilorin, Nigeria 117 Table 2. Treatment characteristics of 160 HIV/AIDS patients in Sobi Specialist Hospital, Ilorin Characteristics Therapy initiation period (months) Patient’s medication-taking behavior Drug allergies N (%) Table 5. Antiretroviral pill burden and quality of life scores of 160 HIV/AIDS patients Domain 2 pills 4 pills 6 pills P value 3–5 15 (9%) Physical 73 72 71 0.022 6–8 18 (11%) Psychological 67 64 65 0.048 9–12 60 (37%) Social 47 44 43 0.242 >12 67 (42%) Environmental 67 66 64 0.006 Use of alarm/self-reminder 71 (44%) Family/clinic counselor 5 (3%) Daily routine 16 (10%) All of the above 68 (43%) Cotrimoxazole 43 (27%) Chloroquine 64 (40%) Tetracycline 5 (3%) Nevirapine 16 (10%) Efavirenz 5 (3%) None 27 (17%) Table 3. Number of antiretroviral drugs taken per day by 160 HIV/AIDS patients Drugs Table 6. Antiretroviral therapy duration and quality of life scores of 160 HIV/AIDS patients Domain 3–5 mo 6–8 mo 9–11 mo ≥12 mo P value Physical 69 71 71 70 0.033 Psychological 62 60 64 68 <0.017 Social 44 45 46 48 0.008 Environmental 64 64 65 63 0.453 Table 7. Distribution of transformed quality of life scores obtained from WHOQoL-BREF questionnaire for 160 HIV/AIDS patients Domain Mean scores (transformed 0–100) Minimum domain Maximum domain 2 (1%) Physical 72 43 80 15 (9%) Psychological 67 43 87 Pills per day (n) N (%) Fixed-dose combination (AZT + 3TC + NVP) 2 98 (61%) Lose dose (AZT + 3TC + NVP ) 6 Combined (AZT + 3TC) + EFV 3 Combined (FTC + TDF) + NVP 3 5 (4%) Social 47 20 60 Combined (FTC + TDF) + EFV 2 24 (15%) Environment 65 47 80 Combined (FTC + TDF) + LPV/r 5 2 (1%) Combined (AZT + 3TC) + LPV/r 6 12 (8%) 3TC + ABC + NVP 6 2 (1%) AZT indicates zidovudine; 3TC, lamivudine; NVP, nevirapine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; LPV, lopinavir; LPV/r, ritonavir-boosted lopinavir; ABC, abacavir. Table 4. Marital status and quality of life scores of 160 HIV/ AIDS patients Domain Single Physical 70 Married Divorced Widowed 72 71 71 P value 0.032 Psychological 66 69 66 67 0.355 Social 45 48 46 45 0.011 Environmental 64 65 62 61 0.428 DISCUSSION The present study showed the prevalence of HIV infection among all age groups but with the highest prevalence for those in their 30s followed by those 18 to 30 years. This is consistent with the findings of Bankole et al (13) and Khan et al (14), who 118 WHOQoL-BREF indicates World Health Organization Quality of Life Questionnaire-Short Version. reported that people within the age bracket of 15 to 24 years were vulnerable to HIV, while those in their 30s were most susceptible (15, 16). The demographic profile of the participants also showed the predominance of the female gender, which is consistent with other studies. Kelly et al (17) showed that 60% of those living with HIV/AIDS are women. In contrast, in the USA, 87% of the patients are men (18). Patients who are more educated can better understand the disease state and the instructions given on drug usage, which invariably enhances their QoL. Almost one third of this study population had received no formal education. Patients on HAART for a longer duration, however, had higher QoL in this study. By this time, patients had perceived medications as part of their daily routine and had also developed coping strategies to overcome the adverse effects of HAART that might have affected their QoL. In line with this work was a study conducted by Mannheimer et al (19), who reported significant improvement in QoL after 1 to 4 months of treatment with antiretroviral therapy, and this improvement persisted at 12 months. Baylor University Medical Center Proceedings Volume 26, Number 2 In this study, patients on a lower pill regimen had better QoL. The explanation is probably related to fewer side effects, fewer tablets to swallow, and a smaller container (easy to convey and a pocket-friendly package). This study confirms the findings of Jack et al (20) that improvements in overall evaluations of QoL occurred for patients on a single daily dose. The present study showed better QoL among married HIV/ AIDS patients than for unmarried women. It is believed that the physical, emotional, and social support the married women received from their partners likely led to improved QoL. Evidence has shown that support from sources outside the family cannot compensate for what is missing in the family (21). Consistent with the present work was a study reported by Nojomi et al (22) that marital status had a significant effect on patients’ QoL. In contrast, Pedram et al (23) showed that marital status had no significant association with any domain of QoL. Overall, however, the social domain showed the lowest score of the four QoL domains in this study. The social domain was affected by societal discrimination and stigmatization, as well as HIV/AIDS’ influences on patients’ sexual desire, personal relationships, and family life. In line with this study was that of Fatiregun et al (24) in Kogi State, Nigeria, who reported a lower QoL in the social relationship domain. The better scores observed in the other three domains—physical, psychological, and environmental—could be attributed to pharmacists’ impact through comprehensive and consistent counseling on patients’ antiretroviral drugs and education on their disease state. RECOMMENDATION HIV/AIDS has affected many lives. Therefore, health care providers and other stakeholders should strengthen their efforts by addressing its social consequences to enhance QoL. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 1. 2. 3. 4. 5. 6. Department of Health and Human Services. Health Resources and Services Administration Justification of Estimates for Appropriations Committees 2012. Available at http://www.hrsa.gov/about/budget/budgetjustification2012.pdf. Dubé MP, Sattler FR. Inflammation and complications of HIV disease. J Infect Dis 2010;201(12):1783–1785. Brooks JT, Kaplan JE, Holmes KK, Benson C, Pau A, Masur H. HIVassociated opportunistic infections—going, going, but not gone: the continued need for prevention and treatment guidelines. Clin Infect Dis 2009;48(5):609–611. National Agency for the Control of AIDS. Available at http://www.naca. gov.ng/. UNAIDS. Report on the Global HIV/AIDS Epidemic 2008. [UNAIDS/08.25E/JC1510E 2008]. Geneva, Switzerland: World Health Organization, 2008. Semba RD, Martin BK, Kempen JH, Thorne JE, Wu AW; Ocular Complications of AIDS Research Group. The impact of anemia on energy and physical functioning in individuals with AIDS. Arch Intern Med 2005;165(19):2229–2236. April 2013 20. 21. 22. 23. 24. Johnson MO, Catz SL, Remien RH, Rotheram-Borus MJ, Morin SF, Charlebois E, Gore-Felton C, Goldsten RB, Wolfe H, Lightfoot M, Chesney MA; NIMH Healthy Living Project Team. Theory-guided, empirically supported avenues for intervention on HIV medication nonadherence: findings from the Healthy Living Project. AIDS Patient Care STDS 2003;17(12):645–656. Au A, Chan I, Li P, Chung R, Po LM, Yu P. Stress and health-related quality of life among HIV-infected persons in Hong Kong. AIDS Behav 2004;8(2):119–129. Odili VU, Ikhuronian BI, Usifoh SF Oparah AC. Determinants of quality of life in HIV/AIDS patients. West Afr J Pharm 2011;22(1):42–48. Folasire OF, Irabor AE, Folasire AM. Quality of life of people living with HIV and AIDS attending the antiretroviral clinic, University College Hospital, Nigeria. Afr J Prm Health Care Fam Med 2012;4(1):294– 301. Mweemba P, Zeller R, Ludwick R, Gosnell D. Quality of life of Zambians living with HIV and AIDS. Med J Zambia 2009;36(4):234–241. Marins JR, Jamal LF, Chen SY, Barros MB, Hudes ES, Barbosa AA, Chequer P, Teixeira PR, Hearst N. Dramatic improvement in survival among adult Brazilian AIDS patients. AIDS 2003;17(11):1675–1682. Bankole A, Singh S, Woog V, Wulf D. Risk and Protection: Youth and HIV/AIDS in Sub-Saharan Africa. New York: Alan Guttmacher Institute, 2004. Khan S, Mishra V. Youth Reproductive and Sexual Health: DHS Comparative. Calverton, MD: Macro International, 2008. Hasanah CI, Zaliha AR, Mahiran M. Factors influencing the quality of life in patients with HIV in Malaysia. Qual Life Res 2011;20(1):91–100. Mini KV, Ramesh A, Parthasarathi G, Mothi SN, Swamy VT. Impact of pharmacist provided education on medication adherence behaviour in HIV/AIDS patients treated at a non-government secondary care hospital in India. J AIDS/HIV Res 2012;4(4):94–99. Cullinan K. Combating HIV infections among African women. Available at http://www.modernghana.com/news/376577/1/combating-hivinfections-among-african-women.html. Tsevat J, Leonard AC, Szaflarski M, Sherman SN, Cotton S, Mrus JM, Feinberg J. Change in quality of life after being diagnosed with HIV: a multicenter longitudinal study. AIDS Patient Care STDS 2009;23(11):931– 937. Mannheimer SB, Matts J, Telzak E, Chesney M, Child C, Wu AW, Friedland G; Terry Beirn Community Programs for Clinical Research on AIDS. Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence. AIDS Care 2005;17(1):10–22. Jackson K. A comparison of single tablet once daily therapeutic options for the treatment of HIV/AIDS. Residency Pharmacotherapy Conference 2012. Bray JH, Campbell TL. The family’s influence on health. In Rakel RE, ed. Family Medicine, 7th ed. Philadelphia: Saunders Elsevier, 2007:25–26. Nojomi M, Anbary K, Ranjbar M. Health-related quality of life in patients with HIV/AIDS. Arch Iran Med 2008;11(6):608–612. Razavi P, Hajifathalian K, Saeidi B, Esmaeeli Djavid G, Rasoulinejad M, Hajiabdolbaghi M, Paydary K, Kheirandish P, Foroughi M, Seyedalinaghi S, Mohraz M, McFarland W. Quality of life among persons with HIV/ AIDS in Iran: internal reliability and validity of an international instrument and associated factors. AIDS Res 2012;8(4):94–106. Fatiregun AA, Mofolorunsho KC, Osagbemi KG. Quality of life of people living with HIV/AIDS in Kogi State, Nigeria. Benin J Postgrad Med 2009;11(1):21–27. Quality of life of HIV/AIDS patients in a secondary health care facility, Ilorin, Nigeria 119 Timing and causes of death after injuries Justin Sobrino, MD, and Shahid Shafi, MD, MPH Currently, long-term outcomes are significant because health care system changes will likely lead to a single payment for each occurrence of care, including readmissions—the “bundled payment” system. Therefore, it is essential to understand the outcomes of trauma patients discharged alive from trauma centers. This article reviews the current knowledge base on the timing and causes of deaths after trauma. The trimodal mortality model (immediate deaths, early deaths, and late deaths) is utilized as the early research describing trimodal distribution is discussed. Also covered is the successive work as trauma systems matured, showing a shift toward a bimodal distribution with a decline in late deaths. Finally, studies of long-term outcomes are highlighted. Deaths occurring within minutes or a few hours of injury are largely unchanged, which underscores the enormity of injuries to the central nervous and cardiovascular systems. Late deaths caused by multiple organ failure and sepsis have declined considerably, however. Also, the causes of death in this patient population remain constant. Lastly, a considerable number of deaths after discharge may be due to nontraumatic causes. S urvival to discharge has long been the primary endpoint for research and quality improvement in trauma (1, 2). More recent studies have begun assessing long-term outcomes such as complications, costs, readmissions, and survival after discharge (3–11). We have recently shown that over a period of 1 year after the initial injury, about half of the deaths occur within the first 30 days but the rest occur afterward (12). It is important to understand the outcomes of trauma patients discharged alive from trauma centers. Baker et al and Trunkey defined timing of trauma deaths as a trimodal distribution in urban environments in the United States (13, 14). However, the development and maturation of regionalized trauma networks in the 1970s and 1980s have shifted the epidemiology of trauma patients and patterns of mortality. Subsequent research has shown a decline in deaths late after trauma, indicating that the trimodal concept may no longer be accurate in urban trauma environments (12, 15–18). A confounding factor is inconsistent time intervals chosen by researchers to define the timing of deaths (18–20). Herein, we review the existing knowledge on timing and causes of deaths after trauma. We use the trimodal mortality model to cover the early research describing the trimodal distribution, 120 the subsequent work as trauma systems matured, and studies of long-term outcomes. TIMING OF DEATHS The first peak in the classic trimodal model of trauma mortality is immediate death occurring within minutes of the injury. These patients are declared dead on the scene or die shortly after arrival to the hospital. In most published reports, these include deaths at the scene, deaths occurring within 1 hour of arrival to the hospital, and all deaths in the emergency department. These deaths are generally a consequence of severe and likely nonsurvivable injuries. The seminal works of Baker et al and Trunkey in the 1970s showed that 64% and 53%, respectively, of trauma deaths occurred on the scene, with the patients not even transported to a hospital (13, 14). Figure 1 displays a summary of studies evaluating immediate deaths (12, 13, 15, 16, 18, 19, 21–24). This recognition led to rapid development of regionalized trauma systems in the United States, led by the work of Dr. Cowley in Maryland (25, 26). The primary purpose of regionalized integrated care was rapid transportation of patients from the scene to definitive care. It is interesting Figure 1. Studies reviewing immediate deaths (12, 13, 15, 16, 18, 19, 21–24). From the Institute for Health Care Research and Improvement, Baylor Health Care System, Dallas, Texas. Corresponding author: Shahid Shafi, MD, MPH, Baylor Health Care System, 1600 W. College Street, Suite LL 10, Grapevine, TX 76052 (e-mail: shahid. shafi@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):120–123 to note in Figure 1 that despite all the progress in emergency medical services and trauma systems, prehospital care, injury prevention, and automotive safety, the proportion of deaths occurring immediately after injury has remained unchanged over time, at 50% to 60%. The second peak in the trimodal distribution is early deaths, defined as deaths within hours of arrival to the hospital. In most published reports, early deaths include deaths within 24 hours of arrival to a trauma center, excluding immediate deaths. These deaths are also a consequence of severe injuries, but the patients arrive at the hospital alive and are potentially treatable with prompt definitive care. Trunkey estimated this group to include approximately 30% of deaths (14). Figure 2 depicts a range of studies evaluating early deaths (12, 13, 15, 16, 19). Again, the proportion of deaths in this group has remained relatively unchanged over time, at 25% to 30% of all trauma deaths. In Trunkey’s original description of the trimodal distribution, 20% of trauma deaths were “late deaths,” defined as those occurring days to weeks after the injury among patients who survived the initial insult (14). In most reports, this category includes deaths occurring after the first 24 hours and all other in-hospital deaths. Figure 3 displays studies evaluating late deaths (12, 13, 15, 16, 19, 22–24). In contrast to the first two Figure 2. Studies reviewing early deaths (12, 13, 15, 16, 19). Figure 3. Studies reviewing late deaths (12, 13, 15, 16, 19, 22–24). April 2013 categories, there has been a definite and dramatic drop in late deaths over time. In the most recent study by Gunst and colleagues, this group included only 9% of deaths (12). Deaths among trauma patients after discharge have largely remained overlooked in the trauma literature. This is due in large part to the difficulty of follow-up in the trauma patient population. First, regionalized trauma networks often mean that patients are transported farther from home for their initial episode of care at designated trauma centers. Second, trauma patients are typically younger individuals who are more mobile in pursuit of work or education. However, several studies have shown that trauma patients have an increased risk of mortality after discharge. Follow-up methods have varied, but the most commonly used are trauma registries, hospital databases, and patient records from single institutions. Combined with a lack of communication between medical record systems, single-institution studies are likely to miss patients who pursue follow-up care closer to home at a different hospital. In order to capture higher percentages of the study population, particularly over longer periods of time, telephone interviews or mail surveys are commonly utilized. More recently, trauma researchers have employed vital statistics records and Social Security data as a means of capturing high percentages of patients while also obtaining cause-of-death data (27–29). In a study of data from 1991 to 1993, Mullins et al reported an in-hospital mortality rate of 12.1 per 100,000 for trauma deaths. This increased to 14.1 per 100,000 when including patients who died within 30 days of discharge (30). Among injured Medicare patients discharged to home, the 30-day mortality ranged from 1.9% to 2.3% (31). In 2004, Clark and colleagues reported that among injured Medicare patients, 30-day mortality was 7.5% compared with 3.7% in-hospital mortality (6). In 2006, MacKenzie et al reported a case fatality rate for in-hospital deaths of 7.6%, which remained stable for 30 days but increased to 10.4% at 1 year (32). In 2008, Gorra et al reported 30-day mortality rates of 4.2% to 5.4% among injured Medicare patients discharged to a long-term care facility (31). A 2010 study by Claridge and colleagues reported a mortality rate of 3.6% at 30 days, 4.1% at 90 days, 5.5% at 1 year, and 8.1% over the entire study period (33). In 2011, Davidson et al demonstrated 9.8% mortality at 1 year and 16% 3-year cumulative mortality (34). The multiinstitutional prospective National Study on Costs and Outcomes of Trauma evaluated patients up to 1 year after discharge. In this study, MacKenzie et al reported an in-hospital mortality rate of 21.3%, but a further 2.6% were dead at 3 months, and an additional 2.2% were dead by 12 months (35). Similarly, in 2005, Wright and colleagues reported a 5-year mortality rate of 22.1% in trauma patients admitted to an intensive care unit during their initial hospitalization (36). In 2011, Timmers et al reported a 1-year mortality rate of 17%, which increased to 29% between 6 and 11 years (37). Finally, our recently published study utilizing Social Security data showed that almost half of the deaths in trauma patients occurred after discharge from the trauma center (27). All these studies are consistent in their findings that the risk of death among trauma patients remains elevated for months to years afterward. Timing and causes of death after injuries 121 Table. Causes of death by timing category Immediate and early deaths Brain injury Hemorrhage Late deaths Postdischarge Infection Multiple-organ failure Brain injury Hemorrhage Cardiovascular disease Second major trauma Neurologic disease Malignancy CAUSES OF DEATH Several studies have investigated the causes of death in trauma patients. Baker et al found that brain injury accounted for a majority of deaths, at 50% (13). Heart or aortic injury (17%), hemorrhage (12%), sepsis (10%), lung injury (6%), burn (3%), and liver injury (2%) accounted for the remainder. The majority of patients with major cardiac, vascular, or liver injury died of hemorrhage. Shackford and colleagues also found that head injury was the most common cause of death, and when combined with spinal cord injury, neurologic injuries were responsible for 49% of deaths (24). On autopsy, secondary brain injury, defined as diffuse cerebral edema; herniation; or cerebral necrosis due to hypoxia, hypotension, or cerebral edema that followed the primary injury was present in just over half of neurotrauma cases. Almost a third (31%) of victims died of hemorrhage in the chest, the abdomen, or both cavities. Other causes of death included asphyxia in 6%, cardiac arrest in 4%, sepsis in 3%, and pneumonia in 2%. The Table lists the most common causes of death for each time interval. Immediate and early deaths are considered together, given the similar etiologies. In Trunkey and Lim’s initial case series in 1972, 45% of the patients in the immediate death category died of irreversible brain injury, such as lacerations of the brain, brain stem, or spinal cord, and 35% died due to hemorrhage resulting from injuries to the heart, aorta, liver, lungs, and pelvic fractures (21). Similarly, Meislin et al showed that for death within 1 hour of injury, 46% were neurologic injuries and 31% were due to circulatory collapse resulting from hemorrhage (19). Likewise, work from Sauaia et al showed that among those dead on the scene, 42% died from central nervous system injuries, 39% from exsanguination, and 7% from organ failure (18). These studies are consistent in reporting that the two most common causes of immediate deaths are head injuries and hemorrhage. The cause of early trauma deaths is similar to that of immediate deaths and likely represents less catastrophic injuries or better prehospital care and shorter transport times to trauma centers. As described by Trunkey and Lim, the causes of death in this group include major internal hemorrhages of the head, respiratory system, or abdominal organs or multiple minor injuries resulting in severe blood loss (21). Sauaia et al reported that among trauma deaths within 48 hours of injury, exsanguination was the most common cause (51%) due to injuries to the liver, heart, or major blood vessels (7). This was particularly true for patients with penetrating injuries. Central nervous system injury was the second most common cause of death, including 122 brain lacerations, contusions, and subdural hemorrhages (18). Meislin et al showed that neurologic injuries and circulatory collapse or hemorrhage accounted for over 80% of early deaths (19). Baker and colleagues showed that most of the deaths due to head injuries were within the first 2 days after injury (13). Trunkey reported that 80% of late deaths in the hospital were due to infections or multiple organ failure (14). Similarly, Baker found that 78% of deaths after 7 days were due to sepsis and multiple organ failure (13). Cowley indicated that the most common causes of death in this group were overwhelming infection and irreversible head injuries (26). Sauaia et al reported that for deaths occurring after 1 week postinjury, organ failure claimed the majority of patients (61%) (18). More recently, Meislin et al reported that for the group dying within 24 to 48 hours, 45% died of neurologic injury, 42% of circulatory collapse or hemorrhage, and 9% of multiple organ failure (19). Similarly, for the group dying 2 days to 3 weeks after injury, 48% died of neurologic injury, 35% of circulatory collapse or hemorrhage, and 16% of multiple organ failure. These studies indicate that head injuries and hemorrhage remain important causes of death among patients who survive the first 24 hours, but multiple organ failure becomes more prominent with the passage of time. Causes of death after discharge from trauma centers are less well studied. This is due, in part, to the difficulties of followup. Mullins evaluated cause-of-death codes reported on death certificates for injured patients who died of nontraumatic causes during their hospital stay and within 30 days after discharge (30). Of 1174 postdischarge deaths, 15% were due to neoplasms, 12% to cerebrovascular disease, 11% to cardiovascular disease, 11% to ischemic heart disease, 9% to chronic obstructive pulmonary disease, and 8% to acute myocardial infarction. Another 20% were due to a myriad of other causes. In a German study, Probst and colleagues described in-hospital and postdischarge causes of death for trauma patients (38). While in-hospital causes of death mirrored those previously discussed, postdischarge deaths included cardiovascular disease in 23%, a second major trauma in 19%, neurologic disease in 16%, suicide in 10%, and malignancies in 6%. Furthermore, trauma patients had increased mortality compared with the general population during the first year after injury. The mortality rates were more closely approximated during years 2 to 10 after injury. Claridge and colleagues classified deaths as trauma related in 33%, possibly related in 23%, and unrelated in 44% (33). Additionally, mortality after discharge was more likely trauma related in younger patients. The authors found that most deaths within the first year after injury were attributable to trauma, after which chronic diseases increased mortality. These studies indicate that postdischarge deaths among trauma patients are related to common chronic diseases within the population. However, the impact of injuries on the outcome of these chronic diseases remains unknown. CONCLUSION Three important conclusions can be drawn from this review. First, deaths occurring within minutes or a few hours of injury are largely unchanged, reflecting the devastating nature of injures Baylor University Medical Center Proceedings Volume 26, Number 2 to the central nervous and cardiovascular systems. Late deaths due to multiple organ failure and sepsis, however, have declined dramatically. Second, the causes of death in this patient population, i.e., those with severe head injuries and hemorrhage, remain persistent. Finally, a large number of deaths in trauma patients that occur after discharge may be related to nontraumatic causes. Reasons for the increased risk of death from nontraumatic causes after discharge need to be studied further. Acknowledgment The authors wish to thank Kelli R. Trungale, MLS, ELS, for editorial assistance. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Hemmila MR, Nathens AB, Shafi S, Calland JF, Clark DE, Cryer HG, Goble S, Hoeft CJ, Meredith JW, Neal ML, Pasquale MD, Pomphrey MD, Fildes JJ. The Trauma Quality Improvement Program: pilot study and initial demonstration of feasibility. J Trauma 2010;68(2):253–262. Shafi S, Nathens AB, Cryer HG, Hemmila MR, Pasquale MD, Clark DE, Neal M, Goble S, Meredith JW, Fildes JJ. The Trauma Quality Improvement Program of the American College of Surgeons Committee on Trauma. J Am Coll Surg 2009;209(4):521–530, e521. Battistella FD, Torabian SZ, Siadatan KM. Hospital readmission after trauma: an analysis of outpatient complications. J Trauma 1997;42(6):1012– 1016; discussion 1016–1017. Cardenas DD, Hoffman JM, Kirshblum S, McKinley W. Etiology and incidence of rehospitalization after traumatic spinal cord injury: a multicenter analysis. Arch Phys Med Rehabil 2004;85(11):1757–1763. Cifu DX, Kreutzer JS, Marwitz JH, Miller M, Hsu GM, Seel RT, Englander J, High WM Jr, Zafonte R. Etiology and incidence of rehospitalization after traumatic brain injury: a multicenter analysis. Arch Phys Med Rehabil 1999;80(1):85–90. Clark DE, DeLorenzo MA, Lucas FL, Wennberg DE. Epidemiology and short-term outcomes of injured Medicare patients. J Am Geriatr Soc 2004;52(12):2023–2030. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med 2009;360(14):1418– 1428. Ladha KS, Young JH, Ng DK, Efron DT, Haider AH. Factors affecting the likelihood of presentation to the emergency department of trauma patients after discharge. Ann Emerg Med 2011;58(5):431–437. Malhotra AK, Martin N, Jacoby M, Tarrant J, Guilford K, Wolfe LG, Aboutanos MB, Duane TM, Ivatury RR. What are we missing: results of a 13-month active follow-up program at a level I trauma center. J Trauma 2009;66(6):1696–1702; discussion 1702–1703. Masini BD, Owens BD, Hsu JR, Wenke JC. Rehospitalization after combat injury. J Trauma 2011;71(1 Suppl):S98–S102. Morris DS, Rohrbach J, Rogers M, Thanka Sundaram LM, Sonnad S, Pascual J, Sarani B, Reilly P, Sims C. The surgical revolving door: risk factors for hospital readmission. J Surg Res 2011;170(2):297–301. Gunst M, Ghaemmaghami V, Gruszecki A, Urban J, Frankel H, Shafi S. Changing epidemiology of trauma deaths leads to a bimodal distribution. Proc (Bayl Univ Med Cent) 2010;23(4):349–354. Baker CC, Oppenheimer L, Stephens B, Lewis FR, Trunkey DD. Epidemiology of trauma deaths. Am J Surg 1980;140(1):144–150. Trunkey DD. Trauma. Accidental and intentional injuries account for more years of life lost in the U.S. than cancer and heart disease. Among the prescribed remedies are improved preventive efforts, speedier surgery and further research. Sci Am 1983;249(2):28–35. Demetriades D, Kimbrell B, Salim A, Velmahos G, Rhee P, Preston C, Gruzinski G, Chan L. Trauma deaths in a mature urban trauma system: is “trimodal” distribution a valid concept? J Am Coll Surg 2005;201(3):343–348. Demetriades D, Murray J, Charalambides K, Alo K, Velmahos G, Rhee P, Chan L. Trauma fatalities: time and location of hospital deaths. J Am Coll Surg 2004;198(1):20–26. April 2013 17. Pang JM, Civil I, Ng A, Adams D, Koelmeyer T. Is the trimodal pattern of death after trauma a dated concept in the 21st century? Trauma deaths in Auckland 2004. Injury 2008;39(1):102–106. 18. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38(2):185–193. 19. Meislin H, Criss EA, Judkins D, Berger R, Conroy C, Parks B, Spaite DW, Valenzuela TD. Fatal trauma: the modal distribution of time to death is a function of patient demographics and regional resources. J Trauma 1997;43(3):433–440. 20. Bamvita JM, Bergeron E, Lavoie A, Ratte S, Clas D. The impact of premorbid conditions on temporal pattern and location of adult blunt trauma hospital deaths. J Trauma 2007;63(1):135–141. 21. Trunkey DD, Lim RC. Analysis of 425 consecutive trauma fatalities: an autopsy study. J Am Coll Emerg Phys 1974;3(6):368–371. 22. Potenza BM, Hoyt DB, Coimbra R, Fortlage D, Holbrook T, Hollingsworth-Fridlund P. The epidemiology of serious and fatal injury in San Diego County over an 11-year period. J Trauma 2004;56(1):68–75. 23. Cothren CC, Moore EE, Hedegaard HB, Meng K. Epidemiology of urban trauma deaths: a comprehensive reassessment 10 years later. World J Surg 2007;31(7):1507–1511. 24. Shackford SR, Mackersie RC, Holbrook TL, Davis JW, HollingsworthFridlund P, Hoyt DB, Wolf PL. The epidemiology of traumatic death. A population-based analysis. Arch Surg 1993;128(5):571–575. 25. Cowley RA. A total emergency medical system for the State of Maryland. Md State Med J 1975;24(7):37–45. 26. Cowley RA. The resuscitation and stabilization of major multiple trauma patients in a trauma center environment. Clin Med 1976;83(1):16–22. 27. Shafi S, Renfro LA, Barnes S, Rayan N, Gentilello LM, Fleming N, Ballard D. Chronic consequences of acute injuries: worse survival after discharge. J Trauma Acute Care Surg 2012;73(3):699–703. 28. Social Security Death Master File. 2011. Available at http://www.ssdmf.com/ FolderID/1/SessionID/%7B1764C2FE-6072-4653-A9C4-C217E454B2 A7%7D/PageVars/Library/InfoManage/Guide.htm; accessed October 23, 2012. 29. National Death Index. 2012. Available at http://www.cdc.gov/nchs/ndi. htm; accessed October 23, 3012. 30. Mullins RJ, Mann NC, Hedges JR, Worrall W, Helfand M, Zechnich AD, Jurkovich GJ. Adequacy of hospital discharge status as a measure of outcome among injured patients. JAMA 1998;279(21):1727–1731. 31. Gorra AS, Clark DE, Mullins RJ, Delorenzo MA. Regional variation in hospital mortality and 30-day mortality for injured Medicare patients. World J Surg 2008;32(6):954–959. 32. MacKenzie EJ, Rivara FP, Jurkovich GJ, Nathens AB, Frey KP, Egleston BL, Salkever DS, Scharfstein DO. A national evaluation of the effect of trauma-center care on mortality. N Engl J Med 2006;354(4):366–378. 33. Claridge JA, Leukhardt WH, Golob JF, McCoy AM, Malangoni MA. Moving beyond traditional measurement of mortality after injury: evaluation of risks for late death. J Am Coll Surg 2010;210(5):788–794; discussion 794–796. 34. Davidson GH, Hamlat CA, Rivara FP, Koepsell TD, Jurkovich GJ, Arbabi S. Long-term survival of adult trauma patients. JAMA 2011;305(10):1001– 1007. 35. MacKenzie EJ, Rivara FP, Jurkovich GJ, Nathens AB, Frey KP, Egleston BL, Salkever DS, Weir S, Scharfstein DO. The National Study on Costs and Outcomes of Trauma. J Trauma 2007;63(6 Suppl):S54–S67; discussion S81–S86. 36. Wright JC, Plenderleith L, Ridley SA. Long-term survival following intensive care: subgroup analysis and comparison with the general population. Anaesthesia 2003;58(7):637–642. 37. Timmers TK, Verhofstad MH, Moons KG, Leenen LP. Long-term survival after surgical intensive care unit admission: fifty percent die within 10 years. Ann Surg 2011;253(1):151–157. 38. Probst C, Zelle BA, Sittaro NA, Lohse R, Krettek C, Pape HC. Late death after multiple severe trauma: when does it occur and what are the causes? J Trauma 2009;66(4):1212–1217. Timing and causes of death after injuries 123 Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease Mina M. Benjamin, MD, and William C. Roberts, MD T he December 2012 Williamsburg Conference on Heart Disease in Williamsburg, Virginia, was the 39th such annual conference to be held in that city. The conference has been directed by one of the authors (WCR) since 1972. The conference provides 16.5 hours of continuing medical education category one credit, and nearly all of the speakers are nationally and internationally recognized. It is one of the 2 longest-running cardiology courses. Its unique feature is that each presentation is 90 minutes, which allows the speakers time to discuss more than one topic and to answer questions from enrollees. This article summarizes the proceedings of the 2012 conference. SOME FACTS AND PRINCIPLES LEARNED AFTER SPENDING 50 YEARS INVESTIGATING CORONARY HEART DISEASE William C. Roberts, MD, Executive Director, Baylor Heart and Vascular Institute; Dean, A. Webb Roberts Center for Continuing Medical Education, Baylor University Medical Center, Dallas, Texas; and Editor in Chief, The American Journal of Cardiology and the Baylor University Medical Center Proceedings Although the same blood flows through both arteries and veins, atherosclerosis affects only the arteries. The arterial system can be subdivided into various regions—coronary, carotid, cerebral, renal, peripheral (arm and leg), and aorta— and one region may cause symptoms of organ ischemia or discomfort and the other regions may be clinically silent. Nevertheless, when one region contains considerable amounts of atherosclerotic plaque such that it produces symptoms or discomfort in that region, necropsy studies have demonstrated that large quantities of atherosclerotic plaque also are present in the other regions. In other words, atherosclerosis is a systemic disease. To demonstrate this principle, detailed studies of the coronary arteries in patients with large abdominal aneurysms and/or peripheral limb ischemia so severe that amputation was required disclosed atherosclerotic plaque in every 5-mm segment of each of the 4 major epicardial coronary arteries (right, left main, left anterior descending, left circumflex). The quantity was so severe that a large portion (about 33%) of the length of the four major coronary arteries had plaques that narrowed the lumens >75% in crosssectional area (1, 2). 124 Multiple necropsy studies have shown that when any particular arterial region produces symptoms of organ ischemia (or discomfort in the case of abdominal aortic aneurysm), the atherosclerotic process in that region is diffuse and severe—i.e., there are no “skip areas” where a 5-mm-long arterial segment does not contain atherosclerotic plaque (3). Multiple necropsy studies of each 5-mm-long segment of the 4 major epicardial coronary arteries in a variety of coronary subsets (those with acute myocardial infarction, stable and unstable angina pectoris, healed myocardial infarction with and without chronic heart failure, and sudden coronary death) have demonstrated that about a third of the entire lengths of the 4 major coronary arteries is narrowed >75% in cross-sectional area by atherosclerotic plaque alone (3, 4). There appears to be a common belief that atherosclerotic plaques consist mainly of lipid material. Several studies have examined the composition of atherosclerotic coronary plaques at necropsy in patients with fatal coronary heart disease (5–8). The studies traced out the various components of plaques from each 5-mm-long segment of each of the 4 major coronary arteries, and fibrous tissue was by far the dominant component of coronary plaques, comprising about 70%, while lipids comprised about 10%; calcium, about 10%; and miscellaneous, the other 10%. Fibrous tissue also was the dominant component of plaques in saphenous veins used for aortocoronary bypass grafts. That the predominant component of coronary plaques is fibrous tissue is probably advantageous for percutaneous coronary intervention (PCI) because that procedure works simply by cracking plaques and not by compressing them to the side. Studying atherosclerosis at necropsy or after endarterectomy has convinced Roberts that the only real long-term therapy for the Western world’s number one disease is prevention. Although the Framingham investigators and others have convinced most physicians and the lay public that atherosclerosis is a multifactorial disease, Roberts is convinced that the disease has a From the Departments of Internal Medicine (Benjamin, Roberts) and Pathology (Roberts), and the Baylor Heart and Vascular Institute (Roberts), Baylor University Medical Center at Dallas. Corresponding author: William C. Roberts, MD, Baylor Heart and Vascular Institute, 621 North Hall Street, Suite H030, Dallas, TX 75246 (e-mail: wc.roberts@ baylorhealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):124–136 Table 1. The differences between carnivores and herbivores Features Carnivore Herbivore Teeth Sharp Flat Intestine Short (3 × BL) Long (12 × BL) Fluids Lap Sip Cooling Pant Sweat Appendages Claws Hands or hoofs Vitamin C Self-made Diet BL indicates body length. Figure 1. The atherosclerotic risk factors showing that the only factor required to cause atherosclerosis is cholesterol. Table 2. Drug treatment guidelines of the Adult Treatment Panel of the National Cholesterol Education Program (2004) to decrease risk LDL (mg/dL) Other RF Goal single cause, namely cholesterol, and that the other so-called >190 ≤1 <160 atherosclerotic risk factors are only contributory at most (9–13). >160 >1 <130 As shown in Figure 1, most of the risk factors do not in themselves cause atherosclerosis. >130 HA <100 (<70) Th ere are in Roberts’ opinion 4 facts supporting the HA indicates heart attack; LDL, low-density lipoprotein cholesterol; RF, risk factor. contention that atherosclerosis is a cholesterol problem: 1) Atherosclerosis is easily produced experimentally in herbivores (monkeys, rabbits) by giving had an atherosclerotic event, who have diabetes mellitus, or them diets containing large quantities of cholesterol who are at an extremely high risk of developing an athero(egg yolks) or saturated fat (animal fat). Indeed, atherosclerosis sclerotic event (e.g., homozygous or heterogeneous familial is one of the easiest diseases to produce experimentally, but hypercholesterolemia). Roberts’ guidelines, in contrast, are dithe recipient must be an herbivore. It is not possible to prorected at preventing atherosclerotic plaques, and when they are duce atherosclerosis in carnivores (tigers, lions, dogs, etc.). In prevented atherosclerotic risk is negated. The only requirement contrast, it is not possible to produce atherosclerosis simply is an LDL-C <50 mg/dL. by raising a rabbit’s blood pressure or blowing cigarette smoke Statins, at least in Roberts’ view, are the finest cardioin its face for an entire lifetime. 2) Atherosclerotic plaques convascular drug ever created (released in the USA in 1987) tain cholesterol. 3) Societies with high average cholesterol levels (14). Table 3 displays the equivalent doses of six statins, their have higher event rates (heart attacks, etc.) than societies with average reductions in total cholesterol and LDL-C, and the much lower average cholesterol levels. 4) When serum cholesterol additional LDL-C–lowering effect when ezetimibe is added levels (especially the low-density lipoprotein cholesterol [LDL-C] to a statin (15). level) are lowered (most readily, of course, by statin drugs), atherosclerotic events fall Table 3. Dosing of six statin drugs, their relative efficacy and effects on cholesterol, accordingly and the lower the level, the and the effect of adding ezetimibe fewer the events (“less is more”). Although most humans consider themselves carniEquivalent dose (mg) vores or at least omnivores, basically we E (10 mg) Total humans have characteristics of herbivores R (C) A (L) S (Z) P (P) L (M) F (L) L TC L LDL L LDL LDL L (Table 1). 1.25 5 10 20 20 40 22% 27% 18% 45% The Adult Treatment Panel of the Na2.5 10 20 40 40 80 27% 34% 18% 52% tional Cholesterol Education Program 5 20 40 80 80 – 32% 41% 14% 55% has provided guidelines for whom to treat 10 40 80 – – – 37% 48% 12% 60% with cholesterol-altering drugs. The latest (2004) guidelines are summarized in Table 20 80 – – – – 42% 55% 10% 65% 2. The guidelines are aimed entirely at re40 – – – – – 45% 62% 10% 72% ducing the risk of atherosclerotic events. R indicates rosuvastatin (C, Crestor); A, atorvastatin (L, Lipitor); S, simvastatin (Z, Zocor); P, pravastatin (P, PravaLowering the LDL-C goal from <100 to chol); L, lovastatin (M, Mevacor); F, fluvastatin (L, Lescol); TC, total cholesterol; LDL, low-density lipoprotein <70 mg/dL is recommended by the comcholesterol; E, ezetimibe. mittee only in patients who have already April 2013 Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 125 ASSESSING THE BENEFIT OF THERAPY THAT RAISES HIGHDENSITY LIPOPROTEIN CHOLESTEROL William E. Boden, MD, Chief of Medicine, Stratton VA Medical Center, Vice-Chairman of Medicine, Albany Medical Center, and Professor of Medicine, Albany Medical College, Albany, New York All the major primary and secondary prevention statin studies have shown an average of 25% cardiovascular risk reduction at 5 years, which means that 75% of the cardiovascular events were not prevented during this time period. Statins act mainly on LDL-C, with much less effect on triglycerides or high-density lipoprotein cholesterol (HDL-C). Fibrates act mainly on triglycerides, reducing it 30% to 35% with a slight increase in HDL-C and only a minor effect on LDL-C (16). In the FIELD study (17), fenofibrate did not significantly reduce coronary events in 9775 patients vs placebo. In the ACCORD trial (18), the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction (MI), or nonfatal stroke, compared with simvastatin alone in 5518 high-risk patients with diabetes mellitus. Niacin raises HDL-C by 30% to 35%, has a lesser effect on triglycerides than fibrates, and reduces LDL-C by 15% to 20%. Niacin also increases LDL particle size, from a small, dense pattern B to the larger nonatherogenic pattern A (19). In the Framingham study (20), LDL-C and HDL-C were independent risk factors of coronary heart disease (CHD). A patient with an LDL-C of 220 and HDL-C of 45 mg/dL had a similar risk to a patient with an LDL-C of 100 and HDL-C of 25 mg/dL. Statins had a maximal relative risk reduction in cardiovascular events of about 30% (21), niacin about 20% (22), and fibrates 23% (16). Although the National Cholesterol Education Program Adult Treatment Panel III guidelines (23) stated that low HDL-C is an independent risk factor for coronary artery disease (CAD) morbidity and mortality, the panel concluded that the risk reduction documented by controlled clinical trials is not sufficient to warrant setting a specific HDL-C goal. Several surrogate marker studies (24–26) demonstrated slowing or even regression of arterial narrowing with niacin. The ARBITER 6-HALTS (26) trial was terminated early on the basis of a prespecified interim analysis showing superiority of niacin over ezetimibe for change in carotid thickness. Major adverse cardiac events occurred at a significantly lower incidence in the niacin (1.2%) vs the ezetimibe group (5.5%). In a metaanalysis of the 14 niacin studies including 2682 patients taking 1 to 3 g/day of niacin and 3934 controls, niacin decreased the rate of progression of atherosclerosis by 41% and decreased carotid intima thickness by 17 μm/year. In the Coronary Drug Project (27), immediate-release niacin (3 g/day) reduced the incidence of CHD death/MI by 14%, nonfatal MI by 26%, and stroke/transient ischemic attacks by 21% after 5 years. There was also a 50% reduction in the need for coronary bypass surgery. In the VA-HIT study (28), gemfibrozil reduced CHD death/MI by 22% vs placebo after 5 years. These patients did not take statins, and the benefit was attributed to a decrease in triglycerides (–31%) and an increase in HDL-C (+6%), as there was no significant change in LDL-C. It took 2 years in the VA-HIT trial for a considerable benefit 126 to be evident with treatment, quite different from the time course seen with statins, where event reduction is seen as early as 2 weeks after institution of treatment. Several single-center trials demonstrated the benefits of adding niacin to other cholesterol-lowering drugs. In the Familial Atherosclerosis Treatment Study (FATS) (29, 30), 126 men with known CHD were randomized to receive conventional therapy or lovastatin plus colestipol or niacin (4 g/day). All patients had a coronary angiogram at baseline. After 2.5 years, coronary narrowing in patients on conventional therapy progressed, while it regressed in the treatment group. Multivariate analysis showed that increasing HDL-C correlated independently with the regression of disease. The HDL Atherosclerosis Treatment Study (HATS) (31) was a 3-year trial of 160 patients with CHD whose HDL-C averaged 31 mg/dL and LDL-C, 125 mg/dL. Patients were administered either niacin (mean dose 2.4 g/day) plus simvastatin (mean dose 13 mg/day) or placebo for 3 years. In the group receiving niacin plus simvastatin, LDL-C levels decreased 42% and HDL-C increased 26%. The combination of niacin and simvastatin reduced CHD events by about 75%. There was a slight regression in coronary narrowing with simvastatin plus niacin but progression in all other groups. Both FATS and HATS were single-center studies with relatively small numbers of patients. Pooled data from 28 different lipid trials (32) showed that there was an aggregation of benefit from adding different cholesterol-altering medicines. Data from the 4S (33), CARE (34), WOSCOPS (35), and LIPID (36) trials demonstrated that a 1% decrease in LDL-C was associated with a 1% decrease in CHD events. A 1% increase in HDL-C was associated with a 3% decrease in events, as seen in HELSINKI (37), AFCAPS/TexCAPS (38), and VA-HIT. The results from the Coronary Drug Project, VA-HIT, and HATS constituted the base for a large, multicenter trial assessing the outcomes for niacin. The AIM-HIGH (39) study was conducted mainly to investigate whether the residual risk associated with low levels of HDL-C in patients with established CHD (whose LDL-C therapy was optimized with statins ± ezetimibe) would be mitigated with extended-release niacin vs placebo. The patients were >45 years of age with CHD, cerebrovascular disease, or peripheral arterial disease and dyslipidemia (HDL-C <40 for men, <50 for women; triglycerides 150–400; LDL-C <180 mg/dL). A total of 3414 patients were randomized to receive extended-release niacin (1.5 to 2 g/day) or placebo. All patients received simvastatin (40 to 80 mg/day) plus ezetimibe (10 mg/ day) (if needed) to maintain an LDL-C of 40 to 80 mg. (The placebo tablets had a small amount of niacin, 200 mg/2 g, to produce similar side effects as in the treatment group.) Patients on statins (94%) had a mean baseline LDL-C of 71 mg/dL. The trial was stopped after a mean follow-up period of 3 years due to a lack of efficacy. There was also an increased incidence of ischemic strokes in the niacin arm (n = 29) vs the placebo arm (n = 18). At study termination, HDL-C had increased from 35 to 42 mg/dL, LDL-C had decreased from 74 to 62 mg/dL, and triglycerides had decreased from 164 to 120 mg/dL. In both the Coronary Drug Project and VA-HIT, in the prestatin era, niacin and gemfibrozil increased HDL and lowered triglycerides Baylor University Medical Center Proceedings Volume 26, Number 2 and also decreased cardiovascular events, but baseline triglycerides and LDL-C were significantly higher than in AIM-HIGH. It appears that the addition of niacin did not work in this population, possibly because these patients had been well treated with statins and the HDL-C had increased to 38 mg/dL in the placebo arm, changes that might have minimized event rate differences between the treatment and placebo groups. The HPS 2-THRIVE trial began in 2004 and is expected to be finished by 2013. It enrolled 25,000 patients with CAD or diabetes mellitus from the UK, Scandinavia, and China. Patients were randomized to simvastatin 40 mg or simvastatin plus extended-release niacin/laropiprant. The use of ezetimibe is allowed. There is no target LDL-C level or attempt to equalize LDL-C levels between groups. COCAINE-ASSOCIATED MYOCARDIAL ISCHEMIA AND INFARCTION L. David Hillis, MD, Professor and Chair, Department of Medicine, Dan F. Parman Distinguished Chair of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas Five million Americans use cocaine daily, 1 million are addicted to it, and 5000 use it for the first time each day. Possible mechanisms of cocaine-induced myocardial ischemia include increased myocardial oxygen demand with severe CAD and decreased myocardial oxygen supply due to coronary arterial vasospasm (40) and/or coronary arterial thrombosis. ␣-Blockers abolish the coronary vasoconstrictor effect of cocaine, while ␤-blockers augment it (41). Cocaine-induced vasoconstriction is more pronounced in coronary arterial segments narrowed by atherosclerosis (42). The time course of cocaine-induced vasoconstriction parallels the blood concentration of cocaine following intranasal administration, after which a second “wave” of vasoconstriction parallels the increasing blood concentrations of cocaine’s major metabolites and occurs as the blood concentration of cocaine is decreasing (43). The deleterious effects of cocaine on myocardial oxygen supply and demand are exacerbated by concomitant cigarette smoking. This combination substantially increases the metabolic requirement of the heart for oxygen but simultaneously decreases the diameter of diseased coronary arterial segments (44). The combination of intranasal cocaine and intravenous ethanol causes an increase in the determinants of myocardial oxygen demand. The combination also causes a concomitant increase in epicardial coronary arterial diameter (45). Morphine can reverse cocaine-induced coronary arterial vasoconstriction (46). Sublingual nitroglycerin (47) 0.4 to 0.8 mg and intravenous verapamil (48) also reverse the coronary vasoconstrictive effect of cocaine, while intravenous labetalol has no effect (49). The mechanism of cocaineinduced vasospasm and its aggravating and relieving factors are summarized in Figure 2. CORONARY ARTERY BYPASS GRAFTING—2012 L. David Hillis, MD Coronary artery bypass grafting (CABG) is superior to medical therapy for eliminating angina pectoris (50). CABG, April 2013 Figure 2. The mechanism of cocaine-induced coronary vasospasm, aggravating factors, and treatment. CAD indicates coronary artery disease; Ca, calcium. however, does not prevent MIs (51, 52). CABG is superior to medical therapy in improving survival only in patients with left main CAD, in those with 3-vessel CAD and left ventricular (LV) ejection fraction (EF) <50%, and in those with 2- or 3-vessel CAD with significant narrowing of the proximal left anterior descending coronary artery. In the VA COOPERATIVE study (53), the survival of patients with 1, 2, and 3-vessel CAD with a normal LVEF (medical therapy vs CABG) was 87% vs 82%, 82% vs 77%, and 68% vs 61% at 5, 7, and 11 years, respectively, while the survival of patients with 3-vessel CAD and LVEF <50% was (medical therapy [n = 97] vs CABG [n = 71]) 66% vs 83%, 52% vs 78%, and 38% vs 50% at 5, 7, and 11 years, respectively. In the STICH trial (54), a total of 1212 patients with an EF < 35% and CAD amenable to CABG were randomly assigned to medical therapy alone (n = 602) or medical therapy plus CABG (n = 610). At 5 years, death from any cause was 41% in the medical therapy arm and 36% in the CABG group (insignificant), and the rate of hospitalization for heart failure was 54% vs 48%. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes. Compared with patients who have CABG, those who have PCI are more likely to require another revascularization procedure in the next 12 months (45), and rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (18% vs 12% for CABG), in large part because of an increased rate of repeat revascularization (13% vs 6%). The determinants of peri-CABG mortality include age (peri-CABG mortality markedly increases above 70 years) (55), LV systolic function, comorbid conditions (chronic obstructive pulmonary disease, diabetes mellitus, azotemia, obesity), extracardiac vascular disease, left main CAD, previous thoracotomy (mortality of the first sternotomy 3% vs 7% for subsequent sternotomies), and gender (1.9% in men vs 4.5% in women in CASS [n = 6630] and 2.6% in men vs 5.3% in women in the Texas Heart Institute [n = 22,284] registry). There was no significant difference in 30-day death, MI, stroke, or renal failure requiring dialysis between patients Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 127 undergoing CABG off-pump or on-pump in a large trial involving 79 centers in 19 countries randomizing 4752 patients. Offpump CABG reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization (56). CARDIOPULMONARY RESUSCITATION AND PUBLIC-ACCESS DEFIBRILLATION Richard L. Page, MD, George R. and Elaine Love Professor, Chair, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin The 2010 American Heart Association guidelines (57) place a strong emphasis on delivering high-quality chest compressions. Rescuers should push hard to a depth of at least 2 inches (5 cm) at a rate of at least 100 compressions per minute, allow full chest recoil, and minimize interruptions in chest compressions. Rescuers also should provide ventilation using a compression:ventilation ratio of 30:2. Longer periods of resuscitation are associated with better outcomes. Goldberger et al (58) studied 64,339 subjects with cardiac arrest in US hospitals. The median duration of resuscitation was 12 minutes in survivors vs 20 minutes in nonsurvivors. The survival to discharge was related to hospital duration of resuscitation. The PAD trial (59) evaluated automated external defibrillator (AED) use vs conventional cardiopulmonary resuscitation (CPR) in 1000 US sites. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR. Weisfeldt et al (60) reported 13,769 out-of-hospital arrests where 32% received CPR but no AED before paramedics arrived and 2.1% had an AED placed before paramedics arrived. The survival to hospital discharge was 9% with CPR only, 24% with AED application, and 38% with AED shock delivery. Page et al reported early results of the first use of the AEDs by a US airline between 1997 and 1999. Of 200 events (mean age 58 years), ventricular fibrillation (VF) was present in 16 patients. All VF episodes were recognized (sensitivity 100%) and shock delivered in 15 of 16. First shock success was 100%. Six of 15 patients receiving shocks for VF survived to hospital discharge (40%). Valenzuela et al (61) published a study where casino officers were trained in the use of AEDs. The first 148 patients were reported: 105 (71%) had VF and 59% survived to hospital discharge. There was a significant difference in survival between defibrillation used before and after 3 minutes of the arrest (26/35 [74%] vs 27/55 [49%]). MANAGEMENT OF VALVULAR HEART DISEASE Robert O. Bonow, MD, Goldberg Distinguished Professor of Cardiology, Director, Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois Only 0.3% of the guidelines for valvular heart disease are at evidence level A, i.e., based on high-quality randomized clinical 128 trial or metaanalysis, while 70% are at evidence level C, i.e., based on expert consensus (62). Mitral regurgitation (MR). The current guidelines for treatment of severe chronic primary (degenerative) MR recommend mitral valve surgery in symptomatic patients (class I), patients with LVEF <0.6 and LV end systolic dimension 50 to 55 mm (class I), asymptomatic patients with atrial fibrillation (class Ia), and asymptomatic patients with pulmonary artery systolic pressure >50 mm Hg at rest or >60 mm Hg with exercise (class Ia). Management of asymptomatic severe MR with preserved EF remains controversial. The mortality of severe asymptomatic MR varies markedly among different studies. Maurice et al (63) studied 456 patients with MR (EF 70 ± 8%): the 5-year mortality rate with severe MR was 42%, while that of moderate MR was 33%. In contrast, Rosenhek et al reported 0% 5-year mortality in 132 patients with severe asymptomatic MR (64); Grigioni and coworkers (65) reported 14% 5-year mortality in 394 patients with severe MR who were followed for an average of 3.9 years; and Kang et al (66) reported 5% 7-year mortality among 286 patients with severe MR and preserved EF who were treated medically. In a retrospective review of outcomes of 13,614 patients having elective surgery for MR between 2000 and 2003 in 575 North American centers (67), the hospital procedural volume was associated with higher frequency of valve repair, higher frequency of prosthetic valve usage in older patients, and lower adjusted operative mortality. There was variation among cardiologists as to the degree of knowledge and adherence to the guidelines about the timing of referral to surgery. In a survey in 2007, among 319 responders, LVEF was rated as extremely important in referral decisions by 71% of those who completed the surveys and moderately important by 26%. In asymptomatic patients, EF of 50% to 60% was correctly identified as a trigger for surgery by 57% of cardiologists, while only 16% of cardiologists correctly referred New York Heart Association (NYHA) class II patients with normal LV function (68). Ischemic MR is managed differently from primary MR. Detection and quantification of ischemic MR provide major information for risk stratification and clinical decision making in the chronic post-MI phase (69). The mitral annulus clip is an evolving technique for treatment of functional MR. Treatment with the clip device in 51 severely symptomatic cardiac resynchronization therapy (CRT) nonresponders with functional MR was feasible, safe, and demonstrated improved functional class, increased LVEF, and reduced ventricular volumes in about 70% of these study patients (70). Aortic stenosis (AS). The current guidelines do not recommend aortic valve replacement (AVR) in patients with severe asymptomatic AS. The producibility of symptoms or hypotension with exercise is currently a class IB indication, according to the American College of Cardiology and American Heart Association. In 123 adults with asymptomatic AS, event-free survival—with endpoints defined as death (n = 8) or aortic valve surgery (n = 48)—was 93%, 62%, and 26% at 1, 3, and 5 years, respectively (71). The likelihood of remaining alive without valve replacement at 2 years was only 21% for a jet velocity >4.0 m/s Baylor University Medical Center Proceedings Volume 26, Number 2 at entry, compared with 66% for a velocity of 3.0 to 4.0 m/s and 84% for a jet velocity <3.0 m/s. In another series of 128 patients with asymptomatic severe AS (72), event-free survival—with the endpoint defined as death (8 patients) or AVR necessitated by the development of symptoms (59 patients)—was 67%, 56%, and 33% at 1, 2, and 4 years, respectively. Rosenhek et al also reported a series of 116 asymptomatic patients (73) with very severe AS, defined by a peak aortic jet velocity ≥5.0 m/s. Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. Patients with a peak aortic jet velocity ≥5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively. Early elective valve replacement surgery should therefore be considered in these patients. The current guidelines recommend AVR in patients with a high likelihood for rapid progression (calcification) and/or very severe AS (maximum velocity >5 m/s, mean gradient >60 mm Hg, AV area <0.6 cm2) (class IB). Exercise-stress echocardiography is very useful for risk stratification of true asymptomatic patients with AS (74). N-terminal beta natriuretic peptide (75) independently predicts symptomfree survival, and preoperative N-terminal beta natriuretic peptide independently predicts postoperative outcome with regard to survival, symptomatic status, and LV function. The STS score (76) is more suitable than the EuroSCORE (77) for estimating the perioperative mortality associated with AVR. Transcatheter aortic valve implantation (TAVI) is an emerging technique with enormous potential (78). The PARTNER trial (79) investigators concluded that TAVI is superior to medical therapy in patients who are not fit for AVR and that TAVI is equivalent to surgical AVR in high-risk patients. In patients with severe AS and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with surgical AVR (80). In 200 patients undergoing surgical AVR and 83 patients undergoing TAVI for severe AS (AV area ≤1 cm2) with LVEF ≤50%, patients who underwent TAVI had better recovery of LVEF compared with those who underwent surgical AVR (ΔLVEF, 14% vs 7%). Stroke and paravalvular regurgitation remain concerns with TAVI. The average hospital mortality for TAVI was 9% (13.0% for low-volume centers vs 6% for high-volume centers). The broad application of TAVI presents challenges for patient selection and the need for dedicated expert heart valve centers. The goal in AS patients is to operate late enough in the natural history to justify the risk of intervention and early enough to prevent irreversible ventricular dysfunction, pulmonary hypertension, and/or chronic arrhythmias and sudden death. OPERATIVE TREATMENT OF CARDIOVASCULAR DISEASE Charles S. Roberts, MD, Trident Health, Hospital Corporation of America, Charleston, South Carolina CABG remains the standard of care for patients with 3-vessel or left main CAD, since the use of CABG, as compared with PCI, results in lower rates of the combined endpoint of major adverse cardiac events or cerebrovascular events at 1 year (81). For patients with less severe CAD, symptom severity and noninvasive test results are used to stratify patients into one of two groups: those who will benefit from immediate revascularization April 2013 and those in whom an initial trial of aggressive medical therapy alone may be safely attempted. In patients without the highestrisk CAD who require revascularization because of unacceptable symptoms or because of noninvasive test results indicating a high risk of failure of medical therapy, PCI with drug-eluting stents and CABG appear to result in similar rates of death and MI. Therefore, the choice depends largely upon how effectively the lesions can be treated with PCI and upon the patient’s feelings about the temporary disability and the slightly increased stroke risk associated with CABG vs the increased risk of repeat revascularization with PCI (82). Stroke predictors from prospective data collected on 4941 patients undergoing cardiac surgery included history of stroke and hypertension, older age, systolic hypertension, bronchodilator and diuretic use, high serum creatinine, surgical priority, great vessel repair, use of inotropic agents after cardiopulmonary bypass, and total CABG time (83). Carotid endarterectomy (CEA). CEA currently remains the first choice of revascularization therapy for an asymptomatic carotid lesion in most centers (84). The Society for Vascular Surgery appointed a committee of experts to formulate evidence-based clinical guidelines for the management of carotid stenosis. In formulating clinical practice recommendations, the committee used systematic reviews to summarize the best available evidence and the GRADE scheme to grade the strength of recommendations (GRADE 1 for strong recommendations; GRADE 2 for weak recommendations) and rate the quality of evidence (high, moderate, low, and very low quality) (85). The following therapies had both GRADE 1 recommendation and high quality of evidence: • Medical therapy for symptomatic patients with <50% stenosis • Medical therapy for asymptomatic patients with <60% stenosis • CEA for symptomatic patients with ≥50% stenosis • CEA for asymptomatic patients with ≥60% stenosis Concomitant carotid and coronary artery surgery is safe and effective, particularly in preventing ipsilateral stroke, and neutralizes the impact of unilateral carotid stenosis on early and late stroke (86). In the US, patients who undergo carotid artery stenting and CABG have significantly decreased inhospital stroke rates compared with patients undergoing CEA and CABG, but the in-hospital mortality is similar. Carotid artery stenting may provide a safer carotid revascularization option for patients who require CABG (87). Surgical treatment of peripheral artery disease. Invasive therapy in peripheral artery disease is indicated for critical limb ischemia (ankle brachial index <0.4), not for claudication, unless it is disabling. The long-term results of the Bypass vs Angioplasty in Severe Ischemia of the Leg (BASIL) trial favor surgery rather than angioplasty if there is a good vein and the patient is fit (88). THORACIC AORTIC ANEURYSMS: DIAGNOSIS AND TREATMENT Randolph P. Martin, MD, Medical Director, Cardiovascular Imaging, Chief, Structural and Valvular Heart Disease, Piedmont Heart Institute; Professor Emeritus of Medicine, Emory University School of Medicine, Atlanta, Georgia Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 129 Thoracic aortic aneurysms (TAA). Each year, 30,000 to 60,000 deaths occur due to TAA. Thus, in the USA, they are the 18th most common cause of death and the 15th most common cause of death in individuals >65 years of age. TAAs are increasing in incidence. TAA is a virulent condition but an indolent process, growing slowly at ~0.1 cm per year. The use of an imaging technique to estimate true aortic size is confounded by its obliquity and asymmetry; thus, multiple imaging techniques may be required (89). Surgical intervention is indicated before TAAs reach 5.5 cm in diameter. A diameter of 5.0 cm may be the cut-off for patients with Marfan syndrome, a bicuspid aorta, or a family history of aortic dissection. Aortic dissection occurs in a circadian and diurnal pattern, with predominance in winter months and early morning. Aortic dissections also occur around the time of extreme physical exertion or emotional distress. The frequency of aortic dissection or through-and-through rupture increases sharply when the ascending aortic diameter reaches 6.0 cm (34% lifetime risk of rupture or dissection) and 7.0 cm in descending thoracic aorta. The Marfan syndrome. Marfan syndrome occurs due to a mutation of the fibrillin-1 gene. Patients with Marfan syndrome have a 50% risk of developing aortic dissection in their lifetime. About 5% of all TAAs are due to Marfan syndrome. TAAs in Marfan syndrome patients grow rapidly (>0.5 cm per year). A family history of aortic dissection may prompt earlier operative intervention at a diameter <5.0 cm. Pregnant patients with Marfan syndrome are at increased risk for aortic dissection if aortic diameter exceeds 4.0 cm. Loeys-Deitz syndrome. Loeys-Deitz syndrome occurs due to mutations in the TGFBR1 and TGFBR2 genes. Patients have skeletal features of Marfan syndrome but with distinct cranial features, including craniosynostosis. Other features include hypertelorism, translucent skin and veins, arterial tortuosity, and aneurysms. Aortic repair should be done at aortic diameters <5.0 cm in patients with Loeys-Deitz syndrome. Osteoarthritis syndrome. Osteoarthritis syndrome is an autosomal dominant disorder (SMAD3 mutations) responsible for 2% of familial TAA dissections. The main features of the disease include early onset of osteoarthritis (the usual reason for patients seeking medical attention), mild craniofacial abnormalities, and tortuosities throughout the arterial tree—mostly the intracranial, iliac, abdominal, and thoracic aorta—leading to aneurysms. Patients have a substantial mortality and a high risk of aortic rupture and dissection with mildly dilated aortas. Penetrating atherosclerotic ulcers. Atherosclerotic lesions may ulcerate (penetrating the internal elastic lamina) and produce hematomas within the media (90% in the descending thoracic aorta). They appear as a mushroom-like outpouching of the aortic lumen with overhanging edges. Pseudoaneurysm of the thoracic aorta. Pseudoaneurysms occur in the descending thoracic aorta due to deceleration or torsional trauma. They can also occur after aortic root or aortic valve surgery, catheter-based interventions, or penetrating trauma. Takayasu’s aortitis. Takayasu’s aortitis (90), a chronic inflammatory vasculitis involving the ascending aorta and carotid, renal, and subclavian arteries, is rare (1–2 cases/million) and 130 of unknown etiology. It affects women more than men (with a ratio of 9:1) and usually begins in the second or third decade of life. Takayasu’s aortitis produces intimal fibroproliferation that results in segmental stenosis, occlusion, dilatation, and aneurysm formation. It is the only aortitis that causes stenosis and occlusion. Takayasu’s aortitis is more prevalent in women of Asian descent, and 90% of the cases occur in patients <30 years of age. In its inflammatory stage, patients present with low-grade fever, tachycardia, pain adjacent to the inflamed arteries (carotodynia), and easy fatigability. Carotid and cervical bruits are often present. The systemic stage can be followed in 5 to 20 years by an occlusive stage. Neurologic symptoms are present in 80% of patients. SEVERE BUT ASYMPTOMATIC AORTIC STENOSIS Randolph P. Martin, MD Severe AS is undertreated. More than 50% of patients with echocardiographic findings of severe AS are not referred for further evaluation for AVR. In the Euro Heart Survey (91), 36% of patients already had significant symptoms at the time of evaluation for AVR: 47% were NYHA class III/IV and 8% were NYHA class IV and had LV dysfunction at the time of surgery. Studies of severe asymptomatic AS suggest that a third of the patients will become symptomatic within 2 years. Within 4 to 5 years, two thirds have either had an AVR or died. The risk for sudden death is about 1% per year. Kang et al (92) showed a risk of sudden cardiac death of 1.7% per year in those with aortic velocity >5.0 m/sec. The assessment of AS severity should be based on valve morphology: calcium, peak jet velocity, mean gradient, aortic valve area, LVEF, LV wall strain, LV wall fibrosis, and beta natriuretic peptide. These parameters should be integrated with presenting symptoms and response to exercise stress testing. The predictors of poor outcome in asymptomatic severe AS are a resting peak transvalvular velocity of 5.0 to 5.5 m/sec (73, 93), densely calcified aortic valve, valve area <0.75 cm2 (94), mean gradient >50 mm Hg, abnormal LVEF, beta natriuretic peptide, and abnormal exercise test (defined as failure of systolic blood pressure to rise or a fall in systolic blood pressure, symptoms, or ST-segment depression with exercise). The echocardiographic predictors of poor outcome in AS also include the degree of valve calcium (95). The degree of valve calcium is not influenced by hemodynamic conditions, which is useful in low flow states. A computed tomography calcium score >1650 AU has 80% sensitivity and specificity for severe AS. Exercise stress testing can uncover symptoms in >40% of “asymptomatic severe AS” patients. Only 20% of patients who have positive stress tests are alive, symptom-free, without AVR at 24 months vs 85% with a negative test. SYSTEMIC HYPERTENSION William H. Frishman, MD, the Barbara and William Rosenthal Professor and Chairman, Department of Medicine, New York Medical College; Director of Medicine, Westchester Medical Center, Valhalla, New York In older adults, hypertension is characterized by an elevated systolic blood pressure with normal or low diastolic blood Baylor University Medical Center Proceedings Volume 26, Number 2 pressure, due to age-associated stiffening of the large arteries. Hypertension prevalence increases markedly with age; ~60% of the population has hypertension by age 60 and ~65% of men and ~75% of women have hypertension by 70 years (96). In the Framingham Study (97), hypertension eventually developed in >90% of subjects with normal blood pressure at age 55 years. Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg (98). Numerous randomized trials have shown substantial reductions in cardiovascular events in cohorts of patients 60 to 79 years old with antihypertensive drug therapy, though the effect on all-cause mortality has been modest. In HYVET, antihypertensive therapy reduced all-cause mortality in people ≥80 years old by 21% at 1.8-year follow-up. Those randomized to indapamide vs placebo had a 30% nonsignificant decrease in fatal/nonfatal stroke, 39% significant decrease in fatal stroke, 21% significant decrease in all-cause mortality, 23% insignificant decrease in cardiovascular death, and 64% significant decrease in heart failure. Although the optimal blood pressure treatment goal in the elderly has not been determined, a therapeutic target <140/90 mm Hg in persons aged 65 to 79 years and a systolic blood pressure of 140 to 145 mm Hg, if tolerated, in persons aged ≥80 years is reasonable. The further lowering of diastolic blood pressure below 60 mm Hg may lead to coronary insufficiency and myocardial ischemic manifestations. ALTERNATIVE MEDICINE FOR THE HEART William H. Frishman, MD About 50% of patients seek an alternative sort of medicine, which is defined as any practice that is put forward as having the healing effects of medicine, but is not based on evidence gathered by the scientific method. The placebo effects on blood pressure, arrhythmia (e.g., decrease in premature ventricular complexes), heart failure symptoms (increase in EF of 5% to 20%–30% of patients) and angina pectoris (about 50% of patients) have been noticed in every cardiovascular trial. Patients also develop common adverse effects to placebo drugs (99). No megavitamin, mineral, or nutraceutical has shown an evidencebased effect on cardiovascular disease. Most trials evaluating homeopathy have shown no benefit on cardiovascular diseases (100). Chelation therapy has theoretical benefits but had no effect on CAD in clinical trials (101). Neither masked prayer nor music, imagery, or touch therapy significantly improved clinical outcomes after elective catheterization or PCI (102). There are some conditions in which herbal medicines are used as cardiovascular treatments. Several adverse cardiovascular reactions have been observed with herbal medicines used for other indications. Also, several herbs have potential and documented interactions with warfarin (103). Age, magnitude of LV hypertrophy, EF, presence of atrial fibrillation, LV obstruction, apical aneurysm, and other cardiovascular risk factors all contribute to the outcome of patients with hypertrophic cardiomyopathy (HC). Morbidity in patients with HC includes sudden death, progressive heart failure, or the development of atrial fibrillation and stroke. The incidence of sudden death is proportional to the LV wall thickness; its incidence is only 0.2%/year in patients diagnosed after the age of 60 years. In a multicenter study of 670 low-risk HC patients, the incidence of sudden death was 0.6%/year. The Bethesda Conference recommended that athletes with an unequivocal diagnosis of HC should not participate in most competitive sports, with the possible exception of those of low intensity. This recommendation includes those athletes with or without symptoms and with or without LV outflow obstruction. Drugs provide only a modest protection from sudden death in HC. A report of 506 patients showed that the implantable cardioverter defibrillator (ICD) intervened appropriately to abort ventricular tachycardia/fibrillation in 20% of patients over an average follow-up period of only 3.7 years, at a rate of about 4% per year in those patients implanted prophylactically, and often with considerable delays of up to 10 years (104). Appropriate device discharges for ventricular tachycardia/ventricular fibrillation occur with similar frequency in patients with 1, 2, or ≥3 noninvasive risk markers. In a study of 1101 patients with HC, the risk of progression to NYHA class III or IV or death specifically from heart failure or stroke was greater among patients with obstruction (relative risk: 4.4) (105). About 70% of HC patients have LV outflow obstruction either at rest (37%) or with provocation (33%). Ommen and colleagues (106) evaluated 1337 consecutive HC patients: 289 patients had surgical myectomy; 228 had LV outflow obstruction without operation; and 820 had nonobstructive HC. Mean follow-up duration was 6 ± 6 years. Their 1-, 5-, and 10-year overall survival after myectomy was 98%, 96%, and 83%, respectively, which did not differ from that of patients with nonobstructive HC or from the general US population matched for age and gender. Compared with nonoperated obstructive HC patients, myectomy patients experienced superior survival free from all-cause mortality (98%, 96%, and 83% vs 90%, 79%, and 61%, respectively), HC-related mortality, and sudden cardiac death. Different cardiology societies in the US and Europe recommend surgical myectomy as the gold standard in HC patients rather than alcohol septal ablation. Several issues remain with alcohol septal ablation: whether the outflow gradient/symptom relief is long-lasting; the relatively high rate of repeat procedures (25%); failure to obliterate the high gradients; and the fact that myectomy after failed ablations is difficult. The infarct/scar produced by ablation also may predispose patients to sudden death. HYPERTROPHIC CARDIOMYOPATHY AND PREVENTING SUDDEN DEATH IN THE YOUNG Barry J. Maron, MD, Director, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota HEART FAILURE GUIDELINES Clyde W. Yancy, MD, Professor of Medicine, Chief, Division of Cardiology, Northwestern University Feinberg School of Medicine, and Associate Director, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois April 2013 Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 131 There is a substantial variation among cardiologists in conformity with quality treatment measures for heart failure patients (107). Fonarow et al (108) reported 15,177 patients with reduced LVEF (≤35%) and chronic heart failure or postMI. The mortality rate at 24 months was 22%. Angiotensinconverting enzyme inhibitor or angiotensin receptor blocker use, ␤-blocker use, anticoagulant therapy for atrial fibrillation, CRT, ICDs, and heart failure education for eligible patients were each independently associated with improved 24-month survival, whereas aldosterone antagonist use was not. Each 10% improvement in guideline-recommended composite care was associated with a 13% lower odds of 24-month mortality. The adjusted odds for mortality risk for patients with conformity to each measure was 38% lower than for those whose care did not conform for one or more measures. The 2013 heart failure guidelines are expected to include changes in the areas of CRT, LV assist device, the role of reduced dietary sodium intake, and evidence-proven methods to reduce readmissions. Cardiac resynchronization therapy. The REVERSE (109) trial was designed to determine if CRT ± ICD modified disease progression over 12 months in patients with asymptomatic and mildly symptomatic heart failure and ventricular dyssynchrony. Patients were in NYHA class II or I (previously symptomatic), normal sinus rhythm, QRS ≥ 120 ms, LVEF ≤ 40%, LV end diastolic diameter ≥ 55 mm, without bradycardia, with or without ICD indication, on optimal medical therapy. All patients received CRT and then were randomized to have the device either on or off. Beginning at 1 year in the US and 2 years in Europe, all patients with CRT ON underwent yearly follow-up over 5 years. The heart failure clinical composite response endpoint indicated 16% worsening with CRT-ON compared with 21% worsening with CRT-OFF. Patients assigned to CRT-ON experienced a greater improvement in LV end-systolic volume index (–18.4 mL/m2 vs –1.3 mL/m2) and other measures of LV remodeling. Time to first heart failure hospitalization was significantly delayed in CRT-ON (hazard ratio: 0.47). The investigators concluded that CRT produced sustained reverse remodeling accompanied by low mortality and need for heart failure hospitalization. The benefits of CRT persisted, indicating that CRT attenuates disease progression in mildly symptomatic heart failure patients with wide QRS over at least 5 years. REVERSE, however, was underpowered to show mortality benefit and there was no long-term comparator. The RAFT (110) and MADI CRT (111) trials also showed the benefit of CRT in mild to moderate heart failure with short follow-up periods. Left ventricular assist device. Several clinical studies (112– 115) have shown improved survival with LV assist devices compared to medical therapy for advanced heart failure. The LV assist devices have not been shown to be cost effective. Salt restriction in systolic heart failure. Taylor et al (116) performed a Cochrane database review and identified 7 randomized controlled trials (3 in normotensives, 2 in hypertensives, 1 in a mixed population of normo- and hypertensives, and 1 in heart failure) with follow-up of at least 6 months comparing restricted 132 dietary salt intake or advice to reduce salt intake to control/no intervention in adults, and reported mortality or cardiovascular disease morbidity data. All-cause mortality and cardiovascular mortality for both normotensives and hypertensives were not reduced compared with the control group. In heart failure patients, salt restriction significantly increased all-cause death. Dinicolantonio and colleagues (117) analyzed 6 randomized controlled trials comparing low-sodium diets (1.8 g/day) with a higher-sodium diet (2.8 g/d) in 2747 patients with systolic heart failure. The low-sodium diet significantly increased allcause mortality, sudden death, death due to heart failure, and heart failure readmissions. Heart failure readmission rates. Hernandez et al studied a population that included 30,136 patients from 225 hospitals (118). Patients who were discharged from hospitals with higher early follow-up rates had a lower risk of 30-day readmission. The proper planning for transition of care and early outpatient follow-up was the only evidence-proven method of decreasing readmission rates for heart failure patients. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Mautner GC, Berezowski K, Mautner SL, Roberts WC. Degrees of coronary arterial narrowing at necropsy in men with large fusiform abdominal aortic aneurysm. Am J Cardiol 1992;70(13):1143–1146. Mautner GC, Mautner SL, Roberts WC. Amounts of coronary arterial narrowing by atherosclerotic plaque at necropsy in patients with lower extremity amputation. Am J Cardiol 1992;70(13):1147–1151. Roberts WC. Qualitative and quantitative comparison of amounts of narrowing by atherosclerotic plaques in the major epicardial coronary arteries at necropsy in sudden coronary death, transmural acute myocardial infarction, transmural healed myocardial infarction and unstable angina pectoris. Am J Cardiol 1989;64(5):324–328. Roberts WC, Kragel AH, Gertz SD, Roberts CS. Coronary arteries in unstable angina pectoris, acute myocardial infarction, and sudden death. Am Heart J 1994;127(6):1588–1593. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989;80(6):1747–1756. Dollar AL, Kragel AH, Fernicola DJ, Waclawiw MA, Roberts WC. Composition of atherosclerotic plaques in coronary arteries in women <40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991;67(15):1223–1227. Gertz SD, Malekzadeh S, Dollar AL, Kragel AH, Roberts WC. Composition of atherosclerotic plaques in the four major epicardial coronary arteries in patients ≥90 years of age. Am J Cardiol 1991;67(15):1228–1233. Mautner GC, Mautner SL, Roberts WC. Composition of atherosclerotic plaques in the epicardial coronary arteries in juvenile (type I) diabetes mellitus. Am J Cardiol 1992;70(15):1264–1268. Roberts WC. Atherosclerotic risk factors: Are there ten or is there only one? Am J Cardiol 1989;64(8):552–554. Roberts WC. Atherosclerosis: its cause and its prevention. Am J Cardiol 2006;98(11):1550–1555. Roberts WC. The cause of atherosclerosis. Nutr Clin Pract 2008;23(5):464– 467. Roberts WC. Shifting from decreasing risk to actually preventing and arresting atherosclerosis. Am J Cardiol 1999;83(5):816–817. Roberts WC. It’s the cholesterol, stupid! Am J Cardiol 2010;106(9):1364– 1366. Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol 1996;78(3):377–378. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol 1997;80(1):106–107. Baylor University Medical Center Proceedings Volume 26, Number 2 16. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J; Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341(6):410–418. 17. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366(9500):1849–1861. 18. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362(17):1563– 1574. 19. Wolfram RM, Brewer HB, Xue Z, Satler LF, Pichard AD, Kent KM, Waksman R. Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation. Am J Cardiol 2006;98(6):711–717. 20. Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins, and the risk of coronary heart disease: the Framingham Study. Ann Intern Med 1971;74(1):1–12. 21. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383–1389. 22. Berge KG, Canner PL; Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231(4):360–381. 23. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of Adult Treatment Panel III: final report. Circulation 2002;106(25):3143–3421. 24. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110(23):3512–3517. 25. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006;22(11):2243–2250. 26. Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, Griffen L, Taylor AJ. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55(24):2721–2726. 27. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8(6):1245– 1255. 28. Scheen AJ. Clinical study of the month. Usefulness of increasing HDL cholesterol in secondary prevention of coronary heart disease: results of the VA-HIT study. Rev Med Liege 1999;54(9):773–775. 29. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323(19):1289–1298. 30. Brown B, Brockenbrough A, Zhao X-Q, Monick EA, Huss Frechette EE, Poulin DC, Rocha AL. Very intensive lipid therapy with lovastatin, niacin and colestipol for prevention of death and myocardial infarction: a 10-year Familial Atherosclerosis Treatment Study (FATS) follow up [abstract]. Circulation 1998;98:I-635. 31. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin April 2013 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583–1592. Brown BG. Expert commentary: niacin safety. Am J Cardiol 2007;99(6A): 32C–34C. Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, Faergeman G, Pyörälä K, Miettinen T, Wilhelmsen L, Olsson AG, Wedel H; Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Atheroscler Suppl 2004;5(3):81–87. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E; Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335(14):1001–1009. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ; West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333(20):1301–1307. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339(19):1349–1357. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317(20):1237–1245. Downs JR, Clearfield M, Tyroler HA, Whitney EJ, Kruyer W, Langendorfer A, Zagrebelsky V, Weis S, Shapiro DR, Beere PA, Gotto AM. Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin. Am J Cardiol 2001;87(9):1074–1079. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365(24):2255–2267. Lange RA, Cigarroa RG, Yancy CW Jr, Willard JE, Popma JJ, Sills MN, McBride W, Kim AS, Hillis LD. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989;321(23):1557–1562. Lange RA, Cigarroa RG, Flores ED, McBride W, Kim AS, Wells PJ, Bedotto JB, Danziger RS, Hillis LD. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112(12):897–903. Flores ED, Lange RA, Cigarroa RG, Hillis LD. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16(1):74–79. Brogan WC 3rd, Lange RA, Glamann DB, Hillis LD. Recurrent coronary vasoconstriction caused by intranasal cocaine: possible role for metabolites. Ann Intern Med 1992;116(7):556–561. Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann DB, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med 1994;330(7):454–459. Pirwitz MJ, Willard JE, Landau C, Lange RA, Glamann DB, Kessler DJ, Foerster EH, Todd E, Hillis LD. Influence of cocaine, ethanol, or their combination on epicardial coronary arterial dimensions in humans. Arch Intern Med 1995;155(11):1186–1191. Saland KE, Hillis LD, Lange RA, Cigarroa JE. Influence of morphine sulfate on cocaine-induced coronary vasoconstriction. Am J Cardiol 2002;90(7):810–811. Brogan WC 3rd, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol 1991;18(2):581–586. Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 133 48. Negus BH, Willard JE, Hillis LD, Glamann DB, Landau C, Snyder RW, Lange RA. Alleviation of cocaine-induced coronary vasoconstriction with intravenous verapamil. Am J Cardiol 1994;73(7):510–513. 49. Boehrer JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med 1993;94(6):608–610. 50. Hueb W, Soares PR, Gersh BJ, César LA, Luz PL, Puig LB, Martinez EM, Oliveira SA, Ramires JA. The Medicine, Angioplasty, or Surgery Study (MASS-II): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease: one-year results. J Am Coll Cardiol 2004;43(10):1743–1751. 51. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78(5 Pt 1):1157–1166. 52. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12(1):56–62. 53. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. N Engl J Med 1984;311(21):1333–1339. 54. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G, Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC, O’Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH, Rouleau JL; STICH Investigators. Coronaryartery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364(17):1607–1616. 55. Horneffer PJ, Gardner TJ, Manolio TA, Hoff SJ, Rykiel MF, Pearson TA, Gott VL, Baumgartner WA, Borkon AM, Watkins L, et al. The effects of age on outcome after coronary bypass surgery. Circulation 1987;76(5 Pt 2):V6–V12. 56. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, Straka Z, Piegas LS, Akar AR, Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC, Novick RJ, Vaijyanath P, Reddy S, Tao L, Olavegogeascoechea PA, Airan B, Sulling TA, Whitlock RP, Ou Y, Ng J, Chrolavicius S, Yusuf S; CORONARY Investigators. Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med 2012;366(16):1489–1497. 57. Sayre MR, Koster RW, Botha M, Cave DM, Cudnik MT, Handley AJ, Hatanaka T, Hazinski MF, Jacobs I, Monsieurs K, Morley PT, Nolan JP, Travers AH; Adult Basic Life Support Chapter Collaborators. Part 5: Adult basic life support: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010;122(16 Suppl 2):S298–S324. 58. Goldberger ZD, Chan PS, Berg RA, Kronick SL, Cooke CR, Lu M, Banerjee M, Hayward RA, Krumholz HM, Nallamothu BK; American Heart Association Get With The Guidelines—Resuscitation (formerly National Registry of Cardiopulmonary Resuscitation) Investigators. Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Lancet 2012;380(9852):1473–1481. 59. Hallstrom AP, Ornato JP, Weisfeldt M, Travers A, Christenson J, McBurnie MA, Zalenski R, Becker LB, Schron EB, Proschan M; Public Access Defibrillation Trial Investigators. Public-access defibrillation and survival after out-of-hospital cardiac arrest. N Engl J Med 2004;351(7):637–646. 60. Weisfeldt ML, Sitlani CM, Ornato JP, Rea T, Aufderheide TP, Davis D, Dreyer J, Hess EP, Jui J, Maloney J, Sopko G, Powell J, Nichol G, Morrison LJ; ROC Investigators. Survival after application of automatic external defibrillators before arrival of the emergency medical system: evaluation in the resuscitation outcomes consortium population of 21 million. J Am Coll Cardiol 2010;55(16):1713–1720. 61. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343(17):1206–1209. 62. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio- 134 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schäfers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33(19):2451–2496. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, Scott C, Schaff HV, Tajik AJ. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352(9):875–883. Rosenhek R, Rader F, Klaar U, Gabriel H, Krejc M, Kalbeck D, Schemper M, Maurer G, Baumgartner H. Outcome of watchful waiting in asymptomatic severe mitral regurgitation. Circulation 2006;113(18):2238– 2244. Grigioni F, Tribouilloy C, Avierinos JF, Barbieri A, Ferlito M, Trojette F, Tafanelli L, Branzi A, Szymanski C, Habib G, Modena MG, EnriquezSarano M; MIDA Investigators. Outcomes in mitral regurgitation due to flail leaflets: a multicenter European study. JACC Cardiovasc Imaging 2008;1(2):133–141. Kang DH, Kim JH, Rim JH, Kim MJ, Yun SC, Song JM, Song H, Choi KJ, Song JK, Lee JW. Comparison of early surgery versus conventional treatment in asymptomatic severe mitral regurgitation. Circulation 2009;119(6):797–804. Gammie JS, O’Brien SM, Griffith BP, Ferguson TB, Peterson ED. Influence of hospital procedural volume on care process and mortality for patients undergoing elective surgery for mitral regurgitation. Circulation 2007;115(7):881–887. Toledano K, Rudski LG, Huynh T, Béïque F, Sampalis J, Morin JF. Mitral regurgitation: determinants of referral for cardiac surgery by Canadian cardiologists. Can J Cardiol 2007;23(3):209–214. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103(13):1759– 1764. Auricchio A, Schillinger W, Meyer S, Maisano F, Hoffmann R, Ussia GP, Pedrazzini GB, van der Heyden J, Fratini S, Klersy C, Komtebedde J, Franzen O; PERMIT-CARE Investigators. Correction of mitral regurgitation in nonresponders to cardiac resynchronization therapy by MitraClip improves symptoms and promotes reverse remodeling. J Am Coll Cardiol 2011;58(21):2183–2189. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, Kraft CD, Miyake-Hull CY, Schwaegler RG. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95(9):2262–2270. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343(9):611–617. Rosenhek R, Zilberszac R, Schemper M, Czerny M, Mundigler G, Graf S, Bergler-Klein J, Grimm M, Gabriel H, Maurer G. Natural history of very severe aortic stenosis. Circulation 2010;121(1):151–156. Maréchaux S, Hachicha Z, Bellouin A, Dumesnil JG, Meimoun P, Pasquet A, Bergeron S, Arsenault M, Le Tourneau T, Ennezat PV, Pibarot P. Usefulness of exercise-stress echocardiography for risk stratification of true asymptomatic patients with aortic valve stenosis. Eur Heart J 2010;31(11):1390–1397. Bergler-Klein J, Klaar U, Heger M, Rosenhek R, Mundigler G, Gabriel H, Binder T, Pacher R, Maurer G, Baumgartner H. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004;109(19):2302–2308. Pocar M, Moneta A, Grossi A, Donatelli F. Coronary artery bypass for heart failure in ischemic cardiomyopathy: 17-year follow-up. Ann Thorac Surg 2007;83(2):468–474. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16(1):9–13. Baylor University Medical Center Proceedings Volume 26, Number 2 78. Desai CS, Bonow RO. Transcatheter valve replacement for aortic stenosis: balancing benefits, risks, and expectations. JAMA 2012;308(6):573– 574. 79. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ; PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364(23):2187–2198. 80. Clavel MA, Webb JG, Rodés-Cabau J, Masson JB, Dumont E, De Larochellière R, Doyle D, Bergeron S, Baumgartner H, Burwash IG, Dumesnil JG, Mundigler G, Moss R, Kempny A, Bagur R, Bergler-Klein J, Gurvitch R, Mathieu P, Pibarot P. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. Circulation 2010;122(19):1928–1936. 81. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Ståhle E, Feldman TE, van den Brand M, Bass EJ, Van Dyck N, Leadley K, Dawkins KD, Mohr FW; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360(10):961–972. 82. May SA, Wilson JM. The comparative efficacy of percutaneous and surgical coronary revascularization in 2009: a review. Tex Heart Inst J 2009;36(5):375–386. 83. Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med 2012;366(3):250–257. 84. Amarenco P, Labreuche J, Mazighi M. Lessons from carotid endarterectomy and stenting trials. Lancet 2010;376(9746):1028–1031. 85. Hobson RW 2nd, Mackey WC, Ascher E, Murad MH, Calligaro KD, Comerota AJ, Montori VM, Eskandari MK, Massop DW, Bush RL, Lal BK, Perler BA; Society for Vascular Surgery. Management of atherosclerotic carotid artery disease: clinical practice guidelines of the Society for Vascular Surgery. J Vasc Surg 2008;48(2):480–486. 86. Akins CW, Hilgenberg AD, Vlahakes GJ, Madsen JC, MacGillivray TE, LaMuraglia GM, Cambria RP. Late results of combined carotid and coronary surgery using actual versus actuarial methodology. Ann Thorac Surg 2005;80(6):2091–2097. 87. Timaran CH, Rosero EB, Smith ST, Valentine RJ, Modrall JG, Clagett GP. Trends and outcomes of concurrent carotid revascularization and coronary bypass. J Vasc Surg 2008;48(2):355–360; discussion 360–361. 88. Beard JD. Which is the best revascularization for critical limb ischemia: endovascular or open surgery? J Vasc Surg 2008;48(6 Suppl):11S–16S. 89. Elefteriades JA, Farkas EA. Thoracic aortic aneurysm: clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010;55(9):841–857. 90. Gravanis MB. Giant cell arteritis and Takayasu aortitis: morphologic, pathogenetic and etiologic factors. Int J Cardiol 2000;75(Suppl 1):S21– S33; discussion S35–S36. 91. Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P, Gohlke-Bärwolf C, Boersma E, Ravaud P, Vahanian A. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26(24):2714–2720. 92. Kang DH, Park SJ, Rim JH, Yun SC, Kim DH, Song JM, Choo SJ, Park SW, Song JK, Lee JW, Park PW. Early surgery versus conventional treatment in asymptomatic very severe aortic stenosis. Circulation 2010;121(13):1502–1509. 93. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, Kraft CD, Miyake-Hull CY, Schwaegler RG. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95(9):2262–2270. 94. Lancellotti P, Lebois F, Simon M, Tombeux C, Chauvel C, Pierard LA. Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis. Circulation 2005;112(9 Suppl):I377–I382. 95. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343(9):611–617. April 2013 96. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 1995;25(3):305–313. 97. Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB, Levy D. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345(18):1291–1297. 98. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903–1913. 99. Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapeutics (2nd ed.). New York: McGraw Hill, 2003:15–25. 100. Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homoeopathy. BMJ 1991;302(6772):316–323. 101. Krucoff MW, Crater SW, Gallup D, Blankenship JC, Cuffe M, Guarneri M, Krieger RA, Kshettry VR, Morris K, Oz M, Pichard A, Sketch MH Jr, Koenig HG, Mark D, Lee KL. Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation of Noetic Trainings (MANTRA) II randomised study. Lancet 2005;366(9481):211–217. 102. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2008;19(10):1118–1126. 103. Frishman WH, Weintraub MI, Micozzi MS. Complementary & Integrative Therapies for Cardiovascular Disease. St. Louis: Elsevier, 2005. 104. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2008;19(10):1118–1126. 105. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348(4):295–303. 106. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46(3):470–476. 107. Fonarow GC, Yancy CW, Albert NM, Curtis AB, Stough WG, Gheorghiade M, Heywood JT, McBride ML, Mehra MR, O’Connor CM, Reynolds D, Walsh MN. Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE heart failure. Circ Heart Fail 2008;1(2):98–106. 108. Fonarow GC, Albert NM, Curtis AB, Gheorghiade M, Heywood JT, Liu Y, Mehra MR, O’Connor CM, Reynolds D, Walsh MN, Yancy CW. Associations between outpatient heart failure process-of-care measures and mortality. Circulation 2011;123(15):1601–1610. 109. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52(23):1834–1843. 110. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363(25):2385–2395. 111. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiacresynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361(14):1329–1338. 112. Miller LW, Pagani FD, Russell SD, John R, Boyle AJ, Aaronson KD, Conte JV, Naka Y, Mancini D, Delgado RM, MacGillivray TE, Farrar DJ, Frazier OH; HeartMate II Clinical Investigators. Use of a continuous-flow device Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease 135 in patients awaiting heart transplantation. N Engl J Med 2007;357(9):885– 896. 113. Starling RC, Naka Y, Boyle AJ, Gonzalez-Stawinski G, John R, Jorde U, Russell SD, Conte JV, Aaronson KD, McGee EC Jr, Cotts WG, DeNofrio D, Pham DT, Farrar DJ, Pagani FD. Results of the postU.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011;57(19):1890–1898. 114. Rogers JG, Butler J, Lansman SL, Gass A, Portner PM, Pasque MK, Pierson RN 3rd; INTrEPID Investigators. Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. J Am Coll Cardiol 2007;50(8):741–747. 115. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, 136 Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345(20):1435– 1443. 116. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review). Am J Hypertens 2011;24(8):843–853. 117. Dinicolantonio JJ, Pasquale PD, Taylor RS, Hackam DG. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis. Heart 2013 Jan 24 [Epub ahead of print]. 118. Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, Heidenreich PA, Yancy CW, Peterson ED, Curtis LH. Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure. JAMA 2010;303(17):1716–1722. Baylor University Medical Center Proceedings Volume 26, Number 2 Our experience as a Health Volunteers Overseas–sponsored team in Huế, Vietnam James I. Ewing, MD, Claude A. Denham, MD, Cynthia R. Osborne, MD, Nathan B. Green, DO, Josephine Divers, RN, and John E. Pippen Jr., MD A group from Texas Oncology and Baylor Charles A. Sammons Cancer Center traveled to Huế, Vietnam, as part of Health Volunteers Overseas. From February 21 to March 6, 2012, five Baylor Sammons medical oncologists and an oncology nurse worked with a medical oncologist and a surgeon at the Huế College of Medicine and Pharmacy, suggesting approaches based on available resources. The two groups worked together to find optimal solutions for the patients. What stood out the most for the Baylor Sammons group was the Huế team’s remarkable work ethic, empathy for patients, and treatment resourcefulness. The Baylor Sammons group also identified several unmet needs that could potentially be addressed by future volunteers in Huế, including creation of an outpatient hospice program, establishment of breast cancer screening, modernization of the pathology department, instruction in and better utilization of pain management, better use of clinic space, and the teaching of oncology and English to medical students. There was a mutual exchange of knowledge between the two medical teams. The Baylor Sammons group not only taught but also learned how to take good care of patients with limited resources. A group of health care professionals from Baylor Charles A. Sammons Cancer Center at Dallas traveled to Vietnam from February 21 to March 6, 2012, to work alongside local caregivers and introduce new concepts, teach new techniques, and identify needs that can be addressed on follow-up trips. The team from Baylor Dallas consisted of two experts in breast cancer (Drs. John Pippen and Cynthia Osborne), two general medical oncologists (Drs. Claude Denham and Nate Green, a former medical oncology fellow who now practices in Lincoln, Nebraska), a second-year oncology fellow (Dr. James Ewing), and an oncology nurse (Josie Divers, RN) (Figure 1). After a formal application was made to the Accreditation Council for Graduate Medical Education, Dr. Ewing received fellowship credit for the time spent in Vietnam. Planning for the trip began when physicians of the Baylor Sammons Cancer Center and Texas Oncology were contacted by Health Volunteers Overseas (HVO), a not-for-profit organization dedicated to improving the availability and quality of health care in developing countries through the training and education of local health care providers. HVO works with numerous professional medical societies to develop training programs for Proc (Bayl Univ Med Cent) 2013;26(2):137–141 Figure 1. Our team in front of the oncology clinic. Left to right: Dr. Osborne and Josie Divers (front row) and Drs. Pippen, Green, Denham, and Van Cau (back row). Not pictured: Dr. Ewing. a wide range of specialties. In its quarter century of existence, HVO has sent over 4000 volunteers to places around the world and has completed close to 8000 assignments. The International Cancer Corps (ICC) of the American Society of Clinical Oncology (ASCO) began partnering with HVO in 2010, with the goal of having highly qualified health care professionals provide relevant, realistic training that focuses on oncologic diseases and health conditions relevant to the geographic area, so this knowledge can be disseminated to other health care providers in the area. The first ICC site chosen was Tegucigalpa, Honduras; the second, Addis Ababa, Ethiopia; and the third, Huế, Vietnam. Huế is a city in central Vietnam that serves as the capital city of the Thua Thien-Huế province. It was once the ancient imperial capital of the Nguyến Lords, who were rulers of what is now Southern and Central Vietnam. In the 1800s, still under the rule of the Nguyến Lords, it became the capital of all of Vietnam. Due to its location near the border of North and South Vietnam, From the Baylor Charles A. Sammons Cancer Center (Ewing, Denham, Osborne, Pippen), Baylor University Medical Center at Dallas; Texas Oncology, PA, Dallas, Texas (Denham, Osborne, Divers, Pippen); and Southeast Nebraska Cancer Center, Lincoln, Nebraska (Green). Corresponding author: John E. Pippen Jr., MD, FACP, Baylor Charles A. Sammons Cancer Center, 3410 Worth Street, Suite 400, Dallas, TX 75246 (e-mail: John. Pippen@usoncology.com). 137 this South Vietnamese city was a site of intense fighting in the Vietnam War, especially during the Tết Offensive of 1968. Now a peaceful large city bisected by the Sông Húóng (Perfume) River (Figure 2), Huế is home to approximately 950,000 residents and the Huế College of Medicine and Pharmacy (Figure 3). The facility was founded in 1957 and has trained over 12,000 graduates in medicine, pharmacy, dentistry, and allied health professions. It has an annual enrollment of over 1000 students, with almost 4000 undergraduates studying various health-related fields on campus at any given time. The college serves the central area of Vietnam, whose population is approximately 20 million people. Since Vietnam is a developing country, a large percentage of the patients served by the college have limited financial means, with the average monthly wage reported to be US $185 last year (1). Many of the patients travel 30 miles or more by bicycle or motorcycle to get to the clinic for an appointment with a doctor. Both the medical school and hospital are run by the government. THE CLINIC Working within the college’s oncology clinic were the Vietnamese hosts, Dr. Nguyen Van Cau, a medical oncologist, and Dr. Phung Phuong, a surgeon. Dr. Van Cau had one oncology fellow who helped with patient care. At least 10 nurses and other assistants also staffed the clinic. The clinic was an airconditioned building built in the 1980s. The first floor housed the Gamma Knife center, and the upper floors housed the clinics and inpatient hospital rooms. The equipment was not new, but it was functional. Dr. Phuong, a surgeon by training, had dual roles, as he planned, mapped, and operated the Gamma Knife, in addition to operating and serving as a clinical professor at the medical school. Dr. Van Cau’s office (where most of the patients were seen) was located on the second floor, and this is where we spent most of our time. In addition to Dr. Van Cau’s office, there was a room for the nursing staff to meet and do charting, a room to prepare the chemotherapy, and another room storing medications. In the chemotherapy preparation room, there was a ventilation hood with a small hole cut in the back wall. A small fan took air from the hood and sent it outside. Most basic chemotherapy drugs and antiemetics were available. The pathology department was on site as well. The department was small and simple, with processing and microscope work done in the same room. Several basic immunohistochemical stains were available for breast cancer, although Ki-67, an immunostain used as a measure of the proliferation index in a b Figure 2. Scenes from Huế, Vietnam: (a) flower vendors and (b) motorbikes. 138 Figure 3. Our first view of the Huế, College of Medicine and Pharmacy. breast tumor specimens, was not routinely used. The oncologists did not generally review the pathology themselves, but relied on written or verbal reports by the pathologists. The pathology reports did not always clearly establish orientation and distance of the tumor from surgical margins. This was one issue we addressed during our stay in Huế. We were able to observe a number of patients undergo treatment during our visit, including a patient with a hepatoma who was being mapped prior to radiation therapy. Additionally, a patient with brain cancer was treated while we were there. The machine was old and was shut down one day by a water leak; however, the oncology team in the clinic did remarkably well with the tools they had available. The gap in wealth in Vietnam is extreme. Those with connections to the communist leaders live quite well, with the rest of the population living in severe poverty. Most drugs and health care are subsidized by the Vietnamese government; however, there is an exception with trastuzumab for HER2-positive breast cancer. This drug is completely unsubsidized, but we did see one patient elect to add it to her adjuvant treatment, at a cost of over US $8000 per month. Obviously, not many in Vietnam can afford this treatment. Rituximab is partially subsidized by the government and is for patients who can afford the large copayments. Thus, during our trip we did see one patient with non-Hodgkin’s lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), but most patients were treated with CHOP or CHOP-E (etoposide), regimens inferior to R-CHOP, for diffuse large B-cell lymphoma. Dr. Van Cau was able to order almost any chemotherapy drug on the World Health Organization (WHO) list. The patients were treated in four rooms, each of which had five beds. As we went from room to room, the patients were quiet, well mannered, and did not ask a lot of questions. Both male and female patients were in the same rooms with no concern for privacy. If there were more patients than beds, the patients shared a bed, with one at each end (Figure 4). Each room had five to 10 Baylor University Medical Center Proceedings Volume 26, Number 2 Figure 4. Dr. Denham visiting with some of the oncology patients staying in the inpatient rooms in the clinic. patients in it. Services such as food, water, and bedding were not provided. Attentive family members took care of these needs. Patients could stay overnight in the clinic if they had special needs or if their treatment took several days. Several nurses were present after hours if there were problems. The clinic was located a few feet from the hospital itself. Dr. Van Cau would usually go to see consults in the hospital in the late afternoon and would direct patients back to the clinic after discharge. Just as patient confidentiality was not a concern in the inpatient rooms, neither was it a concern in the clinic, which seemed unusual coming from our culture. As many as four breast cancer patients might be in the same room at the same time for their follow-up visit. Each disrobed and was examined in turn, which was viewed as perfectly normal by patients and staff. In talking to patients, it seemed that they only saw the doctor for a very brief visit, lasting less than 5 minutes. There was generally little discussion with the physician; rather, most discussions were among the physicians, who then made a declaration of when the patient’s next follow-up visit should be. This was followed by a flurry of stamping a stack of documents, which were then passed back to the patients. Patients seemed to be in charge of holding their own records, and many would come in with their scans and radiology films in hand. Computed tomography images and ultrasound were locally available and performed quickly for the outpatients. The quality of the images was quite good. Most lab tests were available. The subsidized cost to the patient was about US $40. Positron emission tomography imaging required a trip to Ho Chi Minh City or Hanoi, if the patient had the means to pay for it. Bone marrow transplantation also required going to one of the same two larger cities in Vietnam. Otherwise, oncology treatments were performed in Huế. Once the team settled in to work at the clinic, we found an interesting and challenging mix of cases. One breast cancer case involved a 34-year-old woman, 11 weeks pregnant, who presented with a left subareolar breast mass and a palpable axillary node. Dr. Van Cau, as well as the rest of us, encouraged her to keep the baby, but her husband was adamant that the pregnancy be terminated. The patient already had four children, and her husband said he could not take care of another child. We also April 2013 saw a 59-year-old Catholic nun who recently had a mastectomy for a T2N1M0 estrogen receptor–positive, HER2-negative breast cancer. After deciding chemotherapy was needed, she was treated with a combination of epirubicin and paclitaxel. This is the adjuvant chemotherapy regimen of choice for all breast cancer patients deemed to be in need of chemotherapy. The decision of whether or not to use adjuvant chemotherapy was hindered somewhat by the lack of availability of Ki-67 staining. Tests such as Oncotype DX were not used, largely due to cost. Other types of cancer reflected what would be expected in a busy oncology clinic, with a tendency toward tobacco-related and gastric malignancies. Breast cancer and other malignancies seemed to present at a more advanced stage. This is likely related, at least in part, to the lack of screening or effective primary or secondary prevention programs. We were also surprised by the relative youth of the majority of the patients. Today, according to a 2010 WHO report, Vietnam is among the countries with the highest smoking rates in the world, with a prevalence of more than 45% in men aged 18 years or older (2). Several of the physicians we worked with were smokers themselves. Smoking among health care providers was found to have a prevalence >40%. Further efforts towards primary prevention are definitely needed. The high prevalence of smoking and cervical cancer relay the need for better primary prevention in Vietnam. Several patients we saw showed the need for a linear accelerator, which has been used for over 50 years for external beam radiation treatments for cancer. There were several local recurrences of cancer that likely could have been prevented if standard radiation treatment was given either concurrently with or after chemotherapy. One such patient was a young woman with a painful vaginal recurrence of a rectal cancer. The cancer involved the posterior vaginal wall, and the tumor was exuding from the vagina and causing significant pain and bleeding. As stated earlier, the only radiation treatment available in the Huế Oncology Clinic is in the form of Gamma Knife radiosurgery. Access to other types of radiation treatments would have allowed treatment of a much wider range of cancers. PALLIATIVE CARE The lack of palliative care and hospice represents a great need for the people of Huế and is a topic we can explore much more with the medical staff on a subsequent trip. The use of long-acting narcotics was much more uneven between patients. Patients who were at the end stage of their cancer and experiencing a lot of pain could come back to the clinic and receive injections of morphine. Conversely, one of the clinic nurses could go out to the patient if he or she was nearby. Death was a topic not generally discussed with patients. When I asked one of the fellows if she ever told patients that cancer would end their life, the question was met with a surprised look and an emphatic “no, never!” The family was told to “be prepared for anything.” Unfortunately, the “anything” families are prepared for does not usually include death. The differences in palliative care and hospice practices between our two countries were best represented by a patient we saw the first day while rounding on the inpatient service. The Our experience as a Health Volunteers Overseas–sponsored team in Huế, Vietnam 139 patient was a 54-year-old man with a metastatic high-grade sarcoma. He had been diagnosed with a high-grade rhabdosarcoma of his leg 7 months previously. At the time of diagnosis, surgery was advised but the patient refused. Unfortunately, his malignancy progressed despite extensive anthracycline-based chemotherapy. He had been at the hospital since the time of diagnosis and his tumor had grown rapidly, extending from his right knee to above his hip in a circumferential manner. Moreover, he had severe pain and extensive pulmonary metastatic disease. We saw this patient once again several days later, during our next rounding. In talking with one of the fellows, we learned the patient had not been told his tumor would progress and eventually take his life. With help from the fellow in interpreting, we spoke with the patient, who was from a local village, about 30 km from Huế. He and his wife had four children; both of his sons lived with him. He worked in a shoe factory prior to his sarcoma diagnosis. His sister was staying with him to cook and take care of him in the hospital until he “gets better from his tumor.” At that time, his cancer had progressed while on chemotherapy and he was only on intravenous fluids and supportive medications. We found this patient had a real lack of insight and unrealistic expectations regarding his condition, but we were informed that often patients are not told they are going to die from their disease. We discussed through an interpreter with the patient about his diagnosis and how his tumor would continue to grow and likely ultimately take his life. He stated he definitely wanted to be home when he passed. Our conversation was relatively short by American standards, but the patient seemed to take the news well. He thanked us and smiled when we moved on with our rounds. When rounding the following day, we were told he was to be discharged that day to go home to be with family. AN ONCOLOGY FELLOW’S PERSPECTIVE In October 2011, I was asked by Dr. John Pippen, a member of the clinical faculty, if I would like to travel to Huế, Vietnam, to volunteer with a group from ASCO for 2 weeks. Dr. Pippen put together an incredible team for the trip. It took me all of two seconds to say, “Yes, let’s do this!” During my first week, I was fortunate to locate the Englishspeaking club. On our third day I met a unique group of medical students who gathered weekly to practice their English skills. We reviewed core oncology and hematology skills, including how to evaluate a peripheral blood smear. During our time together, we talked extensively about the system of medicine in our two countries, medical training, oncology, and many other topics. I learned that in Vietnam all medical schools are run by the government. Due to the influence of their political system, every medical school has its own Communist Party committee. Typically, the dean or head of the department is appointed by the Communist Party committee. In addition to learning medicine, medical students are taught Marx’s philosophy (during the first few years), Ho Chi Minh’s philosophy, as well as the history of the Communist Party. Upon completion of 6 years of medical school, graduates have several options. Most begin work as general doctors. 140 Many engage in self-study or attend conferences to become specialists without a formalized system of training. For the more competitive 10% to 15% of new physicians, another option is to pursue postgraduate education through the academic track or the clinical track of study. The academic track is designed for those who will teach at a medical school or university. The clinical track is what Dr. Thi, a trainee with Dr. Van Cau, was doing. This program consisted of 3 years in residency training, similar to a US residency program. Admission to these postgraduate programs was highly competitive and required an entrance exam along with an interview. From the students I learned that health care services in Vietnam are often paid for on a cash basis, despite a national health insurance program, known as “Bao Hiem Y Te.” The national plan has two types of health care insurance: obligatory and voluntary. Obligatory insurance is the plan for people who are currently working, and it is paid for by a combination of employer and employee contributions. Voluntary insurance is for those not belonging to the obligatory section, such as students or those out of work. This insurance still may require a fee, but it is much less. All children under 6 years of age have free medical insurance in Vietnam; however, access to medical services varies greatly based on geography and socioeconomic factors. I was told by some that patients who pay cash usually receive more attention and better care; however, we saw no evidence of this in our experience in the clinic. I met with the English club several times on my trip. I continue to correspond with one of the fourth-year medical students whose goal is to pursue a career in oncology. Overall it was an incredibly rewarding opportunity for me as an oncology fellow, and I believe that many of the lessons and experiences we shared with our Vietnamese colleagues will be integrated into their everyday practice. I think that we were able to learn much from the resourcefulness and ingenuity of Dr. Van Cao and his team, and I am looking forward to a future return trip to the site. TRAVEL-RELATED ISSUES FOR THE VOLUNTEER Several minor obstacles, other than just the lengthy air travel, must be overcome to successfully navigate Vietnam. In addition to a valid passport, a tourist visa must be obtained. For a stay longer than 4 weeks, visitors require a different class of visa. Since there are a limited number of Vietnamese consulates in the US, it is easiest to employ a travel service to obtain the tourist visa, which is valid for one entry into Vietnam. The total expense for the visa is around $300. In-country travel is inexpensive, owing to the strength of the dollar relative to the Vietnamese currency. In addition to completion of the necessary paperwork, travel to a developing country requires some advance medical preparations. Vietnam is an area known to be endemic for malaria, so DEET-containing insect repellant is recommended. If traveling outside of urban areas, malaria prophylaxis is advised. Other common-sense travel precautions should be followed, including drinking bottled water, avoiding salad items that may have been washed with tap water, and using sufficient sunscreen, a huge task even for a well-practiced group from Texas. Baylor University Medical Center Proceedings Volume 26, Number 2 IDENTIFICATION OF NEEDS There are opportunities to make a positive impact on subsequent trips to the Huế College of Medicine and Pharmacy. Below is a partial list of opportunities. 1. Modernization of the pathology department. In breast and other cancers, the orientation of the specimens was not always known, and on some specimens it appeared as if cancer was at the margins. The Ki-67 tumor marker test needs to be added to the breast cancer immunohistochemical analysis panel to better gauge the proliferative status of a tumor. A visiting pathologist could go a long way in making sure basic protocols are in place to improve their diagnostic capabilities. 2. Instruction in the use of long-acting oral pain medicines and further instruction on WHO’s pain relief ladder. In addition to managing the pain of cancer patients, managing the side effects of narcotic medications is another area that could be taught. 3. An outpatient hospice. This hospice could be organized by first utilizing the current clinic nursing staff. A discussion with the chief administrators may be helpful in creating a cadre of palliative care nurses to visit patients in their homes. Economic issues may be problematic, but motorbike transportation is relatively inexpensive, and Huế is easy to traverse for an experienced cyclist. 4. More efficient use of space in the clinic. Putting six chairs in each of the rooms may prove more helpful than five cots. Chairs would be more comfortable than cots and would allow more patients to be treated in a shorter amount of time. 5. Mammography and breast conservation training. Again, acquisition of a linear accelerator would make this a possibility and could potentially cut down on the number of local recurrences seen in the cancer patients. Purchase of a new machine, however, may be problematic in a developing nation. Better surgical techniques would include the addition of more accurate sentinel node assessments. 6. Teaching medical students. In Huế, we had the privilege of lecturing to the students, all of whom were respectful and attentive. With many of them interested in oncology, there is great opportunity for volunteers to help with improvement in oncology education and screening. A series of basic lectures in medical oncology would likely be well received. 7. English as a second language. The students wanted to learn better English. Evening practice sessions with team members and students, accompanied by an excellent local beer, would be a good way to facilitate this process. PARTING THOUGHTS Our trip to Vietnam really opened our eyes to what others in the world must contend with in their medical practices. Even though we were able to teach them a great deal, they taught us about how to take good care of patients with limited resources. We were able to experience, on a limited level, what people in Vietnam experience on a daily basis. All was not work on our trip, however, as we took some time to see some of the sites of Vietnam. We stopped in Hố Chi Minh City (formerly Saigon) April 2013 Figure 5. Cao Ðài Temple in Tây Ninh, about 90 km northwest of Hố Chi Minh City (formerly Saigon). Cao Ðài is a faith indigenous to Vietnam, which includes the teachings of the major world religions. and saw the  tunnels of Cu Chi, a vast network used by the Viet Cong guerrillas during the Vietnam War. They were the Viet Cong’s base of operations for the Tết Offensive in 1968 and now an important part of their history. We also took a day trip to Tây Figure 6. A parting gift of flowers from our hosts in front Ninh, about of a statue of Ho Chi Minh. Drs. James Ewing (left) and 90 km north- John Pippen (right). west of Hố Chi Minh City. There we saw the Cao Đài Temple (Figure 5). The Cao Đài faith, indigenous to Vietnam, includes the teachings of the major world religions. It was quite interesting to see how the Vietnamese integrated so many diverse faiths. When our trip came to an end, we were thanked profusely by our hosts, including a presentation of flowers (Figure 6). We all learned much on our journey and hope to make it again soon. 1. 2. Vietnam average monthly wage rises to $185. Thanh Niên Daily News Online, January 25, 2012. Available at http://www.thanhniennews. com/2010/pages/20120125-salaries-rise-in-vietnam-income-gap-stillwide.aspx; accessed January 15, 2013. World Health Organization. Appendix VIII—Table 1: Surveys of adult tobacco use in WHO member states. In WHO Report on the Global Tobacco Epidemic, 2009. Geneva, Switzerland: WHO, 2009. Our experience as a Health Volunteers Overseas–sponsored team in Huế, Vietnam 141 A forgotten landmark medical study from 1932 by the Committee on the Cost of Medical Care Thomas B. Gore, MD M ost physicians are aware of the history of the Flexner Report, published in 1910. It gave a detailed report card of the nation’s medical schools, prepared by Abraham Flexner with funding from the Carnegie Foundation. This report revolutionized medical education in America and will be the subject of a future review article. Why do few physicians know about the work and findings of the Committee on the Cost of Medical Care (CCMC)? During the 1920s, the rising cost of physician and hospital care became a concern to many. At a national economic conference in 1925 in Washington, DC, a committee was self-organized to address this issue and became known as the CCMC. This effort received funding of $1 million from eight foundations, and its activities were directed by a staff of employees. The Carnegie Foundation and Milbank Memorial Fund were the largest contributors. The committee included 15 physicians in private practice and was chaired by Ray Lyman Wilbur, MD, of Stanford University. He was a well-known figure with conservative Republican credentials, and he soon became secretary of the interior under President Hoover. Dr. Stewart R. Roberts of Atlanta was one of the doctors on the panel. He was on the Emory faculty at the time and had been president of the Fulton County Medical Society and was active in the Southern Medical Association. He was later president of the American Heart Association. He was well published and well respected and was considered to be Georgia’s first cardiologist. The CCMC and its staff issued 15 separate reports over 5 years, which were published and available as pamphlets. The final report with all its recommendations was printed in book form (Figure). This was the first time that many economic aspects of medical care in the US were documented. Among its many findings, the CCMC estimated that health care consumed 4% of the gross domestic product. Spending for physician services was the largest category, accounting for 29.8¢ of each dollar. Hospital care consumed 23.4¢, medications 18.2¢, dental care 12.2¢, nursing care 5.5¢, “cultists” 3.4¢, public health 3.3¢, and other 4.2¢. The average gross income of physicians in 1929 was $9000 per year at a time when the average family income was $1700 per year. An overhead of 40% was typical for a physician in practice, and 10% to 20% of fees were uncollected. Despite much charity care by physicians, hospitals, and health departments, in the lowest-income groups about half received 142 Figure 1. The committee’s final report, Medical Care for the American People, published by the University of Chicago Press in 1932. no medical care at all. It was estimated that if medical care was organized economically, all the usual needed care for the entire country could be provided for $20 to $40 per person per year (excluding capital costs). The most quoted statement from the report indicated the basic problem in medical care was “not the system, but the lack of a system” to organize care. The most common physician practice then was the solo private general practitioner. The CCMC also documented other styles of practice, such as industrial medicine, group practice with or without hospital employment, capitated models, public health system practice, and university-sponsored student health care. These nontraditional types of practice needed to grow. The final report supported expansion of group practice and formation of the “community medical center” as the most effective means of providing care. More national spending on overall medical care was required to meet all the needs, especially to provide for those who had no medical care. Preventive care was thought best provided through public health facilities. The most controversial recommendation of the CCMC was for national health insurance, either voluntary or compulsory through taxation. From the Division of Cardiology, West Georgia Medical Center, LaGrange, Georgia. Corresponding author: Thomas B. Gore, MD, 1602 Vernon Road, Suite 300, LaGrange, GA 30240 (e-mail: tbgore@gmail.com). Proc (Bayl Univ Med Cent) 2013;26(2):142–143 Notable was the fact that eight physicians dissented and wrote a minority report. They supported continued experimentation with such models and new proposals but strongly felt that the independent practicing physician should be in charge of any programs or changes. They objected to competition based on price as “unprofessional.” This group felt that even voluntary health insurance would lead to a compulsory national health insurance, as was in place in many European countries. Georgia’s Dr. Roberts supported the work of the committee and signed the final report. Two of the nonphysician committee members felt that the report did not go far enough or make strong enough recommendations for national health insurance. They stated that the purpose of the committee had not been fulfilled. Edgar Sydenstricker and Walton Hamilton were these two. Little time passed before the editor of the Journal of the American Medical Association, Dr. Morris Fishbein, penned a blistering denouncement of the work of the CCMC on December 3, 1932, stating it was “incitement to revolution,” “socialist,” and “communist.” The American Medical Association (AMA), in its 1933 House of Delegates, took a position of opposition to any further government involvement with medical care. Franklin Roosevelt had been elected president in the depth of the Depression, and the winter of 1933 was the nadir of despair. Any changes in the health care system took a back seat to more pressing matters. The famous “First Hundred Days” dealt with banking reforms, help with mortgage foreclosures, and many regulations for businesses in an effort to stabilize a critically damaged economy and put people to work, even if it was “make-work.” The Civilian Conservation Corps, Works Progress Administration, and Public Works Administration were funded with unheralded deficit spending. In many respects, the report of the CCMC was a tiny blip on any graphic of the crisis. Within 2 years, Roosevelt appointed an Economic Security Committee in June 1934, which included several of his cabinet members, and called an Economic Security Conference in Washington in November 1934 under the leadership of Frances Perkins, secretary of labor, and Harry Hopkins, director of federal relief programs. Roosevelt asked for unemployment insurance, old age pensions, and proposals on medical care insurance. He spoke in November and advocated medical efforts “whether soon or at some point later,” indicating ambivalence about the health care proposals. A technical staff had been drafting proposals on all these areas since Roosevelt’s first speech in July 1934 on the subject, including national health insurance models. During the November conference, an invited Medical Advisory Committee attended and expressed their reservations about the program. This group then met separately in January 1935, ostensibly to give their approval. The meeting was chaired by Edgar Sydenstricker, one of the main dissenters of the CCMC. Dr. Walter Bierring, president of the AMA, was among the panel members. The prior work of the CCMC was discussed and provided the statistical basis for many recommendations. The charge of the advisory group was to respond to the proposed changes for April 2013 potential legislation. The minutes of these meetings, available online through the Social Security historical archives, provide interesting insight into medical issues of the time. The advisory committee allowed the recommendation for national health insurance to survive, but there was much internal opposition. Harvey Cushing, the prominent Boston neurosurgeon, was on the advisory committee and spoke outside the committee in opposition. Other physicians on the committee were opposed. Dr. Stewart Roberts appears to have been in support and stated that the medical community was “on trial” and would “regret its actions” if it did not move forward to include medical care with other aspects of Social Security legislation. He apparently felt that the committee members and their work was maligned by the position of the AMA. With leaks from the committee and the impression that health insurance was coming soon, the AMA called an emergency House of Delegates meeting in February 1935 and vehemently opposed any efforts at national health care insurance or government regulation of medicine. The AMA assumed from the committee structure and technical work that a health care proposal was sure to follow. This strong stance by the House of Delegates generated many telegrams from local physicians and state and county medical societies to the White House. It can be safely assumed that the physicians of the day were mostly held in high regard locally and nationally. What impact did this vocal opposition really have on the final decisions? Harry Hopkins continued to favor inclusion of medical assistance, but Frances Perkins advised against it, fearing that the whole Social Security bill would go down. Roosevelt showed caution and held his cards. Whether the medical opposition led to its exclusion or whether Roosevelt was reluctant from the beginning to include national health care in his bold social initiative is the subject of much debate among historians. Roosevelt was known for skillfully making each side feel he agreed with them. The final report of the Medical Advisory Committee did not materialize in 1935 and was not published until many years later. The Senate finance committee gave the Economic Security Bill a beating but ultimately let it through by a small margin, with Senator Thomas Pryor Gore of Oklahoma famously explaining his view that “the dole ruins the soul.” Although some public health funding was given, comprehensive national health programs were excluded from the final bill approved by Congress in June 1935. Many of the proposals advocated in the 1930s still retain their fire as public debate and divided opinions on the Affordable Care Act of 2010 loom large. Flexner A. Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching. Boston: Merrymount, 1910. The Committee on the Costs of Medical Care. Editorial and abstract summary. JAMA 1932;99(23):1950–1952, 1954–1958. The Committee on the Costs of Medical Care. Medical care for the American people. Chicago, IL: University of Chicago Press, 1932. Kooijman J. …And the Pursuit of National Health. The Incremental Strategy Toward National Health Insurance in the United States of America. Amsterdam and Atlanta, GA: Rodopi, B.V., 1999. A forgotten landmark medical study from 1932 by the Committee on the Cost of Medical Care 143 Invited commentary The debate on national health insurance . . . 80 years ago Charles Stewart Roberts, MD A fter much debate, national health insurance was excluded from the Economic Security Bill of 1935, which passed during the first administration of President Roosevelt. As Dr. Thomas B. Gore points out in an adjacent article, my paternal grandfather, Stewart R. Roberts, MD (1) (Figure 1), was involved in this debate and took a rather contrary position as a physician. Roberts was a member of two pertinent groups in this national debate, the Committee on the Cost of Medical Care (CCMC), organized in 1925, and the Medical Advisory Board, organized in 1934. He appears to have been strongly supportive of national health insurance and found himself in direct opposition to the American Medical Association (AMA) under the leadership of Dr. Morris Fishbein, who viewed such a plan as socialist, if not communist. The CCMC final report in 1932 highlighted the disconnect between lay reformers, who generally wanted national health insurance, and physicians, who generally opposed that level of governmental involvement. Some physicians, however, including Roberts, went against the majority view within the medical profession. In his 1999 book, …And the Pursuit of National Health, Jaap Kooijman described the circumstance: The polarization within the medical profession reappeared, however, with a statement by Dr. Stewart Roberts, who bitterly criticized the obstinate position of the AMA. When in 1932 he had signed the CCMC majority report [written by lay members and physicians, advocating national health insurance], Roberts had been, as he claimed, condemned by the editorials in the Journal of the American Medical Association. The medical profession’s obstruction had to stop, Roberts argued: “Now this American Medical Association, we doctors of America, are on trial in this room this afternoon. If we obstruct and reason and dally, we are going to receive the contempt of the American people, and will rightly deserve it” (2). The Medical Advisory Board, organized in 1934 and composed of 11 physicians, appeared to favor the expansion of existing public health services, as an alternative to a national health insurance plan. The “round robin” letter generated by the board (Figure 2) recommended that “experiments in voluntary insurance” be done first, before establishing compulsory health 144 insurance. Roberts was the only board member who did not evidently support this cautious position. My paternal grandfather disliked Roosevelt, but I thought it was because the USA was being drawn into a Second World War in Europe (through the lend-lease program, etc.), an inevitability which Figure 1. Stewart R. Roberts, MD, 1878–1941. my grandfather, an isolationist, like Charles Lindbergh, opposed. The attack on Pearl Harbor, which occurred after my grandfather’s death in 1941, would certainly have changed this view. What did not occur to me until Dr. Gore shared his research was that my grandfather probably disliked Roosevelt more for excluding a national health insurance plan in his Economic Security Bill of 1935. I am grateful to Dr. Gore for reminding us of these national deliberations, which occurred some 80 years before the Affordable Care Act of 2010. It proves again that there is nothing new under the sun (Ecclesiastes 1:9). 1. 2. Roberts CS. Stewart R. Roberts, MD: Georgia’s First Heart Specialist. Spartanburg, SC: Reprint Company, 1992. Kooijman J. …And the Pursuit of National Health. The Incremental Strategy Toward National Health Insurance in the United States of America. Amsterdam and Atlanta, GA: Rodopi, 1999. From Trident Health, HCA, Charleston, South Carolina. Corresponding author: Charles Stewart Roberts, MD, Palmetto Cardiovascular and Thoracic Associates, Trident Health, HCA, 9313 Medical Plaza Drive, Suite 304, Charleston, SC 29406 (e-mail: charles.roberts@hcahealthcare.com). Proc (Bayl Univ Med Cent) 2013;26(2):144–145 Figure 2. Round robin letter from the Medical Advisory Board in 1935 with recommendations concerning national health. April 2013 The debate on national health insurance . . . 80 years ago 145 Radiology Report Lymphoma in the breast Kelli Y. Ha, MD, Jean C. Wang, MD, and Javed I. Gill, MD Lymphoma is a rare neoplasm in the breast. In this location, it may be primary or secondary, depending on whether there is lymphoma elsewhere in the body. The most common presentation of breast lymphoma is a painless palpable mass, indistinguishable from that of breast carcinoma, although the treatment regimens for these two neoplasms differ vastly. Knowledge of the varied mammographic and sonographic presentations of breast lymphoma should prompt more frequent recognition of this unusual malignant entity. Proper diagnosis of this neoplasm is of the utmost importance to guide appropriate treatment planning and prevent unnecessary and potentially harmful surgery. We describe secondary breast lymphoma in a woman who had been diagnosed and treated for non-Hodgkin’s lymphoma several years earlier. A percutaneous, ultrasound-guided core needle biopsy of the ovoid mass within the right breast was consistent with a grade I (low-grade) follicular B-cell lymphoma (Figure 3). The B lymphoid cells stained positive for CD20 and CD79a, and follicular structures demonstrated a 10% positive reaction for BCL-2. A positron emission tomography (PET) scan 2 months later for restaging purposes demonstrated a hypermetabolic ovoid mass within the medial right breast, corresponding to the biopsied lesion at the patient’s palpable area of concern (red circles, Figures 4 and 5). Additional hypermetabolic foci identified at various locations above and below the diaphragm were compatible with recurrent or residual lymphoma (Figure 4). The enlarged right axillary node previously identified on the right breast sonogram showed intense hypermetabolic activity on PET scan. The patient was treated with cyclophosphamide, vincristine, prednisone, and rituximab, and a follow-up PET scan (not shown) performed 1 month following the patient’s last round of chemotherapy demonstrated interval resolution of all hypermetabolic foci previously identified, compatible with a complete CASE REPORT A 49-year-old white woman presented for a bilateral diagnostic mammogram in February 2009 with complaints of a painless, palpable lump in the medial right breast. She had non-Hodgkin’s lymphoma of unknown histologic subtype diagnosed and treated into remission at age 40 a b (2003). Approximately 1 month before presentation, a computed tomography (CT) scan demonstrated a mass within the right breast. Routine craniocaudal and mediolateral oblique views of both breasts demonstrated scattered fibroglandular densities within the breast parenchyma (Figure 1). An additional spot tangential view of the right breast over the patient’s palpable area of concern (Figure 2a) demonstrated a 5 cm gently lobulated, ovoid mass at the 3 o’clock position, located approximately 7 cm from the nipple (yellow circles, Figure 1). A right breast sonogram (Figure 2b) demonstrated Figure 1. Routine (a) craniocaudal and (b) mediolateral oblique views of both breasts demonstrate scattered fibroglandular densities within the breast parenchyma. A dense, gently lobulated ovoid mass a 4 × 2 × 1 cm well-circumscribed, hypoechoic measuring 5 cm is identified at the 3 o’clock position of the right breast, approximately 7 cm from ovoid mass at the 3 o’clock position, 8 cm from the nipple (yellow circle). An intramammary lymph node is also noted at the 11 o’clock position of the the nipple, corresponding to the patient’s pal- right breast (blue circle). pable area of concern. An 0.8 cm ovoid mass at the 11 o’clock position, 8 cm from the nipple, corresponded to From the Department of Radiology, Baylor University Medical Center at Dallas. an intramammary lymph node (blue circle, Figure 1). In addiCorresponding author: Kelli Y. Ha, MD, Department of Radiology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 tion, sonographic evaluation of the right axilla demonstrated a (e-mail: yeek816@gmail.com). 2.7 cm lymph node with a thickened cortex. 146 Proc (Bayl Univ Med Cent) 2013;26(2):146–148 a therapeutic response to chemotherapy. DISCUSSION Breast involvement by lymphoma constitutes ≤0.5% of all mammary malignancies (1–5). The rarity of lymphoma in the breast may be attributed to its relative paucity of lymphoid tissue. Lymphomas demonstrate a bimodal age distribution, with peaks in the fourth b and seventh decades of life (4, 5). Most breast lymphomas are of the non-Hodgkin’s B-cell type, with difFigure 2. (a) Spot tangential view of the right fuse large B-cell lymbreast at the patient’s palpable area of concern, phoma constituting as designated by a metallic BB marker. This addi- the most prevalent tional view confirms the presence of a dense ovoid subtype (6). mass at the 3 o’clock position. (b) Sonographic Intramammary image of the right breast at the 3 o’clock position, masses, most of 8 cm from the nipple, demonstrates a well-defined, hypoechoic mass measuring up to 4 cm at the which are round or patient’s palpable area of concern. oval in shape with circumscribed or gently lobulated margins, are the most common mammographic finding. Calcific deposits and spiculated margins are uniformly absent, and architectural distortion is rare (1, 4). High-grade lymphomas have been reported to manifest more frequently as diffuse breast enlargement, whereas low- to intermediate-grade neoplasms preferentially display a more nodular pattern (4, 7). Sonographically, breast lymphoma appears as a hypoechoic to almost anechoic round or oval-shaped mass with relatively welldefined margins with or without posterior acoustic enhancement (4, 6). In addition, a pseudocystic serpentine mass appearance has been documented on sonographic evaluation of two breast lymphoma cases in a study by Gal-Gombos et al (8). Although few studies have described the magnetic resonance imaging (MRI) characteristics of breast lymphoma, certain features have been elucidated to date. Surov et al (4) and Yang et al (5) characterized these lesions as hyperintense compared with surrounding breast parenchyma on T2-weighted images and isointense on T1-weighted images. Global intense heterogeneous or homogeneous contrast enhancement was identified after the administration of intravenous gadolinium. Kinetic analysis of contrast enhancement demonstrated rapid initial signal increase, which plateaued or rapidly washed out (type 2 or type 3 kinetic curves), the findings of which are characteristic for malignancy. April 2013 Figure 3. BCL-2 stained tissue from the right breast demonstrates an extensive lymphoid infiltrate, vaguely nodular, with the positive BCL-2 stain consistent with a diagnosis of follicular B-cell lymphoma. In an attempt to differentiate between primary and secondary breast lymphoma, a few distinguishing characteristics may be helpful, though they are not pathognomonic in and of themselves. In contrast to primary disease, masses in secondary breast lymphoma often demonstrate smaller diameters upon initial presentation. Sabaté et al (7) indicated that the average diameter of a mass in secondary breast lymphoma measured 2.8 cm compared with an average of 4.6 cm for primary Figure 4. A PET scan performed for restaging breast lymphoma. demonstrates a hypermetabolic ovoid mass within the right breast (red circle). Multiple additional This finding may be hypermetabolic foci are identified both above and partially explained by below the diaphragm. the fact that the duration of symptoms prior to clinical and radiologic examination may be shorter in patients in whom lymphomatous disease is known. Likewise, the number of intramammary masses has been reported to be higher in secondary than in primary breast lymphoma (4), in keeping with the overall extent of primary versus secondary lymphomatous disease. Parenchymal breast involvement in association with bilateral axillary lymph node enlargement may Lymphoma in the breast 147 a b treatment regimen consisting of combination chemotherapy with or without concurrent radiotherapy. 1. Fruchart C, Denoux Y, Chasle J, Peny AM, Boute V, Ollivier JM, Genot JY, Michels JJ. High grade primary breast lymphoma: is it a different clinical entity? Breast Cancer Res Treat 2005;93(3):191–198. 2. Liberman L, Giess CS, Dershaw DD, Louie DC, Deutch BM. Non-Hodgkin lymphoma of the breast: imaging characteristics and correlation with histopathologic findings. Radiology 1994;192(1):157–160. Figure 5. Axial images from (a) PET scan and (b) localization CT demonstrate an ovoid hypermeta3. Meyer JE, Kopans DB, Long JC. Mammographic apbolic mass within the medial right breast (red circles). This lesion corresponds to the ovoid soft tissue pearance of malignant lymphoma of the breast. Radioldensity in this location and to the dense ovoid mass seen on prior mammography and sonography ogy 1980;135(3):623–626. (see Figures 1–4). 4. Surov A, Holzhausen HJ, Wienke A, Schmidt J, Thomssen C, Arnold D, Ruschke K, Spielmann RP. Primary and secondary breast lymphoma: prevalence, be suggestive of lymphoma, particularly secondary breast lymclinical signs and radiological features. Br J Radiol phoma, although widespread metastatic breast carcinoma could 2012;85(1014):e195–e205. also have a similar presentation (7). 5. Yang WT, Lane DL, Le-Petross HT, Abruzzo LV, Macapinlac HA. Breast Treatment of breast lymphoma remains somewhat controlymphoma: imaging findings of 32 tumors in 27 patients. Radiology 2007;245(3):692–702. versial; however, certain guidelines have been elucidated. In a 6. Cox J, Lunt L, McLean L. Haematological cancers in the breast and axilla: study by Fruchart et al (1), all patients undergoing mastectomy, a drop in an ocean of breast malignancy. Breast 2005;14(1):51–56. either alone or in association with chemotherapy, died of their 7. Sabaté JM, Gómez A, Torrubia S, Camins A, Roson N, De Las Heras P, lymphoma. It has been postulated that this may have resulted Villalba-Nuño V. Lymphoma of the breast: clinical and radiologic features from delay of appropriate systemic treatment. Correct diagnosis with pathologic correlation in 28 patients. Breast J 2002;8(5):294–304. 8. Gal-Gombos EC, Esserman LE, Poniecka AW, Poppiti RJ Jr. Is a pseudowith tissue sampling is therefore of the utmost importance to cystic serpentine mass a sonographic indicator of breast lymphoma? Raprevent the morbidity and mortality associated with unnecessary diologic-histologic correlation of an unusual finding. AJR Am J Roentgenol surgery. Alternatively, multiple studies (1, 7) have suggested a 2001;176(3):734–736. 148 Baylor University Medical Center Proceedings Volume 26, Number 2 Radiology Report Inflammatory breast carcinoma Kelli Y. Ha, MD, Shannon B. Glass, MD, and Louba Laurie, MD Inflammatory breast carcinoma is a rare form of invasive breast cancer often characterized by erythema, warmth, and a classic “peau de orange” or “orange peel” appearance of the affected breast. The average age of onset is within the fourth and fifth decades. Lesions are usually detected and evaluated with mammography, sonography, and recently, breast magnetic resonance imaging. We present the case of a 49-year-old woman with inflammatory breast carcinoma in her left breast and describe the imaging appearance of this aggressive lesion on the modalities listed above. Because this lesion may be misdiagnosed as infection (i.e., mastitis) or as the sequelae of a dermatologic disorder, proper characterization of inflammatory breast carcinoma is of the utmost clinical and radiologic importance. CASE REPORT A 49-year-old woman presented with a history of a palpable mass within her left breast, which had been present for 2 years. Routine digital mammographic imaging of the right breast (not shown) did not demonstrate any abnormality. Within the upper outer aspect of the left breast at the palpable area of concern, a region of asymmetry, partially obscured by coarse trabecular thickening, was seen in addition to marked left axillary lymphadenopathy (Figure 1). Diffuse cutaneous thickening was also demonstrated within the left breast. Sonography demonstrated a large heterogeneous mass at the palpable area of concern, in the 2:00 position, 10 cm from the nipple, measuring approximately 4.6 × 4.5 × 4.4 cm (Figure 2). Left axillary lymphadenopathy, measuring up to 4.4 cm in the long axis, was also observed. The patient underwent surgical biopsy, and the histology proved consistent with inflammatory breast carcinoma (IBC). She was subsequently treated with a neoadjuvant chemotherapy regimen consisting of six cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide. Mastectomy was then performed. DISCUSSION IBC is an infrequent form of invasive breast cancer that often presents with a rapid onset of diffuse erythema, warmth, edema, and/or peau d’orange changes of the breast. In addition, these changes are accompanied by breast tenderness and/or pain, palpable mass or masses, and diffuse rapid breast enlargement in conjunction with cutaneous thickening and dermal Proc (Bayl Univ Med Cent) 2013;26(2):149–151 ridging. In the absence of clinical symptoms and abnormal laboratory values, i.e., fever, chills, and/or an elevated white blood cell count, one should immediately consider a diagnosis of IBC. This disease entity accounts for 1% to 6% of all breast cancers in the United States, with the average age of onset between 45 and 54 years (1–3). Similar to other types of breast carcinoma, IBC can occur in men, but usually at an older age (median age at diagnosis 66.5 years) than in women. IBC cases in men constitute between 0.6% and 1.4% of all newly diagnosed breast cancers (4). Pathologic diagnosis of this clinical entity is generally based upon the presence of tumor emboli within dilated lymphatic vessels and a surrounding lymphocytic reaction in the dermis (2, 5; Figure 3). Although infiltration of dermal lymphatics confirms a diagnosis of IBC, the disease may only be evident clinically, and punch biopsies may be negative. In such cases, patients are treated for IBC based upon clinical data. While IBC is relatively uncommon compared with other malignancies, it remains aggressive, with a tendency to metastasize early (3). Therefore, information about this malignancy is of interest and importance to both radiologists and clinicians alike. On mammography, IBC demonstrates a pattern of diffuse “inflammatory change,” to include cutaneous and trabecular thickening, increased parenchymal density, breast distortion, and nipple retraction. Changes on mammography are secondary to dermal lymphatic infiltration and obstruction by tumor, rather than a true inflammatory process. Because of the increased parenchymal density, which is often seen throughout the affected breast, a focal mass lesion or group of suspicious calcifications is less often seen mammographically (2, 6). Additional associated mammographic findings, albeit observed less consistently, include axillary lymphadenopathy and nipple retraction. Of particular note, the contralateral breast should be carefully inspected for developing asymmetry and trabecular and/or cutaneous thickening, given the possibility of cancer spread or a simultaneous lesion in the contralateral breast, which occurs in approximately 1% to 5% of patients with primary IBC (5). From the Department of Radiology, Baylor University Medical Center at Dallas. Corresponding author: Kelli Y. Ha, MD, Department of Radiology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: yeek816@gmail.com). 149 IBC may be divided into two clinical subgroups, first described by Taylor and Meltzer in 1938. The primary form is seen in patients with IBC characteristics that are evident from the onset, while the secondary form is described in those whose clinical features appear subsequent to appropriate treatment of a primary noninflammatory breast carcinoma (7). Given that our current patient presented without a known history of previously treated breast carb cinoma, her disease was characterized as a primary lesion. Sonographic evaluation of IBC is helpful in demonstrating lymphatic dilatation in association with tumor emboli, as well as depiction of hypoechoic shadowing masses, cutaneous thickening, skin/pectoral muscle invasion, and axillary lymphadenopathy. Sonography is notably a better modality for depicting these characteristics and should be used in conjunction with mammography and Figure 1. Routine digital mammographic imaging physical examinaof the left breast: (a) craniocaudal view, (b) medio- tion for diagnosis lateral view. Both views demonstrate a region of whenever possible. asymmetry (arrow), which corresponds to the pal- Sentinel node biopsy pable area of concern in the upper outer quadrant. is ultimately used for Diffuse cutaneous and trabecular thickening is also the diagnosis of axilidentified about the surface of the left breast, which lary involvement, as gives the appearance of increased breast density. skin punch biopsy or ultrasound-guided core needle biopsy of suspicious masses is for IBC (3). a 150 Figure 2. Sonographic image of the left breast demonstrates a large heterogeneous, predominantly hypoechoic mass at the 2:00 position of the left breast, 10 cm from the nipple, measuring approximately 4.6 × 4.5 × 4.4 cm. Figure 3. An example of inflammatory breast carcinoma (taken from a different patient) with a characteristic tumor embolus in a dermal lymphatic channel. Reprinted from Kleer CG, van Golen KL, Braun T, Merajver SD. Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol 2001;14(5):458–464, with permission from Nature Publishing Group. Recently, breast magnetic resonance imaging (MRI) has become a primary modality for the depiction of IBC disease entities, either in conjunction with or in replacement of standard mammography. MRI can be obtained in place of mammography if mammography would be too painful or uncomfortable for the patient or if compression is inadequate secondary to tumor bulk. Although patients are usually evaluated initially with mammography, MRI is useful for determining the extent of disease and may be helpful in monitoring treatment response in some cases. Global skin thickening, enhancing masses, breast enlargement, breast/chest wall edema, and/or tumor infiltration is often obscured on mammography. However, these entities are well characterized on MRI, leading to a higher detection rate of primary breast parenchymal lesions/masses using this modality. Multiple enhancing breast masses are more often described Baylor University Medical Center Proceedings Volume 26, Number 2 on MRI than a single index breast lesion in IBC (1). Primary tumors in IBC often demonstrate low signal intensity on T1WI and heterogeneous iso- or high signal intensity on T2WI. Increased signal intensity and enhancement of the thickened skin are also consistently reported attributes of IBC (2). Inflammatory breast carcinoma is not the only disease process that presents with mammographic or physical signs of breast tissue inflammation. In fact, the differential for these findings remains vast, and correlation with patient history in conjunction with physical and radiologic examination findings remains crucial in these situations. Inflammation of the breast tissue may be seen after surgery and postradiation therapy, as well as from trauma, infection (i.e., mastitis), and various dermatologic disorders. Breast edema may be secondary to other systemic conditions such as superior vena cava syndrome, congestive heart failure, and lymphoma. In patients who present with inflammatory signs that continue despite proper antibiotic treatment, biopsy is indicated to definitively exclude a diagnosis of IBC (3). Goldfarb and Pippen recently reviewed treatment of IBC at Baylor University Medical Center at Dallas (8). As they noted, the recommended therapy is induction chemotherapy with an anthracycline-based regimen with or without the addition of taxanes, followed by mastectomy with axillary lymph node dissection in those who respond well. Preoperative trastuzumab may be considered for patients with HER2-positive disease. Any remaining cycles of planned chemotherapy can be completed after surgery, and patients with hormone receptor–positive disease may begin endocrine therapy after surgery as well. Postsurgical radiotherapy of the chest wall and regional axillary nodes should follow completion of the chemotherapy regimens. April 2013 The current case describes a patient who presented for her first mammogram with an advanced inflammatory breast carcinoma, undoubtedly neglected for some time given initial palpation 2 years prior. This case highlights the importance of mammography in screening for breast carcinoma and of seeking proper and timely evaluation upon palpation of a new breast mass. It is unique given the extensive inflammatory change that was denied evaluation until a late and advanced stage. Although IBC can easily be mistaken for an infection or other disease process as discussed previously, failure to improve with antibiotics/treatment should remain a “red flag” for the relatively rare diagnosis of IBC. 1. 2. 3. 4. 5. 6. 7. 8. Le-Petross HT, Cristofanilli M, Carkaci S, Krishnamurthy S, Jackson EF, Harrell RK, Reed BJ, Yang WT. MRI features of inflammatory breast cancer. AJR Am J Roentgenol 2011;197(4):W769–W776. Lee KW, Chung SY, Yang I, Kim HD, Shin SJ, Kim JE, Chung BW, Choi JA. Inflammatory breast cancer: imaging findings. Clin Imaging 2005;29(1):22–25. Günhan-Bilgen I, Ustün EE, Memiş A. Inflammatory breast carcinoma: mammographic, ultrasonographic, clinical, and pathologic findings in 142 cases. Radiology 2002;223(3):829–838. Anderson WF, Schairer C, Chen BE, Hance KW, Levine PH. Epidemiology of inflammatory breast cancer (IBC). Breast Dis 2005–2006;22:9– 23. Kushwaha AC, Whitman GJ, Stelling CB, Cristofanilli M, Buzdar AU. Primary inflammatory carcinoma of the breast: retrospective review of mammographic findings. AJR Am J Roentgenol 2000;174(2):535–538. Yang WT. Advances in imaging of inflammatory breast cancer. Cancer 2010;116(11 Suppl):2755–2757. Taylor GW, Meltzer A. “Inflammatory carcinoma” of the breast. Am J Cancer 1938;33:33–49. Goldfarb JM, Pippen JE. Inflammatory breast cancer: the experience of Baylor University Medical Center at Dallas. Proc (Bayl Univ Med Cent) 2011;24(2):86–88. Inflammatory breast carcinoma 151 Plasmablastic lymphoma following transplantation Michael J. Van Vrancken, MD, MPH, Latoya Keglovits, MD, and John Krause, MD Posttransplant lymphoproliferative disorder is a serious complication following solid organ as well as hematopoietic stem cell transplantation due to prolonged immunosuppressive therapy. Plasmablastic lymphoma, although classically associated with HIV infection, has since been described in transplant patients as a variant of posttransplant lymphoproliferative disorder with varying clinical presentations. Here we add two additional cases to the literature: one following lung transplantation and one following pancreatic transplantation. In addition, the demographic, therapeutic, and immunophenotypic characteristics from prior reported cases are summarized. P lasmablastic lymphoma was first described in 1997 as an oral mucosal lesion associated with HIV-positive individuals as a subtype of diffuse large cell lymphoma (1, 2). Since its initial description, it has now become well established as an entity seen in HIV-negative individuals as well, albeit rarely (3). In 2003, the first case of plasmablastic lymphoma in a posttransplant lymphoproliferative disorder (PTLD) was reported as a cutaneous leg ulcer (4). Since this original description, several additional cases have been reported following various solid organ and bone marrow transplantations. We present two cases of plasmablastic lymphoma, one following lung transplantation with subsequent immunosuppressive therapy (previously reported in the context of unusual clinical findings) (5) and another following pancreatic transplantation. a respiratory status continued to decline, and he developed worsening pulmonary infiltrates. Repeat biopsy again showed acute lung injury with organization. He was again treated with high-dose corticosteroids as well as a 10-day trial of antithymocyte globulin (Atgam) for possible rejection. The patient began to recover clinically, and at the time of his discharge 45 days later, he was breathing room air and his tracheostomy site was healing. To modulate his posttransplant immune function, the patient was treated with tacrolimus, prednisone, and azathioprine. In February 2012, the patient presented with facial swelling, numbness, right lower lip swelling, and mild erythema within b Figure 1. Wright stain of bone marrow aspirate showing larger “blast”-like plasma cells with abundant cytoplasm, nucleoli, and open chromatin pattern. The cells also have vague perinuclear hofs and eccentrically placed nuclei. ×1000. a b CASE 1 A 67-year-old man with idiopathic pulmonary fibrosis diagnosed at age 63 (2008) underwent sequential bilateral lung transplantation in October 2011. The patient had a complicated Figure 2. (a) Hematoxylin and eosin staining of the aspirate clot preparation showing sheet-like infiltrate predominantly composed of larger “blast”-like cells with prominent nucleoli. ×400. (b) Epstein-Barr virus clinical course thereafter with repeated episodes early RNA in situ hybridization showing strong nuclear positivity within the infiltrative cells. ×400. of respiratory failure requiring reintubation and eventual tracheostomy. He subsequently develFrom the Department of Pathology, Baylor University Medical Center at Dallas. oped bilateral pulmonary infiltrates and was placed on antibiotics. Corresponding author: Michael J. Van Vrancken, MD, MPH, Department of Biopsy showed acute lung injury, and the patient was placed on Pathology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: michael.van.vrancken@gmail.com). high-dose steroids for presumed acute rejection. The patient’s 152 Proc (Bayl Univ Med Cent) 2013;26(2):152–155 the inner lip with corresponding numbness. He had macrocytic anemia with normal folate and vitamin B12 levels. Brain magnetic resonance imaging revealed multifocal patchy regions of marrow signal abnormality involving the calvaria, skull base, and visualized upper cervical spine. He had elevated copies of Epstein-Barr virus (EBV). Histologic analysis of a bone marrow biopsy specimen disclosed scattered cellular sheets of a plasmacytoid infiltrate composed of medium- to large-sized cells with an abundant amount of basophilic cytoplasm, eccentrically located nuclei with a clock-faced chromatin, and a perinuclear hof. Many malignant cells displayed a large central nucleolus with finely dispersed immature chromatin consistent with a “plasmablast”-type morphology (Figures 1 and 2). Occasional cells showed bi- and trinucleated forms, and mitotic activity was increased with many atypical figures seen. Immunophenotypically, these cells were characterized by strong immunohistochemical staining to CD138 with patchy membranous positivity seen with CD56. CD30 and CD20 were negative in the plasmacytoid cells. Most malignant infiltrates were negative for both kappa and lambda in situ hybridization with rare scattered cells showing positivity. Additionally, most cells stained positively for EBV early RNA (EBER) by in situ hybridization (Figure 2). Figure 3. Hematoxylin and eosin staining of the mesenteric mass showing large cells with open chromatin and prominent nucleoli consistent with a “blast”-type morphology. ×400. After a diagnosis of posttransplant plasmablastic lymphoma was made, the patient was started on a cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone/ Table 1. Reported cases of plasmablastic lymphoma in transplanted patients Study No. Sex Age (years) Transplant Location Treatment Status (months) Nicol et al, 2003 (4) 1 F 68 Heart Cutaneous Local radiotherapy Alive (9) Teruya-Feldstein et al, 2004 (19) 1 M 73 Kidney Cutaneous Chemotherapy Alive (7) Verma et al, 2005 (20) 1 F 38 Kidney Cutaneous Resection and radiotherapy Alive (32) Borenstein et al, 2007 (21) 4 M 27 Kidney Prostate Not reported Not reported M 46 Heart Oral cavity M 48 Bone marrow Lymph node M 57 Kidney Cutaneous F 14 mo Small bowel, liver Cutaneous IR Progression (<1) Apichai and Hernandez et al., 2009 (22, 23) 1 Zimmermann et al, 2012 (24) 8 Present study (including Shahriar et al, 2012 [5]) 2 F 30 Heart, lung Disseminated IR + chemo Progression (<1) M 37 Heart Nasal cavity IR + chemo + radiation Alive (48) F 42 Kidney Disseminated None Progression (<1) M 44 Heart Disseminated IR + chemo Progression (4) M 49 Kidney Subcutaneous IR + chemo + radiation Alive (14) M 54 Heart Disseminated Chemo Progression (6.5) M 62 Heart Disseminated IR + chemo Alive (29.5) M 67 Kidney Disseminated IR + chemo Progression (10) M 67 Lung Bone marrow Limited chemo Alive (<1) F 42 Pancreas Mesenteric Resection Progression (<1) IR indicates immunosuppressant reduction. April 2013 Plasmablastic lymphoma following transplantation 153 Table 2. Immunophenotypes in reported cases of plasmablastic lymphoma in transplanted patients VS38c CD79a CD20 ␬ ␭ EBER CD138 CD56 IgG IgM CD30 EMA LCA HHV-8 Ki-67 Nicol et al, 2003 (4) 1/1 0/1 0/1 0/1 – – 0/1 0/1 1/1 – – 0/1 – – – TeruyaFeldstein et al, 2004 (19) – 0/1 0/1 – – 1/1 1/1 – – – – – Weak 1/1 – >80% Verma et al, 2005 (20) – 1/1 0/1 0/1 1/1 1/1 – 1/1 – – 0/1 – – 1/1 – Borenstein et al, 2007 (21) 4/4 Weak 4/4 0/4 2/4 1/4 3/4 2/3 0/3 – – 1/2 1/3 – – 70%– 90% Apichai and Hernandez et al, 2009 (22, 23) – Weak 1/1 0/1 0/1 1/1 – 1/1 1/1 – – 0/1 – – – >90% Zimmermann et al, 2012 (24) – – 0/7 4/7 2/7 5/8 6/8 1/6 – – – – – – 80%– 100% Present study (including Shahriar et al, 2012 [5]) – – 0/2 0/2 0/2 2/2 2/2 2/2 – – 0/2 – – – – Study ␬ indicates kappa; ␭, lambda; EBER, Epstein-Barr virus early RNA; EMA, epithelial membrane antigen; LCA, leukocyte common antigen; HHV-8, human herpes virus-8. prednisolone (CHOP) chemotherapy regimen. After 1 cycle of treatment, the patient elected to receive palliative care only. CASE 2 In 2008, a 45-year-old woman received a pancreas transplant for brittle diabetes mellitus type I. Over the next year, the patient was hospitalized multiple times with abdominal pain, which was attributed to pancreatitis. In May 2009, the patient was hospitalized for abdominal pain, again with a failed pancreatic transplant. She underwent a planned pancreatectomy. During the procedure, a 16-cm loop of small bowel was identified wrapping around a 6.0 × 5.0 × 4.0 cm soft tissue mass within the abdomen, and it was resected. Histomorphologically, the mass was composed of large round to oval-shaped cells with finely dispersed immature chromatin and prominent nucleoli consistent with a “blast”type morphology (Figure 3). Immunohistochemically, the cells had a positive stain for CD138 and CD56 and were positive for EBER by in situ hybridization, confirming the diagnosis of plasmablastic lymphoma. Postoperatively, the patient had a complicated course and died 7 days following the procedure due to overwhelming gram-negative sepsis. DISCUSSION PTLD is a heterogenous disease seen in patients who have undergone solid organ or hematopoietic stem-cell transplantation. It was first described in 1968 in association with renal 154 transplantation. In patients who have received a transplant, the risk of lymphoma is increased 20% to 120% compared with the general population (6). Additionally, several risk factors have been shown to increase the risk of PTLD, including immunosuppression (6–8), EBV (9–12), genetic susceptibility (13), and a host of other miscellaneous factors including Caucasian race (14), hepatitis C, cytomegalovirus, and human herpes virus-8 infection (15–17). PTLD is classified into four categories based on immunophenotype, morphology, and molecular criteria. These include early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma (18). Traditionally, plasmablastic lymphomas have been described in HIV-positive individuals, typically occurring in the mucosa of the oral cavity. The lesion is characterized morphologically by blastic cells with a plasma cell immunophenotype. In recent years, this entity has also been described in individuals who have previously undergone a transplantation procedure, including kidney, heart, heart/lung, liver/small bowel, and bone marrow (Table 1) (4, 19–24). To our knowledge, the present report is the first describing plasmablastic lymphoma following pancreatic transplantation. Morphologically, PTLD plasmablastic lymphoma is characterized by larger immature cells with abundant cytoplasm, nucleoli, and an open chromatin pattern. Immunophenotypically (Table 2), previously reported cases have been predominantly positive for CD138 and VS38 and usually display either a kappa or lambda restriction. B-cell markers, such as CD20 Baylor University Medical Center Proceedings Volume 26, Number 2 and CD79a, are typically negative, and the proliferative index (Ki-67) is invariably high, usually above 80%. The preponderance of reports demonstrates positivity for EBER through in situ hybridization, with one other case demonstrating an EBV and human herpes virus-8 coinfection (20). The role of EBV in the development of PTLDs (including plasmablastic lymphoma) is well established. EBV preferentially infects B cells, where its genome can lay dormant as an episome (25). In healthy immunocompetent individuals, activated T cells play an important role in controlling the proliferation and elimination of infected B cells. Due to immunosuppressive therapy severely impairing T-cell activity, immunosuppressed patients are at risk for uncontrolled proliferation of the infected B cells. The treatment for PTLD has many modalities with varying degrees of effectiveness. Antiviral therapies, particularly ganciclovir, have been used as prophylactic agents to prevent EBV-related PTLD, although the data are not definitive. Donor-derived EBV-specific cytotoxic T-cell lymphocyte infusions (adoptive immunotherapy) have also been shown to play a role in PTLD prophylaxis in both adult and pediatric populations (26, 27). Treatment modalities of diagnosed PTLD have included reduced immunosuppression as well as CHOP-based chemotherapy with or without rituximab. A recent study looking at treatment options for PTLD plasmablastic lymphoma by Zimmermann et al found that immunosuppression with systemic chemotherapy (CHOP-21) achieved a more lasting and complete remission than immunosuppression with local therapy (24). Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, Huhn D, Schmidt-Westhausen A, Reichart PA, Gross U, Stein H. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997;89(4):1413–1420. 2. Flaitz CM, Nichols CM, Walling DM, Hicks MJ. Plasmablastic lymphoma: an HIV-associated entity with primary oral manifestations. Oral Oncol 2002;38(1):96–102. 3. Lee OJ, Kim KW, Lee GK. Epstein-Barr virus and human immunodeficiency virus-negative oral plasmablastic lymphoma. J Oral Pathol Med 2006;35(6):382–384. 4. Nicol I, Boye T, Carsuzaa F, Feier L, Collet Villette AM, Xerri L, Grob JJ, Richard MA. Post-transplant plasmablastic lymphoma of the skin. Br J Dermatol 2003;149(4):889–891. 5. Shahriar R, Alexander CT, Quirk CR, Keglovits L, Van Vrancken M. Numb chin syndrome as the initial presentation of posttransplant lymphoproliferative disorder. Proc (Bayl Univ Med Cent) 2012;25(3):243–245. 6. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342(8886–8887):1514–1516. 7. Hartmann C, Schuchmann M, Zimmermann T. Posttransplant lymphoproliferative disease in liver transplant patients. Curr Infect Dis Rep 2011;13(1):53–59. 8. Bhatia S, Ramsay NK, Steinbuch M, Dusenbery KE, Shapiro RS, Weisdorf DJ, Robison LL, Miller JS, Neglia JP. Malignant neoplasms following bone marrow transplantation. Blood 1996;87(9):3633–3639. 9. Oton AB, Wang H, Leleu X, Melhem MF, George D, Lacasce A, Foon K, Ghobrial IM. Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant. Leuk Lymphoma 2008;49(9):1738–1744. 10. Johnson LR, Nalesnik MA, Swerdlow SH. Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: a histogenetic study. Am J Surg Pathol 2006;30(12):1604–1612. 11. Novoa-Takara L, Perkins SL, Qi D, Shidham VB, Vesole DH, Hariharan S, Luo Y, Ewton A, Chang CC. Histogenetic phenotypes of B 12. 13. 14. 15. 16. 17. 18. 19. 1. April 2013 20. 21. 22. 23. 24. 25. 26. 27. cells in posttransplant lymphoproliferative disorders by immunohistochemical analysis correlate with transplant type: solid organ vs hematopoietic stem cell transplantation. Am J Clin Pathol 2005;123(1):104–112. Paya CV, Fung JJ, Nalesnik MA, Kieff E, Green M, Gores G, Habermann TM, Wiesner PH, Swinnen JL, Woodle ES, Bromberg JS; ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. Transplantation 1999;68(10):1517–1525. Reshef R, Luskin MR, Kamoun M, Vardhanabhuti S, Tomaszewski JE, Stadtmauer EA, Porter DL, Heitjan DF, Tsai DE. Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solidorgan transplant recipients. Am J Transplant 2011;11(4):817–825. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE; North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation. Transplantation 2001;71(8):1065–1068. Buda A, Caforio A, Calabrese F, Fagiuoli S, Pevere S, Livi U, Naccarato R, Burra P. Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection. Transpl Int 2000;13(Suppl 1):S402–S405. Mañez R, Breinig MC, Linden P, Wilson J, Torre-Cisneros J, Kusne S, Dummer S, Ho M. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis 1997;176(6):1462–1467. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007;131(8):1209– 1218. Swerdlow SH, Harris NL. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, 4th ed. Lyon: International Agency for Research on Cancer, 2008:441. Teruya-Feldstein J, Chiao E, Filippa DA, Lin O, Comenzo R, Coleman M, Portlock C, Noy A. CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients. Ann Oncol 2004;15(11):1673–1679. Verma S, Nuovo GJ, Porcu P, Baiocchi RA, Crowson AN, Magro CM. Epstein-Barr virus- and human herpesvirus 8-associated primary cutaneous plasmablastic lymphoma in the setting of renal transplantation. J Cutan Pathol 2005;32(1):35–39. Borenstein J, Pezzella F, Gatter KC. Plasmablastic lymphomas may occur as post-transplant lymphoproliferative disorders. Histopathology 2007;51(6):774–777. Apichai S, Rogalska A, Tzvetanov I, Asma Z, Benedetti E, Gaitonde S. Multifocal cutaneous and systemic plasmablastic lymphoma in an infant with combined living donor small bowel and liver transplant. Pediatr Transplant 2009;13(5):628–631. Hernandez C, Cetner AS, Wiley EL. Cutaneous presentation of plasmablastic post-transplant lymphoproliferative disorder in a 14-month-old. Pediatr Dermatol 2009;26(6):713–716. Zimmermann H, Oschlies I, Fink S, Pott C, Neumayer HH, Lehmkuhl H, Hauser IA, Dreyling M, Kneba M, Gärtner B, Anagnostopoulos I, Riess H, Klapper W, Trappe RU. Plasmablastic posttransplant lymphoma: cytogenetic aberrations and lack of Epstein-Barr virus association linked with poor outcome in the prospective German Posttransplant Lymphoproliferative Disorder Registry. Transplantation 2012;93(5):543–550. Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 2003;31(3):145–155. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 1998;92(5):1549–1555. Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG. Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 2000;95(3):807–814. Plasmablastic lymphoma following transplantation 155 Recurrent acute inflammatory demyelinating polyradiculoneuropathy following R-CHOP treatment for non-Hodgkin lymphoma Jackson J. Liang, DO, Preet P. Singh, MD, and Thomas E. Witzig, MD Acute flaccid paralysis following chemotherapy has a wide differential diagnosis, including drug toxicity, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and malignant nerve infiltration. We present a case of recurrent acute quadriparesis due to AIDP following chemotherapy for non-Hodgkin lymphoma, which resolved each time following administration of intravenous immunoglobulin. Although many chemotherapeutic agents can cause neurologic side effects, such as peripheral neuropathy, drug toxicity as a cause is a diagnosis of exclusion. A cute flaccid paralysis following chemotherapy has a wide differential diagnosis, including drug toxicity, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and malignant nerve infiltration. We present a case of recurrent acute quadriparesis due to AIDP following chemotherapy for non-Hodgkin lymphoma, which resolved each time following administration of intravenous immunoglobulin (IVIG). CASE PRESENTATION A 62-year-old man with recently diagnosed stage IV diffuse large B-cell lymphoma presented for his first cycle of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The diagnosis had been confirmed by pleural and testicular biopsies. Pretreatment positron emission tomography (PET) scan had revealed diffuse nodal activity and extranodal involvement in the pleura, testicles, and bones (Figure 1a). The patient had been otherwise healthy. He tolerated his first cycle of R-CHOP chemotherapy with no issues. Two days after completing the R-CHOP cycle, he began to notice bilateral lower-extremity weakness, which began at his feet and gradually moved upwards to his hip girdle muscles. The weakness gradually worsened to the point where he needed to use his hands to push off and stand from a seated position. Shortly thereafter, he noted bilateral arm weakness and became unable to stand due to the inability to push off with his arms. He also developed numbness in all four extremities from his mid forearms distally and the knees down. Throughout this time, he retained bowel and bladder function. His severe weakness and 156 footdrop prompted a trip to the emergency department, and he was admitted for workup. Examination at this time revealed mild upper-extremity weakness proximally with moderate to severe upper-extremity distal weakness. He had profound lower-extremity weakness, distal worse than proximal. While lying supine, he could move his legs minimally from side to side but was unable to lift them against gravity. He was unable to move his feet at all. Deep tendon reflexes at the knees were markedly diminished bilaterally, and ankle reflexes were completely absent. The Babinski sign was negative. Due to concern for Guillain Barré syndrome, lumbar puncture and electromyography with nerve conduction studies were ordered. Cerebrospinal fluid from the lumbar puncture exhibited albuminocytologic dissociation with an elevated protein (77 g/dL) and a cell count of 1 cell per microliter. Electromyogram revealed diffusely abnormal motor nerve conduction with low amplitude; slow, dispersed compound muscle action potentials; and conduction block in the median, ulnar, tibial, and peroneal nerves. HIV and hepatitis studies were negative. He was diagnosed with AIDP, and IVIG was initiated at 400 mg/ kg/day for 5 days. Shortly after being given the first dose of IVIG, his strength began to improve. Upon awakening the following morning, he was able to raise both knees and his left arm against gravity. By that afternoon, he was able to stand and walk a few steps with a wheeled walker and assistance. Upon completion of the 5-day course of IVIG, the numbness in his forearms and hands had resolved completely. He was discharged to the inpatient rehabilitation unit, where he continued to recover. At discharge after just 4 days of rehabilitation, he was able to ambulate without the assistance of a cane. During his second R-CHOP cycle, the vincristine dose was halved. Afterwards he experienced a brief episode of tingling and mild weakness in his hands and feet, which resolved completely after 48 hours. Follow-up PET scan prior to cycle 3 demonstrated complete radiologic remission (Figure 1b) with From the Department of Medicine (Liang) and the Divison of Hematology and Medical Oncology (Singh, Witzig), Mayo Clinic, Rochester, Minnesota. Corresponding author: Jackson Liang, DO, 200 1st Street SW, Rochester, MN 55905 (e-mail: Liang.Jackson@Mayo.edu). Proc (Bayl Univ Med Cent) 2013;26(2):156–158 peripheral nerves. The weakness was not likely due to vincristine or rituximab, as the symptoms developed after the first dose. Furthermore, vincristine toxicity was unlikely as he had a severe recurrence of weakness following his fourth cycle when vincristine was withheld. His malignancy responded extraordinarily to R-CHOP, as his testicles decreased to normal size a few days after his first cycle. Ultimately, his recurrent neurologic symptoms were attributed to AIDP from the underlying lymphoma, as his miraculous rapid improvement with IVIG did not fit with drug toxicity or direct lymphomatous nerve infiltration. Non-Hodgkin lymphoma is the most common cause of lymphomatous neuropathy syndromes (1). Although AIDP is most classically associated with Hodgkin lymphoma (2, 3), non-Hodgkin lymphoma can also cause a clinical picture of AIDP with evidence of demyelination on electromyelography and needle conduction studies. R-CHOP, a frequently used regimen in the treatment of non-Hodgkin lymphoma, has been linked to the Figure 1. (a) Pretreatment PET scan demonstrating diffuse nodal activity and extranodal involvement in the pleura, development of AIDP (4, 5), partictesticles, and bones. (b) Follow-up PET scan prior to R-CHOP cycle 3 demonstrating complete radiologic remission. ularly rituximab (6) and vincristine (7–10). AIDP, the major variant of no sign of lymphomatous involvement of the nerves. Full-dose the group of neurologic disorders commonly referred to by the vincristine was given with his third R-CHOP cycle. After 5 days, eponym “Guillain Barré syndrome,” is believed to be due to he noted complete loss of sensation in his fingers and feet. His autoimmune attack on the myelin of peripheral nerves, leading symptoms resolved over the next few days and were attributed to to electrical conduction slowing and muscular weakness. It is vincristine. As such, vincristine was withheld during his fourth often preceded by an upper respiratory or gastrointestinal tract cycle. Five days following this fourth cycle, he experienced severe infection, most commonly due to Campylobacter jejuni, Epsteinweakness in his legs bilaterally in addition to numbness in his Barr virus, or cytomegalovirus (11). Other systemic illnesses hands and feet, similar to his initial episode of AIDP. A repeat associated with AIDP include HIV, viral hepatitis, sarcoidosis, electromyogram once again demonstrated findings consistent and systemic lupus erythematosus (2). with polyradiculoneuropathy. Lumbar puncture demonstrated The diagnosis is multifaceted. Clinical findings include protein of 98 g/dL with 1 total nucleated cell per microliter. A progressive symmetric muscle weakness and diminished or complete serum and cerebrospinal fluid paraneoplastic panel absent deep tendon reflexes. Lumbar puncture with analysis and cerebrospinal fluid cytology sent at that time were negative. of cerebrospinal fluid typically reveals normal cell count with He was treated again with a 5-day course of IVIG (400 mg/kg/ elevated protein, also known as albuminocytologic dissociaday) with complete resolution of symptoms. tion. Electromyography with needle conduction study is helpful in the diagnosis of AIDP, typically revealing slowing of nerve DISCUSSION conduction with conduction block or abnormal dispersion, The differential diagnosis in our patient’s acute ascending prolonged distal latencies, and delayed F waves (12). weakness included autoimmune AIDP secondary to his underTreatment consists of supportive care and disease-modifying lying lymphoproliferative malignancy, vincristine or rituximab therapy. Up to 30% of patients require mechanical ventilation neurotoxicity, and direct lymphomatous involvement of the due to weakness of muscles of respiration or inability to swallow a April 2013 b Recurrent AIDP following R-CHOP treatment for non-Hodgkin lymphoma 157 and protect the airway. Plasmapheresis and IVIG are the main therapies for AIDP. Plasmapheresis removes circulating autoantibodies in the blood, while IVIG may neutralize autoantibodies (13) and prevent complement-mediated nerve damage (14). 1. 2. 3. 4. 5. 6. 7. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clinical review. Muscle Nerve 2005;31(3):301–313. Ropper AH. The Guillain-Barré syndrome. N Engl J Med 1992;326(17):1130–1136. Hughes RA, Britton T, Richards M. Effects of lymphoma on the peripheral nervous system. J R Soc Med 1994;87(9):526–530. Magné N, Foa C, Castadot P, Otto J, Birtwisle-Peyrottes I, Thyss A. Guillain-Barré syndrome and non-Hodgkin’s lymphoma. Report of one case and review of literature. Rev Med Brux 2005;26(2):108–111. Terenghi F, Ardolino G, Nobile-Orazio E. Guillain-Barré syndrome after combined CHOP and rituximab therapy in non-Hodgkin lymphoma. J Peripher Nerv Syst 2007;12(2):142–143. Carmona A, Alonso JD, de las Heras M, Navarrete A. Guillain-Barre syndrome in a patient with diffuse large B-cell lymphoma, and rituximab maintenance therapy. An association beyond anecdotal evidence? Clin Transl Oncol 2006;8(10):764–766. Weiden PL, Wright SE. Vincristine neurotoxicity. N Engl J Med 1972;286(25):1369–1370. 8. 9. 10. 11. 12. 13. 14. Wanschitz J, Dichtl W, Budka H, Löscher WN, Boesch S. Acute motor and sensory axonal neuropathy in Burkitt-like lymphoma. Muscle Nerve 2006;34(4):494–498. Bahl A, Chakrabarty B, Gulati S, Raju KN, Raja A, Bakhshi S. Acute onset flaccid quadriparesis in pediatric non-Hodgkin lymphoma: vincristine induced or Guillain-Barré syndrome? Pediatr Blood Cancer 2010;55(6):1234–1235. Moudgil SS, Riggs JE. Fulminant peripheral neuropathy with severe quadriparesis associated with vincristine therapy. Ann Pharmacother 2000;34(10):1136–1138. Jacobs BC, Rothbarth PH, van der Meché FG, Herbrink P, Schmitz PI, de Klerk MA, van Doorn PA. The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study. Neurology 1998;51(4):1110– 1115. Cornblath DR. Electrophysiology in Guillain-Barré syndrome. Ann Neurol 1990;27(Suppl):S17–S20. Buchwald B, Ahangari R, Weishaupt A, Toyka KV. Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barré syndrome. Ann Neurol 2002;51(6):673–680. Jacobs BC, O’Hanlon GM, Bullens RW, Veitch J, Plomp JJ, Willison HJ. Immunoglobulins inhibit pathophysiological effects of anti-GQ1bpositive sera at motor nerve terminals through inhibition of antibody binding. Brain 2003;126(10):2220–2234. Avocations A red fox from Alaska. Copyright © Jed Rosenthal, MD. Dr. Rosenthal is a cardiologist in Dallas, Texas (e-mail: jedr2@sbcglobal.net). 158 Baylor University Medical Center Proceedings Volume 26, Number 2 Radiology Report Endolymphatic sac tumor and otalgia Mehrzad Zarghouni, MD, Michael L. Kershen, MD, Lauren Skaggs, MD, Amol Bhatki, MD, Steven C. Gilbert, MD, Conan E. Gomez, MD, and Michael J. Opatowsky, MD a b c d e f Otalgia is a common complaint seen by general practitioners, but its etiology is vast. Rarely, otalgia could be secondary to a neoplasm. We describe a case of otalgia and ear discharge in which the imaging revealed a rare neoplasm, an endolymphatic sac tumor, which contributed to the patient’s symptoms. The primary diagnosis was made via characteristic imaging features that were later confirmed by histology. Endolymphatic sac tumor is an uncommon neoplasm arising from the endolymphatic sac or endolymphatic duct. This tumor is generally classified as a papillary adenoma. We report a case of endolymphatic sac tumor in which the patient presented with otalgia and ear discharge. CASE DISCUSSION A 49-year-old woman presented with recent onset of left ear pain and Figure 1. (a, b) Head CT and (c–f) MRI images from this patient presenting with otalgia, showing characteristic discharge. The patient had a remote features of endolymphatic sac tumor. history of left ear tumor resection as a DISCUSSION child; however, the type of tumor was not known with certainty at The most common clinical presentation of endolymphatic the time of the current evaluation. A noncontrast head computed sac tumor is sensorineural hearing loss (1). Tinnitus, vertigo, tomography (CT) as part of the initial examination revealed an exand facial nerve palsy can also occur. While these tumors pansile mass destroying much of the temporal bone (Figures 1a–1b, are generally benign, they can be lethal. Late recurrence is white arrows). Given the absence of parenchymal brain edema, possible, although there is generally a very favorable prognoan indolent slow-growing tumor was suspected. Unenhanced and sis following complete resection. This tumor may be associgadolinium-enhanced magnetic resonance imaging (MRI) showed ated with the neurocutaneous syndrome von Hippel-Lindau a large, heterogeneous, and avidly enhancing mass centered on the left mastoid and petrous bones (Figures 1c–1f, white arrows). A fluid-fluid level within the dependent portion of the mass on the T2 From the Departments of Radiology (Zarghouni, Kershen, Skaggs, Gilbert, Gomez, axial image (Figure 1c, yellow arrow) was present. Areas of T1 bright Opatowsky) and Otolaryngology (Bhatki), Baylor University Medical Center at hyperintensity were suggestive of hemorrhage (Figure 1d, yellow Dallas. arrow). An endolymphatic sac tumor was ultimately confirmed by Corresponding author: Mehrzad Zarghouni, MD, Department of Radiology, Baylor histologic correlation following operative resection. The patient was University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: mzarghouni@gmail.com). discharged postoperatively without adverse neurological deficits. Proc (Bayl Univ Med Cent) 2013;26(2):159–160 159 disease (2, 3). In contrast to its sporadic form in which hearing loss is inevitable, in von Hippel-Lindau disease these tumors are generally small, which allows for hearing preservation (2, 3). The best diagnostic clues on imaging for an endolymphatic sac tumor include its characteristic location in addition to central calcified deposits and bone spicules on CT along with intratumoral high signal intensity on noncontrast T1 MRI evaluation (1–3). This is seen in conjunction with avid 160 enhancement on gadolinium-enhanced T1-weighted MRI sequences. 1. 2. 3. Lo WW, Applegate LJ, Carberry JN, Solti-Bohman LG, House JW, Brackmann DE, Waluch V, Li JC. Endolymphatic sac tumors: radiologic appearance. Radiology 1993;189(1):199–204. Leung RS, Biswas SV, Duncan M, Rankin S. Imaging features of von Hippel-Lindau disease. Radiographics 2008;28(1):65–79. Ayadi K, Mahfoudh KB, Khannous M, Mnif J. Endolymphatic sac tumor and von Hippel-Lindau disease: imaging features. AJR Am J Roentgenol 2000;175(3):925–926. Baylor University Medical Center Proceedings Volume 26, Number 2 Inguinal lymphadenopathy as the initial presentation of sarcoidosis Jim George, MD, Reese Graves, MD, and Robert Meador Jr., MD Sarcoidosis is a multisystem disease of unknown etiology characterized by granuloma formation. Despite pulmonary involvement in most patients, sarcoidosis can have a varied presentation. Lymph node involvement is rarely found in isolation. Even rarer are cases of sarcoidosis presenting with peripheral edema. We describe a case of sarcoidosis presenting with isolated unilateral peripheral edema. CASE PRESENTATION A 50-year-old African American woman with iron deficiency anemia secondary to menorrhagia and uterine fibroids was admitted for symptomatic anemia, requiring blood transfusions. The patient reported worsening right groin swelling and right leg swelling over the last 10 years with progressive pain with activity. A brother had lymphoma. On admission, she was afebrile and normotensive. Her right leg was 1.5 times larger in circumference than her left leg with nonpitting edema and a negative Homan’s sign. A 7 × 4 cm nodular mass was palpable in her right groin. There was no associated erythema or tenderness to palpation. Her white blood cell count was 4.6 K/uL, hemoglobin 6.5 g/dL, and platelets 331 K/uL. She had a positive antineutrophil antibody result with a 1:320 titer, an angiotensin-converting enzyme level of 25 mg/L, a vitamin D level of 52.9 ng/mL, an erythrocyte sedimentation rate of 47 mm/hr, a C-reactive protein level of 4.8 mg/ dL, a complement 3 (C3) level of 147 g/L, and a complement 4 (C4) level of 48.4 g/L. A computed tomography (CT) scan of the chest, abdomen, and pelvis revealed right deep pelvic and inguinal bulky adenopathy, with an 8.1 × 5.3 cm right pelvic sidewall mass, multiple enlarged right inguinal lymph nodes measuring 6 cm, and a large left uterine mass, measuring 8 cm (Figure 1). No abnormalities were noted in the chest or abdomen. A dilatation and curettage with endometrial biopsy was completed. An ultrasound-guided core needle biopsy was performed to further evaluate her inguinal mass. Her endometrial biopsy showed numerous myometrial tissue fragments and acute and chronic inflammation with squamous metaplasia, all suggestive of underlying submucosal leiomyoma and atrophy. The tissue sample was negative for granulomas, atypia, or malignancy. The ultrasound-guided core needle biopsy of the large right inguinal lymph node showed noncaseating granulomatous Proc (Bayl Univ Med Cent) 2013;26(2):161–162 Figure 1. Admission CT scan with right inguinal lymphadenopathy. Figure 2. Low power field microscopy of lymph node biopsy showing a granuloma without central necrosis, suggestive of sarcoidosis; 100× magnification, hematoxylin and eosin stain. inflammation with special stains negative for acid-fast bacilli and fungi (Figure 2). Flow cytometric analysis showed no evidence of a malignant hematolymphoid process. From the Department of Family Medicine (George, Graves), and the Division of Rheumatology, Department of Internal Medicine (Meador), Baylor Medical Center at Garland, Garland, Texas. Corresponding author: Jim George, MD, 1009 East Grubb Drive, Mesquite, TX 75149 (e-mail: Jim.george.dallas@gmail.com). 161 The patient was started on prednisone 40 mg daily and discharged home. She experienced an initial yet short-lived improvement in her right groin and lower extremity swelling. Attempts to taper the prednisone dose below 20 mg daily resulted in worsening right lower leg lymphedema. Multiple ultrasounds of her right lower extremity were done to rule out deep venous thrombosis, all of which were negative. A repeat CT scan of her chest, abdomen, and pelvis 5 months after her initial diagnosis suggested progressive sarcoidosis with increasing pelvic and inguinal lymphadenopathy, new low-density areas within the spleen, and multiple subcentimeter scattered pulmonary nodules. One month later, she died. The cause of death was not known. DISCUSSION Three main mechanisms of sarcoidosis causing asymmetric peripheral edema have been described. The first is lymphatic obstruction due to peripheral lymphadenopathy. Our patient’s edema illustrated this mechanism and, to our knowledge, is only the sixth case reported to date. Of these cases, four (including ours) were described in black patients, one in an Indian patient, and one in an Asian patient (1–5). This distribution is consistent with findings from a US study that demonstrated that extrathoracic lymph node involvement is more common in black patients than in white patients (6). The location of the obstructing lymph nodes was inguinal in three cases and retroperitoneal in two (1–5). In these cases, systemic steroid treatment resulted in prompt resolution of the lymphadenopathy and associated edema within 2 months. A second mechanism by which sarcoidosis can cause peripheral edema is by direct infiltration into surrounding tissues. Two cases displaying this mechanism have been reported. One involved a 39-year-old black man (7). He had known sarcoidosis with pulmonary and skin involvement and presented with asymmetric lower-extremity edema. A CT scan revealed “diffuse, infiltrative masses involving the subcutaneous tissues of the right leg” (7). His symptoms abated within 1 month following 162 systemic steroids. A second case involved a 59-year-old woman with cutaneous nodules, bilateral lower-extremity edema, and ulceration (8). Her symptoms improved with prednisolone but recurred when doses were decreased below 15 mg. A third mechanism is tenosynovitis, producing distal peripheral edema. In one case series, five patients presented with lower-extremity pitting edema localized to the dorsal foot and ankle associated with acute sarcoidosis (9). Magnetic resonance imaging showed extensive tenosynovitis. As with previous cases, all responded quickly to systemic steroid treatment. Acknowledgments The authors thank Paul Bannister, MD, from the Department of Pathology at Baylor Medical Center at Garland, for providing histology images. 1. 2. 3. 4. 5. 6. 7. 8. 9. Tomoda F, Oda Y, Takata M, Futamura A, Fujii N, Inoue H, Kitagawa M. A rare case of sarcoidosis with bilateral leg lymphedema as an initial symptom. Am J Med Sci 1999;318(6):413–414. Nathan MP, Pinsker R, Chase PH, Elguezabel A. Sarcoidosis presenting as lymphedema. Arch Dermatol 1974;109(4):543–544. Silver HM, Tsangaris NT, Eaton OM. Lymphedema and lymphography in sarcoidosis. Arch Intern Med 1966;117(5):712–714. Sweeney T, Ramsby G, Keohane M. Edema of the lower extremities secondary to obstructive sarcoidosis. Angiology 1980;31(1):69–71. Mahajan VK, Sharma NL, Sharma RC, Sharma VC. Cutaneous sarcoidosis: clinical profile of 23 Indian patients. Indian J Dermatol Venereol Leprol 2007;73(1):16–21. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H, Brsnitz EA. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164(10):1885–1889. Hoover RD Jr, Stricklin G, Curry TW, Carmichael LC. Unilateral lower extremity edema caused by infiltrative sarcoidosis. J Am Acad Dermatol 1994;30(3):498–500. Muhlemann MF, Walker NP, Tan LB, Champion RH. Elephantine sarcoidosis presenting as ulcerating lymphoedema. J R Soc Med 1985;78(3):260–261. Cantini F, Niccoli L, Olivieri I, Barozzi L, Pavlica P, Bozza A, Macchioni PL, Padula AA, Salvarani C. Remitting distal lower extremity swelling with pitting oedema in acute sarcoidosis. Ann Rheum Dis 1997;56(9):565– 566. Baylor University Medical Center Proceedings Volume 26, Number 2 Levamisole-induced vasculitis Raghad Abdul-Karim, MD, Caitriona Ryan, MD, Christina Rangel, and Michael Emmett, MD Levamisole-contaminated cocaine is an increasingly reported cause of a syndrome characterized by vasculitic skin lesions and immunologic abnormalities. With approximately 70% of cocaine in the United States now contaminated with levamisole, the incidence of this syndrome is likely to increase. We report two cases of this syndrome and review its clinical presentation, course, and prognosis. a b c Figure 1. Case 1: (a) leg ulcer, (b) nasal skin necrosis, and (c) ear skin necrosis. DESCRIPTION a b c The first patient, an African American woman, presented with recurrent necrotizing vasculitis of her ears (Figure 1) and was found to have positive serology for cytoplasmic antineutrophil cytoplasmic antibody, human neutrophil elastase antibody, and anticardiolipin antibody. The second patient was an African American woman with widespread necrotizing vasculitis of her ears, nose, cheeks, and about 30% of her body surface area (Figure 2). She also had necrotizing pneumonia. Figure 2. Case 2: (a) ear necrosis, (b) facial scar, and (c) leg scars and bullae formation. Serologic findings were similar to those of the first case. She did not improve despite maximum human market in 1999 because of serious side effects including supportive management and died. The Table shows the major leukopenia, agranulocytosis, and skin vasculitis (2). It is still laboratory and clinical features of the cases. available as a veterinarian deworming drug. Relevant to this manuscript, levamisole has also been recogDISCUSSION nized as an adulterant in illicit cocaine since 2003 (3). A 2009 Levamisole-induced vasculitis was first described in the national survey found that approximately 70% of cocaine in the 1970s. This syndrome produces a characteristic clinical presUSA is contaminated with levamisole (2, 3). Levamisole is added entation of vasculitis in association with a variable pattern of to cocaine because it potentiates its stimulant effects by inhibitimmunologic disturbances. In a case series of five children treating both monoamine oxidase and catechol-O-methyltransferase ed with levamisole for nephrotic syndrome, all five developed activity, thereby prolonging the action of catecholamines in necrosis of their ears, with variable involvement of their cheeks the neuronal synapse and increasing the reuptake-inhibition and extremities (1). Levamisole was originally marketed as an anthelmintic agent but was also found to have major immunomodulatory properties. It induced interferon synthesis and From the Department of Internal Medicine, Baylor University Medical Center at synergized the effect of steroids and other immunosuppressants. Dallas (Abdul-Karim, Ryan, Emmett); and the University of Texas Southwestern It was used in cancer therapy, to treat various immunological Medical School, Dallas (Rangel). renal diseases, and to treat a number of skin diseases, including Corresponding author: Raghad Abdul-Karim, MD (e-mail: raghadkareem@ Behçet’s disease. However, the drug was withdrawn from the yahoo.com). Proc (Bayl Univ Med Cent) 2013;26(2):163–165 163 involves the ears, but purpura can also be observed on the nose, cheeks, extremities, and diffusely. Cutaneous lesions tend to be stellate Variable Case 1 Case 2 with a bright erythematous border and necrotic Age (years) 40 50 center. This lesion usually resolves spontaneously Race African American African American within a few weeks of drug discontinuation and Urine cocaine screen Positive Positive recurs with subsequent contaminated cocaine abuse. ESR (mm/hr) 52 40 The half-life of levamisole is 5.6 hours, and CRP (mg/dL) 4.5 13.8 only 3% to 5% of the drug is found in urine Serum levamisole Negative Not checked within 48 hours of last use. Leukopenia can Antinuclear antibody titer 1:12,560 1:640 occur in 50% to 60% of cases (3) and can first Antineutrophil cytoplasmic p-ANCA, 1:2,560 p-ANCA, 1:10,240 develop after as long as 12 months of continuous antibody (indirect immunoc-ANCA, negative c-ANCA, 1:320 use (5). Agranulocytosis has also been reported fluorescence) in patients with cocaine/levamisole abuse (6). Anti-HNE, positive Antibodies against neutrophil Anti-HNE, positive The syndrome has a very interesting spectrum cytoplasmic antigens (ELISA Anti-PR3, positive Anti-PR3, positive of autoantibody findings. High-titer perinuclear capture) Anti-MPO, positive Anti-MPO, negative antineutrophil antibodies (p-ANCA) are almost IgM anticardiolipin antibody 21.4 14.4 always found (86%–100%), and about 50% of (normal 0.0–12.4 U/mL) the cases also have cytoplasmic antineutrophil Extensive black discolorSkin findings Markedly tender, black antibodies (c-ANCA) (4–10). However, the speation and necrosis of the discoloration and necrosis cific antigens responsible for generating these ears, eyelashes, forehead, of the helices and antihepositive ANCA fluorescent patterns are not yet and bilateral cheeks; digital lices of both ears; a large, clearly defined. Antibodies against proteinase-3 necrosis of both hands and necrotic, indurated, inflam(anti-PR3), the autoantibody most commonly feet; rapidly progressive areas matory plaque on her nose; associated with a c-ANCA pattern, are present a 5.0-cm-diameter punched- of epidermal detachment, in about 50% of these patients, while antibodnecrosis, and bulla formation out ulcer on her left lateral of the trunk and upper and shin; an indurated livedoid ies against myeloperoxidase (anti-MPO), the plaque on her left upper arm; lower limbs antibody most often responsible for a p-ANCA nailfold infarcts pattern, are found in almost every case (3, 10). Skin biopsy Gangrenous necrosis with Leukocytoclastic vasculitis In addition, antiphospholipid antibodies and acute inflammation and with fibrinoid necrosis of the antinuclear antibodies are also often present. The fibrosis blood vessel walls and subMayo group has reported another antibody in epidermal bullae formation these patients that is directed against human neuTreatment Short course of high-dose Mechanical ventilation; steroid trophil elastase. Anti–human neutrophil elastase prednisone tapering induced worsening (anti-HNE) is also present in most patients with of her respiratory status and cocaine-induced midline destructive lesions, but skin lesions not in patients with classic ANCA vasculitis (4, Outcome Spontaneous resolution of Deep eschars of the face with 9). Both PR3 and HNE belong to the same family skin lesions extensive destruction of nasal of serine proteases, and cross-reactivity between and ear cartilages; death after these antibodies/antigens may occur. These two 60 days in the hospital cocaine abuse–associated syndromes are distinctly ESR indicates erythrocyte sedimentation rate; CRP, C-reactive protein; c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; anti-PR3, anti-proteinase different. Cocaine-induced midline destructive 3 antibody; anti-MPO, anti-myeloperoxidase antibody; ELISA, enzyme-linked immunosorbent assay. lesions may be caused by the cocaine itself and do not generate the distinctive skin involvement that occurs with the levamisole-related condition effect of cocaine. Levamisole metabolites also have a stimulatory (11). Conversely, the levamisole-related vasculitis does not usually effect. Very importantly, levamisole reacts as cocaine in the cause destructive damage to the nose, sinuses, and palate. “bleach test,” a quick, widely utilized street test for cocaine The histology of cutaneous lesions typically shows thrompurity. Therefore, it adds bulk to illicit cocaine without reducing botic vasculitis or leukocytoclastic vasculitis with or without the native drug’s apparent purity, as occurs with other bulking vascular occlusion (2–4). The natural history of levamisoleagents such as sugar or lidocaine (2). Both snorting and smoking induced vasculitis is spontaneous resolution without treatment levamisole-contaminated cocaine have been associated with the when the levamisole is withdrawn. Immunologic abnormalities vasculitic syndrome (4). generally resolve within 2 to 14 months of withdrawal of the Levamisole-induced syndrome has a characteristic presenlevamisole (2). However, some severe cases may not improve, as tation (2, 4). The distinctive vasculopathic purpura typically in our second patient, who had a fulminant form of vasculitis Table. Characteristics of the two cases of levamisole-induced vasculitis 164 Baylor University Medical Center Proceedings Volume 26, Number 2 and a fatal outcome. Although steroids have been used for treatment of this syndrome, it is unclear if they provide any benefit. The side effects may be harmful, especially since most reported cases had no internal organ involvement (3, 4). 1. 2. 3. 4. 5. Rongioletti F, Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, Gambini C, Rizzoni G, Rebora A. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999;140(5):948–951. Chang A, Osterloh J, Thomas J. Levamisole: a dangerous new cocaine adulterant. Clin Pharmacol Ther 2010;88(3):408–411. Gross RL, Brucker J, Bahce-Altuntas A, Abadi MA, Lipoff J, Kotlyar D, Barland P, Putterman C. A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. Clin Rheumatol 2011;30(10):1385–1392. Trimarchi M, Gregorini G, Facchetti F, Morassi ML, Manfredini C, Maroldi R, Nicolai P, Russell KA, McDonald TJ, Specks U. Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis. Medicine (Baltimore) 2001;80(6):391–404. Chung C, Tumeh PC, Birnbaum R, Tan BH, Sharp L, McCoy E, Mercurio MG, Craft N. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol 2011;65(4):722–725. 6. Buchanan JA, Oyer RJ, Patel NR, Jacquet GA, Bornikova L, Thienelt C, Shriver DA, Shockley LW, Wilson ML, Hurlbut KM, Lavonas EJ. A confirmed case of agranulocytosis after use of cocaine contaminated with levamisole. J Med Toxicol 2010;6(2):160–164. 7. Gross RL, Brucker J, Bahce-Altuntas A, Abadi MA, Lipoff J, Kotlyar D, Barland P, Putterman C. A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. Clin Rheumatol 2011;30(10):1385– 1392. 8. Bhinder SK, Majithia V. Cocaine use and its rheumatic manifestations: a case report and discussion. Clin Rheumatol 2007;26(7):1192–1194. 9. Wiesner O, Russell KA, Lee AS, Jenne DE, Trimarchi M, Gregorini G, Specks U. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum 2004;50(9):2954–2965. 10. McGrath MM, Isakova T, Rennke HG, Mottola AM, Laliberte KA, Niles JL. Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol 2011;6(12):2799–2805. 11. Specks U. The growing complexity of the pathology associated with cocaine use. J Clin Rheumatol 2011;7(4):167–168. Avocations “Medusa of the Sea” by Jay Hoppenstein, MD. Dr. Hoppenstein (e-mail: navigato@aol.com) is a surgeon who was on the medical staff at Baylor University Medical Center at Dallas from 1971 until his retirement in 2005. He also served as chairman of the Department of Surgery at Presbyterian Hospital of Dallas. April 2013 Levamisole-induced vasculitis 165 Kayser-Fleischer rings of acute Wilson’s disease Alexander Michael Mantas, MD, Jennifer Wells, MD, and James Trotter, MD Here we describe a case of a 22-year-old woman who presented with acute liver failure and Kayser-Fleischer rings suggesting the diagnosis of Wilson’s disease. A 22-year-old woman with no known past medical history presented to an emergency department with a 3-week history of fatigue, decreased appetite, and jaundice. Her initial laboratory workup indicated acute liver injury with a total bilirubin level of 12.1 mg/dL (reference range, 0.2– 1.0); alkaline phosphatase of 45 U/L (reference range, 50–136); aspartate aminotransferase of 111 U/L (reference range, 15–37); alanine aminotransferase of 27 U/L (reference range, 12–78); ceruloplasmin of 19 mg/dL (reference range, 20–60); and prothrombin time of 29.11 seconds (reference range, 9.0–12.0). Additionally, she was found to have concurrent acute kidney injury and a Coombs-negative hemolytic anemia. The patient underwent a laparoscopic cholecystectomy at an outside hospital that revealed the presence of ascites and a nodular liver with an otherwise normal gallbladder. The patient quickly decompensated into acute liver failure during her postoperative course, and physical examination revealed the presence of Kayser-Fleischer (KF) rings (Figure). The presence of KF rings and jaundice with abnormal liver function tests, including low ceruloplasmin and alkaline phosphatase, suggested the diagnosis of Wilson’s disease. The patient was transferred to Baylor University Medical Center at Dallas, where she underwent evaluation for orthotopic liver transplantation, which was successfully performed on hospital day 4. Elevated hepatic copper (2145 mcg/g; reference range, 10–35) on dry weight liver biopsy was consistent with the diagnosis of Wilson’s disease. Mutation analysis indicated that the patient was homozygous for the pathogenic mutation 3201 C>A in exon 14, resulting in the amino acid change His1069Gln. DISCUSSION Wilson’s disease is an autosomal recessive mutation of the ATP7B gene, whose protein both traffics excess copper into the bile canaliculus for excretion and binds copper to apoceruloplasmin, forming holoceruloplasmin. Oxidative damage ensues when uncomplexed copper begins to accumulate in hepatocytes. Liver injury can present in various forms ranging from asymptomatic abnormal liver function tests to acute and chronic liver failure. With ongoing hepatic damage, uncomplexed copper is released from the liver and deposited in other organs, including the lenticular nucleus of the basal ganglia, resulting in Parkinson-like symptoms; the proximal renal tubule, resulting in Fanconi’s syndrome; and the red blood cells, resulting in a Coombs-negative hemolytic anemia. Other organs affected include the heart, pancreas, Figure. Kayser-Fleischer ring in a patient with acute liver failure from Wilson’s disease. 166 From the Division of Gastroenterology, Department of Internal Medicine (Mantas), and the Department of Transplant Hepatology (Wells, Trotter), Baylor University Medical Center at Dallas. Corresponding author: Alexander Michael Mantas, MD, Baylor University Medical Center at Dallas, 3600 Gaston Avenue, Wadley Tower, Suite 260, Dallas, TX 75246 (e-mail: aleximan@BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):166–167 parathyroid gland, and bone. The eye is uniquely affected, as copper accumulates in Descemet’s membrane of the corneal limbus, resulting in KF rings (Figure), and in the lens, resulting in sunflower cataracts. The observation of the characteristic brown-gold-yellow KF ring at the margin of the cornea and sclera generally requires a slit-lamp examination, but some rings can be seen under normal light. Each of these ocular findings resolves over time following transplant (1, 2). 1. 2. Cox DW, Roberts EA. Wilson disease. In Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 9th ed. Philadelphia: Elsevier Saunders, 2010:1249–1258. Schilsky ML, Tavill AS. Wilson disease. In Schiff ER, Maddrey WC, Sorrell MF, eds. Schiff’s Diseases of the Liver, 11th ed. Hoboken, NJ: WileyBlackwell, 2011:805–824. Avocations A Chihuly exhibit, Dallas Arboretum, © Amanullah Khan, MD, PhD. Dr. Khan (e-mail: aman1963@gmail.com) is an oncologist on the medical staff of Baylor Medical Center at McKinney. April 2013 Kayser-Fleischer rings of acute Wilson’s disease 167 Ascites with elevated protein content as the presenting sign of constrictive pericardial disease Betsy Ann George, MD, Gregory dePrisco, MD, James Ford Trotter, MD, Albert Carl Henry III, MD, and Robert Craig Stoler, MD Two men, one 63 and one 52 years old, presented with ascites. Analysis of the ascitic fluid in both patients revealed a high protein content and an elevated serum-ascites gradient. Various studies showed the cause of the ascites to be constrictive pericardial disease. Total excision of their parietal pericardia relieved their symptoms, decreased their cardiac filling pressures, and increased their cardiac indices. These cases highlight the importance of suspecting pericardial constriction as an etiology for high-protein-count ascites. W e describe two patients who presented with highprotein-count ascites as the initial sign of constrictive pericardial disease. These cases highlight the importance of early recognition of a cardiac etiology for ascites, as prompt treatment with a total pericardiectomy significantly improved the patients’ quality of life. DESCRIPTION OF CASES Pertinent clinical features in each of the two patients prior to surgery are summarized in Table 1. The two patients had evidence of ascites for 6 and 60 months, respectively. Both received multiple therapeutic paracenteses and escalating doses of diuretics for refractory ascites. The first patient had no attributable hepatic cause for his ascites, but the second had a history of heavy alcohol use prior to its cessation at age 47. Despite receiving a Denver shunt, the second patient continued to have intractable ascites so was referred for possible transjugular intrahepatic portosystemic shunt and liver transplantation. Both patients had no previous cardiothoracic surgery, pericarditis, radiation treatment, or collagen vascular diseases. Neither patient had cardiopulmonary symptoms. Physical examination in these patients revealed normal blood pressure and heart rate, distended jugular veins, clear lungs, and no precordial murmurs or abnormal heart sounds. Their abdomens had clear evidence of ascites. Laboratory tests in the first patient were normal. The second patient had renal insufficiency and mildly elevated bilirubin. Analysis of their ascitic fluid revealed an elevated total protein content and a high serum-ascites albumin gradient. The patients were then referred to cardiology for evaluation of a cardiac cause of the ascites. Transthoracic echocardiograms in both patients revealed a bright, thickened parietal pericar168 Table 1. Pertinent features of the two men prior to pericardiectomy Variable Case 1 Case 2 Age (years) 63 52 Age of onset of ascites (years) Previous hepatitis or alcohol use 62 0 47 + Serum creatinine (mg/dL) 1.3 1.8 International normalized ratio 1.0 1.1 Total bilirubin (mg/dL) 0.4 1.8 Aspartate aminotransferase (U/L) 17 19 Alanine aminotransferase (U/L) 15 8 Alkaline phosphatase (U/L) 100 169 Ascitic fluid total protein (g/dL) 4.2 4.6 Serum-ascites albumin gradient (g/dL) 1.6 1.7 dium, “septal bounce,” exaggerated respiratory variation across the tricuspid and mitral valves, a dilated inferior vena cava, expiratory hepatic vein diastolic flow reversal, normal tissue Doppler velocities, and no pericardial effusion (Figure 1). Cardiac catheterization pressure waveforms in each showed equalization of the elevated diastolic pressures and discordance of right and left ventricular systolic pressures (Figure 2). Cardiac magnetic resonance imaging scans disclosed marked thickening of the parietal pericardium (Figure 3). Both patients underwent total excision of their parietal pericardia with resolution of their ascites and elevated cardiac filling pressures. Hemodynamics before and after pericardiectomy are shown in Table 2. The parietal pericardium in each was severely thickened by dense fibrous tissue (Figure 4). From the Department of Internal Medicine, Division of Cardiology (George, Stoler) and Division of Hepatology (Trotter), the Department of Radiology (dePrisco), and the Department of Cardiothoracic Surgery (Henry), Baylor University Medical Center at Dallas. Corresponding author: Betsy Ann George, MD, Baylor Heart and Vascular Institute, 621 N. Hall Street, #H030, Dallas, TX 75226-1312 (e-mail: Betsy. George@BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):168–170 a b c d Figure 1. Case 1. Transthoracic echocardiogram. (a) Apical view of bright, thickened parietal pericardium (arrows). (b) Doppler analysis showing exaggerated variation of tricuspid valve blood flow with respiration. (c) Hepatic vein diastolic flow reversal during expiration (arrows). (d) Normal Doppler tissue velocities at the lateral mitral annulus. Figure 2. Case 1. Simultaneous right ventricular (RV) and left ventricular (LV) cardiac catheterization pressure waveform tracings demonstrating equalization of diastolic pressures (arrow) and discordance of systolic pressures. The arrow also depicts the square root sign or dip and plateau sign—a finding due to diastolic pressures rising abruptly to a level that is sustained until systole because of the restricted filling from the pericardium. DISCUSSION Constrictive pericardial disease is a rare cause of recurrent ascites. Both of our patients had high-protein-count ascites with an elevated serum-ascites albumin gradient, a finding well described in previous reports of constrictive pericarditis (1–3). A serumascites albumin gradient ≥1.1 g/dL and an ascites fluid total protein >2.5 g/dL is typical of constrictive pericardial disease and other postsinusoidal causes of ascites. Sinusoidal diseases, such April 2013 as liver cirrhosis, exhibit a serum-ascites albumin gradient >1.1 g/dL but an ascites fluid total protein <2.5 g/dL (1). A common finding in our cases was jugular venous distention, a sign not usually seen in patients with hepatic cirrhosis. Previous case series indicate that about 80% of patients with constrictive pericardial disease present with elevated jugular venous pressures. Neither of our patients had dyspnea or orthopnea. As many as half of the patients who undergo a pericardiectomy lack cardiopulmonary symptoms (4). Therefore, a high index of suspicion is required to diagnose this entity, especially in patients with elevatedprotein-count ascites, jugular venous distention, and no cardiopulmonary symptoms. The echocardiograms in our two patients were quite specific for constrictive pericardial disease. However, a transthoracic echocardiogram typically has low sensitivity in detection of this entity, and a constrictive pericardium may easily be overlooked. Thus, a physician should not be reassured with a negative echocardiogram if there is a high concern for this disease. Constrictive disease differs from restrictive disease by having normal tissue Doppler velocities on echocardiogram and discordance of right and left ventricular systolic pressures on cardiac catheterization. Constrictive pericardial disease can lead to significant morbidity. Both patients suffered from the sequelae of ascites with repeated therapeutic paracenteses and escalating doses of diuretics before the proper diagnosis was made. Pericardiectomy is the treatment of choice for patients with symptomatic chronic constrictive pericardial disease. The early hospital mortality is about 7% (5). The most common cause of death in the perioperative period is low-output heart failure (6). The long-term survival curves after pericardiectomy differ according to the etiology of the constrictive pericarditis and the type of surgery. Idiopathic/viral and postsurgical constrictive pericardial disease have the best 10year survival rates after pericardiectomy of about 67% and 56%, respectively, while postradiation pericarditis has the worst at 11% (5). Also, total pericardiectomy has a better survival rate than partial pericardiectomy (7). Acknowledgments We gratefully acknowledge William Clifford Roberts, MD, for editorial assistance with the report and Jong Mi Ko, BA, for the photography of the surgical specimens. 1. Howard JP, Jones D, Mills P, Marley R, Wragg A. Recurrent ascites due to constrictive pericarditis. Frontline Gastroenterol 2012;3(4):233–237. Ascites with elevated protein content as the presenting sign of constrictive pericardial disease 169 a b Figure 4. Necropsy specimens contrasting (a) abnormal thickened parietal pericardium in Case 2 constrictive disease with (b) normal, thin parietal pericardium. Figure 3. Case 2. A magnetic resonance imaging scan showing marked asymmetric pericardial thickening preferentially over the right ventricle (arrows) and gynecomastia in this patient with cirrhosis (ovals). Van der Merwe S, Dens J, Daenen W, Desmet V, Fevery J. Pericardial disease is often not recognised as a cause of chronic severe ascites. J Hepatol 2000;32(1):164–169. 3. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate Table 2. Hemodynamics before and after pericardiectomy concept in the differential diagnosis of ascites. Ann Intern Med 1992;117(3):215–220. Case 1 Case 2 4. Wood P. Chronic constrictive pericarditis. Am J Cardiol 1961;7(1):48–61. Measurement Preop Postop Preop Postop 5. George TJ, Arnaoutakis GJ, Beaty CA, Kilic A, Baumgartner WA, Conte JV. Contemporary etiologies, 19 – 19 – Mean right atrial pressure (mm Hg) risk factors, and outcomes after pericardiectomy. Ann Thorac Surg 2012;94(2):445–451. Right ventricular pressure (mm Hg) 35/19 – 28/15 – 6. Bertog SC, Thambidorai SK, Parakh K, Schoenhagen P, Pulmonary artery pressure (mm Hg) 38/18 – 41/19 – Ozduran V, Houghtaling PL, Lytle BW, Blackstone EH, Lauer MS, Klein AL. Constrictive pericarditis: etiology Pulmonary capillary wedge pressure (mm Hg) 19 – 20 – and cause-specific survival after pericardiectomy. J Am Coll Cardiol 2004;43(8):1445–1452. Left ventricular pressure (mm Hg) 111/22 – 95/16 – 7. Chowdhury UK, Subramaniam GK, Kumar AS, Airan B, Singh R, Talwar S, Seth S, Mishra PK, Pradeep KK, Central venous pressure (mm Hg) 19 3* 27 13* Sathia S, Venugopal P. Pericardiectomy for constrictive 2.1 3.9* 1.2 2.8* Cardiac index (L/min/m2) pericarditis: a clinical, echocardiographic, and hemodynamic evaluation of two surgical techniques. Ann Thorac *Intraoperatively. Surg 2006;81(2):522–529. 170 2. Baylor University Medical Center Proceedings Volume 26, Number 2 Congenitally bicuspid aortic valve in brothers: coarctation of the aorta with a normally functioning aortic valve in one and no coarctation but severe aortic stenosis in the other Saleha Zafar, MD, and William C. Roberts, MD Described herein are two brothers, both with a congenitally bicuspid aortic valve—one of which was stenotic and one of which functioned normally—and one with associated aortic isthmic coarctation. Summarized also are previously reported families with more than one member with a congenitally bicuspid aortic valve. T he occurrence of a congenitally bicuspid aortic valve (BAV) in more than one family member has been described in several published reports (1–7). Of the 47 family members in whom the BAV was confirmed at the time of aortic valve replacement or at necropsy, the valve was stenotic in at least 27 of them, and none had associated aortic isthmic coarctation. In this report we describe two brothers with a congenitally BAV—stenotic in one and functionally normal in the other—and aortic coarctation in one of them (Figure). PATIENT DESCRIPTIONS Case 1 A 16-year-old white boy had been well until about a month before hospitalization when he had an episode of severe dizziness followed by progressive breathlessness. He was hospitalized for “pneumonia” but never had any microorganisms cultured from sputum. When the chest radiograph cleared, cardiac catheterization disclosed the following pressures in mm Hg: pulmonary artery wedge a wave 34, v 32, and mean 32; pulmonary trunk 55/38; right ventricle 57/29; left ventricle 133/36 and aorta 77/66, yielding a peak systolic pressure gradient of 56 mm Hg; and mean systolic gradient 39 mm Hg. The calculated aortic valve area was 0.6 cm2, and the cardiac output was 4.6 L/min/m2. A cardiac operation was performed, and he died 2 weeks later. Case 2 This 21-year-old white man had been well until he was found dead in the bathroom at home, shortly after taking an amphetamine. He apparently never had evidence of cardiac dysfunction. Necropsy disclosed the pericardial sac to be filled with blood (550 mL). The ascending aorta had a 5-cm long tear without dissection with a through-and-through perforation. Proc (Bayl Univ Med Cent) 2013;26(2):171–173 Figure 1. Diagram showing the cardiovascular features of each of the two patients. Both had congenitally bicuspid aortic valves. In case 1, the valve was severely stenotic, and there was no coarctation of the aorta. In case 2, the valve functioned normally, and there was a severe coarctation of the aorta. A indicates anterior aortic valve cusp; I, innominate artery; L, left; LCC, left common carotid; LMCA, left main coronary artery; LS, left subclavian; P, posterior aortic valve cusp; R, right aortic valve cusp; RCA, right coronary artery. The ascending aorta was quite dilated. At the aortic isthmus (that portion of aorta just distal to the origin of the left subclavian artery), a severe coarctation was found. The aortic valve was congenitally bicuspid but the cusps were very pliable and noncalcified. Thus, the aortic valve function was considered to have been normal. A fibrous, nonstenotic ring was located in the left ventricular outflow tract about 1 cm below the base of the aortic valve cusps. The mitral valve was normal. The left main coronary artery ostium was located about 1 cm cephalad to the sinotubular junction. From the Baylor Heart and Vascular Institute (Zafar, Roberts) and the Departments of Internal Medicine (Division of Cardiology) and Pathology (Roberts), Baylor University Medical Center at Dallas. Corresponding author: William C. Roberts, MD, Baylor Heart and Vascular Institute, 621 North Hall Street, Dallas, TX 75226 (e-mail: wc.roberts@ BaylorHealth.edu). 171 Table. Previously published reports of patients with a familial congenitally bicuspid aortic valve with aortic valve replacement or necropsy Family Case number McKusick I 1 44 46 2 – 19 Son + – – Gale I 3 38 – Brother – + – 4 44 – Brother + + – 6 – 62 Uncle – + – 7 – – Mother – – – 8 20 – Son – – – 9 – – Mother – – – 10 41 – Son – + – 11 – – Mother – – – 12 – – Son – + – 13 – – Niece + + – 14 – – Nephew – + – 15 – 68 Grandfather – + – 16 – – Mother – – – 17 16 – Son – + – 18 93 – Mother – + – 19 – – Son – – – 20 – 97 Mother – + – 21 – – Son – – – Year of publication First author 1972 1977 1978 Emanuel* I II III IV V VI 1987 1989 1994 Bicuspid aortic valve Patient age (yrs) at AVR Godden McDonald Glick I I I II III IV V VI Patient age (yrs) at death Patient relation AR AS Functionally normal Father + – – 22 57 – Brother – + – 23 57 61 Brother + + – 24 – 19 Brother – + – 25 23 – Brother – + – 26 26 – Brother + + – 27 58 58 Father 0 + – 28 – – Daughter + 0 – 29 44 58 Father + + – 30 26 26 Son + 0 – 31 53 60 Sister – + – 32 72 – Brother + + – 33 – 70 Sister – + – 34 21 – Brother + 0 – 35 26 26 Brother + 0 – 36 – – Sister – – – 37 – – Sister – – – 38 – – Brother – – – 39 70 80 Brother – + – 40 69 73 Brother – + – 41 78 – Mother – + – continues 172 Baylor University Medical Center Proceedings Volume 26, Number 2 Table. Continued. Year of publication 1996 First author Clementi Family I II Patient age (yrs) at death Bicuspid aortic valve Case number Patient age (yrs) at AVR 42 65 – Daughter – + – 43 – – Daughter – + – 44 – 47 Brother – + – 45 42 – Brother + – – 46 – – Sister + – – 46 – – Mother + – – 47 – – Son + 0 + Patient relation AR AS Functionally normal *The bicuspid nature of the aortic valve was “surgically proven” in all patients listed here. AR indicates aortic regurgitation; AS, aortic stenosis; AVR, aortic valve replacement; –, no information or not applicable. DISCUSSION The Table lists previously published reports (1–7) describing a BAV in more than one family member with study of the valve at either aortic valve replacement or at necropsy. In the 18 families, 47 members had a congenitally BAV: 11 families had 2 members, 5 families had 3 members, and 2 families had 5 members with a BAV. Of the involved family members, 3 were fathers, 8 were mothers, 20 were sons, 8 were daughters, and the remaining were siblings or other relatives. Of the 47 family members, 30 (64%) were male and 17 (36%) were female. Twenty-three family members had aortic valve replacement; their ages ranged from 16 to 93 years (mean 47). Sixteen family members had died, 9 after aortic valve replacement. In the 18 families, all with BAVs were male in 3 families, all were female in 1 family, and both males and females were represented in 14 families. In addition to the studies where the bicuspid structure of the aortic valve was confirmed morphologically, an echocardiographic study (8) described 11 families in whom 28 members April 2013 had a BAV, 3 (11%) of whom had associated coarctation of the aorta. 1. 2. 3. 4. 5. 6. 7. 8. McKusick VA. Association of congenital bicuspid aortic valve and Erdheim’s cystic medial necrosis. Lancet 1972;1(7758):1026–1027. Gale AN, McKusick VA, Hutchins GM, Gott VL. Familial congenital bicuspid aortic valve: secondary calcific aortic stenosis and aortic aneurysm. Chest 1977;72(5):668–670. Emanuel R, Withers R, O’Brien K, Ross P, Feizi O. Congenitally bicuspid aortic valves. Clinicogenetic study of 41 families. Br Heart J 1978;40(12):1402–1407. Godden DJ, Sandhu PS, Kerr F. Stenosed bicuspid aortic valves in twins. Eur Heart J 1987;8(3):316–318. McDonald K, Maurer BJ. Familial aortic valve disease: evidence for a genetic influence? Eur Heart J 1989;10(7):676–677. Glick BN, Roberts WC. Congenitally bicuspid aortic valve in multiple family members. Am J Cardiol 1994;73(5):400–404. Clementi M, Notari L, Borghi A, Tenconi R. Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance. Am J Med Genet 1996;62(4):336–338. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol 1997;30(7):1809–1812. Congenitally bicuspid aortic valve in brothers 173 Electrocardiographic Report A 21-year-old pregnant woman with congenital heart disease D. Luke Glancy, MD Figure 1. Admission electrocardiogram. See text for explication. A 21-year-old woman was transferred from another hospital in her 23rd week of pregnancy. She had had an audible precordial murmur the day of her birth and had had pneumonia three times in the first few years of life. Otherwise, she was asymptomatic during childhood and adolescence. Aside from being small (4′11″ tall and 85 lbs before becoming pregnant), she had developed normally. When she was transferred, she was asymptomatic and on no medication. Pertinent physical findings were a regular pulse at 96 beats/ min; a blood pressure of 116/60 mm Hg; normal neck veins; brisk, full, symmetrical arterial pulses in the arms and legs with no radial-femoral delay; a loud and palpable second heart sound along the upper and mid left sternal border; and a small apical impulse just outside the left mid-clavicular line. A harsh, grade 4/6, systolic ejection murmur, heard over the entire chest and back and in the neck, was loudest at the cardiac base and of 174 equal intensity on the right and left sides. A decrescendo diastolic murmur was maximal in the third left intercostal space. There was no gallop, ejection click, cyanosis, or clubbing. The admission electrocardiogram showed normal sinus rhythm, left axis deviation of the QRS complex, and no septal Q waves in leads I, aVL, V5, or V6, but Q waves were present in leads II, III, aVF, and V1 (Figure 1). The history, physical examination, chest radiograph (Figure 2), and electrocardiogram provided some, albeit incomplete, insight into the patient’s congenital cardiac malformations and the consequent pathophysiology. A systolic murmur heard the day From the Sections of Cardiology, Departments of Medicine, Louisiana State University Health Sciences Center and the Interim Louisiana State University Public Hospital, New Orleans. Corresponding author: D. Luke Glancy, MD, 7300 Lakeshore Drive, #30, New Orleans, LA 70124 (e-mail: dglanc@lsuhsc.edu). Proc (Bayl Univ Med Cent) 2013;26(2):174–176 Figure 2. Admission posterior-anterior chest radiograph. The proximal right and left pulmonary arteries are at the same level. A hump is seen on the left cardiac border, and the ascending aorta is seen on the left side of the cardiac base rather than the right. The right border of the descending aorta can be seen to cross the spine obliquely from right to left and arrive in its usual location at the level of the diaphragm. These are features suggesting congenitally corrected transposition of the great arteries. In addition, the dilated pulmonary arteries suggest poststenotic dilation and/or increased pulmonary arterial pressure/flow. of birth suggested right or left ventricular outflow obstruction; it would have taken several days for pulmonary vascular resistance to fall sufficiently for the murmur of a ventricular septal defect to be heard. The patient’s brisk pulses excluded aortic stenosis, so the outflow tract obstruction had to be right ventricular. Frequent bouts of pneumonia in infancy suggested a sizable left-to-right shunt, a supposition supported by the large pulmonary arteries and pulmonary plethora noted on chest radiograph (Figure 2). The absence of septal Q waves in leads I, aVL, V5, and V6 and their presence in leads V1, II, III, and aVF suggested ventricular inversion, an integral feature of congenitally corrected transposition of the great arteries, a diagnosis also brought to mind by the chest radiograph (Figure 2) (1). The anterior position of the aortic valve in that condition would have produced the loud and palpable second heart sound. In congenitally corrected transposition of the great arteries, there are discordant atrioventricular and ventriculo-arterial connections. The right atrium receives blood from the two vena cavas and sends it across a mitral valve into a morphologic left ventricle that pumps it across a pulmonic valve, which is in fibrous continuity with the mitral valve, and into the pulmonary artery. Pulmonary venous blood travels through the left atrium and across a tricuspid valve into a morphologic right ventricle that pumps the blood across the infundibulum and the aortic valve into the aorta. Thus, ventriculoarterial discordance “corrects” the atrioventricular discordance, and the path of the blood through the heart is normal if there are no other malformations (2). Such patients have lived into their 70s (3). Whether the morphologic right ventricle, i.e., the systemic ventricle, in a patient with isolated congenitally corrected transposition of the great arteries functions as long and as well as a morphologic left April 2013 ventricle does in a normal person has been affirmed by some experts (4) and denied by others (5). The vast majority of patients with congenitally corrected transposition of the great arteries, however, have associated cardiac malformations. Three of these occur frequently enough to be considered part of the anomaly: ventricular septal defect in approximately two thirds of patients (2); left ventricular (pulmonary ventricular) outflow tract obstruction, which can be valvular and/or subvalvular, in one half (1); and anatomic abnormalities of the tricuspid (systemic atrioventricular) valve in 90%, many of which are not clinically significant and the most common of which is Ebstein’s anomaly (2). Other malformations seen in patients with congenitally corrected transposition of the great arteries include atrial septal defect; subaortic obstruction, which is often associated with coarctation of the aorta; aortic valve atresia with hypoplasia of the morphologic right ventricle; and pulmonary atresia with hypoplasia of the morphologic left ventricle. Because of malalignment of the atrial septum with the inlet ventricular septum, the atrioventricular conduction system is abnormal (2), and up to 75% of patients with congenitally corrected transposition of the great arteries eventually have atrioventricular block ranging from first degree to third degree (1). Wolff-Parkinson-White type ventricular preexcitation may occur, as it does in other persons with Ebstein’s anomaly of the tricuspid valve, and some, but not all, supraventricular arrhythmias in congenitally corrected transposition of the great arteries are associated with a left-sided accessory pathway (1). Because the morphologic left ventricle and the left bundle branch lie to the right of the morphologic right ventricle in congenitally corrected transposition of the great arteries, initial septal depolarization is from right to left and often inferosuperiorly as well, as seen in Figure 1. As is often the case, especially with congenital heart disease, the echocardiogram and Doppler examination added important diagnostic information to that obtained by history, physical, chest radiograph, and electrocardiogram. In this patient, echo-Doppler confirmed congenitally corrected transposition of the great arteries, a nonrestrictive ventricular septal defect, and pulmonic valvular and subvalvular stenosis with a 75 mm Hg peak systolic pressure gradient between the pulmonary ventricle (morphologic left ventricle) and the pulmonary artery. Because her systemic arterial systolic pressure at the time was 105 mm Hg and the ventricular septal defect was nonrestrictive, her pulmonary arterial systolic pressure was approximately 30 mm Hg. The echo-Doppler also revealed a restrictive patent ductus arteriosus, which explained the full, brisk pulses and the decrescendo diastolic murmur. The systolic component of the continuous murmur of the patent ductus was obscured by the louder murmur of pulmonic stenosis. Both ventricles had normal systolic function, and both atrioventricular valves were completely competent. The patient stayed on the obstetrical service throughout the remainder of her pregnancy. She entered active labor at 34 weeks of gestation and under epidural anesthesia delivered a 2425 g daughter with Apgar scores of 8 and 9. Bilateral tubal ligation A 21-year-old pregnant woman with congenital heart disease 175 was then performed. Mother and daughter were doing well at discharge on postoperative day 4. Two questions remain. First, why, with such a complex congenital cardiac malformation, was this woman asymptomatic after the first years of life and able to have a successful pregnancy? It was because the severe malformations were balanced in such a way that the circulatory system was quite adequate. Pulmonic stenosis prevented early severe heart failure or subsequent Eisenmenger reaction from the nonrestrictive ventricular septal defect. At the same time, there was sufficient blood flow through the pulmonic valve and the restrictive ductus to prevent cyanosis and allow normal activity and a successful pregnancy. Thus far she has avoided two common accompaniments of congenitally corrected transposition of the great arteries, i.e., tricuspid (systemic atrioventricular) valvular regurgitation and atrioventricular block. Second, should the patient undergo operative repair? An article from the Mayo Clinic points out that most persons with congenitally corrected transposition of the great arteries eventually undergo cardiac surgery and that for many, the operation comes too late for optimal results (6). Those statements are difficult to refute. On the other hand, in this patient, so-called complete repair would require extensive complicated surgery, 176 which is difficult to recommend to an asymptomatic patient. In addition, few institutions have a Gordon Danielson, one of the paper’s authors and one of the foremost congenital cardiac surgeons of his or any other day. Most importantly, the patient prefers not to undergo an operation as long as she feels well. 1. 2. 3. 4. 5. 6. Perloff JK. The Clinical Recognition of Congenital Heart Disease, 4th ed. Philadelphia: WB Saunders, 1994:67–90. Ho SY, Baker EJ, Rigby ML, Anderson RH. Color Atlas of Congenital Heart Disease: Morphologic and Clinical Correlations. London: Mosby-Wolfe, 1995:145–156. Lieberson AD, Schumacher RR, Childress RH, Genovese PD. Corrected transposition of the great vessels in a 73-year-old man. Circulation 1969;39(1):96–100. Benson LN, Burns R, Schwaiger M, Schelbert HR, Lewis AB, Freedom RM, Olley PM, McLaughlin P, Rowe RD. Radionuclide angiographic evaluation of ventricular function in isolated congenitally corrected transposition of the great arteries. Am J Cardiol 1986;58(3):319–324. Graham TPJ Jr, Parrish MD, Boucek RJ Jr, Boerth RC, Breitweser JA, Thompson S, Robertson RM, Morgan JR, Friesinger GC. Assessment of ventricular size and function in congenitally corrected transposition of the great arteries. Am J Cardiol 1983;51(2):244–251. Beauchesne LM, Warnes CA, Connolly HM, Ammash NM, Tajik AJ, Danielson GK. Outcome of the unoperated adult who presents with congenitally corrected transposition of the great arteries. J Am Coll Cardiol 2002;40(2):285–295. Baylor University Medical Center Proceedings Volume 26, Number 2 Persistent giant U wave inversion with anoxic brain injury Matthew N. Peters, MD, Morgan J. Katz, MD, Lucius A. Howell, MD, John C. Moscona, MD, Thomas A. Turnage, MD, and Patrice Delafontaine, MD Figure. Electrocardiogram revealing deeply inverted U waves, most notable in the lateral precordial leads, V3–V5. Various electrocardiographic changes have been reported in the setting of acute neurological events, among them large, upright U waves. In contrast, the occurrence of inverted U waves is strongly suggestive of cardiovascular disease, most commonly hypertension, coronary artery disease, or valvular abnormalities. Presented herein is the case of a 29-year-old man with previous anoxic brain injury (but without apparent cardiovascular disease) whose electrocardiogram demonstrated persistent giant inverted U waves. CASE PRESENTATION A 29-year-old Caucasian man with previous anoxic brain injury presented to our facility with a 3-day history of nausea and vomiting. According to his mother, he had overdosed on alprazolam in an apparent suicide at the age of 17 and was in a coma for several days. During the subsequent year, he had daily seizures and was started on levetiracetam, eventually becoming seizure free. Current medications (all of which were administered via percutaneous endoscopic gastrostomy tube) included Proc (Bayl Univ Med Cent) 2013;26(2):177–178 twice-daily levetiracetam, daily 20 mg citalopram, and daily 40 mg esomeprazole. Initial vital signs were all within normal limits. His blood pressure was 100/70 mm Hg. He was nonverbal. Complete blood count, complete metabolic profile, and thyroid studies were within normal limits. A chest radiograph revealed no evidence of acute cardiopulmonary processes, and an abdominal radiograph revealed a nonobstructive bowel gas pattern. An initial electrocardiogram (ECG) demonstrated deep, symmetric T wave inversions in the inferior and lateral leads followed by large negative deflections, of varying amplitude, most prominent in the lateral precordial leads (Figure). Three sets of cardiac troponins separated by 6 hours each were <0.05 g/dL. A transthoracic echocardiogram showed a normal left ventricular ejection fraction, normal intracardiac chamber sizes, From the Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, LA (Peters, Katz, Howell, Moscona, Turnage); and Tulane University Heart and Vascular Institute, New Orleans, LA (Delafontaine). Corresponding author: Matthew N. Peters, MD, 1430 Tulane Avenue SL-50, New Orleans, LA 70112 (e-mail: mattpeters25@gmail.com). 177 and no regional wall motion abnormalities. Repeat ECGs over the subsequent 36 hours revealed a similar pattern. An ECG when he was 26 years old (9 years following the anoxic brain injury) appeared almost identical. After 24 hours of intravenous fluid administration and cessation of tube feedings, the patient demonstrated marked clinical improvement and 12 hours later was discharged. DISCUSSION The T wave and U wave are thought to represent the terminal component of ventricular repolarization. While the mechanism of U wave genesis remains uncertain, the clinical specificity of a negative U wave (defined as any discrete negative deflection >0.05 mV within the T-P segment) for heart disease is high (1). Occurring in only 1% of all hospital ECGs, the presence of an inverted U wave suggests the presence of coronary artery disease, valvular heart disease, or hypertension (2). Historically, the correlation of negative U waves with acute myocardial infarction has been felt to be important, given the ability of negative U waves to precede typical ECG changes of acute myocardial infarction by several hours (1). When combined with the presence of T wave inversion, a negative U wave has specificity for coronary artery disease as high as 88% (1). In the presence of myocardial ischemia, U wave vectors are typically directed away from the akinetic or dyskinetic myocardial segment (1). It is difficult to assess whether or not U wave vectors would have similar orientation in the presence of ischemia without wall motion abnormalities because these two entities usually occur in tandem and subsequent revascularization typically leads to the complete disappearance of inverted U waves (1). While association with ischemic heart disease has been regarded as the most clinically important cause of negative U waves, the most common cause (according to a 1982 study of 488 patients with negative U waves) has been found to be hypertension (39.5%), followed by coronary artery disease (33.2%) and valvular heart disease (15.4%). Other less common causes of negative U waves include congenital heart disease (2.5%), hyperthyroidism (1.4%), primary cardiomyopathy (0.8%), and in 7.2%, no manifestations of heart disease (2). 178 Association between ECG changes and acute neurological events is well known, with causes including subarachnoid hemorrhage, subdural hematoma, neoplasm, infection, epilepsy, and cerebrovascular accident (3). Associated ECG changes include prolonged QT interval, deep, symmetrical T wave inversions, pathologic Q waves, and tall, upright U waves. Cardiac insult related to an acute neurological event is thought to be related to alterations in the autonomic nervous system. Specifically, release of norepinephrine from sympathetic nerve terminals causes widespread opening of calcium channels within the myocardium and subsequent calcium ion influx (4). Consequently, ECG changes do not typically persist past the acute setting. We believe that the occurrence of persistent giant negative U waves in the absence of apparent cardiac disease is a unique clinical finding and likely somehow related to our patient’s previous anoxic brain injury. The possibility of artifact was also considered but deemed unlikely given the fact that multiple ECGs obtained during the patient’s hospitalization as well as an ECG obtained from 3 years prior appeared nearly identical. The actual mechanism of these findings is uncertain. His current medications have not been reported to produce any such abnormalities. Coronary artery disease cannot be completely excluded as an etiology (since coronary arteriography was not performed), but we think it very unlikely in a 29-year-old person without other evidence of heart disease. It is possible that the changes may be related to ongoing autonomic nervous system dysfunction, especially in light of his hypotension, although this explanation is purely speculative at the present time. 1. 2. 3. 4. Pérez Riera AR, Ferreira C, Filho CF, Ferreira M, Meneghini A, Uchida AH, Schapachnik E, Dubner S, Zhang L. The enigmatic sixth wave of the electrocardiogram: the U wave. Cardiol J 2008;15(5):408–421. Kishida H, Cole JS, Surawicz B. Negative U wave: a highly specific but poorly understood sign of heart disease. Am J Cardiol 1982;49(8):2030– 2036. Reinig MG, Harizi R, Spodick DH. Electrocardiographic T- and U-wave discordance. Ann Noninvasive Electrocardiol 2005;10(1):41–46. Strauss WE, Samuels MA. Electrocardiographic changes associated with neurologic events. Chest 1994;106(5):1316–1317. Baylor University Medical Center Proceedings Volume 26, Number 2 The calcium-alkali syndrome Mariangeli Arroyo, MD, Andrew Z. Fenves, MD, and Michael Emmett, MD The milk-alkali syndrome was a common cause of hypercalcemia, metabolic alkalosis, and renal failure in the early 20th century. It was caused by the ingestion of large quantities of milk and absorbable alkali to treat peptic ulcer disease. The syndrome virtually vanished after introduction of histamine-2 blockers and proton pump inhibitors. More recently, a similar condition called the calcium-alkali syndrome has emerged as a common cause of hypercalcemia and alkalosis. It is usually caused by the ingestion of large amounts of calcium carbonate salts to prevent or treat osteoporosis and dyspepsia. We describe a 78-year-old woman who presented with weakness, malaise, and confusion. She was found to have hypercalcemia, acute renal failure, and metabolic alkalosis. Upon further questioning, she reported use of large amounts of calcium carbonate tablets to treat recent heartburn symptoms. Calcium supplements were discontinued, and she was treated with intravenous normal saline. After 5 days, the calcium and bicarbonate levels normalized and renal function returned to baseline. In this article, we review the pathogenesis of the calcium-alkali syndrome as well as the differences between the traditional and modern syndromes. T he milk-alkali syndrome was originally described in the early 20th century when patients developed hypercalcemia, metabolic alkalosis, and renal failure after ingesting large quantities of milk, cream, and absorbable alkali to treat peptic ulcer disease (1, 2). For a period of time after the introduction of histamine-2 blockers and proton pump inhibitors, this syndrome was virtually eliminated. However, a new form of milk-alkali syndrome, that some have proposed should be called calcium-alkali syndrome, has more recently emerged as a relatively common cause for hypercalcemia and metabolic alkalosis (3). The calcium-alkali syndrome is caused in part by the ingestion of large quantities of calcium carbonate, which is available over the counter. The use of calcium carbonate has steadily increased as an antacid and as a calcium supplement to treat or prevent osteoporosis (3). We report a case of calciumalkali syndrome. CASE REPORT A 78-year-old Caucasian woman presented to the emergency department after falling and injuring her right arm. She complained of general malaise, weakness, and dizziness for sevProc (Bayl Univ Med Cent) 2013;26(2):179–181 eral days. She denied fevers, chills, weight changes, bone pains, dyspnea, chest pains, palpitations, or urinary symptoms. Her past medical history was significant for chronic obstructive pulmonary disease, hypertension, atrial fibrillation, and chronic kidney disease with a baseline creatinine of 1.3 mg/dL. Her regular medications included verapamil 180 mg twice daily, ramipril 5 mg daily, warfarin 5 mg daily, ibandronate 2.5 mg daily, and calcium with vitamin D over-the-counter supplements. The patient lived in an independent living facility. She had a previous 15 pack-year history of tobacco use but quit 17 years ago. She denied any alcohol or recreational drug use. On initial examination, her blood pressure was 215/90 mm Hg, pulse 100 beats/minute, respiratory rate 20 breaths/minute, and temperature 97°F. She was alert and oriented to person, place, and time; however, she was irritable, drowsy, and slow to answer questions. She had dry mucous membranes and poor skin turgor. Her chest was clear to auscultation bilaterally. On precordial examination, no murmurs were heard. Her abdomen was soft, nontender, and nondistended. Her extremities had full range of motion and normal strength. Initial laboratory results included hemoglobin, 16.2 g/ dL; hematocrit, 48.2%; sodium, 138 mEq/L; potassium, 4.2 mEq/L; chloride, 96 mEq/L; bicarbonate, 32 mEq/L; blood urea nitrogen, 35 mg/dL; creatinine, 2.9 mg/dL; calcium, 14.4 mg/dL; albumin, 4.0 g/dL; ionized calcium, 1.52 mmol/L; phosphorus, 5.2 mg/dL; intact parathyroid hormone, 21.0 pg/dL; thyroid-stimulating hormone, 2.66 microIU/L; free thyroxine, 1.26 ng/dL; and 25-hydroxy-vitamin D, 11.0 pg/dL. Serum and urine protein electrophoreses did not reveal any monoclonal proteins. Her chest radiograph was normal. Renal sonography showed bilateral increased echogenicity and cortical thinning, consistent with chronic renal disease. Upon further questioning, the patient reported that she had ingested about one bottle (>50 tablets) of calcium carbonate tablets (500 mg) over the previous 3 days to treat heartburn From the Department of Internal Medicine, Baylor University Medical Center at Dallas. Corresponding author: Mariangeli Arroyo, MD, Department of Internal Medicine, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, Texas 75246 (e-mail: Mariangeli.Arroyo@BaylorHealth.edu). 179 symptoms. During this time she also continued taking her regular calcium and vitamin D supplements. The diagnosis of calcium-alkali syndrome was made. Intravenous normal saline was administered, and all calcium and vitamin D supplements were discontinued. On day 2, the patient was more lucid, awake, and able to readily communicate. Calcium and creatinine levels dropped to 12.8 mg/dL and 2.7 mg/dL, respectively. On day 5, the calcium and bicarbonate levels were normal at 9.6 mg/dL and 27 mEq/L. The creatinine and blood urea nitrogen were at her baseline values of 1.3 mg/ dL and 16 mg/dL, respectively. The patient was educated on the proper use and dosing of all over-the-counter medications, including calcium and vitamin D supplements. She was discharged home on the fifth day of hospitalization. DISCUSSION The calcium-alkali syndrome is the third leading cause of hypercalcemia in hospitalized patients after primary hyperparathyroidism and malignant neoplasms (4). The current version of this syndrome has several biochemical and epidemiological differences from the traditional milk-alkali syndromes described in the early to mid 1900s. The historic conditions were more common in middle-aged men with peptic ulcer disease and were due to the hourly ingestion of sodium bicarbonate, magnesium carbonate, and bismuth subcarbonate (“Sippy Powder”) together with cream and milk. In 1949, Burnett et al described a chronic, more persistent variant of this disorder (5). The introduction of histamine-2 receptor blockers (in 1976) and proton pump inhibitors (in 1989) to block acid secretion, as well as treatments directed at eradicating Helicobacter pylori, virtually eliminated the classic acute and chronic forms of the milk-alkali syndrome. Over the last several decades, the “modern” version was recognized. This form more commonly affects postmenopausal women who ingest large amounts of calcium supplements, sometimes together with vitamin D and occasionally with thiazide diuretics to prevent or treat osteoporosis (6–8). It has also occurred in transplant patients taking high doses of calcium carbonate to prevent osteoporosis related to chronic steroid use (6). The use of calcium-containing antacids to treat dyspepsia also may occur, as was the case in the current report. It has been suggested that the modern syndrome be called the calcium-alkali syndrome because it is due to ingestion of soluble calcium salts instead of milk, cream, and the other alkali sources listed above (3). The calcium-alkali syndrome, similar to the traditional version, is characterized by hypercalcemia, metabolic alkalosis, and renal injury. However, serum phosphorus levels were usually high in the historic forms due to the high phosphorus load from cream and milk and the development of acute and chronic renal injury. The current calcium-alkali syndrome more typically presents with a normal or even low serum phosphorus concentration resulting from the dietary phosphate-binding properties of calcium carbonate (6–8). Although serum vitamin D is usually suppressed in patients with calcium-alkali syndrome, it may be normal or even 180 increased if vitamin D supplements have contributed to the disorder (8). Serum parathyroid hormone levels, which would be expected to be low, are sometimes normal. This may be due to renal insufficiency or related to a rapid fall in serum calcium soon after initiation of aggressive intravenous saline infusion (7). The pathogenesis of calcium-alkali syndrome involves the interplay of multiple organ systems, including bone, intestines, and the kidney. The ingestion of large amounts of calcium-containing compounds increases intestinal absorption of calcium and causes hypercalcemia. Hypercalcemia will constrict the renal arterioles, reduce the glomerular filtration rate, and decrease renal calcium excretion (9). Calcium-sensing receptors (CaSRs) are located in many tissues throughout the body, including the renal tubules, the intestines, and the parathyroid and thyroid glands. When high calcium levels activate the CaSRs in the thick ascending loop of Henle, sodium chloride reabsorption at this site is inhibited, causing diuresis and increasing renal calcium excretion (i.e., a loop diuretic-like effect). This effect also contributes to volume depletion and metabolic alkalosis (10). CaSRs are also present on the luminal membrane of the distal convoluted tubules, and activation of these receptors (by high renal tubule calcium concentrations) increases calcium reabsorption via TRVP5 channels (10). In addition, CaSRs are found on the luminal membranes of the collecting duct cells, and their activation reduces expression of aquaporin 2 water channels. This reduces renal tubule water reabsorption and causes the excretion of dilute urine (10). The net effect is a salt and water diuresis with variable impact on renal calcium excretion. Metabolic alkalosis helps to perpetuate this cycle by increasing the affinity of the CaSRs to calcium, which enhances the natriuresis. An alkaline pH also stimulates the activity of an important calcium selective receptor called the transient receptor potential vanilloid member 5 (TRPV5); this enhances calcium reabsorption and leads to worsening hypercalcemia (10, 11). To the extent hypercalcemia suppresses serum parathyroid hormone, renal bicarbonate reabsorption is promoted. Additionally, hypercalcemia may generate nausea and vomiting, which worsens the volume depletion and alkalosis (9). The diagnosis of calcium-alkali syndrome should be considered when a patient presents with acute renal injury, metabolic alkalosis, hypercalcemia, and a history of excessive calcium (± vitamin D) intake. Generally, the first and most important treatment for calcium-alkali syndrome is extracellular volume expansion with intravenous saline. This will hopefully improve renal function and increase renal calcium and bicarbonate excretion. It is also essential to identify all calcium salt and vitamin D–containing medications that the patient is taking and to provide education about appropriate dosing. It may be difficult to determine the appropriate dose of calcium salts for a given patient. The syndrome has been reported after ingestion of doses as low as 1 g of elemental calcium daily (11). However, most reported cases of the syndrome document ingestion of at least 4 g of elemental calcium per day. Although a daily intake of 2 g of calcium is considered safe for the general population, smaller doses of 1.2 to 1.5 g daily should be used when patients Baylor University Medical Center Proceedings Volume 26, Number 2 have risk factors that increase their likelihood of developing the calcium-alkali syndrome (3, 8, 9). For example, the elderly and patients with chronic kidney disease are more susceptible because they will have a lower glomerular filtration rate and decreased calcium clearance (9, 11). Additionally, the skeleton of elderly subjects does not buffer calcium loads as well as that of younger subjects (9). Thiazide diuretic use may also predispose to the development of this condition by enhancing renal tubule calcium absorption and by promoting volume depletion and alkalosis. Furthermore, any medications that reduce glomerular filtration rate, such as nonsteroidal antiinflammatory drugs and angiotensin-converting enzyme inhibitors, can contribute to the development of the syndrome (9). 1. 2. 3. Hardt LL, Rivers AB. Toxic manifestations following the alkaline treatment of peptic ulcer. Arch Intern Med 1923;31(2):171–180. Cope CL. Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies. Clin Sci 1936;2:287–300. Patel AM, Goldfarb S. Got calcium? Welcome to the calcium-alkali syndrome. J Am Soc Nephrol 2010;21(9):1440–1443. April 2013 4. Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. Medicine (Baltimore) 1995;74(2):89–96. 5. Burnett CH, Commons RR, Albright F, Howard JE. Hypercalcemia without hypercalciuria or hypophosphatemia, calcinosis and renal insufficiency: a syndrome following prolonged intake of milk and alkali. N Engl J Med 1949;240(20):787–794. 6. Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffman AR. Milkalkali syndrome in patients treated with calcium carbonate after cardiac transplantation. Arch Intern Med 1986;146(10):1965–1968. 7. Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: a historical review and description of the modern version of the syndrome. Am J Med Sci 2006;331(5):233–242. 8. Medarov BI. Milk alkali syndrome. Mayo Clin Proc 2009;84(3):261– 267. 9. Felsenfeld AJ, Levine BS. Milk alkali syndrome and the dynamics of calcium homeostasis. Clin J Am Soc Nephrol 2006;1(4):641–654. 10. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol 2010;298(3):F485–F499. 11. Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf ) 2005;63(5):566–576. The calcium-alkali syndrome 181 Hepatitis C and recurrent treatment-resistant acute ischemic stroke Aneeta Saxsena, MD, Joseph Tarsia, MD, Casey Dunn, MD, Aimee Aysenne, MD, Basil Shah, MD, and David F. Moore, MD, PhD Since the introduction of recombinant tissue plasminogen activator and thrombolysis, acute ischemic stroke has become a treatable disorder if the patient presents within the 4.5-hour time window. Typically, sporadic stroke is caused by atherosclerotic disease involving large or small cerebral arteries or secondary to a cardioembolic source often associated with atrial fibrillation. In the over-65-year age group, more rare causes of stroke, such as antiphospholipid syndromes, are unusual; such stroke etiologies are mostly seen in a younger age group (<55 years). Here we describe acute ischemic stroke in three patients >65 years with hepatitis C–associated antiphospholipid antibodies. We suggest that screening for antiphospholipid disorders in the older patient might be warranted, with potential implications for therapeutic management and secondary stroke prevention. T he risk factors for ischemic stroke have been well categorized by major epidemiological studies, such as the Framingham population-based study established in the 1950s. Such epidemiological studies particularly highlight modifiable risk factors of ischemic stroke such as hypertension, diabetes mellitus, smoking, alcohol usage, and dyslipidemia. The contribution of other risk factors for ischemic stroke, such as hypercoagulable states, is typically found in persons <55 years old (1). The typical antiphospholipid patient with acute ischemic stroke is a young woman of childbearing age with recurrent miscarriages (2). The etiology of stroke is customarily defined according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, with the presumption that the main attributable stroke risk factors are derived in the general stroke population from the presence of atherosclerotic vascular disease (3). The occurrence of other modifiable risk factors in the multifactorial etiology of acute ischemic stroke is an area of active study. In this report, we present three patients >65 years where we found an association between hepatitis C and the occurrence of antiphospholipid antibodies more typically found in younger patients. CASE REPORTS In all patients, coagulation screens were performed, including factor 8, homocysteine, antiphospholipid, factor V Leiden, antithrombin III, Russell viper venom assay, and protein C and 182 S. Only the antiphospholipid screen was found to be abnormal in our patients. The Table summarizes patient demographic data and results of the antiphospholipid screens. Case 1 Six months prior to his third hospital admission, a 72-yearold right-handed African American man presented with a past medical history of hyperlipidemia and a 2-day history of left leg weakness, dizziness, and left-sided facial numbness with a National Institutes of Health Stroke Scale (NIHSS) score of 3. Evaluation for acute stroke with diffusion-weighted magnetic resonance imaging (MRI) demonstrated a subacute lesion in the right posterior internal capsule. The extended symptom time course precluded use of recombinant tissue plasminogen activator (rt-PA) or another neurovascular intervention. The patient was admitted to address secondary stroke prevention and was found to have a cholesterol of 142 mg/dL; high-density lipoprotein cholesterol of 9 mg/dL; low-density lipoprotein cholesterol of 71 mg/dL; triglycerides of 639 mg/dL; cardiac ejection fraction of ~60%; regular cardiac rhythm; and no persistent foramen ovale or pulmonary hypertension. In addition, blood cultures showed no growth, and cerebral computed tomographic angiography showed minimal atherosclerotic disease in the carotid bulbs with a hypoplastic left vertebral artery. A diagnosis of small vessel stroke was made and the patient was encouraged to be more compliant with his hypertension regime and adopt a heart and stroke–healthy diet together with smoking cessation. Secondary prevention therapy included lisinopril, aspirin, and atorvastatin. An albumin-immunoglobulin protein gap was noted, and the patient was subsequently screened and diagnosed with hepatitis C; he was referred to gastroenterology for further evaluation. Approximately 5 months later, the patient presented with sudden onset of right facial numbness, slurred speech, and right From the Department of Neurology (Saxsena, Tarsia, Dunn, Aysenne) and Department of Radiology (Shah), Tulane University Medical Center, New Orleans, Louisiana; and the Baylor Neuroscience Center, Baylor University Medical Center at Dallas (Moore). Corresponding author: David F. Moore, MD, PhD, FAAN, Baylor Neuroscience Center, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: davidf.moore@BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2013;26(2):182–184 he received rt-PA with a doorto-needle time of approximately 2.5 hours. Since his NIHSS score Variable Case 1 Case 2 Case 3 was estimated to be 19 and he was Age (years) 72 67 65 noted to be in atrial fibrillation, his stroke was presumed to have a Blood pressure (mm Hg) treated 147/74 treated 140/90 189/100 cardioembolic etiology. A diffusionNIHSS score 3 19 5 weighted MRI after administration Total cholesterol (mg/dL) 142 141 146 of rt-PA showed a small ischemic LDL cholesterol (mg/dL) 71 92 85 area in the right posterior parietal HDL cholesterol (mg/dL) 9 47 25 cortical area. The patient was discharged on warfarin with a theraTriglycerides (mg/dL) 639 57 219 peutic INR goal of 2 to 3. Smoker 1–3 packs/day 1–2 packs/day N/A Over the next 6 months, the Hemoglobin A1C (%) <4.5 <3.5 10.7 patient’s warfarin regime was difIgM anticardiolipin antibody (0–12 MPL U/mL)* 13 <9 13 ficult to maintain within goal deIgG anticardiolipin antibody (0–14 GPL U/mL)* spite patient adherence. The patient 21 12 20 then presented with a further acute IgA anticardiolipin antibody (0–11 APL U/mL)* 31 10 <9 ischemic stroke episode with inIgM β-2 glycoprotein (GPI IgM units) <9 <9 9 creased left-sided weakness and IgG β-2 glycoprotein (GPI IgG units) <9 <9 <9 problems with gait and balance over IgA β-2 glycoprotein (GPI IgA units) 18 <9 10 a 3- to 4-day period. MRI demonIgM phosphatidylcholine (0–25 MPS IgM)* 29 6 23 strated a new lesion in the left cerIgG phosphatidylcholine (0–11 GPS IgG)* 7 48 24 ebellar hemisphere, together with a IgA phosphatidylcholine (0–20 APS IgA)* 21 10 1 lesion in the right parieto-occipital region and a further lesion on the *Units indicate the value showing absence (versus low, moderate, or high positivity). left frontal area. The patient’s INR HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; NIHSS, National Institutes of Health at the time of presentation was 1.7, Stroke Scale. and a diagnosis of cardioembolic stroke secondary to chronic atrial arm and leg weakness. These symptoms were confirmed on fibrillation was again made. The patient’s warfarin regime was physical examination. Presentation to the emergency room was discontinued, and he was started on dabigatran. outside the 4.5-hour window, and thrombolysis with rt-PA was Approximately 2 months after this admission, the patient not administered. Diffusion-weighted MRI was positive for a presented with a generalized tonic-clonic seizure, and epilepsy left thalamic lacunar stroke, again consistent with small vessel secondary to ischemic stroke structural damage was diagnosed. disease. The patient’s final admission was due to statin-induced The patient was started on antiepileptic drugs and at that time rhabdomyolysis and an associated pancreatitis. During this adwas also noted to have an albumin-immunoglobulin protein mission, the patient’s creatinine kinase was >8000 mcg/L with gap. Screens for hepatitis and HIV were performed with the an elevated aspartate transaminase of 1735 IU/L and an alanine patient’s consent. The hepatitis C screen returned positive, and transaminase of 395 IU/L. Diffusion-weighted MRI was cona full gastroenterology workup was performed. As part of an sistent with no new acute ischemic stroke and represented T2 extended workup for etiological factors associated with the “shine through.” During the final admission, the patient was patient’s stroke, antiphospholipid screening was performed. examined for a hypercoagulable state and was found to have Antiphosphatidylcholine IgG returned elevated at 48. The paelevated values for several antiphospholipid antibodies: IgM tient was continued on dabigatran, with the introduction of anticardiolipin, 13; IgA anticardiolipin, 31; IgA phosphatidylaspirin 81 mg daily as part of his secondary stroke prevention choline, 21; and IgM phosphatidylcholine, 29. The patient was regime. started on warfarin for antiplatelet failure and has not had any further acute ischemic strokes on extended warfarin therapy Case 3 for 12 months with an international normalized ratio (INR) A 65-year-old right-handed Caucasian man with a history goal of 2 to 3. of hypertension, dyslipidemia, posttraumatic stress disorder, and hepatitis C contracted during service in Vietnam was admitted Case 2 with significant left-sided weakness affecting the face, arm, and A 67-year-old right-handed African American man with leg. The patient initially presented at an out-of-state hospital and a past medical history of hypertension presented to the emerwas not treated with rt-PA. Computed tomography and MRI gency department with sudden onset of weakness on the left showed ischemic lesions in the right parietal area. The patient side of his body. Since he was within the 4.5-hour window, underwent angiographic evaluation and a stent placement in Table 1. Patient demographics and antiphospholipid screen in the three described male patients April 2013 Hepatitis C and recurrent treatment-resistant acute ischemic stroke 183 the right M1 branch of the middle cerebral artery for a critical large vessel stenosis. The stroke was believed to be caused by large vessel disease, and the patient was continued on aspirin 325 mg and clopidogrel 75 mg once daily for secondary stroke prevention. The patient was found to have elevated anticardiolipin antibody at IgG 20, anticardiolipin antibody at IgM 13, and antiphosphatidylcholine at IgG 24. DISCUSSION We present a single-center observational case series of hepatitis C and antiphospholipid antibody positivity in the older stroke patient population (>65 years) that altered therapeutic management from antiplatelet therapy to warfarin in two cases and from warfarin to dabigatran in one case. Screening for antiphospholipid antibodies is not part of the usual clinical workup for modifiable stroke risk factors in those >65 years, although it is well described as an independent risk factor for acute ischemic stroke in those <55 years. We suggest that in patients with hepatitis C and acute ischemic stroke, such screening may have a higher yield than in the <55-year demographic. There are limited references reporting hepatitis C–associated antiphospholipid antibodies and stroke, and most consist of incidental case reports (4–6). One case report described a 43-year-old woman with ischemic stroke, while a further case report described a 54-year-old man with chronic hepatitis C and antiphospholipid-positive serology and ischemic stroke. Of interest, the treatment of hepatitis C with interferon appeared to contribute to the patient’s remission from further ischemic stroke events (6). The only case-control patient series came from a Romanian publication, where 58 patients (age range 46–77 years, mean 62 years; 39 women and 19 men) were found to have a higher prevalence (P < 0.001) of antiphospholipid antibodies in the hepatitis C–positive group with stroke compared to age- and sex-matched controls (5). The presence of antiphospholipid antibodies is known to contribute to the development of acute ischemic stroke. Our small 184 observational case series suggests that no particular type of stroke is favored, since we had patients with both small- and large-vessel disease together with cardioembolic stroke. The additional risk of antiphospholipid-positive serology should suggest optimization of antiplatelet therapy and possibly extension of therapy to anticoagulation with warfarin or direct thrombin inhibitors such as dabigatran. The control of hepatitis C virus expression through interferon therapy is a further therapeutic consideration in these patients and may reduce the risk of stroke (5). Our patients were all noted to have an elevated albumin-immunoglobulin protein gap, suggesting that there is an abnormal immune response to hepatitis C. The infection of vascular endothelial cells by hepatitis C may result in the exposure of previously nonimmunogenic antigens to immunocompetent cells, promoting endothelial dysfunction and potential stroke. However, dysregulation of hepatic synthetic function following hepatitis C infection may also be an important etiologic consideration. 1. 2. 3. 4. 5. 6. Wolf PA, Kannel WB. Epidemiology of stroke. In Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, eds. Stroke: Pathophysiology, Diagnosis and Management. Philadelphia: Saunders Elsevier, 2011:198–218. Coull BM, Drake K. Coagulation abnormalities in stroke. In Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, eds. Stroke: Pathophysiology, Diagnosis and Management. Philadelphia: Saunders Elsevier, 2011:772–789. Gordon DL, Bendixen BH, Adams HP Jr, Clarke W, Kappelle LJ, Woolson RF; TOAST Investigators. Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. Neurology 1993;43(5):1021–1027. Rafai MA, Fadel H, Gam I, Hakim K, El Moutawakkil B, Kissani N, Slassi I. Recurrent stroke revealing catastrophic antiphospholipid syndrome with hepatitis C viral infection [article in French]. Rev Neurol (Paris) 2006;162(11):1131–1134. Cojocaru IM, Cojocaru M, Iacob SA. High prevalence of anticardiolipin antibodies in patients with asymptomatic hepatitis C virus infection associated acute ischemic stroke. Rom J Intern Med 2005;43(1–2):89–95. Malnick SD, Abend Y, Evron E, Sthoeger ZM. HCV hepatitis associated with anticardiolipin antibody and a cerebrovascular accident. Response to interferon therapy. J Clin Gastroenterol 1997;24(1):40–42. Baylor University Medical Center Proceedings Volume 26, Number 2 Diagnosis and management of delayed hemoperitoneum following therapeutic paracentesis Morgan J. Katz, MD, Matthew N. Peters, MD, John D. Wysocki, MD, and Chayan Chakraborti, MD Abdominal paracentesis is a frequently employed diagnostic and therapeutic procedure for patients with refractory ascites, typically in patients with cirrhosis. It is generally regarded as a safe procedure with significant complications occurring in <1% of cases. Most hemorrhagic complications are due to abdominal wall trauma, during which clear evidence of active bleeding is usually visualized during the procedure. Delayed hemoperitoneum is a rare complication of large-volume paracentesis in which clinical evidence of active bleeding is typically absent until substantial blood loss has taken place (often several days to a week later), leading to an exceedingly high mortality rate. Herein we describe a case of delayed hemoperitoneum in a 55-year-old man with heart failure. This case emphasizes the importance of identifying patients who are at high risk for delayed hemoperitoneum as well as the need to closely monitor complete blood counts in the days following a large-volume paracentesis. CASE DESCRIPTION A 55-year-old man presented with a 2-week history of worsening dyspnea and abdominal distention. He had atrial fibrillation, chronic heart failure (last known ejection fraction 25%), and chronic kidney disease. He reported nonadherence to his furosemide for 3 weeks. He had a massively tense and protruding abdominal wall and 3/4+ pitting lower extremity edema to his knees bilaterally. His international normalized ratio was 2.3 (on warfarin), serum creatinine 2.33 mg/dL (baseline: 2.0–3.0 mg/dL), and albumin 2.3 g/dL. Abdominal ultrasound revealed hepatomegaly without cirrhosis. Two doses of 80 mg intravenous furosemide led to minimal reduction of his abdominal ascites. A paracentesis under ultrasound guidance was performed in the left lower quadrant and yielded 5 L of clear, transudative fluid. No evidence of hematoma was noted, and the procedure provided immediate symptomatic relief. Three days later the patient began complaining of mild, diffuse abdominal discomfort. Over the previous 3 days his hemoglobin level had dropped from 8.4 to 6.9 g/dL. No evidence of gastrointestinal or genitourinary blood loss was noted. The patient, a Jehovah’s Witness, refused transfusion of any blood products and in the next 2 days his hemoglobin declined to 2.9 g/dL. A repeat diagnostic paracentesis was performed and showed 10 mL of blood-tinged fluid. The following day a tagged red blood cell scan indicated evidence of increased activity near the duodenum Proc (Bayl Univ Med Cent) 2013;26(2):185–186 and gastric antrum (Figure 1). An urgent upper endoscopy demonstrated no evidence of active upper gastrointestinal bleeding but did demonstrate a bluish hue on the posterior stomach wall, suggestive of a possible intraperitoneal or retroperitoneal bleed. Subsequent noncontrast computed tomography (CT) of the abdomen and pelvis showed likely hemoperitoneum localized to the mid-lower abdominal wall (Figure 2). An urgent epigastric and gastroduodenal angiogram did not reveal any evidence of active bleeding. The patient continued to refuse blood transfusion and was treated supportively with intravenous fluid and albumin infusions. Slight improvements in serum creatinine (3.6 mg/dL) and hemoglobin (4.1 g/dL) were noted. The patient refused any further intervention and was discharged to home hospice; he died 3 days later, 11 days after the initial paracentesis. DISCUSSION Large-volume paracentesis (>4 L) is a common bedside procedure utilized in patients with refractory abdominal ascites with Figure 1. Red blood cell scan tagged with Technetium-99m to evaluate for active gastrointestinal bleed shows increased activity in the region of the duodenum and the gastric antrum. From the Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana. Corresponding author: Morgan J. Katz, MD, 1430 Tulane Avenue, SL-50, New Orleans, LA 70112 (e-mail: katz.morgan@gmail.com). 185 poor response to diuretic therapy. The procedure is typically regarded as safe and carries a hemorrhagic complication rate of <1% (1, 2) (further reduced with ultrasound guidance and a left lower quadrant approach [3, 4]). When hemorrhagic complications occur, they are typically due to abdominal wall vessel puncture, with visible bleeding during the procedure (2). Consequently, many patients are discharged soon after the procedure and without close follow-up. Delayed hemoperitoneum is a rare hemorrhagic complication of large-volume paracentesis. The proposed mechanism is the large volume fluid removal, which results in a rapid drop in intraperitoneal pressure. This promotes a transient pressure gradient in the splanchnic circulation, promoting dilation and rupture of friable mesenteric varices (1, 5, 6). Due to slow venous bleeding rates, patients are often initially asymptomatic. The most commonly reported symptom is vague abdominal pain (1), which may be overlooked in patients with chronic ascites. Peritoneal signs typically do not occur until late stages (if at all), and any clinical signs of bleed may be absent until substantial blood loss has taken place as long as several days to a week later (1, 5). Consequently, patients have been known to present in hemorrhagic shock, and mortality rates are reported to exceed 70% (5). Given the rare occurrence of delayed hemoperitoneum, clinicians must be made aware of high-risk patient groups. Previously established risk factors include advanced cirrhosis with refractory ascites, history of previous large-volume paracentesis, and the appearance of retrograde mesenteric venous flow on ultrasound (due to the occurrence of large mesenteric collaterals, which are predisposed to rupture) (5). Additionally, an association between postparacentesis hemorrhagic complications and chronic kidney disease has also been noted (likely due to platelet dysfunction) (6). Surprisingly, no associations between coagulopathy and hemorrhagic complications of paracentesis have been shown, so there are currently no guidelines for either preprocedural coagulation parameters that contraindicate paracentesis or the prophylactic administration of fresh frozen plasma or platelets (3, 5). Previously described cases of delayed hemoperitoneum have not demonstrated evidence of intraprocedural abdominal wall trauma or other complications; thus, it is critical to recognize potential warning signs (1, 6). Complete blood counts should be closely monitored for a minimum of several days in high-risk groups, and once a notable drop in hemoglobin is detected, a diagnostic paracentesis should be performed to assess the presence of visible blood (5). If blood is detected on diagnostic paracentesis, an abdominal CT scan or ultrasound should be performed to evaluate for abdominal wall hematoma. In the absence of apparent hematoma formation, angiography should be strongly considered (5, 6). Initial management should focus on identification of a bleeding source with interim supportive management. Coagulopathies should be corrected, and patients should be fluid resuscitated with normal saline and packed red blood cells as needed (6). In the event of patient blood transfusion refusal (as in our case), albumin or artificial colloid solution should be given. Previously described successful interventions include portocaval shunting and embolization or surgical ligation of bleeding vessels (2, 5). Unfortunately, angiographic visualization of bleeding vessels is often difficult, and in the setting of hemodynamic instability, laparotomy may be needed for adequate visualization of the bleeding site (5). The most important preventative measure in delayed hemoperitoneum is daily monitoring of complete blood counts for a minimum of several days to ensure rapid detection and minimize blood loss (1, 5). Patients with underlying renal dysfunction may benefit from prophylactic transfusion of fresh frozen plasma or desmopressin acetate—a target of future studies (6). Finally, patients with risk factors for hemoperitoneum may benefit from either a lower-volume paracentesis, slower drainage of ascites, or concurrent administration of albumin to guard against rapid changes in the intraperitoneal pressure gradient (1). 1. 2. 3. 4. 5. 6. Figure 2. CT of the abdomen and pelvis without contrast reveals hemoperitoneum (arrows) localized to the lower left and middle quadrant. 186 Webster ST, Brown KL, Lucey MR, Nostrant TT. Hemorrhagic complications of large volume abdominal paracentesis. Am J Gastroenterol 1996;91(2):366–368. Martinet O, Reis ED, Mosimann F. Delayed hemoperitoneum following large-volume paracentesis in a patient with cirrhosis and ascites. Dig Dis Sci 2000;45(2):357–358. Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49(6):2087–2107. Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ, Kamath PS. Performance standards for therapeutic abdominal paracentesis. Hepatology 2004;40(2):484–488. Arnold C, Haag K, Blum HE, Rössle M. Acute hemoperitoneum after large-volume paracentesis. Gastroenterology 1997;113(3):978–982. Pache I, Bilodeau M. Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease. Aliment Pharmacol Ther 2005;21(5):525–529. Baylor University Medical Center Proceedings Volume 26, Number 2 Baylor news ■ Baylor, Scott & White sign agreement of intent to join forces, create new health system The boards of Baylor Health Care System (BHCS) and Scott & White Healthcare signed an agreement of intent to combine the strengths of their two health systems to create a $7.7 billion organization with the vision and resources to offer its patients continued exceptional care while creating a model system for an industry undergoing fundamental transformation. The alliance reflects a vision to create a new health system engineered to meet the demands of health care reform, the changing needs of patients and payers, and the extraordinary advances in clinical care. With approval of the agreement of intent, the organizations have entered a period of exclusive negotiations and due diligence. The next stage in the transaction—a definitive agreement—is anticipated to be complete in 2013. The new system, named Baylor Scott & White Health, would include the organizations’ combined 42 hospitals, more than 350 patient care sites, more than 4000 active physicians, 34,000 employees, and the Scott & White Health Plan. It would be the largest not-for-profit health system in Texas and one of the largest in the United States. It would be governed by a single board with equal representation from both founding members. “Baylor has a century-long tradition of quality, innovation, and service. And in this time of great change in the health care industry, Baylor is looking forward and preparing to once again lead by joining forces with Scott & White to ACCOLADES Paul Grayburn, MD, of the Baylor Heart and Vascular Institute received the Simon Dack Award for Outstanding Scholarship from the Journal of the American College of Cardiology. Becker’s Hospital Review included the Jack and Jane Hamilton Heart and Vascular Hospital in its “100 Hospitals with Great Heart Programs” list. Hospitals included on the list offer outstanding heart care, and the Becker’s editorial team selected them based on clinical accolades, recognition for quality care, and contributions to the field of cardiology and cardiovascular surgery. Proc (Bayl Univ Med Cent) 2013;26(2):187–190 create this new model of care,” said Joel Allison, president and CEO, BHCS. “Scott & White is a perfect partner for us as it is nationally known for its high-quality, efficient care. Our proposed new organization reflects many months of discussion between our two like-minded systems on how we could work together to continue to meet the needs of the communities we serve in this dramatically changing environment. The new organization will continue to honor and carry forward Baylor’s 100-plus-year legacy as a Christian ministry of healing.” “Our new organization will not only prepare us for health care reform but will help drive and shape what health care delivery in this country will become,” said Robert Pryor, MD, president and CEO, Scott & White Healthcare. “Scott & White has been recognized as a national leader for our strong physician-led population health model. Our shared vision with Baylor is to build upon our unique approach and create an innovative health care delivery model enhanced by medical education and research.” Both organizations are affiliated with Texas A&M Health Sciences Center and have extensive investments in medical education and research. Baylor Scott & White Health will have the ability to expand training opportunities for the next generation of health care professionals by integrating education programs at both organizations. Some details of the agreement of intent: • Unified board: A unified board of trustees will comprise 14 individuals, with an equal number of representatives from each institution. Drayton McLane Jr., the chair of the Scott & White board of trustees, will serve as chair of the new organization’s board. Jim Turner, the chair of the BHCS board of trustees, will serve as chair-elect of the new organization’s board. • Leadership: The new organization will be led by a single executive leadership team. Joel Allison will serve as chief executive officer of the new company. Dr. Robert Pryor will serve as president and chief operating officer of the new organization. • Operations: The new system will have two operating divisions, which will consolidate over time. The Scott & White division will be headquartered in Temple, and the Baylor division will be headquartered in Dallas. • Brands: The new organization will be called Baylor Scott & White Health. Both Baylor and Scott & White will retain their individual brand names. • Foundations: The foundations will remain separate. • Medical staffs: The medical staffs will remain independent. “This partnership is the right thing for Baylor. It’s the right thing for Scott & White. And, it’s the right thing for our communities,” said Drayton McLane Jr., chair of the Scott & White board of trustees. “Both health systems are wellorganized, well-run, best-in-class organizations. We can learn from each other, and I think this only benefits the patients we serve by allowing us to deliver better quality care and increased access to care.” For patients, the new organization will ultimately mean • Greater, more convenient access to highquality care through an extensive network of physicians, advanced practice professionals, medical centers and hospitals throughout North and Central Texas • Increased coordination of patient care • Improved patient outcomes, by combining the expertise of primary care physicians and medical specialists and adopting the best practices of both organizations • The ability to attract, retain, and train the very best national and international talent • Greater access to world-class primary and pediatric care and centers of excellence in cardiology, oncology, transplant, rehabilitative medicine, and other specialties “Together, our two health systems will cover two geographically diverse areas that are nearly contiguous and highly complementary,” said Jim Turner, chair of the BHCS board of trustees. “We strongly believe our neighboring geographies will allow us to be well positioned to lead the transformation of health care in Texas and beyond.” ■ Introducing the Baylor Charles A. Sammons Cancer Center Network For the past 2 years, Baylor medical centers throughout North Texas have been working to achieve the distinction of using the Baylor Sammons Cancer Center name for their oncology programs by meeting or exceeding the stringent criteria established by BHCS. In addition to the 187 RECENT GRANTS • JC virus and human colorectal neoplasia Principal investigator: C. Richard Boland, MD Sponsor: National Cancer Institute Funding: $267,374 Award period: 2/1/2013–8/1/2013 • Glycemia reduction approaches in diabetes: a comparative effectiveness study Principal investigator: Priscilla Hollander, MD Sponsor: George Washington University/ National Institute of Diabetes and Digestive and Kidney Diseases Funding: $186,241 Award period: 1/1/2013–7/31/2013 • Molecular mechanisms of pDC interactions Principal investigator: Yong-Jun Liu, MD Sponsor: MD Anderson Cancer Center/ National Cancer Institute Funding: $313,600 Award period: 9/1/2012–8/31/2013 • Expanding the impact of the Baylor Health Care system delirium research program Principal investigator: Andrew Masica, MD Sponsor: The Discovery Foundation Funding: $36,080 Award period: 12/4/2012–6/15/2015 • The high value healthcare collaborative: engaging patients to meet the triple aim Principal investigator: Andrew Masica, MD Sponsor: Dartmouth College/Centers for Medicare and Medicaid Services Funding: $176,952 Award period: 7/1/2012–6/30/2013 • Enhancing clinical effectiveness research with natural language processing EMR Principal investigator: Andrew Masica, MD Sponsor: Kaiser Foundation Research Institute Funding: $209,336 Award period: 9/30/2012–9/29/2013 • Vaccination with IL-15 dendritic cells to generate melanoma-specific protective memory T cells Principal investigator: A. Karolina Palucka, MD Sponsor: National Cancer Institute Funding: $230,897 Award period: 2/1/2013–1/31/2014 • Role of mucosal DC subsets in the control of influenza A virus immunity Principal investigator: A. Karolina Palucka, MD Sponsor: Mt. Sinai School of Medicine/ National Institute of Allergy and Infectious Diseases Funding: $74,000 Award period: 7/15/2012–6/30/2013 • MIRA—Cellular therapy for cancer (C1) Principal investigator: A. Karolina Palucka, MD original Baylor Charles A. Sammons Cancer Center at Dallas, six other BHCS facilities are now Sammons Cancer Centers: • Baylor Charles A. Sammons Cancer Center at Fort Worth • Baylor Charles A. Sammons Cancer Center at Irving • Baylor Charles A. Sammons Cancer Center at Garland • Baylor Charles A. Sammons Cancer Center at Grapevine • Baylor Charles A. Sammons Cancer Center at Plano • Baylor Charles A. Sammons Cancer Center at Waxahachie The cancer programs at the two newest hospitals in the health care system—Baylor Medical Center at Carrollton and Baylor Medical Center at McKinney—are well on their way to achieving accreditation and designation. Each BHCS institution that wanted to join the network had to submit a request to BHCS oncology leadership showing its readiness. To qualify, they had to be accredited by the Commission on Cancer of the American College of Surgeons as an approved cancer program. They also had to demonstrate active participation in a number of areas, including BHCS oncology strategic initiatives; oncology safety and health care improvement projects; oncology educational efforts in nursing, medicine, or other ancillary education related to oncology; and research initiatives, either within the facility or by supporting other Baylor facilities and their oncology research by making clinical trials available to patients, regardless of the location of the trials. After a 188 Baylor University Medical Center Proceedings • • • • Sponsor: Baylor College of Medicine/Cancer Prevention and Research Institute of Texas Funding: $46,303 Award period: 7/1/2012–6/30/2013 MIRA—Cellular therapy for cancer (C2) Principal investigator: A. Karolina Palucka, MD Sponsor: Baylor College of Medicine/Cancer Prevention and Research Institute of Texas Funding: $102,612 Award period: 7/1/2012–6/30/2013 North Texas Hepatitis B Consortium: clinical site for the Hepatitis B network Principal investigator: Robert Perrillo, MD Sponsor: UT Southwestern Medical Center Funding: $114,527 Award period: 6/1/2012–5/31/2013 Role and function of prohibitin in intestinal inflammation Principal investigator: Arianne L. Theiss, MD Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases Funding: $146,459 Award period: 2/1/2013–1/31/2014 A novel replication competent flavivirus-based HIV vaccine platform, i.e. RepliVax, as a priming component for improving antibody response Principal investigator: Gerard Zurawski, MD Sponsor: Centre Hospitalier UV/Gates Foundation Funding: $92,222 Award period: 9/6/2012–8/31/2015 determination that all criteria have been met, the Baylor facility has the distinction of using the Baylor Charles A. Sammons Cancer Center name. Patients will be the major beneficiaries of the Baylor Sammons Cancer Center network. When initially deciding upon a treatment center, they will have the assurance that any institution carrying the Baylor Sammons brand will offer quality cancer care. By receiving care at a Baylor Charles A. Sammons Cancer Center, patients can be treated close to home for most of their cancer care needs. Vikas Aurora, MD, hematologist and medical oncologist on the medical staff as well as the chairman of the Cancer Committee at Baylor Grapevine, is excited about the growth of the program. “We are working to be at the forefront Volume 26, Number 2 of community cancer care by integrating physician and nurse enthusiasm with administrative support,” he said. “It takes time and resources to fuel growth but we have it here, with the strong support of Baylor Health Care System.” Rather than having to “reinvent the wheel” at each site to develop new treatment options or patient outreach programs, physician leaders from each institution can come to the quarterly BHCS Oncology Council to share ideas and best practices with colleagues at their sister facilities. A program that has been developed and perfected at one center can be used as a model at other sites. Cooperation among cancer centers can bring the strength of numbers to bear on conducting new clinical trials that make innovative treatment options available to patients. ■ Ultragenyx announces in-licensing of clinical-stage product from Baylor Research Institute Ultragenyx Pharmaceutical Inc., a biotechnology company focused on the development of treatments for rare and ultrarare genetic disorders, announced on January 10, 2013, that it has in-licensed rights for triheptanoin, a promising treatment for long-chain fatty acid oxidation disorders, from Baylor Research Institute (BRI), the research arm of BHCS. “It is gratifying to see the fruits of everyone’s labor as this agreement moves forward,” said Dr. Raphael Schiffmann, director of BRI’s Institute of Metabolic Disease. “Staff have put a lot of time and effort into the study of triheptanoin UPCOMING CME PROGRAMS The A. Webb Roberts Center for Continuing Education of Baylor Health Care System is offering the following programs: Urology Update 2013 with Clinical Cases in Oncology, April 5–6, 2013, at BUMC Wound Care: The Next Generation, April 27, 2013, at BUMC Fourth Annual Latest Advances in Ischemic and Hemorrhagic Stroke Therapy Conference, May 18, 2013, at Westin Galleria Dallas 40th Annual Williamsburg Conference on Heart Disease, December 8–10, 2013, at the Williamsburg Conference Center, Williamsburg, Virginia For more information, call 214-820-2317 or visit www.cmebaylor.org. and its use for fat oxidation and glycogen storage diseases, among others. Triheptanoin has a potential benefit for these disorders and others with an underlying energy deficit, many of which do not have adequate therapy. We are confident that Ultragenyx will advance triheptanoin therapy for the benefit of these patients in the US and abroad.” donates mobile clinic to local charity Less than a month after opening its doors in October 2012, the Avenue F Family Health Center, one of the first charity care clinics in Collin County, was quickly running out of space. That’s when leaders at Baylor Medical Center at Garland stepped in with a solution, donating a fully functioning mobile clinic on wheels. The vehicle had been unused for a number of years. “We are thrilled to be able to help Avenue F Family Health Center with this donation. It truly is a win-win situation for everyone involved. The mobile clinic van will allow the organization to reach more patients in need within the community and continue to honor Baylor’s mission to serve all people through exemplary healthcare,” said Tom Trenary, president, Baylor Medical Center at Garland. The Avenue F Family Health Center serves patients who are uninsured and live in the 75074 and 75075 zip codes of Plano, with a particular focus on the Douglass and East Plano communities. The clinic is open 5 days a week but visits with the physician are currently available only on Mondays and Wednesdays. Avenue F Church of Christ serves as the current location of the clinic and founding institution of AFFECT, Inc. The mobile clinic van will be parked on the church campus and used as the interim home of the clinic until a permanent physical space is transform lives and the communities we serve. To date, more than $160 million has been raised toward the $250 million goal, including transformational gifts from the men and women of Sammons Enterprises, Inc., Annette C. and Harold C. Simmons, and T. Boone Pickens. “We are grateful for the support our community has already shown and encouraged by the momentum we have,” said Rowland K. Robinson, Foundation president. “We are proud that we have made it two thirds to our goal, but we have not yet met our challenge.” Completely donor-driven, this comprehensive campaign focuses on four priorities—capital, education, research, and programmatic initiatives at Baylor—and offers significant opportunity to redefine health care, both locally and nationally. Donors can determine where they wish to make an impact and give to the area for which they have the greatest passion. With increased community support, we can develop innovative models of care, utilize advanced medical technology, engage in game-changing research, and train more physicians to care for future generations. While Baylor has already earned national recognition for safety, quality, leadership, and bedside care, sustaining this level of excellence requires more than stewardship; it requires investment and innovation. “With your partnership and support, we can maintain Baylor’s steadfast commitment to excellence and secure the future of health care for our community,” said Joel Allison, president and chief executive officer of BHCS. For more information, visit Give. BaylorHealth.com. ■ Baylor Medical Center at Garland PHILANTHROPY NOTES ■ Baylor Foundation launches $250 million campaign BHCS Foundation formally launched the first comprehensive campaign in Baylor’s history with an event at the AT&T Performing Arts Center’s Wyly Theatre on February 27. The $250 million fundraising effort—Campaign 2015: Baylor Makes Us All Better—marks Baylor’s most ambitious fundraising effort to date and is designed to strengthen every aspect of Baylor, from patient-centered programs and capital needs to innovative research and medical education. The simple phrase, “Baylor Makes Us All Better,” was the impetus for a bold vision: take BHCS to national preeminence in areas of health care that have the power to April 2013 Baylor news 189 located and built. Once that goal is achieved, the mobile unit will travel around Plano and Dallas to help meet the needs of uninsured and underinsured individuals in those communities. ■ Five Baylor hospitals chosen to pioneer state project to improve breastfeeding rates Despite the benefits of breastfeeding, Texas has one of the lowest breastfeeding rates in the US, with only 13.7% of Texas mothers exclusively breastfeeding for 6 months. Five BHCS hospitals—Baylor All Saints Medical Center, Baylor Medical Center at Carrollton, Baylor Medical Center at McKinney, Baylor Regional Medical Center at Grapevine, and Baylor University Medical Center at Dallas—were recently chosen to join a 190 pioneering group of hospitals hoping to reverse this trend. They are among 20 hospitals/facilities in North Texas selected to be part of the “Texas Ten Step Star Achiever Breastfeeding Learning Collaborative,” a 5-year quality improvement project designed to improve facility environments to better support a mother’s choice to breastfeed. What distinguishes this new project is collaboration. What these hospitals learn will be shared among other participants, helping more mothers across the state become more successful in exclusively breastfeeding their babies. ■ Baylor Irving awarded advanced certification for primary stroke centers The Joint Commission, in conjunction with the American Heart Association/American Baylor University Medical Center Proceedings Stroke Association, has awarded Baylor Medical Center at Irving Advanced Certification for Primary Stroke Centers. This certification demonstrates that the program meets critical elements of performance to achieve longterm success in improving outcomes for stroke patients. “This designation has given us the opportunity to highlight the quality stroke care we provide for our patients,” said Cindy Schamp, president, Baylor Irving. “In collaboration with the emergency department physicians on our medical staff and our staff, we remain poised and ready to serve the residents who present in our hospital with signs and symptoms of stroke.” Volume 26, Number 2 An underappreciated problem with auscultation Allen B. Weisse, MD W hen it comes to the depiction of the medical world on the motion picture screen or on television, you can count me out. The errors and inconsistencies that pop up there are more than this observer can tolerate. A story set in the 1930s or 1940s meticulously observes the clothing, furniture, and even automobile models of the period. Then, when a senior physician appears, he is not wearing a long white laboratory coat appropriate to his position but, rather, a short white jacket, more properly worn by medical students and junior houseofficers. We are shown a scene in an examining room or operating suite, and there on the x-ray view box is the chest film of the patient—inserted backwards. (And no, Virginia, the story is not about an outbreak of situs inversus.) On the popular series ER, we witnessed junior residents in the emergency room performing all kinds of sophisticated diagnostic and therapeutic procedures short of open heart surgery. Then there was Dr. House, showing up week after week badly in need of a shave, a haircut, and, possibly, delousing judging from his appearance. The only thing more distasteful than that was his personality. When he strode with impunity into an isolation unit, alarms should have gone off rather than the welling up of stirring background music. How this character became an icon simply baffles me. Complaining about such misrepresentations as these might be called nitpicking. They are clearly in the realm of fiction. There is another example of malpractice in the world of make believe that, unlike the other transgressions, extends into the real world. What I refer to is the practice of attempting to auscult the chest through one or more layers of clothing. Aside from seeing this on TV and in films, I had noticed it occurring every once in a while in real life, most often in the setting of a busy outpatient clinic with doctors pressed to rush patients through that particular gantlet. The presence of any layers of clothing lying between the stethoscope head and the patient’s skin is bound to muffle any findings—normal or otherwise—that might be present. Faint heart murmurs and gallops as well as fine rales in the lungs might well be lost to detection. Appreciation of the splitting of the heart sounds, present in most patients, even those without heart disease, might be reduced as well. Such failures in auditory perception might lead to serious failures in diagnosing heart or Proc (Bayl Univ Med Cent) 2013;26(2):191–192 lung pathology and following up with appropriate diagnostic technologies. Conversely, a patient with dramatic symptoms unsupported by history or physical findings may prompt a physician, uncertain of his bedside skills, to order a number of expensive tests that might only increase the patient’s fears as well as his medical bill. Such considerations got me to wondering how widespread this deviation from good clinical practice had become. To get some idea of this, I began tabulating all representations of chest auscultation in the public media, almost exclusively television, and noting whether proper technique was being demonstrated (SKINS) or the improper technique of listening to the chest through one or more layers of apparel (CLOTHES). All these examples were placed in the category of either professional representations (doctors and nurses on newscasts and in documentaries) or commercials (actors in dramas, pharmaceutical advertisements, or health care facility promotions). I also made note of the sex of the subject being examined. (Would the reluctance about representing free frontal nudity of women on television work against their being included among the SKINS?) Instances in which the clothing remained in place but with the stethoscope inserted under it to make contact with the skin were registered as SKINS. It took about 2 years to collect the 100 cases I wished to accumulate for analysis. It turned out that of the 100 individuals portrayed, 71 appeared in the professional category and 29 in the commercial category. Among the latter, only 16% were SKINS, not terribly surprising considering the source. I turned my attention to the professional group. Here 37% were SKINS. Surprisingly, gender did not have a hand in this distribution: among men the proportion of SKINS was 36% and among women the finding was 42%. In both groups, however, the number of correctly performed examinations was depressingly low. Recent studies evaluating skills in performing physical examinations by medical students, housestaff, and even medical school faculty have uniformly shown a 20% to 80% error rate in recognizing actual or simulated findings (1–5). Such deficiencies From the Department of Medicine (retired), University of Medicine and Dentistry of New Jersey, Newark. Corresponding author: Allen B. Weisse, MD, 164 Hillside Avenue, Springfield, NJ 07081 (e-mail: weisseab@umdnj.edu). 191 can only be exacerbated by improper auscultatory technique such as that described here. For those of us too easily prone to become overwrought or even incensed at certain troubling realities, our friends and colleagues may properly caution, “Keep your shirt on.” But when our patients’ bodies are trying to tell us through an examination of the heart and lungs, for example, what may or may not be troubling them and when such findings are so clearly obfuscated by faulty technique, perhaps we should be swayed by a different kind of advice. Recall the sultry Swedish blonde in that classic Noxzema shaving cream commercial who urged us to “Take it off. Take it all off.” 1. 2. 3. 4. 5. St Clair EW, Oddone EZ, Waugh RA, Corey GR, Feussner JR. Assessing housestaff diagnostic skills using a cardiology patient simulator. Ann Intern Med 1992;117(9):751–756. Mangione S, Nieman LZ. Cardiac auscultatory skills of internal medicine and family practice trainees. A comparison of diagnostic proficiency. JAMA 1997;278(9):717–722. Roldan CA, Shively BK, Crawford MH. Value of the cardiovascular physical examination for detecting valvular heart disease in asymptomatic subjects. Am J Cardiol 1996;77(15):1327–1331. March SK, Bedynek JL Jr, Chizner MA. Teaching cardiac auscultation: effectiveness of a patient-centered teaching conference on improving cardiac auscultatory skills. Mayo Clin Proc 2005;80(11):1443–1448. Vukanovic-Criley JM, Criley S, Warde CM, Boker JR, Guevara-Matheus L, Churchill WH, Nelson WP, Criley JM. Competency in cardiac examination skills in medical students, trainees, physicians, and faculty: a multicenter study. Arch Intern Med 2006;166(6):610–616. Reader comments Dear Dr. Roberts: Thank you for including the image of mine, Vespers, in the January edition of the BUMC Proceedings in the Avocations “department.” It is an honor to have an image of mine presented. This issue is another wonderful publication. Dr. O’Brien’s article, “My Surgical Heroes,” included many surgeons that I know and hold in the same high esteem: Dr. Sparkman and Dr. Bookatz, both of whom were examples to me of excellent physicians. I met Dr. Bookatz as a medical student during my rotation through surgery at Parkland as a junior and senior medical student at Southwestern Medical School in 1963 and 1964. I later met Dr. Sparkman when I joined the surgical staff at Baylor in 1971 as a member of his surgical department. Dr. Sparkman influenced not only the residents that he trained but also the staff members of his department. He set an example for perfection and extracted the utmost from those who strove to practice medicine up to the standards he set. My own surgical heroes include Dr. Owen Wangansteen and Dr. Walton Lillehei, under whom I trained at the University of Minnesota in 1954–1955. Your article, “Facts and ideas from anywhere,” is an exciting compendium of revelations concerning so many aspects of medicine and helps one focus on the timeline of medical 192 thought and practice. It is a marvel the way you can accumulate and present such a wide spectrum of ideas. —Jay Hoppenstein, MD Dallas, Texas Dear Dr. Roberts: I keep a stack of “to-read” magazines and journals on my coffee table for times of leisure reading, and any unread Baylor Proceedings is always at the top. Last Saturday, with a fire going in the den fireplace and our cat beside me in our chair (the cat thinks it is her chair), I opened up the new January issue of the Proceedings and, as I always do, read it cover to cover. Your “Facts and ideas from anywhere” is the first thing I always read, and the section on hydrophobia was really fascinating—so much so I gave it to my wife, who also read it and enjoyed it as well. You have an easy-to-read writing style for this section that is unmatched. The other articles were excellent as well—important and right to the point. The ECG in hypothermia even prompted me to add this to our Internet-based disease surveillance program. The ECG stood out particularly well on that great paper you use. Please keep up the good work and keep those Proceedings coming for their place at the top of the stack! — Vincent E. Friedewald, MD, FACC Spicewood, Texas Baylor University Medical Center Proceedings Volume 26, Number 2 In memoriam GEORGE E. HURT JR., MD Department of Urology, Baylor University Medical Center at Dallas George Ellison Hurt Jr., MD, died on November 11, 2012, after a long illness. He was born on December 21, 1932, in Dallas and spent most of his life there, graduating from Highland Park High School, Southern Methodist University, and the University of Texas Southwestern Medical School. Graduating first in his medical school class, he received the Ho Din award for the graduating student deemed most outstanding by his peers and the faculty. Dr. Hurt completed his internship at Denver General Hospital and his general surgery and urology residencies at Parkland Memorial Hospital in Dallas. He then enjoyed a thriving private urology practice at Baylor University Medical Center for 41 years, with partners Drs. Alexander, King, Fuqua, and Ware. He was a member of the Combined Examination Committee of the American Board of Urology and the American Urological Association and served as president of both the National Society for Pediatric Urology and the South Central Section of the American Urological Association, in addition to holding many other leadership and service positions. Beyond his practice at Baylor, he founded the urology clinic for spina bifida patients at Texas Scottish Rite Hospital and directed it for 40 years. He was also associate clinical professor of urology at UT Southwestern, a member of medical advisory committees at Parkland Memorial Hospital, and director of the pediatric urology service at Children’s Medical Center. He was internationally regarded as a surgeon, educator, and innovator in urology and was the recipient of numerous community and humanitarian awards. Tributes to Dr. Hurt appear on p. 194 of this issue. HAROLD C. URSCHEL JR., MD Department of Thoracic Surgery, Baylor University Medical Center at Dallas Harold Clifton Urschel Jr. died on November 12, 2012, at the age of 82. He was interviewed in Proceedings (2003;16(3):315– 333), and the introduction to his interview by Dr. Roberts appears below. Tributes to Dr. Urschel appear on p. 196 of this issue. Hal Urschel was born in Toledo, Ohio, in 1930 and grew up primarily in Bowling Green, 20 miles away. After public schools, he went to Princeton University on a football scholarship and graduated cum laude in 1951. The Princeton team was undefeated during his freshman and senior years. He also had a scholarship to Harvard University School of Medicine, where he again graduated cum laude in 1955. His internship, residency, and chief residency in general, vascular, cardiac, and thoracic surgery were at the Massachusetts General Hospital in Boston. After serving in the US Navy as chief of experimental surgery at the National Naval Medical Research Center in Bethesda, Maryland, he and his young family moved to Dallas. In addition to his practice at Baylor University Medical Center at Dallas, Dr. Urschel taught Proc (Bayl Univ Med Cent) 2013;26(2):193 extensively and was clinical professor of cardiovascular and thoracic surgery at the University of Texas Southwestern Medical School. He published over 300 articles in medical journals or chapters in books and was an editor of and major contributor to seven books. He was visiting professor at a number of medical centers in the USA and abroad and was an honorary member of the thoracic surgery faculty of the University of Toronto and the Harvard Medical School. He served as president of five major surgical societies: the Society of Thoracic Surgeons, American College of Chest Physicians, International Academy of Chest Physicians, Southern Thoracic Surgical Association, and Texas Surgical Society. He received a number of honors for his achievements, including two honorary doctorates. He and his lovely and brilliant wife, Betsey, were the proud parents of five children, all of whom are graduates of Princeton University. ELGIN WILLIS WARE JR., MD Department of Urology, Baylor University Medical Center at Dallas Dr. Elgin Willis Ware Jr. died on November 20, 2012, at the age of 88. He recently established a lectureship in medical history at Baylor, and the introduction to the lecture provided by Dr. Michael Emmett appears below. A tribute to Dr. Ware appears on p. 199 of this issue. Dr. Elgin Ware, a long-time urologist at Baylor University Medical Center at Dallas and chief of urology from 1986 to 1987, spent his entire life in Dallas: he graduated from Highland Park High School, Southern Methodist University, and the University of Texas Southwestern Medical School before completing an internship at Baylor Hospital and a urology residency at Parkland Hospital. After completing his training, Elgin entered the practice of urology and quickly became a leader at the local, state, and national level. He was the president of the Dallas County Medical Society in 1976, was a delegate of the Texas Medical Association (TMA) for many years, and served as a trustee of the TMA from 1980 to 1990. He was elected president of the American Association of Clinical Urologists in 1978. Beyond the hospital, he served as a member of the Highland Park School Board for 14 years, worked as a volunteer and then director of the Stewpot, a downtown Dallas soup kitchen, and initiated a medical clinic to provide care to the indigent. Finally, Elgin had a profound interest in medical history. He chaired the History of Medicine Committee of the TMA from 1989 to 2001. In 1995, he established the Elgin W. Ware Jr. TMA collection of prints and drawings at the Blanton Museum of Art on the University of Texas campus to educate the public about the profound connections between medicine, art, and print making from the renaissance to the present. He also coestablished, with Robert Mickey, the History of Medicine Photography Gallery at the TMA. The Elgin W. Ware Jr., MD, Lectureship in Medical History at Baylor is one of three lecture series he endowed. 193 Tributes to George E. Hurt Jr., MD BOB ALLISON, MD Happy, with apologies to Rodgers and Hammerstein’s Sound of Music, “How do you hold a ‘sunbeam’ in your hand?” I met George Hurt poolside at a Phi Chi rush party, September 1953, just prior to entry into the freshman class at Southwestern Medical School. We pledged Phi Beta Pi. He organized our anatomy table—six students to a cadaver in the shacks on Oak Lawn Avenue. It was a macabre scene: 18 bodies and 100+ students in a relatively small space with no air-conditioning! This was Dr. Hal Weathersby’s first year at Southwestern. George was one of the smartest people I’ve ever known, if not the smartest. He was academically number one in our medical school class. He was five average points ahead of the next classmate. The next 20 guys were within two average points of each other. He was the obvious choice for the Ho Din award of the class. We had a great time in medical school, playing widow whist or ping-pong at lunch the first 2 years. Ann and George married after our freshman year. Happy drove a yellow cab that summer. Catherine was born our senior year. We topped off the fourth year by wearing our tuxes with short pants with long white socks to the spring formal at the Dallas Country Club. George completed his urology training at Parkland Memorial Hospital with Dr. Harry Spence. He joined the firm of Alexander, King, Fuqua, and Ware in Dallas. Happy did a lot of things for a lot of people, most of which he took little or no credit for. George founded the urology clinic for spina bifida patients at Texas Scottish Rite Hospital and served as director of the clinic for 40 years. He really helped a lot of friends and acquaintances down on their luck as well as visiting national and international professors and others. I once sent one of the principals of Texas Instruments to see Happy as a work-in without calling ahead; George questioned my judgment. I told him it did not make any difference. He treated all patients the same, rich or poor, famous or infamous. George was honored as a Distinguished Alumnus at both Highland Park High School and Southern Methodist University. His senior year in high school, he was recognized as the best allaround athlete, lettering in football, basketball, and baseball. Happy always had time for his children: coaching Y teams, going horseback riding, skiing, going on hunting and fishing trips and multiple trips in and out of the USA. I can never adequately express my admiration for the care Ann provided Happy during the years of his very protracted illness. 194 I may not be able to hold a sunbeam in my fingers, but I can in my heart. CATHERINE HURT SCHEIHING You can read about my father’s many honors and accolades, but the true essence of this amazing man was much more than a title. Daddy was a brilliant man with the heart of a child. That translated into incredible adventures for us, his kids. He was always laughing and thinking of crazy fun stuff. The list of our activities—like helicopter rides, horses in our front yard, river rafting, and so much more—reads like an adventure series. Family road trips in the station wagon were a vacation staple. The Hurts traveled to both coasts, more than once, plus a couple of times to Canada, south into Mexico, and everywhere in between. Daddy was happiest behind the wheel, in control, going 80 miles an hour, faster if Mother wasn’t looking. Every winter there were road trips to Colorado. He was the most beautiful skier I have ever seen. You could spot him from far away gliding like an angel down the black slopes. He proudly skied until his late 60s, finally qualifying for a free senior lift pass. Most of the time you could find Daddy on the bunny slopes, always helping whomever was the youngest at that time—since you never knew when another Hurt kid would enter this world. One summer Daddy called one of his famous family meetings. With great joy, we felt certain that all the begging for a swimming pool had come to fruition. Instead we were stunned to find out that instead of a pool, we were getting a new baby brother. Hello Gregory, good-bye swimming pool. All of these multiple car trips made for terrific memories, tremendous family times, outrageous laughter, singing, story telling, and catching Daddy’s contagious thirst for learning and seeing all there was to our wonderful nation. On one trip after many battlefield visits and historical sites, Daddy instilled such a powerful reverence for our country that Doug and I are saluting in every photo from that trip. Daddy also traveled around the globe. For many of the years, Mama stayed home with “the baby,” whoever that was at the time. Daddy almost always took one or two or even three of us with him on his travels. Eventually even Mama joined in on the adventures. Once Daddy crossed the border leaving Texas, his cowboy hat was on his head and his boots on his feet. He was so proud to be a Texan. Carolyn went with him to Red China as it first began to open its borders to Americans. He took the boys to Africa; all of Proc (Bayl Univ Med Cent) 2013;26(2):194–195 us went to Europe, many times. We went to Israel, too. Other travels included India, Saudi Arabia, South America, Australia, and countless other places. The language barrier was never a problem for Daddy. He had his own universal language. Daddy would smile from ear to ear and give a Tootsie Pop. In Kazakhstan, on the far eastern side of what was then the Soviet Union, Daddy was the first American most of the people there had ever seen. They were terribly afraid of him at first, but Daddy’s sincerity, smile, and Tootsie Pop language won their hearts. Once I witnessed this myself. We were driving through Yugoslavia just when Eastern Europe had begun to allow a few people in. We were on a one-lane road barely passing ox-pulled carts. We saw a group of children and their mothers in the field harvesting their wheat with scythes. Daddy stopped the car, hopped out, gave a loud whistle, and the curious folks walked over. When the mothers saw his smile and the Tootsie Pops Daddy was holding high in the air, they gave a nod and the children rushed forward laughing and smiling. Tootsie Pops for everyone! Daddy was magical with children. He was the kind of person that sat on a bench at a park and before you knew it, little children had gathered around him. He took our entire neighborhood on bike rides; I’m talking 20 to 25 kids on bikes and one adult, Daddy. The youngest would be sitting in the front basket of his bike. Our doorbell would ring, and when we answered we were likely to hear, “Can Dr. Hurt come out and play?” Daddy coached every sport offered at the YMCA to every age group imaginable. He loved every second of it. I remember when he first started coaching Ellison’s soccer team. None of the parents even knew the rules of soccer at the time, so volunteers were few. Daddy went into coaching soccer full steam ahead, just like all the other sports. He just loved being with his kids and their friends. At my wedding, the overwhelming memory most people have is that we had an ice cream Sundae bar. Why? Because my dad said, “I don’t like to eat cake without ice cream.” Dad proved that a human could live on coffee, Diet Dr. Pepper, and Bluebell ice cream. Daddy really lived. He burned the candle at both ends. Daddy worked long, hard hours, but when he got home, he would go to the front porch and whistle. The Hurt kids would come running, along with a few other neighbors. Once Daddy was home, he was all ours. The fun had arrived! One year in high school, the school phone book came out. There was an ad in it that read simply, “No phone calls after 9:00 pm. Dad.” I was mortified and went straight home and demanded to know if he had put that ad in the phone book. Daddy looked at me puzzled. His answer? “How did you know?” Daddy liked to go to bed by 9:00 pm. That rarely happened, but that was always his plan. He was up and gone by 4:30, 5:00 at the latest. His rounds were done by 6:00 am and then surgery started. By mid morning he was in the office seeing patients. Every Tuesday afternoon was Daddy’s time off. Instead of taking the time off, this was his day to work at the Texas Scottish Rite Hospital and later the hospital’s Spina Bifida Clinic April 2013 that he founded. It was a labor of love. He loved on all those special kids, and they loved him back. Those donated afternoons gave him countless wealth in his heart. He showed us how to be generous with our time in helping others. So many people I know and have met have wonderful stories about how Daddy saved their life or changed their life for the better. He was a true physician. He cared tremendously about his patients. The time and concern he gave each one was genuine. Daddy loved people—all people, every kind of person imaginable. He had the uncanny gift to make each person feel as if he or she mattered. Indeed, each person did matter to Daddy. Daddy loved his children and grandchildren. Most of all he loved Mama. It was a joy to see Daddy come home and grab Mama in a bear hug and tell her he loved her. Then Mama would shake her head and say, “Oh Happy!” It made us all laugh. Daddy was passionate about many things. He showed us by the way he lived that love of family mattered. He showed us to love the Lord with all your heart. He showed us that love of country and the great state of Texas should be ingrained. Do your best. Never stop trying. Do what is right. Forgive. Find the best in all people. Friends are a blessing and a joy. Daddy told us often that family is enormously important. You stick together. Family is whom you can count on. Never let anything come between us brothers and sisters. I guess somehow that got through to us. My younger brothers and sister and I have muddled through all these years, sticking together and loving each other as Daddy taught us. I can’t say it was always easy; we are so different. But to this day we remain very close. I am proud to have passed that belief on to my own children, who are each other’s best friends. The stories about Daddy are countless, incredible, crazy, hilarious, and all true. I imagine all those who knew him have their own encyclopedia of hair-raising tales about or including Happy Hurt. I know I do. If I told even a small amount, we’d be laughing, we’d be crying. And we would still be here when the sun came up. I know that Daddy would say to each of you here: You matter so much to me. I love you. Now go out and love others. Laugh and take a handful of Tootsie Pops with you to share. WILLIAM C. ROBERTS, MD I was fortunate at Southern Methodist University to be a classmate and fraternity brother of George Hurt. I knew no one when arriving in Dallas, but George and his friends rapidly took me in. A trip to Mexico with George and several others and then a visit to his family’s ranch remain vivid in my mind all the years since. The more I learned about George, the more I was awed by him. I heard that he had never made less than an A through junior high and high school, and he never made less than an A in college either, going to medical school after 3 years. George, I believe, could walk out of a class and quote the lecture he had just heard, and read a page and recite it. He certainly had one of the most brilliant minds that I have encountered. Additionally, George was a wonderful athlete. You name the sport and he was good at it. And all the time he was friendly, fun, humble, and modest. His nickname “Happy” was most appropriate. George, you were special and you will be missed. Tributes to George E. Hurt Jr., MD 195 Tributes to Harold C. Urschel Jr., MD AMANDA URSCHEL GOLDSTEIN I am Hal’s fourth child and first girl (in the whole generation on both sides, as he would always say). Dad was one of my very favorite people in this world, my biggest inspiration. He was a man of excellence, a man of great faith, and a man who made it his mission to serve others. His devotion to his family and friends proved paramount. Dad loved to learn and even more to teach. Humor was his modus operandi. We are so lucky to have had him so long and so great until the end! When he died, he was 82 and still working full-time, still on the cutting edge. In fact, he had just finished a weekend in Los Angeles, coordinating research on the use of stem cells to treat heart failure. While it is so sad and shocking for those of us left behind, we take great comfort in knowing that he went the way he told us he had hoped to go—instantly and traveling while working on what he loved most. What a blessing for him. The Lord was especially nice to take him the day before the election. As many of you know from his fabulous stories, Dad grew up in Bowling Green, Ohio, as Tubby. Having witnessed his dad dying from a heart attack when he was just 13 years old, Dad was determined to find a way to prevent that for others by committing himself to study heart surgery. At home, he quickly took over as the head of the household to help his mom raise his younger brother, Bill, and his sister, Ann, who had Down’s syndrome. They counted completely on their friends for food and the basics of life. I believe this is why he cherished every friend, more than most do. His faith carried him through those days and proved to be the foundation of his life. We always joke that nobody had more best friends than Dad—but it was true! He constantly called to check in, remembered something significant, or thanked us for a simple deed. Every little gesture was noticed and appreciated. He was a man who managed dozens of tasks simultaneously, yet when you called, it seemed as if he had nothing else on his mind but you. He was so proud of his family. He would send out e-mails to hundreds of people describing his grandkids’ accomplishments—with excessive exaggeration. He always fought for and supported those in need. In fact, he had a special gift with those in need and took care of so many for years. Dad approached life with humor. He was perpetually telling jokes, many of which can’t be repeated. One of his favorites was: When I die, I want to go peacefully in my sleep like my grandfather did, not screaming like the other passengers in the 196 back of his car. Then he’d laugh and laugh—usually with tears streaming down his face. Dad loved sports and loved to win. He loved football, particularly the St. Mark’s Lions, the Princeton Tigers, and the Dallas Cowboys. He believed sports taught one more about life than anything else. And he believed that coaches are the most influential people in one’s life, next to one’s parents. As we watched the Cowboys this past Sunday, as he did faithfully, we could hear him cheering along with us. In high school, we had to be the captain of every sport we played. If a coach didn’t put his kid or grandkid in the game, you could hear Dad yelling across the field to put his kid in, with a few choice expletives added. Many of you know that Dad could out-cuss anyone— whether at home, in the OR, or at Grandparents’ Day. Nurses would tally his f-bombs in the OR, and he clearly set records. And then, after each operation, he would grade them on how they performed in the surgery. He left owing Liam (his youngest grandson) 9 minutes for bad language. On Liam’s timeout chart the penalty was 1 minute for each bad word. Grandpa would cuss and laugh, and Liam would say, “Grandpa, you are up to 9 minutes already!” Dad always amazed us with the latest technology and medical advances. He always had the latest camera and took so many pictures that it was painful. He’d bark to us, “Smile, and like it!” Then we were lucky enough to be forced to sit and watch the unedited versions of countless family movies over the holidays. Growing up in the Urschel family was always entertaining. We always had breakfast/dinner together. Often Dad would come home to eat, then go back to work. He would serenade us on his ukulele with his two favorite songs: Take Me Out to the Ballgame and Mr. Moon. Dad also often embarrassed us. We were known as the family that showed up to church on Christmas morning in our pajamas and thought that was normal. Dad and Mom, out of sheer enthusiasm, belted out hymns during the service, as if they were competing to see who could sing the loudest. My friend would come pick me up early on Sunday mornings and hope she didn’t arrive as Dad was out getting the paper—naked. Other times, he would lecture and then force my friends to eat their vegetables at our dinner table. Dad could roar louder than most. It didn’t take me long to realize, though, that if you just gave it right back to him, he would respect you. My kids would just smile as Dad yelled, Proc (Bayl Univ Med Cent) 2013;26(2):196–198 and he would soon break and start laughing himself. While he seemed like a big, burly grizzly bear, he was really a big, snuggly teddy bear. He would pull out the yellow legal pad every few months and call me in to go over everything I had done wrong. I would just smile and say, “Yes, Sir.” Nobody was ever good enough for his daughters. In fact, no boy was allowed on our property when we lived at home. Dad loved St. Mark’s, Harvard Medical School, and especially Princeton. Our Christmas presents were always Princeton glasses, blankets, doormats, and trash cans. He bled orange and black. And he played the Tigertones in his car until the very end. PawPaw also loved to hunt and fish. He cherished sharing the outdoors with us and enjoying things as simple as watching a cardinal in a tree. He would give us guns for Christmas or birthday presents and we’d go to the shooting range for family outings over the holidays—again a little different than most. Dad traveled the world and wanted everyone else to. He and Mom would pack all seven of us in the station wagon and drive to Colorado in the summer. We would laugh too much in the back seat and get screamed at, only to make us laugh harder and get in more trouble. We always had to stop at the Big Tex Steak House in Amarillo so all four boys in the family could eat the 72-oz steak, appetizer, baked potato, roll, and a dessert in less than an hour, so we could get it free. They succeeded every time, of course. Once Brad and Hal could drive, we started taking two cars. Mom would quiz us on vocabulary words over the CB radio, only to get bashed by the truckers using that same channel. We were known for our eating contests at the hotel buffets and our tanning contests on the beach. Dad always wanted the best and nothing less. Dad often preached to us that “learning is fun!” His excitement about learning was clearly contagious. He lived every single minute of his life. He worked at night and then would fall asleep sitting up, mid meal, or mid conversation the next day. He would come in our rooms at 7:00 am on weekends, raise the curtains, and say, “Wake up. You are wasting your day!” Dad never settled for the status quo or mediocrity. Do everything to perfection, regardless of what you were doing. Marry the best, as he did, and marry for good breeding genes. Fight for what is right and refuse to lose. Our stories with Dad are endless, just as our love for him is. The love he doled out will last forever more. Dad was our biggest fan and our biggest inspiration. What an example. What a gift to this world! I challenge you: Be the friend he was, laugh as he did, love to learn, take care of others, and live life to the very fullest—just as Hal Urschel would have. What a beautiful life! How lucky we are to have had him as our Dad in full form for as long as we did. We are truly blessed! Dad, I love you! Save us all a big hug! MICHAEL RAMSAY, MD Hal was described to me recently as an icon of cardiothoracic surgery by Dr. Mike Mack—what a fitting description of a great physician and man. We celebrate the life of a truly amazing individual who has contributed so much to medicine, April 2013 research, and mankind. I knew Hal as a great family person; in the operating room as a world-class surgeon; and in research as a cutting-edge physician-scientist. I first met Hal and Betsey when Zoe and I arrived in Dallas at Baylor 36 years ago at a cardiac surgery meeting at the Petroleum Club that he and his good friend Denton Cooley were hosting. Hal gave many talks—an invited speaker around the world—scientific as well as “after dinner.” He was never at a loss for words and could ad lib on any topic. He would also give great introductions to renowned individuals like Denton Cooley, but somewhere he would often include the sentence, “I taught him everything he knows—but not everything I know!” Hal published extensively, and this included the authoritative tome on thoracic surgery that he edited with Joel Cooper. Family first—always—Betsey, Hal, Brad, Locke, Amanda, and Susanna. He was always supporting the young. He would call my children and tell them in no uncertain terms which schools to go to—no discussion! Tara, my daughter, came to me one day and said, “Dad, Hal Urschel just called. I am going to Williams College!” In the operating room, it was not for the weak, faint-hearted. or incompetent. Hal was intolerant of incompetence, complacency, and particularly less than 110% commitment. He was very fast to unleash expletives but always had patients’ best interest at heart. At the peak, he, Drs. Donovan Campbell, Maruf Razzuk, and Guy Prater were a world-leading team in cardiovascular and thoracic surgery and in bringing new innovations to the patient. Hal had the personality to make things happen. He did not pull punches and was very direct in his commentary. He awarded grades to everyone after a surgery, and F minus was frequently given; he set the bar high. Later Hal kept his prominence with his unique transaxillary approach to cure thoracic outlet syndrome, which he continued to this day. Hal was the epitome of the clinical scientist, bringing research from the bench to the bedside. As he slowed down his surgery practice, he increased his drive to make major advances in cardiovascular research. He was the Baylor Chair in Cardiovascular and Thoracic Research and Clinical Excellence. With Cara East, Baron Hamman, Greg Pearl, Jeff Schussler, and the team, he led a stem cell program where bone marrow cells were taken, prepared, and injected back into damaged heart muscle to grow back into healthy heart cells. Hal was the “behindthe-scenes” mantra, always striving to make the field and the patients better. He was preparing his presentation on this work for the American Heart Association when he sustained his cardiac arrest. I was asked by Hal and Betsey to join them on a trip to Israel a couple of months ago, where Hal was going to teach the lead surgeons how to do his thoracic outlet procedure. I almost did not go because of commitments back at Baylor but I am so glad I did. It was truly a trip to remember. Zoe and I arrived in Tel Aviv and were picked up at the airport. We had just brought carry-on bags—we travel light—but we had to wait for the Urschels’ checked bags. The physician greeting us announced, “OK, we need 6 camels for the Urschels and one mule for the Ramsays.” Hal operated at the Rabin Medical Center, Tributes to Harold C. Urschel Jr., MD 197 teaching the whole cardiothoracic surgical team. Then we went to Jerusalem—escorted by Dr. Dan Meyer’s sister, Devorah, who runs the YMCA there, and her husband, Robert Buerger, the CBS reporter who you will hear every morning on KRLD reporting on latest events in the Middle East. In Jerusalem we visited Calvary and the site of Christ’s crucifixion. Hal confided to me there that it would not be too much longer before he would join him. I wondered if God realized what he was taking on. I am sure he did! At least he surely does now! Hal will be remembered for his strong personality, his drive, and his impatience with anyone who was preventing progress, but also for his compassion, family first, and inspiration for the young. He was committed to making Baylor Health Care System great. He was at Baylor for 50 years and loved it and did 198 everything he could to make it thrive in the forefront of medicine. In his pursuit of excellence, Hal would say: “Excellence is a result of caring more than others think is wise, dreaming more than others think is practical, risking more than others think is safe, and expecting more than others think is possible.” It does not seem that long ago that Hal joined a team climbing Mt. Everest. He would often say: Life is short And the art long The occasion instant The experiment perilous The decision difficult. Hal, your life was too short, but you lived it to the full. We love you and Betsey—you will never be forgotten. Baylor University Medical Center Proceedings Volume 26, Number 2 Tribute to Elgin W. Ware Jr., MD STEVE FROST, MD The city of Dallas, and for that matter, the state of Texas, has lost a legend. Elgin W. Ware Jr., MD, passed away recently. And with his passing, we’ve lost a truly great physician. His contributions to medicine were multiple. I first met him as a resident here at Baylor, where he would patiently teach surgical technique but also “the art” of medicine. I was fortunate to later join him in private practice where his partners all called him “the Squire “ because he was such a gentleman to all we came in contact with and always had a story to share. He was born, educated, and trained in Dallas and joined the urology group at Baylor in 1953, where he practiced until 2003. He held many leadership positions, including chief of urology at Baylor, president of the American Association of Clinical Urologists, president of the Texas Medical Association 50 Year Club, president of the Texas Urological Society, and president of the Dallas County Medical Society, among others. When he retired from the practice of medicine, he became the Proc (Bayl Univ Med Cent) 2013;26(2):199 medical director of the Stewpot Medical Clinic, caring for the homeless of Dallas. He was also very interested in the history of medicine. In an article in Texas Medicine in 2008, he reflected on a comment from a colleague that his generation was the greatest generation in medicine. He first noted, “Beginning after World War II, this ‘greatest generation’ witnessed and indeed was involved in a veritable explosion of knowledge in all areas of medicine, discoveries and advances far too many to enumerate.” Yet, what had set the generation apart probably had more to do with the art of medicine, “nothing more or less than a sincere and compassionate care and caring for the patient.” He hoped that for the younger generations, “their claim to greatness might be marked not only by those scientific advances, but more importantly, by an awareness and a continuation of their long heritage of those qualities that are a vital component of the Art of Medicine”—an art he practiced so well. Good job, Squire! You will be missed! 199 Book Review Making Rounds with Oscar: The Extraordinary Gift of an Ordinary Cat by David Dosa New York, NY: Hyperion, 2010. Paperback, 256 pp., $13.99. Reviewed by James Marroquin, MD n a 2007 issue of the New England Journal of Medicine, amid the usual fare of the latest and greatest in biomedical research, there appeared a short piece about a cat named Oscar (1). Living as a pet in a nursing home dementia unit, Oscar demonstrated an uncanny ability to predict which of its residents were about to die. The furry creature’s presence at a person’s bedside invariably signaled that life’s end was near. The story generated a good deal of interest, earning the feline 15 minutes of fame. Now, years later, a book entitled Making Rounds with Oscar chronicles a doctor’s discovery of the animal’s special gift. The author, David Dosa, is a geriatrician at the Steere House Nursing Center in Rhode Island where Oscar lives. He begins the book by explaining why he made the unusual choice to specialize in care for the elderly. I call his career decision unusual because gerontology remains among the least popular fields of practice for medical students to enter. Geriatric fellowship training programs at even the most prestigious institutions are sometimes unable to find willing candidates. Why is this the case at a time when our aging population needs more practitioners equipped to care for its elderly members? In a fee-for-service system that pays physicians for performing procedures and seeing a high volume of patients, the time-intensive nature of geriatric medicine makes it a specialty with some of the lowest reimbursement for the greatest amount of work. And while many young people enter medicine hoping to someday be the celebrated bearers of miracle cures, geriatric care focuses on helping individuals adapt to the inevitable frailties and limitations that come with age. But Dosa does not lament or even mention what he has foregone in money, power, and prestige. The fulfillment he derives from his vocation among the elderly does not seem to leave much room for feelings of martyrdom or envy. It is a fulfillment, he says, that comes from bearing witness to the stories of his patients as they live the last of their days. These stories form the heart of the book, and Oscar’s tale serves as an ideal vehicle for sharing them. When a trustworthy nurse at the Steere House tells Dosa about the cat’s extraordinary talent, he is at first skeptical and I 200 sets about investigating the matter. One by one, he interviews the families of the patients Oscar accompanied in their final hours. Since all of them suffered from dementia, a revealing portrait of this devastating illness emerges. Dementia is characterized by deterioration in cognition, resulting in behavioral problems and difficulty performing the basic activities of daily life. Alzheimer’s, defined by the accumulation of certain proteins in the brain, is the most common form of dementia, accounting for 60% to 70% of cases. Dr. Dosa’s clinical expertise and the poignant narratives of patients and families dealing with this disease combine to make the book a valuable educational resource. In fact, the afterword contains some explicit guidance for those doing the admirable and arduous work of caring for people with intellectual disabilities. But beyond being useful, Making Rounds with Oscar’s depiction of dementia speaks profoundly to the nature of personhood and the practice of modern medicine. Since at least the time of John Locke, philosophers have reflected upon the idea of personal identity. As an individual changes, what remains constant and defining, allowing him or her to be considered to be the same person over time? For the loved one of somebody with dementia, this can be much more than a matter for idle speculation. When the essential qualities and traits of your parent, spouse, or sibling are no longer present in their diminished state, who is it exactly that you are caring for and relating to? The son of one Steere House patient implicitly responds to this question by remarking, “I said good-bye to my mother a long time ago. Now I’ve just fallen in love with this little lady!” Other characters in the book do not share such a sanguine approach to what has been lost. When one day, after 63 years together, the wife of a man named Frank Rubenstein no longer recognizes him, he never again returns to the nursing home to see her. Though Rubenstein continues to call daily to check on his wife’s status, he cannot bear to see the fear and suspicion on her face when she encounters him as a stranger entering her room. But even as dementia surrounds a self in isolating darkness, creative acts of engagement can sometimes reconnect us, if only briefly, to the person we once knew. For example, Jean Ferretti, the wife of the pioneering musical composer and Steere House patient Ercolino Ferretti, reports to Dosa that “one of the things I found most interesting about my husband’s disease was that even toward the end of his life he responded to music. Here was this man who could no longer do much of anything. Sometimes he would get agitated. If you put on a jazz record, though, he would just sit there contentedly for hours.” As dementia transforms these individuals’ relationships with their affected loved ones, what does not and cannot change are the covenantal bonds they share with them. No matter how faintly these victims of Proc (Bayl Univ Med Cent) 2013;26(2):200–201 dementia resemble who they once were, to their family they are still father, mother, husband, wife, sister, and brother. Closely related to the issue of personal identity is the question of what makes human beings valuable and worthy of care. The residents of the Steere House dementia unit have lost capacities that many people see as essential for a meaningful life. In their impaired state, they can no longer contribute anything to society. Given these realities, is the tremendous work required to care for them warranted? Based on a certain utilitarian calculus, the answer to this question is no. But if all people are considered to have intrinsic dignity and worth, then a radically different response is demanded. For instance, in the Christian tradition, the Gospel is most manifest when people embody Jesus’ special love for those who can offer nothing in return. But we must not confuse our sacred call to care for people with dementia with the automatic, reflexive use of all available technologies in efforts to extend their lives. When a medical intervention is more likely to be burdensome than beneficial, the more loving course of action may be to aim for comfort rather than the prolongation of life at all costs. This is illustrated in a heartrending story about a frail, debilitated Steere House resident named Saul Strahan. When Strahan develops a severe infection, Dosa discusses his grave condition with Strahan’s daughter and recommends against sending her father to the hospital’s intensive care unit (ICU) for aggressive and likely futile treatment. He suggests instead that Strahan remain in the familiar surroundings of the nursing home with a focus on providing him a peaceful death as the infection worsens. Viewing this approach as giving up on her dad, she insists that “everything be done,” even if there is very little chance of his recovery. Dosa later finds Saul Strahan in the ICU on life support—a breathing tube down his throat, a central line in his neck, and a dialysis machine at his bedside about to be used as a substitute for his failing kidneys. Dosa is saddened, but not surprised to soon thereafter learn of his patient’s death. April 2013 All available medical technology had been utilized on this man’s behalf. But amid the heroic efforts to save his life, nobody was really present with him during his lonely transition into the unknown. This tragic irony reflects many patients’ and practitioners’ conflicted experience of contemporary medicine. The past century witnessed the emergence of biomedical innovations our ancestors could have scarcely imagined. We can administer vaccines and antibiotics to prevent and eliminate previously fatal infections. We can replace insulin and other vital hormones when our bodies’ production of them is insufficient. We can open obstructed arteries during heart attacks and strokes, halting lethal damage to our hearts and brains. We can cure certain cancers with surgery, radiation, and chemotherapy. This growing, seemingly limitless capacity to triumph over afflictions before which humans had hitherto been helpless has radically altered our expectations of health care. For the first 23 centuries of Western medical practice (dating from the time of Hippocrates), clinicians’ primary role was to accompany and guide their patients through the experience of illness. In contrast, now that efficacious interventions are available, achieving desirable results is what matters. Yet positive outcomes are not always possible. Indeed, despite modern medicine’s numerous successes, death is still the ultimate outcome for us all. And as the focus has turned to most efficiently fixing patients’ problems, the healing, pastoral aspect of care that once constituted the heart of medicine has been neglected, to the frustration of patients and physicians alike. The simple example of a cat lying lovingly at a dying person’s side calls health care practitioners back to the sacred role of being a compassionate presence. 1. Dosa DM. A day in the life of Oscar the cat. N Engl J Med 2007;357(4):328– 329. The reviewer, James Marroquin, MD, completed his residency at Baylor University Medical Center at Dallas and now is an internist in Austin, Texas. He can be reached at jamesmarroquin@gmail.com. Book Review 201 From the Editor Facts and ideas from anywhere US HEALTH An expert panel appointed by the US Institute of Medicine reported their findings in January 2013 (1, 2). We in the US live shorter lives than any of 16 peer nations, including Australia, Canada, Japan, and 13 European countries (Figure 1). Swiss men live nearly 4 years longer than William C. Roberts, MD. American men, and Japanese women live >5 years longer than American women. Americans get their health care in a less coordinated system than in any of the 16 other nations, and we in the US pay more for it. The cost of care in the US in 2011 was $2.7 trillion, or $8680 for each American. The closest among the other 16 nations was Switzerland, which spent $5489 per person. Americans are more reckless than those in the other 16 countries. Only Italians wear seatbelts less often. Nowhere else do motorcyclists go without helmets as often. Americans die more often in traffic accidents linked to alcohol consumption, and they own far more guns (89 per 100 people compared with 46 per 100 people in Switzerland, the peer group country with the next highest rate of gun ownership). Far fewer Americans than in the past use tobacco, and only the Swedes now smoke fewer cigarettes than Americans. This is a reversal of the situation in the 1950s, when Americans smoked the most. Nevertheless, in 2003, smoking accounted for 1 in 5 deaths among Americans >50 years of age. But, smoking-related deaths are expected to decline further in the USA with the drop in the number of smokers and the rise in countries like France, where 46% of adults smoke. The panel pointed out, of course, that what we eat is a major factor in the lower US lifespan. Americans eat, on average, 3770 calories a day. That’s 1100 more calories than the average adult male needs, and 1700 more calories than an average woman should consume. Between 1999 and 2001, Austrians, Belgians, and Italians ate more but, by 2007, Americans were well ahead of anyone else. Th e average Swede consumes 17% fewer calories daily than the average American. 202 Figure 1. Mortality from noncommunicable diseases in 17 peer countries, 2008. Reprinted with permission from National Academies Press. GLOBAL OBESITY Overweight and obese people now outnumber the malnourished by nearly 2 to 1. According to the World Health Organization (WHO), in 2010, 80% of American adult men and 77% of women were overweight (3). Obesity costs at least $150 billion a year in American health care spending. But obesity is spreading rapidly in other parts of the world. Saudi Arabia and other Arab states and many Pacific Island nations are fatter than in the USA. Most of the adult population of Samoa is obese; in 2008, 46% of Egyptian women were obese. Mexican women are heavier than US women, and Mexican men will soon eclipse US men in poundage. These changes in part reflect advances in public health. In 1900, pneumonia, tuberculosis, and childhood diarrhea were the leading killers of Americans. Now, the top causes of death are noninfectious diseases, mainly atherosclerosis, hypertension, and cancer. In 2008, 63% of deaths around the world were caused by noncommunicable diseases and 80% of them occurred in low- and middle-income countries. Many countries are trying to come to grips with this major shift in public health. Japanese companies require employees to undergo annual physicals that include waistline measurements. Proc (Bayl Univ Med Cent) 2013;26(2):202–211 Measurements of over 33.5 inches in men and over 35.4 inches in women count against the company. If too many fail the test, the firm has to increase its contribution to public health care for the elderly. Several countries tax soft drinks and other sugared beverages. Mexican legislators introduced a bill in December 2012 that would add a 20% tax to the cost of such drinks. In 2011, the average Mexican adult consumed 728 servings of Coca-Cola; the average American, 403 servings. The China Health Ministry has asked Dr. Kenneth Cooper of Dallas, founder and chairman of Cooper Aerobics, to explore the introduction of Fitness Gram Testing among its schoolchildren. Cooper indicated that Ross Perot contributed $2 million to help pay for a computer system to aggregate the results. Ten years ago there was hardly any obesity in China, according to Cooper. WHO estimates that 45% of Chinese men and 32% of Chinese women are now overweight or obese. The fast-food chains are rapidly expanding in China. Yum Brands, which owns Pizza Hut, KFC, and Taco Bell restaurants, has 38,000 restaurants globally, including 740 Pizza Huts and 4,043 KFC establishments in China. Business groups complain that taxes, regulations, and unfair trade practices hurt their international competitiveness. Now, we can add body weight to that list. The Organization for Economic Cooperation and Development (OECD) in 2012 updated an obesity epidemic watch among its 34 country members (usually described as the wealthier developed countries) and found that the average rate of obesity across the OECD was 17% (4); in the USA, 34%; in Korea, 4%; in Germany, nearly 15%; in the UK, 23%; and in Mexico, 30%. In 19 of the 34 OECD countries, most of the population is now either obese or overweight. In the US and in Texas, more than two thirds of the population is either obese or overweight (Figure 2). Texas comptroller Susan Combs has estimated that obesity costs Texas employers nearly $10 billion in 2009. drinks in 2005 was over 50 gallons, and by 2012, 42 gallons. Soda companies raised prices in 2011 and again in 2012 and volumes kept falling. The sugary bubbles are simply unhealthy. Sodas’ traditional target market, namely youth, is often now turning to water, energy drinks, and coffee instead. This of course is good news unless you happen to be an investor in Coca-Cola, PepsiCo, or Dr. Pepper/Snapple, which I avoid. US MILK CONSUMPTION In 1975, the US milk consumption per capita was 28.6 gallons and by 2011 it had fallen to 20.2 gallons (7). This decline is good news. Cows are the biggest source of our cholesterol, including their muscle, milk, butter, and cheese, and also our biggest source of saturated fat. RELATION OF PHYSICAL ACTIVITY AND SEDENTARY BEHAVIOR TO SERUM PROSTATE-SPECIFIC ANTIGEN A recent piece in the Mayo Clinic Proceedings (8) involving 1672 men found that for every 1-hour increase in sedentary behavior, the participants were 16% more likely to have an elevated prostate-specific antigen (PSA) concentration, and for every 1-hour increase in light physical activity, participants were 18% less likely to have an elevated PSA concentration. We men sit on our prostate gland. Get up and keep moving. FASTING VS NONFASTING MEASUREMENTS OF BLOOD LIPIDS Current guidelines recommend that total lipids and lipid subclass levels be measured with a patient in a fasting state BODY WEIGHT AND LEADERSHIP ABILITY New research suggests that extra pounds or enlarged waistlines affect an executive’s perceived leadership ability as well as stamina on the job (5). Leadership experts and executive recruiters say that staying trim is now virtually required for anyone on track for the CEO corner office. Executives with larger waistlines and higher body mass indexes tend to be perceived as less effective both in performance and interpersonal relationships. While weight remains a taboo conversation topic in the workplace, heavy executives are judged to be less capable because of assumptions about how weight affects health and stamina. A business school professor recently stated that he could not name a single overweight Fortune 500 CEO. SODA CONSUMPTION Figure 2. Prevalence of obesity among adults, 2009 (or nearest year). Reprinted with permission from In the USA, soda consumption is declining OECD (2011), “Overweight and obesity among adults,” in Health at a Glance 2011: OECD Indicators, (6). Per capita consumption of carbonated soft OECD Publishing. http://dx.doi.org/10.1787/health_glance-2011-18-en April 2013 Facts and ideas from anywhere 203 (>8 hours after the last meal). Fasting recommendations were originally introduced to decrease variability and achieve consistency in the metabolic states of patients at the time of sample collection. Several studies, however, suggest that measurement of lipid subclasses in a nonfasting state is an acceptable alternative, with some nonfasting markers being better at predicting the risk of cardiac events. Sidhu and Naugler (9) measured various lipid levels with fasting intervals varying from 1 to >16 hours in 209,180 individuals. The mean levels of total cholesterol and high-density lipoprotein cholesterol differed little among individuals with various fasting times. The mean calculated low-density lipoprotein cholesterol levels showed up to 10% variation among groups of patients with differing fasting intervals. The mean triglyceride levels showed variations of up to 20%. MORE ON TATTOOS Tattoos have become increasingly popular in recent years. In the USA, in 2012, an estimated 21% of adults had tattoos, up from 14% in 2008. The process of tattooing exposes the recipient to risks of infections, some of which are serious and difficult to treat. Historically, as LeBlanc and colleagues (10) emphasize, the control of tattoo-associated dermatologic infections has focused on ensuring safe tattooing practices and preventing contamination of ink used in the tattoo parlors—a regulatory task overseen by state and local authorities. In 2012, several outbreaks of nontuberculous microbacterial infections associated with contaminated tattoo ink raised questions about the adequacy of prevention efforts implemented at the tattoo-parlor level. The Food and Drug Administration (FDA) began reaching out to health care providers, public health officials, consumers, and the tattoo industry to develop more effective measures for tattoo ink-related public health problems. Some reports of tattoo-related nontuberculous microbacterial infections suggested that tap water or distilled water used to dilute inks at tattoo parlors was a likely source of contamination. Findings from more recent outbreaks suggested that the inks were contaminated before distribution. Under the Federal Food, Drug, and Cosmetic Act, tattoo inks are considered to be cosmetics, whereas the pigments used in the inks are color additives that require premarketing approval. This law requires that cosmetics and their ingredients not be adulterated or misbranded, which means, among other things, that they cannot contain poisonous or deleterious substances or unproved color additives, be manufactured or held in unsanitary conditions, or be falsely labeled. Furthermore, cosmetic manufacturers are supposed to ensure the safety of a product before marketing it. But, the FDA does not have the authority to require premarketing submission of safety data from manufacturers, distributors, or marketers of cosmetic products, with the exception of most color additives (dyes, pigments, or other substances used to impart color). The FDA, however, can conduct investigations, request that a manufacturer recall volatile products, issue advisory letters, and request that the Department of Justice conduct seizures, enjoin a firm or person from manufacturing or distributing products, or file criminal charges against a firm or responsible persons on behalf of the FDA. 204 It is particularly important to increase awareness about certain types of tattoo ink–related infections because of several features of nontuberculous microbacteria. They may be difficult to diagnose and treat. It can take up to 6 weeks to identify the organism. A special culture medium and a skin biopsy may be required. Antibiotic choices are limited by the susceptibility profile of the organism, and prolonged treatment may be necessary to clear the infection. Moreover, complications such as co-infections with pathogens such as methicillin-resistant Staphylococcus aureus may pose additional challenges. Beware of tattoos. RENAL SYMPATHETIC DENERVATION FOR DRUG-RESISTANT HYPERTENSION Esler and colleagues (11) for the Symplicity HTN-2 investigators indicate that among the 7 billion people residing on Planet Earth, nearly 1 billion adults have high blood pressure. Despite the availability of numerous effective antihypertensive medicines, hypertension remains uncontrolled for various reasons, including inadequate treatment. Among hypertensive patients receiving treatment, the estimated proportion of patients with blood pressure uncontrolled (>140/90 mm Hg) ranges from 45% to 85% in Europe and North America. Furthermore, a subset of patients who adhere to a prescribed pharmaceutical regimen of ≥3 drugs, including a diuretic, continue to have uncontrolled or resistant hypertension. In the US, estimates of resistant hypertension prevalence range from 10% to 30% of adults receiving drug treatment for hypertension. These numbers reflect a serious health challenge because every 20/10 mm Hg increase in blood pressure leads to a doubling of cardiovascular mortality. The sympathetic nervous system plays an important role in hypertension. Catheterization-based renal denervation is a minimally invasive procedure involving the application of radiofrequency energy in short bursts along the length of the main renal arteries to ablate the renal nerves that lie within and just beyond the artery’s adventitia. The Symplicity HTN-2 trial randomized patients with resistant hypertension to either renal denervation or to no renal denervation, with both groups maintained for 6 months on antihypertensive medications. The primary endpoint, change in office-based systolic blood pressure at 6-month follow-up, demonstrated a significant difference in systolic blood pressure between the treatment and control groups. Patients in the control group then had the option to receive the renal denervation procedure. The 1-year results of this second trial, which included 6-month outcomes for the control group who were treated with renal denervation, resulted in a significant drop in blood pressure similar to that observed in patients receiving immediate denervation. Thus, renal denervation appears to provide a safe and sustained reduction of blood pressure to 1 year in patients with previous resistant hypertension. WHY PATIENTS VISIT DOCTORS St. Sauver and colleagues (12) from the Mayo Clinic analyzed medical records of 142,377 patients in the county Baylor University Medical Center Proceedings Volume 26, Number 2 in which the Mayo Clinic is located to learn of the various conditions that prompted patients to visit their physicians during a 5-year period (2005–2009). Fifty-three percent of the patients were female. The 20 most common conditions among these individuals were as follows: skin disorders, 43%; osteoarthritis and joint disorders, 34%; back problems, 24%; disorders of lipid metabolism, 22%; upper respiratory disease (excluding asthma), 22%; anxiety, depression, and bipolar disorders, 20%; chronic neurologic disorders, 20%; hypertension, 18%; headaches, including migraine, 14%; diabetes mellitus, 14%; arrhythmias, 13%; esophageal disorders, 10%; asthma, 9%; thyroid disorders, 9%; iron deficiency and other anemia, 9%; bowel disorders, 9%; cancer, 8%; biliary and liver disorders, 8%; obstructive pulmonary disorders, 8%; and coronary heart disease, 8%. Ten of the 15 most prevalent disease groups were more common in women in almost all age groups, whereas disorders of lipid metabolism, hypertension, and diabetes were more common in men. The prevalence of 7 of the 10 most common groups increased with advancing age. Prevalence also varied across ethnic groups (whites, blacks, and Asians). steak, sausage, biscuit and gravy, fried okra and squash, strawberries, black-eyed peas, grits, corn, cornbread, and pecan pie. A survey by the Centers for Disease Control and Prevention (CDC), published in 2012, indicates that only 1% of adults in Oklahoma are free from risk factors for or behaviors increasing the risk for heart disease—the highest rate for any state in the nation (15). Oklahomans also are less likely to report eating 5 or more servings of fruits and vegetables a day, and they are the most likely to be overweight. BEDBUGS AND SNIFFING DOGS Canines trained to detect bedbugs did big business in Dallas during the summer of 2012 (13), and that infestation may be back this summer. Bedbugs are resilient and can travel on everything. As someone said, “It’s basically a hitchhiker. It goes on suitcases and people spread it to other people. And once they make their way into a home, getting rid of them can cost several thousand dollars.” Apparently there is a pheromone in the bedbugs that dogs can smell. Dogs are about 97% accurate in finding the bugs, while humans are only about 30% accurate. DROWSY DRIVING According to a study by the CDC, one in 24 motorists admitted to falling asleep behind the wheel in the past month (16, 17). The problem is more common in men than women and in drivers aged 25 to 34 compared to older drivers. According to Angie Wheaton, the lead author of the CDC study, approximately 2.5% of all fatal motor vehicle crashes (around 730 in 2009) involved drowsy drivers, as did 2% of crashes that resulted in nonfatal injuries (around 30,000 in 2009). They also found that around 4% of respondents fell asleep while driving in the previous year. The government estimated that approximately 3% of fatal traffic crashes involve drowsy drivers, but some studies have put that estimate as high as 33%. Brief moments of nodding off can be extremely dangerous, particularly when traveling 60 miles per hour. A single second translates to moving 90 feet, the length of 2 school buses. According to Dr. Kingman Strohl, a pulmonologist in Cleveland, a typical driver makes about 1000 decisions a minute. If a person has not slept for 18 consecutive hours, his or her impairment on those decision-making tasks is similar to that of someone above the legal alcohol limit. Everyone knows about driving and alcohol drinking, but there is much less emphasis on the importance of sleep before driving. GRAPHOLOGY I have kept a visitor’s book in my office for years and request a signature and address from all those willing to provide it. A number of years ago, while visiting The Greenbrier in West Virginia, I took a class on graphology. The teacher talked about letters leaning to the left or right, whether or not the long letters touched the top line or the lower letters went below the lower line, and whether or not there were lively movements in the top one and flamboyant swirls in the lower ones and what they meant. She recommended that potential spouses before marriage have a couple of paragraphs of their handwriting analyzed by a graphologist. Sherlock Holmes asked Dr. Watson in The Sign of Four, “What do you make of this fellow’s scribble?” (14). “Look at his long letters,” he said. “They hardly arise above the common herd. That d might be an a, and that l an e. Men of character always differentiate their long letters, however illegibly they may write. There is vacillation in his k’s and self-esteem in his capitals.” FALLING TELEVISIONS According to Kim Painter, falling TV sets have killed >200 children since 2000 (18). The Consumer Products Safety Commission showed that 29 people in the US, most of them children, were killed by falling TVs in 2011 alone, and 18,000 people a year in the US, most of them children, are treated for injuries from falling TVs. That is happening despite the widespread switch to lighter flat-screens. Safety experts say the switch may actually be making the problem worse, because consumers often take old, heavy sets out of their family rooms and put them atop unstable bedroom dressers and playroom shelves. Children climb up on furniture to turn the TV on and there goes the heavy television as well as the piece of furniture. The 50- to 100-pound TVs can crush a child. The TVs often are on shelves never designed to hold the heavy weight. Flatscreen TVs also fall on kids because parents do not install them in the safest way. Let’s secure these TVs, and if anchoring is not an option, place the TV on a low sturdy base and remove any items from the top that might attract children. THE LEAST HEART-HEALTHY STATE IN THE USA The official state meal of Oklahoma—designated by the legislature in 1988—includes barbecue pork, chicken-fried GUNS The US has about 315 million people and about 290 million guns. Germany has about 80 million people and 5.5 million April 2013 Facts and ideas from anywhere 205 guns (19). Germany has recently initiated a large registry that details every legal gun owner in the country, along with information about all of their firearms. The new gun database, which went into service January 1, 2013, allows law enforcement officials to scroll through lists of owners and their guns in seconds on their computers. And the gun owners did not resist the establishment of this registry. Many gun advocates in Germany say that if cars can be registered and regulated, so can weapons. It’s not quite that way in the USA, but the US has about 50 times as many guns as are present in Germany. In the US it is easy to acquire any number of weapons and unlimited amounts of ammunition. Those who pass laws make it possible. The National Rifle Association traditionally muzzles any congressional attempts at gun control laws. Surely there is a relation between the number of people killed with guns and the number of guns available. VIRGINIA TECH, FORT HOOD, AURORA, SANDY HOOK . . . Using news accounts and records from the Federal Bureau of Investigation (FBI) from 2006 through 2010, the most recent years for which complete records were available, USA Today identified 156 murders that met the FBI definition of mass killings, in which 4 or more people are killed by the attacker (20). The attacks killed 774 people, including at least 161 children aged 12 or younger. Mass killers, in other words, target Americans once every 2 weeks on average, in attacks that range from robberies to horrific public shooting sprees like the massacre in Newtown, Connecticut. The USA Today review did not include murders in 2011 or 2012, both of which were marked by a series of high-profile public shootings. The 2006 to 2010 killings offer a portrait of mass murder that in many ways belies the stereotype of a lone gunman targeting strangers: lone gunmen, such as the one who terrorized Sandy Hook Elementary School, account for fewer than half of the nation’s mass killers. About one quarter of mass murderers involved 2 or more killers. A third of mass killings did not involve guns. Mass murderers tend to be older than other killers, an average of nearly 32 years of age. Like all killers, they are overwhelmingly men. The mass killings during those 5 years accounted for about 1% of all murders during that time in the USA. DALLAS CRIME Despite increases in some major areas—rape, robbery, and murder—overall reported crime in Dallas dropped nearly 11% in 2012 compared to 2011, a record ninth consecutive year crime has fallen in the city (21, 22). The drop is in line with what is happening nationally and was driven by significant decreases in every area of property crime, which had about 7600 fewer offenses in 2012 than the previous year. Twenty percent more thieves were arrested in 2012 than in 2011 through the help of a task force that targets rings that buy and sell stolen property. Police Chief David Brown indicated that the longer a thief is in jail, the better the stats are going to be. Murders in Dallas in 2012 numbered 151, an increase from 133 the previous year. In comparison, Chicago had 506 206 murders in 2012, nearly twice as many killed than US troops in Afghanistan. MILITARY SUICIDES Suicides in the US military surged to a record 349 in 2012, far exceeding American combat deaths in Afghanistan (n = 295 Americans), and up from 301 in 2001 (23). Defense Secretary Leon Panetta and others have called the problem an epidemic. The problem appears to reflect severe strains on military personnel burdened with more than a decade of combat in Afghanistan and Iraq, complicated by anxiety over being forced out of a shrinking workforce. The 349 total in 2012 was the highest since the Pentagon began tracking suicides in 2001. The army, by far the largest of the military services, had the highest number of suicides among active-duty troops in 2012 at 182. The Marine Corps had the highest percentage increase—a 50% jump to 48. The Air Force had 59, and the Navy, 60 suicides, an increase in each of about 15% over the previous year. GENDERCIDE There are too many examples of global violence against women. Beverly Hill, who is founder and president of the Gendercide Awareness Project, calls it gendercide—the elimination of females, both young and old, through sex-selective abortion, infanticide, gross neglect, and in the case of older women (particularly widows), lack of access to food and shelter (24). The United Nations Population Fund, which tracks this problem, has estimated that 117 million women are missing in the world because of these practices. “Missing,” as Ms. Hill indicates, equals death. That’s more deaths than World War I and World War II combined. She indicates that it is no exaggeration to say that gendercide is an atrocity as colossal as any the world has seen. East Asia, South Asia, West Asia, the Middle East, Africa, and Southeastern Europe are all ravaged by gendercide. Every year, according to Ms. Hill, we lose 2 million baby girls to sex-selective abortion and infanticide alone. That equates to 4 girls every minute. The United Nations reports that China has the greatest sex imbalance in the world, with 10% of its female population eliminated; India and Afghanistan follow with 7%. These sex imbalances lead to a host of social problems. Contrary to popular belief, the status of women does not improve when females are in short supply. In fact, just the opposite occurs. Sex trafficking increases, as does the buying and selling of brides. Aging bachelors, unable to find women of appropriate age, marry ever younger girls. These child brides leave school and begin bearing children. Maternal death rates are high. Ms. Hill goes on to indicate that there is a strong correlation between sex imbalance and crime. Sex ratios apparently are the best predictors of murder rates in India—better predictors than poverty, illiteracy, or urbanization. Crime spiked in the Chinese regions where sex-selective technology first became available. And finally, Ms. Hill writes: “Gendercide proceeds from the belief that female life is disposable. Gendercide devastates the hopes of women everywhere. It is unworthy of us as human beings. It is time to end this slaughter.” Baylor University Medical Center Proceedings Volume 26, Number 2 WOMEN IN CONGRESS Of the 100 US Senators, 20 (20%) are women and of the 435 House Representatives, 78 (18%) are women; both of these are records (25). FIBRONACCI NUMBERS By definition, the first 2 numbers of the Fibronacci sequence are 0 and 1. Each subsequent number is the sum of the previous two (26). The Fibronacci sequence is: 0, 1, 1, 2, 3, 5, 8, 13, 21, 34, 55, 89, 144, etc. The ratio of any two consecutive numbers eventually approaches the “golden ratio” of 0.618. 1/11/22/33/55/88/1313/2121/3434/5555/8989/144 1.00.500.6670.600.6250.6150.6190.6180.6180.6180.618 The sequence made its first appearance in the West in the book Liber Abaci (1202) by Leonardo of Pisa, also known as Fibronacci. (The sequence first appeared in Indian literature centuries before.) The Fibronacci sequence is important in nature: it describes the branching in trees, the arrangement of leaves on a stem, the fruitlets of a pineapple, the flowering of an artichoke, the uncurling of a fern, and the arrangement of a pine cone. Fibronacci numbers are truly fascinating. They have many implications for mathematicians. PUBLIC HIGH SCHOOL GRADUATION RATES The percentage of students at public high schools who graduate on time has reached its highest level in nearly 40 years (27). The public high school graduation rate, i.e., students earning a diploma within 4 years of starting high school, reached 78% for the class of 2010, the highest rate since 1974. Graduation rates improved for every race and ethnicity in 2010. The student graduation rates were as follows: Asians, 93%; Whites, 83%; Hispanics, 74%; American Indians and Alaskan natives, 69%; African Americans, 66%. In 2010, 38 states had higher graduation rates, while rates for the other 12 states were flat. SMART DEVICES WINNING Using a cellphone during class used to mean possible confiscation and perhaps detention for students (28). Now, a growing number of schools are turning to the smart phones students bring to school as an instructional device that can augment classroom learning. Teachers ask students to use their smart phones to look up vocabulary words, take photos of an assignment written on the board, or text themselves homework reminders. Teachers use countless apps to better connect students with coursework on a platform they are familiar with. The Verizon Foundation chose 12 schools in 2012 and 24 in 2013 to receive up to $50,000 in grant funding to bring laptops, tablets, and mobile phones to class. The focus is on science, math, and technology studies. The apps offer an easy way to do research, solve problems quickly, and motivate students. IQ The average American in 1900 had an IQ that by today’s standards would measure about 67 (29). Since the traditional April 2013 definition of mental retardation was an IQ < 70, that leads to the remarkable conclusion that most Americans at the beginning of the 20th century would today be considered “intellectually disabled.” The trend of rising intelligence is known as the Flynn effect, named for James R. Flynn, the New Zealander who pioneered this area of research. The average American IQ has been rising steadily by 3 points a decade. Spaniards gained 19 points over 28 years, and the Dutch, 20 points over 30 years. Kenyan children gained nearly 1 point a year. These figures are from Flynn’s new book entitled Are We Getting Smarter? It’s an uplifting tale, a reminder that human capacity is on the upswing. The country that tops the IQ charts is Singapore, at 108. Singaporeans have great respect for learning and an outstanding school system. Flynn argues that IQ is rising because in industrialized societies we give our brains a constant mental workout, much greater than when we were mostly living on isolated farms. Modern TV shows and other entertainment can be cognitively demanding, and video games require more thought that Solitaire. It appears that talent is universal but opportunity is not. Our public school budgets are being slashed. According to Nicholas Kristof, some 61 million children in the world still don’t attend primary school. The cost of a single F-35 fighter could pay for more than 4 years of the Reading Is Fundamental program in the entire USA. DEGREES AND INCOMES OF US ETHNIC GROUPS As reported by Siegel (30), in 2010, the percentages of Americans aged 25 and older with at least a bachelor’s degree were as follows: all US, 28%; Asians, 49%; Whites, 31%; Blacks, 18%; and Hispanics, 13%. The median household income in the US in 2010 was as follows: all US, $49,800; Asians, $66,000; Whites, $54,000; Hispanics, $40,000; and Blacks, $33,300. TWO INTERESTING HERBIVORES My friend, Dr. Vince Friedewald in Austin, sent me the following information on camels and kangaroos (31). Camels can live where food and water are scarce. They have an amazing ability to conserve water. When dehydrated, a camel can drink as much as 120 liters (32 gallons) in 15 minutes. To conserve water, camels can regulate their body temperature so that they hardly sweat, their kidneys can concentrate the urine, and they store a lot of water in their erythrocytes, which have the ability to swell to over twice their normal size without bursting. The camel’s hump functions as a reservoir of adipose tissue that they can metabolize to provide emergency energy. As the fat is depleted, the hump wilts and flops to one side. The fatty humps also help keep the animal cool, as fat conducts the sun’s heat relatively slowly and their woolly covering provides extra insulation. Thus, camels can go for weeks with little or no water or food. Kangaroos in Australia have the ability to cross vast distances in search of food and water, keys to their survival. Capable of an 8-meter (25-foot) single bound across level ground, the red kangaroo is one of the world’s greatest long jumpers. Thanks to large feet and strong legs, it can travel at over 50 kilometers (30 miles) per hour for hours. While a kangaroo’s hind legs are big and powerful, they can’t work independently of each other, Facts and ideas from anywhere 207 and so kangaroos have to hop on two feet. The hind leg tendons are strong and elastic. With every hop, elastic energy is recaptured in the tendons ready for the next jump. The kangaroos use their long tail for balance and counterbalance. It swings up as the animal leaves the ground and down as the legs swing back with every bounce to help propel the kangaroo. A kangaroo’s big toes are in the center of the other toes, not to one side like in humans, and are thus in line with their leg bones, enabling them to push off with great force. The kangaroo has a pouch to carry the newborn for about 10 months after birth. To win the Olympics a human has to jump further than a kangaroo (to nearly 9 meters). The best jumper of all is the snow leopard, who can leap 15 meters. THE AVALANCHE OF UNFUNDED DEBT Mortimer B. Zuckerman, the editor of U.S. News & World Report and the publisher of The New York Daily News, in a December 2012 column paints the picture well (32, 33): “A sound in the mountain range. . . . It’s the sound made by an avalanche, the trillions of dollars of debt that’s heading our way, gathering speed and mass. For most people, it’s out of earshot.” Liabilities are not set out by our government in accordance with well-established norms of the private sector, where our overhang of liabilities would set off alarm bells in the markets, with boards of directors in emergency sessions. We have gone from being the world’s largest creditor nation, with no foreign debt at the end of World War II, to the world’s largest debtor, with half of our public debt held by foreign countries. During the last 4 years alone, our national debt has grown by more than $5 trillion to over $16 trillion. Although the Federal Reserve is keeping borrowing rates historically low, the cost of paying interest on the debt for fiscal year 2012 was just under $360,000,000,000! Despite our huge annual deficit, the greatest fiscal challenge to the US government, opines Zuckerman, is its total liabilities. Our federal balance sheet, he indicates, does not include the unfunded obligations of Medicare, Social Security, and the future retirement benefits of federal employees. The estimated unfunded total of these commitments is more than $87 trillion, or 550% of our gross domestic product. And the debt per household is more than 10 times the median family income! The real annual accrued expense of Medicare and Social Security is $7 trillion. The government’s balance sheet does not include any of these obligations but focuses on the current year deficits and the accumulated national debt. The annual budget deficit, however, is only about one fifth of the more accurate figure! Zuckerman argues that if Americans saw our financial statements in the same way that public companies report their pension liabilities, these liabilities would require borrowing on a scale that would not only bankrupt the programs themselves but would bankrupt the entire government. Zuckerman adds that the Social Security programs and other mandatory programs are not subject to an annual spending limit. Today, <40% of our budget is actually decided by Congress and the president, down from 62% 40 years ago. Our liabilities are so huge and are multiplying so fast that eventually they cannot be honored. Today, all payroll taxes for Social Security and Medicare are spent in the year that they 208 are collected, leaving no leftovers for the unfunded obligations! And this does not take into account other risks such as the fact that the Federal Housing Authority confronts a $16.3 billion net deficit after its latest audit that may force a taxpayer bailout for the first time in its 78-year history. And, by 2016, the Disability Insurance Trust Fund will be fully depleted. US TAX RATES Taking into account all taxes on earnings and consumer spending—including federal, state, and local income taxes, Social Security and Medicare payroll taxes, excise taxes, and state and local sales taxes—the US average effective tax rate is around 40%. High tax rates—on labor, income, and consumption, as indicated by Prescott and Ohanian (34)—reduce the incentive to work by making consumption more expensive relative to leisure. The incentive to produce goods for the market is particularly depressed when the tax revenue is returned to households either as government transfers or transfers in kind—such as public schooling, police and fire protection, food stamps, and health care—that substitute for private consumption. In the 1950s, when European tax rates were low, many Western Europeans, including the French and Germans, worked more hours per capita than did Americans. Over time, tax rates that affect earnings and consumption rose substantially in Western Europe and have accounted for much of the nearly 30% decline in work hours in several European countries—to 1000 per adult per year today from around 1400 in the 1950s. The average American today works just over 1300 hours per year, the same as Japan, which has the same tax rate essentially as does America. OBAMACARE’S INDEPENDENT PAYMENT ADVISORY BOARD The Independent Payment Advisory Board (IPAB) is a government-appointed panel to help slow the growth of Medicare spending (35). The 15-person IPAB will propose Medicare cuts if the growth in the program’s spending exceeds inflationary targets. Some fear that their decisions will lead to rationing. The law, however, gives the panel no authority to ration care or cut benefits for Medicare recipients. It can’t touch reimbursement to hospitals until 2020. Instead, it is expected to find savings by eliminating fraud and reducing payments to private insurance companies that work with Medicare and prescription drug providers. And, it can only do that if the government is projected to spend more than it’s supposed to. Each spring, the Office of the Actuary of the Centers for Medicare and Medicaid Services forecasts how much the programs will cost 2 years in the future. On April 30, 2013, the panel will issue its per capita estimates for 2015. The actuary also will release a spending target, based on predictions about the pace of health care inflation. If the increase in expected Medicare costs exceeds the spending target, the IPAB steps in to propose cuts. It will take a 60% Senate vote to reject its recommendations, and then legislators must find alternate cuts that achieve the same savings. The law allows them to debate the IPAB’s proposal for 30 hours maximum, making it filibuster proof. How will the White House recruit the board members? So far no IPAB members have been appointed, even though the Baylor University Medical Center Proceedings Volume 26, Number 2 board is supposed to get to work by April 2013. The law requires the panel to be made up of prominent physicians, economists, hospital executives, and insurance industry representatives. Candidates are subject to Senate approval, which means that they must endure potentially hostile public hearings. Board members willing to go through all that must also agree to serve for 6 years, full time; they have to quit their current jobs because of conflict of interest concerns. The annual salary for each board member is $165,300. And, the life of an IPAB member may be rather dull since its powers kick in only if spending is surging. It’s no wonder that Obama has yet to announce his candidates. If there is no IPAB in place by the time its services are needed, the law allows the secretary of the US Department of Health and Human Services to do its job until the panel is up and running. I can’t imagine who would want to be one of the 15 on that panel! US OIL BOOM It’s really unbelievable, at least to me. The US oil output is surging so fast that the USA could soon overtake Saudi Arabia as the world’s biggest producer (37). Driven by high prices and new drilling methods, US production of crude and other liquid hydrocarbons rose approximately 7% in 2012 to an average of just under 11 million barrels per day. This is the fourth straight year of crude increases and the biggest single year since 1951. The Energy Department forecast that US production of crude and other liquid hydrocarbons, which include biofuels, will average 11.4 million barrels per day in 2013. That would be a record for the US and just below Saudi Arabia’s output of 11.6 million barrels per day. The production is forecast to reach 13 to 15 million barrels per day in the US by 2020, helping to make North America “the new Middle East.” I used to think that making the US “energy independent” was a joke, but it is great to see that it isn’t. WATER When the headline of the Dallas Morning News reads “The word on water: Conserve,” we have a problem (36). The state is running out of water, as shown in Figure 3. The projected Texas population in the next 50 years is expected to grow from 25 million to about 46 million (54%↑) and the projected need for additional water from 3.62 to 8.33 million acre-feet per year (43%↑). Get ready. Life with limited water will not be the same. Quick showers, low-flush toilets, and irrigation restrictions will be the norm. San Antonio, Texas, apparently is already in the swing of water conservation, and we must follow in Dallas. BALLPOINT PEN We all use them. Peter Pesic summarized the book Ballpoint written by Hungarian author György Muldova (38, 39). The Hungarians are astonishingly creative. Eleven won the Nobel Prize during the 20th century, far more per capita than from other nations. There were other Hungarian geniuses, including mathematician John Von Neumann and physicists Leo Szilard and Edward Teller. Talented students flourished in some Budapest schools until the 1920s when the government began limiting university admissions to those “who are completely reputable in respect of their national allegiance,” effectively excluding Jews, who thereafter emigrated when they could. One of the Jewish beneficiaries of those Budapest schools was László Biró (1899–1985), a journalist and artist in the 1930s who noted that the ink used for newspapers dried relatively quickly compared with the ink for fountain pens. Handwritten papers had to be carefully blotted or set aside until the ink dried. Biró tried using quick-drying ink in a fountain pen, but the fluid was too thick to flow down to the nib and simply clogged the reservoir. He solved the problem of how to deliver thick, quick-drying ink to a paper surface without requiring the ink to flow by closing the end of the pen instead of using a nib, leaving an opening with just enough room for a tiny metal ball that would spin against the ink in the reservoir, distributing it to the paper. Through much trial and error and with the help of an early backer and business partner, Endor Goy (1896–1991), Biró developed a working ballpoint pen. The two men signed a contract to produce and market the pen in 1938. Biró kept refining the pen and experimenting with recipes for the ink paste essential for his concept while fleeing dangers in Europe and finally settling in Argentina. Though Biró faced the hardships of wartime immigration, he soon started up a pen-manufacturing operation in Argentina. Biró’s story is relatively well known in much of the English-speaking world. “Biró” is synonymous with ballpoint pen. In Argentina, the pen is known as a “Birome,” and Biró’s birthday, September 29, is celebrated as “Inventor’s Day” in Argentina. Thus, the ballpoint took its place alongside the zipper, the pencil, and the paperclip devised by inventors who long struggled to produce objects we now take for granted. Figure 3. The supply and demand for water in Texas. Reprinted with permission from The Dallas Morning News. April 2013 Facts and ideas from anywhere 209 EPPIE AND POPO These were their nicknames. They were identical twins, Esther Pauline Friedman Lederer and Pauline Esther Friedman Phillips, aka Abigail Van Buren, born in Sioux City, Iowa, on July 4, 1918. They shared a joint wedding and honeymoon trip. Esther was the first to become a columnist, taking over the Chicago Sun-Times’ “Ann Landers” column in 1955. Pauline, living in California, started a replacement advice column for the San Francisco Chronicle, “Dear Abby,” in 1956. She created her own byline, combining a biblical wise woman with the eighth president of the US. Within 2 years, both columns were in a combined 400 newspapers. Pauline’s Dear Abby column at its peak appeared in 1400 papers. Life magazine in 1958 said the sisters were “the most widely read and most quoted women in the world.” For a long time they did not speak to each other, but their differences were eventually patched up. Mother and daughter started sharing the byline in 2000, and Jeanne Phillips took over in 2002. Amazing (40). SPORTS Stan Musial: Years ago I was invited to give a talk in St. Louis by the son-in-law of Stan Musial, a physician, who brought me a baseball signed by Stan-the-Man. It is one of my favorite sport collectibles. When I was growing up, Musial was one of my baseball heroes. He played 22 years in the Major Leagues, all with St. Louis, in 3026 games. He had 10,972 at-bats and only struck out just over 600 times (41). He had 3630 hits, scored 1942 runs, had 6134 total bases, and hit 475 home runs. He won the National League batting title 7 times and participated in 24 all-star games. And all the time he was a great guy. He contributed to his community generously. He was 6 feet tall and weighed 175 pounds. Those also are my dimensions, but Musial had a much better eye for the ball. Stacy Lewis: She is the first American to be named Player of the Year on the Ladies Professional Golf Association tour since 1994 (42). She had severe scoliosis and wore a back brace 18 hours a day for 7 years as a child. She had a steel rod with 5 screws installed in her spine just after getting her high school diploma. She didn’t know at that time whether she could play golf again, but she certainly did. Johnny Manzial: As a red-shirt freshman, “Johnny Football” won the Heisman Trophy Award for 2012 and shortly after doing so set the Cotton Bowl record for total offense with 516 yards (43, 44). Seven other college football players have played in the Cotton Bowl after receiving the Heisman Award, but none came close to doing what Johnny Manzial did in the January 2013 classic. Golf: The average professional golfer takes 15,000 steps during an 18-hole round, walks 7 miles, and burns 2000 calories. The numbers when using a cart are unclear. BODY WEIGHT IN THE NATIONAL FOOTBALL LEAGUE Fran Tarkenton, a National Football League quarterback from 1961 to 1978 and member of the Pro Football Hall of Fame, in a recent piece in The Wall Street Journal discussed body weight of professional football players when he played 210 and subsequently (45). When Tarkenton entered pro football in 1961, every member of his offensive line weighed <250 pounds. During his last year, 1978, the biggest lineman on his team weighed 260 pounds. No Super Bowl–winning team had a 300 pounder on its roster until the 1982 Washington Redskins. Now, it is unusual for a team to have fewer than ten 300 pounders. This year’s Super Bowl teams, the San Francisco 49ers and the Baltimore Ravens, had twenty-four 300 pounders between them. Have players gotten bigger thanks to genetics, diet, and nutrition? Or is there something else going on? Shortly after retiring from football, Tarkenton learned from an owner of one of the biggest gym chains in the country that muscles can only get so big by weightlifting regimes alone. Huge muscles come from performance-enhancing drugs, which Tarkenton indicated were just starting to enter professional football during his time. The National Football League does not talk about steroids or human growth hormone, but these drugs make players bigger, faster, and stronger, and they are used widely in football. Why do so many former players look like miniature versions of themselves after they retire? In their most recent collective-bargaining agreement, signed in 2011, the National Football League and the Player’s Union agreed to start testing players for human growth hormone. Yet, two seasons later there still isn’t any testing! (In contrast, Major League Baseball in recent years worked out a testing regime that includes human growth hormone.) At the college football level, meanwhile, testing looks almost exclusively for recreational drugs, with practically no attention to performance-enhancing ones. Although everyone claims to care about player safety at all levels of the game, the use of performance-enhancing drugs, which have made current players bigger and stronger than ever, causes collisions to be more violent and players therefore to suffer worse injuries. These violent encounters on the field not only affect the safety of the players during games but they clearly affect long-term health—dementia, Alzheimer’s disease, depression, suicide, and early death. William Clifford Roberts, MD 1 February 2013 1. 2. 3. 4. 5. 6. Landers J. U.S. losing ground on health frontier. Dallas Morning News, January 15, 2013. Tavernise S. Study: People living longer around world. New York Times, December 14, 2012. Landers J. Obesity spreads in wider world. Dallas Morning News, January 20, 2013. Landers J. Obesity weighs on U.S. productivity. Dallas Morning News, August 14, 2012. Kwoh L. Want to be CEO? What’s your BMI? Wall Street Journal, January 16, 2013. Esteri M. Is this the end of the soft drink era? Wall Street Journal, January 19–20, 2013. Baylor University Medical Center Proceedings Volume 26, Number 2 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Berry I, Gee K. The U.S. milk business is in ‘crisis.’ Wall Street Journal, December 11, 2012. Loprinzi PD, Kohli M. Effect of physical activity and sedentary behavior on serum prostate-specific antigen concentrations: results from the National Health and Nutrition Examination Survey (NHANES), 2003–2006. Mayo Clin Proc 2013;88(1):11–21. Sidhu D, Naugler C. Fasting time and lipid levels in a community-based population: a cross-sectional study. Arch Intern Med 2012;172(22):1707– 1710. LeBlanc PM, Hollinger KA, Klontz KC. Tattoo ink-related infections—awareness, diagnosis, reporting, and prevention. N Engl J Med 2012;367(11):985–987. Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA; Symplicity HTN-2 Investigators. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126(25):2976– 2782. St Sauver JL, Warner DO, Yawn BP, Jacobson DJ, McGree ME, Pankratz JJ, Melton LJ 3rd, Roger VL, Ebbert JO, Rocca WA. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc 2013;88(1):56–67. Lopez R. Business booming for dogs trained to sniff out bedbugs. Dallas Morning News, September 2, 2012. Campbell J. The vacillation of his k’s [Review of the book The Missing Ink, by P. Hensher, Faber, 270 pages]. U.S. News & World Report, December 2012. Fang J, Yang Q, Hong Y, Loustalot F. Status of cardiovascular health among adult Americans in the 50 states and the District of Columbia, 2009. J Am Heart Assoc 2012;1(6):e005371. Wheaton AG, Chapman DP, Presley-Cantrell LR, Croft JB, Roehler DR; Centers for Disease Control and Prevention (CDC). Drowsy driving—19 states and the District of Columbia, 2009–2010. MMWR Morb Mortal Wkly Rep 2013;61:1033–1037. Strobbe M. 4% admit dozing while they drove. Dallas Morning News, January 4, 2013. Painter K. Falling TVs can kill, but few parents are aware of the risk. U.S. News & World Report, December 13, 2012. Birnbaum M. Germany begins gun registry. Washington Post, January 20, 2013. Hoyer M, Heath B. Virginia Tech, Fort Hood, Aurora, Sandy Hook . . . names only hint at mass killings crisis: one every two weeks. USA Today, December 19, 2012. Eiserer T. Crime stats down again. Property offenses lead drop in 2012, but rape, murder rise slightly. Dallas Morning News, January 15, 2013. Eiserer T. ‘12 murder total up, still among lowest. Dallas Morning News, January 3, 2013. April 2013 23. Burns R. Suicides in military hit record in ‘12. Dallas Morning News, January 15, 2013. 24. Hill B. Females fall victim to ‘gendercide.’ Dallas Morning News, January 15, 2013. 25. Camia C. Record number of women in Congress. USA Today, January 4, 2013. 26. Doroghazi RM. Fibronacci numbers. Physician Investor Newsletter, May 14, 2012. 27. Layton L. More making it through high school. Washington Post, January 22, 2013. 28. Shane B. Smart devices make for smart kids. USA Today, December 28, 2012. 29. Kristof N. As long as IQs are climbing . . . Dallas Morning News, December 26, 2012. 30. Siegel L. Rise of the tiger nation. Wall Street Journal, October 27–28, 2012. 31. Why camels have the hump? Why are kangaroos expert jumpers? www. howitworksdaily.com, October 2009. 32. Zuckerman MB. Brace for an avalanche of unfunded debt. U.S. News & World Report, January 6, 2013. 33. Zuckerman MB. For the U.S. economy the news is bad and worse. U.S. News & World Report, January 6, 2013. 34. Prescott EC, Ohanian LE. Taxes are much higher than you think. Wall Street Journal, December 12, 2012. 35. Leonard D. The boring, awful life of a death panelist. Bloomberg Businessweek, January 21–27, 2013. 36. Shannon K. The word on water: conserve. Dallas Morning News, January 23, 2013. 37. Fahay J. U.S. sees oil output surge. Dallas Morning News, October 24, 2012. 38. Pesic P. The man who changed the way we write. Wall Street Journal, August 17, 2012. 39. Moldova G. Ballpoint: A Tale of Genius and Grit, Perilous Times, and the Invention That Changed the Way We Write. North Adams, MA: New Europe, 2012. 40. Miller S. Dear Abby columnist gave advice to millions. Wall Street Journal, January 18, 2013. 41. Nightengale B. “The Man” crush. USA Today, January 21, 2013. 42. DiMeglio S. Underdog Lewis now atop LPGA. USA Today, November 15, 2012. 43. Hairopoulos K. Aggies make loud statement. Dallas Morning News, January 5, 2013. 44. Sherrington K. Can’t be beat. Dallas Morning News, January 5, 2013. 45. Tarkenton F. When it comes to doping, pro football punts. Wall Street Journal, January 31, 2013. Facts and ideas from anywhere 211 Selected published abstracts of Baylor researchers AMERICAN JOURNAL OF CARDIOLOGY Necropsy findings early after transcatheter aortic valve implantation for aortic stenosis Roberts WC, Stoler RC, Grayburn PA, Hebeler RF Jr, Ko JM, Brown DL, Brinkman WT, Mack MJ, Guileyardo JM Am J Cardiol 2013;111(3):448–452. Reprinted with permission from Elsevier. Although transcatheter aortic valve implantation has been available for 10 years, reports of cardiovascular morphologic studies after the procedure are virtually nonexistent. The investigators describe such findings in 2 patients, both 86 years of age, who died early (hours or several days) after transcatheter aortic valve implantation. Although the prosthesis in each was seated well, and each of the 3 calcified cusps of the native aortic valves was well compressed to the wall of the aorta, thus providing a good bioprosthetic orifice, the ostium of the dominant right coronary artery in each was obliterated by the native right aortic valve cusp. Atherosclerotic plaques in the common iliac artery led to a major complication in 1 patient, who later died of hemorrhagic stroke. The other patient developed fatal cardiac tamponade secondary to perforation of the right ventricular wall by a pacemaker catheter. AMERICAN JOURNAL OF NEURORADIOLOGY Interobserver variability in retreatment decisions of recurrent and residual aneurysms McDonald JS, Carter RE, Layton KF, Mocco J, Madigan JB, Tawk RG, Hanel RA, Roy SS, Cloft HJ, Klunder AM, Suh SH, Kallmes DF AJNR Am J Neuroradiol 2012 Oct 25 [Epub ahead of print]. Reprinted with permission from the American Society of Neuroradiology. Background and purpose: The degree of variation in retreatment decisions for residual or recurrent aneurysms among endovascular therapists remains poorly defined. We performed a multireader study to determine what reader and patient variables contribute to this variation. Materials and methods: Seven endovascular therapists (4 neuroradiologists, 3 neurosurgeons) independently reviewed 66 cases of patients treated with endovascular coil embolization for ruptured or unruptured aneurysm. Cases were rated on a 5-point scale recommending for whether to retreat and a recommended retreatment type. Reader agreement was assessed by intraclass correlation coefficient and by identifying cases with a “clinically meaningful difference” (a difference in score that would result in a difference in treatment). Variables that affect reader agreement and retreatment decisions were examined by using the Wilcoxon signed-rank test, Pearson χ2 test, and linear regression. Results: Overall interobserver variability for decision to retreat was moderate (ICC = 0.50; 95% CI, 0.40–0.61). Clinically meaningful differences between at least 2 readers were present in 61% of cases and were significantly more common among neuroradiolo212 gists than neurosurgeons (P = .0007). Neurosurgeons were more likely to recommend “definitely retreat” than neuroradiologists (P < .0001). Previously ruptured aneurysms, larger remnant size, and younger patients were associated with more retreat recommendations. Interobserver variability regarding retreatment type was fair overall 0.25 (95% CI, 0.14–0.41), but poor for experienced readers 0.14 (95% CI, 0–0.34). Conclusions: There is a large amount of interobserver variability regarding the decision to retreat an aneurysm and the type of retreatment. This variability must be reduced to increase consistency in these subjective outcome measurements. BREAST CANCER RESEARCH AND TREATMENT Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer Blum JL, Barrios CH, Feldman N, Verma S, McKenna EF, Lee LF, Scotto N, Gralow J Breast Cancer Res Treat 2012;136(3):777–788. Reprinted with permission from Springer. We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0%, respectively, odds ratio 0.70; 95% CI: 0.5–1.0) and significantly shorter progression-free survival (PFS: median 112.0 days [3.7 months] vs. 150.0 days [4.9 months]; P < 0.0001) and overall survival (OS: median 396.0 days [13.0 months] vs. 666.0 days [21.9 months]; P < 0.0001). In multivariate analysis by backward elimination, significantly improved ORR (P = 0.0036), PFS (P < 0.0001) and OS (P < 0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63% of patients. Overall, 7% of patients discontinued and two patients (<1%) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (P < 0.0001 PFS/OS) or diarrhea (P = 0.004 OS; P = 0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in line with previous phase III trials in MBC. Proc (Bayl Univ Med Cent) 2013;26(2):212–214 CLINICAL TRANSPLANTATION Safety and tolerability of the T-cell depletion protocol coupled with anakinra and etanercept for clinical islet cell transplantation Takita M, Matsumoto S, Shimoda M, Chujo D, Itoh T, Sorelle JA, Purcell K, Onaca N, Naziruddin B, Levy MF Clin Transplant 2012;26(5):E471–E484. Reprinted with permission from John Wiley and Sons. Background: Islet cell transplantation (ICT) is a promising approach to cure patients with type 1 diabetes. We have implemented a new immunosuppression protocol with antithymoglobulin plus anti-inflammatory agents of anakinra and eternacept for induction and tacrolimus plus mycophenolate mofetil for maintenance [T-cell depletion with anti-inflammatory (TCD-AI) protocol], resulting in successful single-donor ICT. Methods: Eight islet recipients with type 1 diabetes reported adverse events (AEs) monthly. AEs were compared between three groups: first infusion with the TCD-AI protocol (TCD-AI-1st) and first and second infusion with the Edmonton-type protocol (Edmonton-1st and Edmonton-2nd). Results: The incidence of symptomatic AEs within the initial three months in the TCD-AI-1st group was less than in the Edmonton-1st and Edmonton-2nd groups, with a marginally significant difference (mean ± SE: 5.5 ± 0.3, 7.5 ± 0.5, and 8.3 ± 1.3, respectively; P = 0.07). A significant reduction in liver enzyme elevation after ICT was found in the TCD-AI-1st group compared with the Edmonton-1st and Edmonton-2nd groups (P < 0.05). Because of AEs, all patients in the Edmonton protocol eventually converted to the TCD-AI protocol, whereas all patients tolerated the TCD-AI protocol. Conclusions: TCD-AI protocol can be tolerated for successful ICT, although this study includes small cohort, and large population trial should be taken. GENE THERAPY Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasoundtargeted microbubble delivery Chen S, Shimoda M, Chen J, Grayburn PA Gene Ther 2012 Nov 15 [Epub ahead of print]. Reprinted with permission from Nature Publishing Group. It has been proposed that thymosin beta 4 (TB4)-protein delivery stimulates differentiation of resident adult WT1-positive cardiac progenitor cells, but with very low efficiency. We determined whether gene therapy with human TB4 stimulates proliferation of resident adult cardiac progenitor cells in normal rat heart. Ultrasound-targeted microbubble destruction (UTMD) was used to deliver the human TB4 gene under a piggybac transposon plasmid to normal rat heart. The rat hearts were assayed by quantitative reverse transcription-PCR and immunohistology with a confocal microscope at 1, 2, 3, 4 and 12 weeks after UTMD. Exogenous TB4 stimulation resulted in the presence of WT1-positive cardiac progenitor cells from epicardium to endocardium. TB4 stimulated angiogenesis and arteriogenesis. One month after TB4 gene therapy by UTMD, the percentage of NKX2.5-positive cardiomyocytes was 5.5 ± 1.0% and NKX2.5 mRNA was 24-fold higher than in the control groups (P < 0.001). Similar results were found for ISL-1, BrDu, Ki-67, April 2013 PHH3 and aurora B (P < 0.001). Cardiac-specific delivery of exogenous human TB4 gene efficiently stimulates proliferation and differentiation of resident WT1-positive adult cardiac progenitor cells into three intact cardiac cell lineages—vascular endothelial cells, coronary artery smooth muscle cells and cardiac muscle cells in normal adult rat heart. JOURNAL OF INTERVENTIONAL CARDIOLOGY A pilot study of prasugrel followed by post-procedural maintenance with clopidogrel in patients receiving percutaneous coronary intervention Benjamin MM, Filardo G, Donsky MS, Schussler JM J Interv Cardiol 2012 Dec 30 [Epub ahead of print]. Reprinted with permission from John Wiley and Sons. Background: Dual anti-platelet therapy including clopidogrel or prasugrel is standard of care for patients receiving stents. Prasugrel has quicker onset so it can be loaded later than clopidogrel with greater efficacy. However, prasugrel is much more expensive than clopidogrel. Objectives: To describe the incidence of 30-day death from cardiovascular causes, myocardial infarction, unstable angina requiring intervention, and minor and major bleeding in patients loaded with 60 mg of prasugrel prior to percutaneous coronary intervention (PCI) and then continued on 75 mg of clopidogrel daily after the procedure. Methods: We reviewed sequential medical records of 102 patients (mean age: 67.8, male 68.6%, smokers: 22.6%, BMI: 29.5%, hypertension: 90.2%, DM: 33.3%, average ejection fraction: 49.7%) who underwent PCI (3.9% STEMI, 12.7% NSTEMI, 35.3% unstable angina and 48.1% electively) at Baylor University Medical Center between October 2009 and December 2011 who were loaded with prasugrel 60 mg prior to procedure, and then continued on 75 mg clopidogrel daily. Results: None of the patients died or experienced a myocardial infarction (MI) within 30 days of the procedure. Three patients experienced unstable angina requiring intervention but none had in-stent thrombosis or restenosis on repeat angiography. None of the patients experienced a major bleeding event. One patient developed a gastrointestinal bleed which did not require blood transfusion and the bleeding resolved on discontinuation of the clopidogrel. Conclusion: In this retrospective pilot study, a strategy of loading patients needing PCI with prasugrel 60 mg immediately prior to coronary intervention, then continuation of anti-platelet therapy with 75 mg clopidogrel daily was safe and effective. JOURNAL OF NURSING ADMINISTRATION Decisional involvement in Magnet®, magnet-aspiring, and nonmagnet hospitals Houston S, Leveille M, Luquire R, Fike A, Ogola GO, Chando S J Nurs Adm 2012;42(12):586–591. Reprinted with permission from Wolters Kluwer Health. Background: Empowered decision making can help establish innovative work cultures. Objective: This study used the Decisional Involvement Scale to determine differences in actual and preferred decisional involvement among staff RNs and administrators in Magnet®, Magnet-aspiring, and non-Magnet hospitals. Selected published abstracts of Baylor researchers 213 Methods: Two facilities were Magnet designated, 3 were Magnet aspiring, and 9 were non-Magnet. A total of 5000 staff RNs and administrators were asked to participate in the nonexperimental descriptive survey. Results: The difference observed in actual global scale score by Magnet status was statistically significant (P = .01). Respondents in Magnet hospitals had the highest actual global scale score on average, followed by Magnet-aspiring, then non-Magnet. Conclusions: Decisional involvement is higher among Magnet-designated than non-Magnet facilities. MICROBIAL PATHOGENESIS Dendritic cells and vaccine design for sexually-transmitted diseases Duluc D, Gannevat J, Joo H, Ni L, Upchurch K, Boreham M, Carley M, Stecher J, Zurawski G, Oh S Microb Pathog 2012 Nov 29 [Epub ahead of print]. Reprinted with permission from Elsevier. Dendritic cells (DCs) are major antigen presenting cells (APCs) that can initiate and control host immune responses toward either immunity or tolerance. These features of DCs, as immune orchestrators, are well characterized by their tissue localizations as well as by their subset-dependent functional specialties and plasticity. Thus, the level of protective immunity to invading microbial pathogens can be dependent on the subsets of DCs taking up microbial antigens and their functional plasticity in response to microbial products, host cellular components and the cytokine milieu in the microenvironment. Vaccines are the most efficient and cost-effective preventive medicine against infectious diseases. However, major challenges still remain for the diseases caused by sexually-transmitted pathogens, including HIV, HPV, HSV and Chlamydia. We surmise that the establishment of protective immunity in the female genital mucosa, the major entry and transfer site of these pathogens, will bring significant benefit for the protection against sexually-transmitted diseases. Recent progresses made in DC biology suggest that vaccines designed to target proper DC subsets may permit us to establish protective immunity in the female genital mucosa against sexually-transmitted pathogens. TRANSPLANTATION Sirolimus and cardiovascular disease risk in liver transplantation McKenna GJ, Trotter JF, Klintmalm E, Ruiz R, Onaca N, Testa G, Saracino G, Levy MF, Goldstein RM, Klintmalm GB Transplantation 2013;95(1):215–221. Reprinted with permission from Wolters Kluwer Health. Background: Two adverse effects of sirolimus are hypertriglyceridemia and hypercholesterolemia. These elevated levels often lead clinicians to discontinue the sirolimus from concerns of an increased cardiovascular disease (CVD) risk; however, evidence suggests that sirolimus might be cardioprotective. There are no published reports of sirolimus CVD in liver transplantation. Methods: We reviewed all 1812 liver recipients who underwent transplantation from 1998 to 2010, identifying a cohort using sirolimus as part of the initial immunosuppression (SRL Cohort) and a control group of the remaining patients from this period where SRL was never given (Non-SRL Control). A prospectively maintained database identified all episodes of myocardial infarction (MI), congestive heart failure (CHF), abdominal aortic aneurysm (AAA), and cerebrovascular accident and tracked triglyceride, high-density and low-density lipoproteins, and total cholesterol levels. A Framingham Risk Model calculated the predicted 10-year risk of CVD for both groups. Results: The SRL Cohort (n = 406) is older, more predominantly male, with more pretransplantation hypertension and diabetes and posttransplantation hypertension compared to Non-SRL Controls (n = 1005). The SRL Cohort has significantly higher triglyceride, lowdensity lipoprotein, and cholesterol levels at 6 months and 1 year. There is no difference in MI incidence in the SRL Cohort (1.0% vs. 1.2%) and no difference in AAA, cerebrovascular accident, and CHF. The Framingham Risk Model predicts that the SRL Cohort should have almost double the 10-year risk of CVD compared to the NonSRL Control (11% vs. 6%). Conclusions: Sirolimus causes hypertriglyceridemia and hypercholesterolemia, but it does not increase the incidence of MI or other CVDs. Considering the SRL Cohort has more cardiac risk factors and nearly double 10-year predicted CVD risk, the fact that the CVD incidence is similar suggests that sirolimus is in fact cardioprotective. If you are a Baylor researcher and would like your published abstract to be included in this section, please e-mail the PubMed citation to Cynthia. Orticio@BaylorHealth.edu. 214 Baylor University Medical Center Proceedings Volume 26, Number 2 2012 publications of the Baylor Health Care System medical and scientific staff ANESTHESIOLOGY AND PAIN MANAGEMENT 1. Mason KP, Green SM, Piacevoli Q; International Sedation Task Force. Adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the World SIVA International Sedation Task Force. Br J Anaesth 2012; 108(1):13–20. CARDIOLOGY/CARDIAC, VASCULAR, AND THORACIC SURGERY 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Adams J, Jordan S, Spencer K, Belanger J, Cheng D, Shock T, Karcher J. Energy expenditure in US automotive technicians and occupationspecific cardiac rehabilitation. Occup Med (Lond) 2012 Nov 8 [Epub ahead of print]. Askar M, Hsich E, Reville P, Nowacki AS, Zhang AW, Klingman L, Bakdash S, Baldwin W, Smedira N, Taylor D, Starling R, Gonzalez-Stawinski G. Ventricular assist devices (VAD) are highly significantly associated with class I HLA allosensitization. Hum Immunol 2012;73(Suppl):53. Benjamin MM, Filardo G, Donsky MS, Schussler JM. A pilot study of prasugrel followed by post-procedural maintenance with clopidogrel in patients receiving percutaneous coronary intervention. J Interv Cardiol 2012 Dec 30 [Epub ahead of print]. Benjamin MM, Khetan RA, Kowal RC, Schussler JM. Diagnosis of left ventricular noncompaction by computed tomography. Proc (Bayl Univ Med Cent) 2012;25(4):354–356. Benjamin MM, Roberts WC. Fatal aortic rupture from nonpenetrating chest trauma. Proc (Bayl Univ Med Cent) 2012;25(2):121–123. Brown CR, Brozzi NA, Vakil N, Shafii AE, Murthy SC, Pettersson GB, Mason DP. Donor lungs with pulmonary embolism evaluated with ex vivo lung perfusion. ASAIO J 2012;58(4):432–434. Chamogeorgakis T, Koval CE, Smedira NG, Starling RC, Gonzalez-Stawinski GV. Outcomes associated with surgical management of infections related to the HeartMate II left ventricular assist device: Implications for destination therapy patients. J Heart Lung Transplant 2012;31(8): 904–906. Chamogeorgakis T, Lima B, Shafii AE, Nagpal D, Pokersnik JA, Navia JL, Mason D, Gonzalez-Stawinski GV. Outcomes of axillary artery side graft cannulation for extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2012 Sep 20 [Epub ahead of print]. Chen S, Shimoda M, Chen J, Grayburn PA. Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasound-targeted microbubble delivery. Gene Ther 2012 Dec 6 [Epub ahead of print]. Deja MA, Grayburn PA, Sun B, Rao V, She L, Krejca M, Jain AR, Leng Chua Y, Daly R, Senni M, Mokrzycki K, Menicanti L, Oh JK, Michler R, Wróbel K, Lamy A, Velazquez EJ, Lee KL, Jones RH. Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation 2012;125(21):2639–2648. Dolmatch BL, Duch JM, Winder R, Butler GM, Kershen M, Patel R, Trimmer CK, Lopera JE, Davidson IJ. Salvage of angioplasty failures and complications in hemodialysis arteriovenous access using the FLUENCY Plus Stent Graft: technical and 180-day patency results. J Vasc Interv Radiol 2012;23(4): 479–487. Edgerton JR. Surgical therapy for atrial fibrillation. J Cardiovasc Med (Hagerstown) 2012;13(2):125–130. Proc (Bayl Univ Med Cent) 2013;26(2):215–230 14. Edgerton ZJ, Edgerton JR. A review of current surgical treatment of patients with atrial fibrillation. Proc (Bayl Univ Med Cent) 2012;25(3):218–223. 15. Falcone AM, Matter GJ, Schussler JM. Right atrial appendage thrombus found in a patient in normal sinus rhythm with normal right ventricular systolic function. Echocardiography 2012 Nov 27 [Epub ahead of print]. 16. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB 3rd, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR Jr, Smith SC Jr, Spertus JA, Williams SV. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol 2012;60(24):e44– e164. Also published in Circulation 2012;126(25):e354–e471, with executive summary published in Circulation 2012;126(25):3097–3137. 17. Filardo G, Hamilton C, Grayburn PA, Xu H, Hebeler RF Jr, Hamman B. Established preoperative risk factors do not predict long-term survival in isolated coronary artery bypass grafting patients. Ann Thorac Surg 2012;93(6):1943–1948. 18. Friedewald VE, Hare JM, Miller LW, Walpole HT Jr, Willerson JT, Roberts WC. The editor’s roundtable: advances in stem cell therapy for treatment of cardiovascular disease. Am J Cardiol 2012;110(6):807–816. 19. Friedewald VE, Kowal RC, Olshansky B, Yancy CW, Roberts WC. The editor’s roundtable: medical management of atrial fibrillation. Am J Cardiol 2012;109(4):563–569. 20. George BA, Roberts BJ, Grayburn PA. Diastolic left main coronary flow reversal as a marker of severe aortic regurgitation. Tex Heart Inst J 2012;39(5):764–765. 21. Glower D, Ailawadi G, Argenziano M, Mack M, Trento A, Wang A, Lim DS, Gray W, Grayburn P, Dent J, Gillam L, Sethuraman B, Feldman T, Foster E, Mauri L, Kron I; EVEREST II Investigators. EVEREST II randomized clinical trial: predictors of mitral valve replacement in de novo surgery or after the MitraClip procedure. J Thorac Cardiovasc Surg 2012;143(4 Suppl):S60–S63. 22. Gonzalez-Stawinski GV, Mountis MM, Cohn WE, Frazier OH. Inflow graft interruption as a simple method for left ventricular assist device removal after successful bridge to recovery. J Card Surg 2012;27(3): 397–399. 23. Grayburn PA. Interpreting the coronary-artery calcium score. N Engl J Med 2012;366(4):294–296; 366(16):1551. 24. Grayburn P, Sangli C, Massaro J, Mauri L, Weissman N, Glower D, Feldman T, Foster E. The relationship between the magnitude of reduction in mitral regurgitation severity and left ventricular and left atrial volumes post-treatment with the MitraClip device. J Am Coll Cardiol 2012;59(13, Suppl 1):59. 25. Grayburn PA, Weissman NJ, Zamorano JL. Quantitation of mitral regurgitation. Circulation 2012;126(16):2005–2017. 26. Hall S, Gonzalez-Stawinski G, Meyer D, Bethea B, Kuiper J, Hardaway B. Unplanned hospital readmissions and continuous flow pump therapy. J Cardiac Fail 2012;18(Suppl 1):S37. 27. Hall S, Hardaway B, Meyer D, Bethea B, Kuiper J. Reducing length of stay in the Heartmate II era. J Cardiac Fail 2012;18(Suppl 1):S46–S47. 28. Hall S, Kuiper J, Grimsley B, Pearl G, Matter G, Hamman B, Hardaway B. The use of Impellas 5.0/LD in the management of heart failure patients 215 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 216 with cardiogenic shock: a multidisciplinary team approach. J Cardiac Fail 2012;18(Suppl 1):S47-S47. Head SJ, Holmes DR Jr, Mack MJ, Serruys PW, Mohr FW, Morice MC, Colombo A, Kappetein AP; SYNTAX Investigators. Risk profile and 3-year outcomes from the SYNTAX percutaneous coronary intervention and coronary artery bypass grafting nested registries. JACC Cardiovasc Interv 2012;5(6):618–625. Holmes DR Jr, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD, Harrington RA, Bhatt DL, Ferrari VA, Fisher JD, Garcia MJ, Gardner TJ, Gentile F, Gilson MF, Hernandez AF, Jacobs AK, Kaul S, Linderbaum JA, Moliterno DJ, Weitz HH. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2012;144(3):e29–e84. Jett GK. Thoracic robotics at the Heart Hospital Baylor Plano: the first 20 cases. Proc (Bayl Univ Med Cent) 2012;25(4):324–326. Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodés-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60(15):1438–1454. Also published in Eur J Cardiothorac Surg 2012;42(5):S45–S60; Eur Heart J 2012;33(19):2403–2418; and EuroIntervention 2012;8(7):782–795. Kennedy K, Adams J, Cheng D, Berbarie RF. High-intensity track and field training in a cardiac rehabilitation program. Proc (Bayl Univ Med Cent) 2012;25(1):34–36. Keshava HB, Farver CF, Brown CR, Shafii AE, Murthy SC, Yun JJ, Vakil N, Pettersson GB, Mason DP. Timing of heparin and thrombus formation in donor lungs after cardiac death. Thorac Cardiovasc Surg 2012 Dec 3 [Epub ahead of print]. Khvilivitzky K, Mountis MM, Gonzalez-Stawinski GV. Heartmate II outflow graft ligation and driveline excision without pump removal for left ventricular recovery. Proc (Bayl Univ Med Cent) 2012;25(4):344–345. Kowal RC. PVI’s inconvenient truths: lights out for dormant reconnection? J Cardiovasc Electrophysiol 2012;23(3):261–263. Kowal RC. The allure of the F-files. J Cardiovasc Electrophysiol 2012;23(12):1286–1268. Krucoff MW, Brindis RG, Hodgson PK, Mack MJ, Holmes DR Jr. Medical device innovation: prospective solutions for an ecosystem in crisis. Adding a professional society perspective. JACC Cardiovasc Interv 2012;5(7):790–796. Loor G, Gonzalez-Stawinski G. Pulsatile vs. continuous flow in ventricular assist device therapy. Best Pract Res Clin Anaesthesiol 2012;26(2): 105–115. Loor G, Khani-Hanjani A, Gonzalez-Stawinski GV. Use of RotaFlow (MAQUET) for temporary right ventricular support during implantation of HeartMate II left ventricular assist device. ASAIO J 2012;58(3):275– 277. Lopes RD, Williams JB, Mehta RH, Reyes EM, Hafley GE, Allen KB, Mack MJ, Peterson ED, Harrington RA, Gibson CM, Califf RM, Kouchoukos NT, Ferguson TB, Lorenz TJ, Alexander JH. Edifoligide and long-term outcomes after coronary artery bypass grafting: PRoject of Exvivo Vein graft ENgineering via Transfection IV (PREVENT IV) 5-year results. Am Heart J 2012;164(3):379–386.e1. Mack M. Frailty and aortic valve disease. J Thorac Cardiovasc Surg 2012 Dec 20 [Epub ahead of print]. Mack MJ. Access for transcatheter aortic valve replacement: which is the preferred route? JACC Cardiovasc Interv 2012;5(5):487–488. Mack MJ. Transcatheter aortic valve implantation: changing patient populations and novel indications. Heart 2012;98(Suppl 4):iv73–79. McMaster KS, Tandon A, Schussler JM. Renal infarction secondary to cor triatriatum sinister. Am J Cardiovasc Dis 2012;2(4):331–333. 46. Mihaljevic T, Jarrett CM, Gonzalez-Stawinski G, Smedira NG, Nowicki ER, Thuita L, Mountis M, Blackstone EH. Mechanical circulatory support after heart transplantation. Eur J Cardiothorac Surg 2012; 41(1):200–206. 47. Murray SS, Smith EN, Villarasa N, Nahey T, Lande J, Goldberg H, Shaw M, Rosenthal L, Ramza B, Alaeddini J, Han X, Damani S, Soykan O, Kowal RC, Topol EJ; GAME Investigators. Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias. PLoS One 2012;7(1):e25387. 48. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Safety 2012;3:241–253. 49. Patankar GR, Donsky MS, Schussler JM. Delayed takotsubo cardiomyopathy caused by excessive exogenous epinephrine administration after the treatment of angioedema. Proc (Bayl Univ Med Cent) 2012;25(3): 229–230. 50. Pearl GJ. Arterial thoracic outlet syndrome in the competitive athlete. In Illig KA, Thompson RW, Freischlag JA, Donahue DM, Jordan SE, Edgelow PI, eds. Thoracic Outlet Syndrome. New York: Springer Verlag, 2012. 51. Pearl GJ. Neurogenic thoracic outlet syndrome in the competitive athlete. In Illig KA, Thompson RW, Freischlag JA, Donahue DM, Jordan SE, Edgelow PI, eds. Thoracic Outlet Syndrome. New York: Springer Verlag, 2012. 52. Pearl GJ. Treatment of arterial thoracic outlet syndrome: results and longterm outcomes. In Illig KA, Thompson RW, Freischlag JA, Donahue DM, Jordan SE, Edgelow PI, eds. Thoracic Outlet Syndrome. New York: Springer Verlag, 2012. 53. Pinard EA, Fazal S, Schussler JM. Catastrophic paradoxical embolus after hemodialysis access thrombectomy in a patient with a patent foramen ovale. Int Urol Nephrol 2012 Feb 25 [Epub ahead of print]. 54. Pokersnik JA, Buda T, Bashour CA, Gonzalez-Stawinski GV. Have changes in ECMO technology impacted outcomes in adult patients developing postcardiotomy cardiogenic shock? J Card Surg 2012;27(2):246–252. 55. Reading DW, Oza U. Unilateral absence of a pulmonary artery: a rare disorder with variable presentation. Proc (Bayl Univ Med Cent) 2012;25(2):115–118. 56. Reynolds MR, Magnuson EA, Lei Y, Wang K, Vilain K, Li H, Walczak J, Pinto DS, Thourani VH, Svensson LG, Mack MJ, Miller DC, Satler LE, Bavaria J, Smith CR, Leon MB, Cohen DJ; PARTNER Investigators. Cost-effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results of the PARTNER (Placement of Aortic Transcatheter Valves) trial (Cohort A). J Am Coll Cardiol 2012;60(25):2683–2692. 57. Roberts WC. Determining the quantity of alcohol consumed. Am J Cardiol 2012;110:761. 58. Roberts WC. Pathology of coronary artery disease. In Franco KL, Thourani VH, eds. Cardiothoracic Surgery Review. Philadelphia: Wolters Kluwer, 2012:38–40. 59. Roberts WC. Pathology of heart failure. In Franco KL, Thourani VH, eds. Cardiothoracic Surgery Review. Philadelphia: Wolters Kluwer, 2012. 60. Roberts WC. Pathology of valvular heart disease. In Franco KL, Thourani VH, eds. Cardiothoracic Surgery Review. Philadelphia: Wolters Kluwer, 2012:199–202. 61. Roberts WC. Pathology of diseases of the aorta. In Franco KL, Thourani VH, eds. Cardiothoracic Surgery Review. Philadelphia: Wolters Kluwer, 2012:453–454. 62. Roberts WC. Two observations suggesting that we die in ventricular systole. Am J Cardiol 2012;110(6):915–917. 63. Roberts WC, Alpert J, Hillis WD. Ten things all physicians should know about cardiovascular disease. Med Roundtable Gen Med 2012;1(2):145–151. 64. Roberts WC, Janning KG, Ko JM, Filardo G, Matter GJ. Frequency of congenitally bicuspid aortic valves in patients ≥80 years of age undergoing aortic valve replacement for aortic stenosis (with or without aortic regurgitation) and implications for transcatheter aortic valve implantation. Am J Cardiol 2012;109(11):1632–1636. Baylor University Medical Center Proceedings Volume 26, Number 2 65. Roberts WC, Janning KG, Vowels TJ, Ko JM, Hamman BL, Hebeler RF Jr. Presence of a congenitally bicuspid aortic valve among patients having combined mitral and aortic valve replacement. Am J Cardiol 2012;109(2):263–271. 66. Roberts WC, Roberts CC, Ko JM, Hall SA, Capehart JE. Cardiac transplantation in adults with aortic valve disease with focus on the bicuspid aortic valve. Am J Cardiol 2012;109(8):1212–1214. 67. Roberts WC, Roberts CC, Vowels TJ, Ko JM, Filardo G, Hamman BL, Matter GJ, Henry AC 3rd, Hebeler RF Jr. Effect of coronary bypass and valve structure on outcome in isolated valve replacement for aortic stenosis. Am J Cardiol 2012;109(9):1334–1340. 68. Roberts WC, Taylor MA, Shirani J. Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis. Medicine (Baltimore) 2012;91(3):165–178. 69. Roberts WC, Vowels TJ, Ko JM. Natural history of adults with congenitally malformed aortic valves (unicuspid or bicuspid). Medicine (Baltimore) 2012;91(6):287–308. 70. Roberts WC, Vowels TJ, Ko JM, Guileyardo JM. Acute aortic dissection with tear in ascending aorta not diagnosed until necropsy or operation (for another condition) and comparison to similar cases receiving proper operative therapy. Am J Cardiol 2012;110(5):728–735. 71. Rosenthal RL, Carrothers IA, Schussler JM. Benign or malignant anomaly? Very high takeoff of the left main coronary artery above the left coronary sinus. Tex Heart Inst J 2012;39(4):538–541. 72. Satiani B, Matthews MA, Gable D. Work effort, productivity, and compensation trends in members of the Society for Vascular Surgery. Vasc Endovascular Surg 2012;46(7):509–514. 73. Satiani BB, Motew SJ, Darling RC 3rd, Jain KM, Wixon CL, Johnson BA, Weiss VJ, Gable DR. Changing practice paradigms: negotiating your future. J Vasc Surg 2012;55(4):1206–1212. 74. Serruys PW, Farooq V, Vranckx P, Girasis C, Brugaletta S, Garcia-Garcia HM, Holmes DR Jr, Kappetein AP, Mack MJ, Feldman T, Morice MC, Ståhle E, James S, Colombo A, Pereda P, Huang J, Morel MA, Van Es GA, Dawkins KD, Mohr FW, Steyerberg EW. A global risk approach to identify patients with left main or 3-vessel disease who could safely and efficaciously be treated with percutaneous coronary intervention: the SYNTAX Trial at 3 years. JACC Cardiovasc Interv 2012;5(6):606–617. 75. Shafii AE, Brown CR, Murthy SC, Mason DP. High incidence of upper-extremity deep vein thrombosis with dual-lumen venovenous extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2012;144(4):988–999. 76. Shafii AE, Chamogeorgakis T, Mountis M, Gonzalez-Stawinski G. Fate of retained right ventricular assist device outflow grafts after right ventricular recovery. J Heart Lung Transplant 2012;31(6):672–673. 77. Shafii AE, Gillinov AM, Mihaljevic T, Stewart W, Batizy LH, Blackstone EH. Changes in left ventricular morphology and function after mitral valve surgery. Am J Cardiol 2012;110(3):403–408.e3. 78. Shahian DM, He X, Jacobs JP, Rankin JS, Welke KF, Filardo G, Shewan CM, O’Brien SM. The Society of Thoracic Surgeons isolated aortic valve replacement (AVR) composite score: a report of the STS Quality Measurement Task Force. Ann Thorac Surg 2012;94(6):2166–2171. 79. Shafii AE, Mason DP, Brown CR, Vakil N, Johnston DR, McCurry KR, Pettersson GB, Murthy SC. Growing experience with extracorporeal membrane oxygenation as a bridge to lung transplantation. ASAIO J 2012;58(5):526–529. 80. Shafii AE, McCurry KR. Subclavian insertion of the bicaval dual lumen cannula for venovenous extracorporeal membrane oxygenation. Ann Thorac Surg 2012;94(2):663–665. 81. Shafii AE, Vivacqua A, Albacker TB, Sheih C, Svensson LG. Total arch replacement after a failed repair for Takayasu’s ascending aortitis. Ann Thorac Surg 2012;93(1):300–302. 82. Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Härtter S, Harper R, Kappetein AP, Lehr T, Mack MJ, Noack H, Eikelboom JW. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients April 2013 after heart valve replacement (RE-ALIGN). Am Heart J 2012;163(6): 931–937.e1. 83. Van de Werf F, Connolly SJ, Kappetein AP, Brueckmann M, Mack MJ, Granger CB, Eikelboom J. Letter by Van de Werf et al regarding article, “Using dabigatran in patients with stroke: a practical guide for clinicians.” Stroke 2012;43(5):e46–e47. DERMATOLOGY 84. Abramovits W, Oquendo M, Granowski P, Gupta A, Cather J. Pralatrexate (Folotyn). Skinmed 2012;10(4):244–246. 85. Abramovits W, Oquendo M, Scheinfeld N, Gupta AK. Sorilux (calcipotriene) foam 0.005%. Skinmed 2012;10(5):301–304. 86. Abramson A, Menter A. An unusual facial ulcer. Proc (Bayl Univ Med Cent) 2012;25(1):85–86. 87. Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol 2012;67(6):1349–1361. 88. Corey K, Mattei P, Houston N, Tebbey PW, Menter A, van de Kerkhof PCM, Kimball AB. Psoriasis, a proof-of-principle condition for immunemediated inflammatory disorders: perspectives toward optimal clinical trial design. Clin Invest 2012;2(7):671–678. 89. Dhaliwal S, Patel M, Menter A. Secondary syphilis and HIV. Proc (Bayl Univ Med Cent) 2012;25(1):87–89. 90. Feldman SR, Matheson R, Bruce S, Grande K, Markowitz O, Kempers S, Brundage T, Wyres M; U0267-301 & 302 Study Investigators. Efficacy and safety of calcipotriene 0.005% foam for the treatment of plaque-type psoriasis: results of two multicenter, randomized, doubleblind, vehicle-controlled, phase III clinical trials. Am J Clin Dermatol 2012;13(4):261–271. 91. Heller MM, Wong JW, Nguyen TV, Lee ES, Bhutani T, Menter A, Koo JY. Quality-of-life instruments: evaluation of the impact of psoriasis on patients. Dermatol Clin 2012;30(2):281–291, ix. 92. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, Duffin KC, Stuart PE, Goldgar D, Hayashi G, Olfson EH, Feng BJ, Pullinger CR, Kane JP, Wise CA, Goldbach-Mansky R, Lowes MA, Peddle L, Chandran V, Liao W, Rahman P, Krueger GG, Gladman D, Elder JT, Menter A, Bowcock AM. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet 2012;90(5):796–808. 93. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, Ryan C, Duan S, Helms CA, Liu Y, Chen Y, McBride AA, Hwu WL, Wu JY, Chen YT, Menter A, Goldbach-Mansky R, Lowes MA, Bowcock AM. PSORS2 is due to mutations in CARD14. Am J Hum Genet 2012;90(5):784–795. 94. Kircik L, Jones TM, Jarratt M, Flack MR, Ijzerman M, Ciotti S, Sutcliffe J, Boivin G, Stanberry LR, Baker JR; NB-001 Study Group. Treatment with a novel topical nanoemulsion (NB-001) speeds time to healing of recurrent cold sores. J Drugs Dermatol 2012;11(8):970–977. 95. Kragballe K, Menter A, Lebwohl M, Tebbey PW, van de Kerkhof PC; International Psoriasis Council. Long-term management of scalp psoriasis: perspectives from the International Psoriasis Council. J Dermatolog Treat 2012 Jun 5 [Epub ahead of print]. 96. Lloyd P, Ryan C, Menter A. Psoriatic arthritis: an update. Arthritis 2012;2012:176298. 97. Menter A. Clobetasol propionate spray 0.05% for the treatment of moderate to severe plaque psoriasis. Cutis 2012;89(2):89–94. 98. Menter A. Psoriasis and psoriatic arthritis: similarities and differences. Value-Based Care in Rheumatology, September 2012. 99. Menter A. Response to the letter to editor re: “Methotrexate and psoriasis: consensus conference.” J Am Acad Dermatol 2012;66(4):689. 100. Menter MA, Caveney SW, Gottschalk RW. Impact of clobetasol propionate 0.05% spray on health-related quality of life in patients with plaque psoriasis. J Drugs Dermatol 2012;11(11):1348–1354. 101. Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA. Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis 2012 publications of the Baylor Health Care System medical and scientific staff 217 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 218 is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther 2012;342(3):696–708. Olsen EA, Whiting DA, Savin R, Rodgers A, Johnson-Levonas AO, Round E, Rotonda J, Kaufman KD; Male Pattern Hair Loss Study Group. Global photographic assessment of men aged 18 to 60 years with male pattern hair loss receiving finasteride 1 mg or placebo. J Am Acad Dermatol 2012;67(3):379–386. Oquendo M, Abramovits W, Morrell P. Topical vitamin D analogs available to treat psoriasis. Skinmed 2012;10(6):356–360. Paller AS, Mercy K, Kwasny MJ, Choon SE, Cordoro KM, Girolomoni G, Menter A, Tom WL, Mahoney AM, Oostveen AM, Seyger MM. Association of pediatric psoriasis severity with excess and central adiposity: an international cross-sectional study. Arch Dermatol 2012:1–11. Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, Hu C, Day RM. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet 2012;380(9843):738–746. Papp K, Menter A, Poulin Y, Gu Y, Sasso EH. Long-term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: subanalysis of REVEAL and the open-label extension study. J Eur Acad Dermatol Venereol 2012 Mar 16 [Epub ahead of print]. Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EH, Baumgartner S. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012;366(13):1181–1189. Papp KA, Menter A, Strober B, Langley RG, Buonanno M, Wolk R, Gupta P, Krishnaswami S, Tan H, Harness JA. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol 2012;167(3):668–677. Papp KA, Strober B, Augustin M, Calabro S, Londhe A, Chevrier M; PSOLAR investigators and Steering Committee. PSOLAR: design, utility, and preliminary results of a prospective, international, disease-based registry of patients with psoriasis who are receiving, or are candidates for, conventional systemic treatments or biologic agents. J Drugs Dermatol 2012;11(10):1210–1217. Patel M, Day A, Warren RB, Menter A. Emerging therapies for the treatment of psoriasis. Dermatol Ther (Heidelb) 2012;2(1):16. Ryan C, Abramson A, Patel M, Menter A. Current investigational drugs in psoriasis. Expert Opin Investig Drugs 2012;21(4):473–487. Ryan C, Menter A. Psoriasis and cardiovascular disorders. G Ital Dermatol Venereol 2012;147(2):179–187. Ryan C, Patel M, Menter A. Are drug treatments for psoriasis a cardiovascular risk? Clin Pract 2012;9:5–9. Strober BE, Armour K, Romiti R, Smith C, Tebbey PW, Menter A, Leonardi C. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. J Am Acad Dermatol 2012;66(2):317–322. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, Ding J, Li Y, Tejasvi T, Gudjonsson JE, Kang HM, Allen MH, McManus R, Novelli G, Samuelsson L, Schalkwijk J, Ståhle M, Burden AD, Smith CH, Cork MJ, Estivill X, Bowcock AM, Krueger GG, Weger W, Worthington J, Tazi-Ahnini R, Nestle FO, Hayday A, Hoffmann P, Winkelmann J, Wijmenga C, Langford C, Edkins S, Andrews R, Blackburn H, Strange A, Band G, Pearson RD, Vukcevic D, Spencer CC, Deloukas P, Mrowietz U, Schreiber S, Weidinger S, Koks S, Kingo K, Esko T, Metspalu A, Lim HW, Voorhees JJ, Weichenthal M, Wichmann HE, Chandran V, Rosen CF, Rahman P, Gladman DD, Griffiths CE, Reis A, Kere J; Collaborative Association Study of Psoriasis (CASP); Genetic Analysis of Psoriasis Consortium; Psoriasis Association Genetics Extension; Wellcome Trust Case Control Consortium 2, Nair RP, Franke A, Barker JN, Abecasis GR, Elder JT, Trembath RC. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet 2012;44(12):1341–1348. Tyring SK, Plunkett S, Scribner AR, Broker RE, Herrod JN, Handke LT, Wise JM, Martin PA; Valomaciclovir Zoster Study Group. Valomaciclovir versus valacyclovir for the treatment of acute herpes zoster in immunocompetent adults: a randomized, double-blind, active-controlled trial. J Med Virol 2012;84(8):1224–1232. 117. Wofford J, Patel M, Readinger A, Menter A. Widespread dermal ulcerations and bullae. Proc (Bayl Univ Med Cent) 2012;25(2):155–158. EMERGENCY MEDICINE/TRAUMA 118. Abdalla A, Gunst M, Ghaemmaghami V, Gruszecki AC, Urban J, Barber RC, Gentilello LM, Shafi S. Spatial analysis of injury-related deaths in Dallas County using a geographic information system. Proc (Bayl Univ Med Cent) 2012;25(3):208–213. 119. Cook A, Cade A, King B, Berne J, Fernandez L, Norwood S. Groundlevel falls: 9-year cumulative experience in a regionalized trauma system. Proc (Bayl Univ Med Cent) 2012;25(1):6–12. 120. Michetti CP, Fakhry SM, Ferguson PL, Cook A, Moore FO, Gross R; AAST Ventilator-Associated Pneumonia Investigators. Ventilator-associated pneumonia rates at major trauma centers compared with a national benchmark: a multi-institutional study of the AAST. J Trauma Acute Care Surg 2012;72(5):1165–1173. 121. Newgard CD, Fildes JJ, Wu L, Hemmila MR, Burd RS, Neal M, Mann NC, Shafi S, Clark DE, Goble S, Nathens AB. Methodology and analytic rationale for the American College of Surgeons Trauma Quality Improvement Program. J Am Coll Surg 2012 Oct 10 [Epub ahead of print]. 122. Rayan N, Barnes S, Fleming N, Kudyakov R, Ballard D, Gentilello LM, Shafi S. Barriers to compliance with evidence-based care in trauma. J Trauma Acute Care Surg 2012;72(3):585–592. 123. Shafi S, Ogola G, Fleming N, Rayan N, Kudyakov R, Barnes SA, Ballard DJ. Insuring the uninsured: potential impact of Health Care Reform Act of 2010 on trauma centers. J Trauma Acute Care Surg 2012;73(5): 1303–1307. 124. Shafi S, Rayan N, Barnes S, Fleming N, Gentilello LM, Ballard D. Moving from “optimal resources” to “optimal care” at trauma centers. J Trauma Acute Care Surg 2012;72(4):870–877. 125. Shafi S, Renfro LA, Barnes S, Rayan N, Gentilello LM, Fleming N, Ballard D. Chronic consequences of acute injuries: worse survival after discharge. J Trauma Acute Care Surg 2012;73(3):699–703. ENDOCRINOLOGY See also Transplantation for articles on islet cell transplantation and Health Care Research and Improvement for articles on improving diabetes care. 126. Chaudhuri A, Rosenstock J, DiGenio A, Meneghini L, Hollander P, McGill JB, Dandona P, Ilgenfritz J, Riddle M. Comparing the effects of insulin glargine and thiazolidinediones on plasma lipids in type 2 diabetes: a patient-level pooled analysis. Diabetes Metab Res Rev 2012;28(3):258–267. 127. DeVries JH, Bain SC, Rodbard HW, Seufert J, D’Alessio D, Thomsen AB, Zychma M, Rosenstock J; Liraglutide-Detemir Study Group. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care 2012;35(7):1446–1454. 128. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa JE, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S 3rd, Bertrand M, Fuster V; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367(25):2375–2384. 129. Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Francisco AM, Hollander P; NN12503582 (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultralongacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012;379(9825):1498–1507. 130. Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Francisco AM, Pei H, Bode B; BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): Baylor University Medical Center Proceedings Volume 26, Number 2 131. 132. 133. 134. 135. 136. 137. 138. a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012;379(9825):1489–1497. Hollander P, Spellman C. Controversies in prediabetes: do we have a diagnosis? Postgrad Med 2012;124(4):109–118. Hollander PA. Insulin detemir for the treatment of obese patients with type 2 diabetes. Diabetes Metab Syndr Obes 2012;5:11–19. Lingvay I, Roe ED, Duong J, Leonard D, Szczepaniak LS. Effect of insulin versus triple oral therapy on the progression of hepatic steatosis in type 2 diabetes. J Investig Med 2012;60(7):1059–1063. Punthakee Z, Bosch J, Dagenais G, Diaz R, Holman R, Probstfield J, Ramachandran A, Riddle M, Rydén LE, Zinman B, Afzal R, Yusuf S, Gerstein H; TIDE Trial Investigators. Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia 2012;55(1):36–45. Roe ED, Raskin P. Managing inpatient hyperglycemia in a resource-constrained county hospital. Hosp Pract (Minneap) 2012;40(3):116–125. Roe ED, Yoo JS, Raskin P. Doctor, stop needling me: an update on alternative routes of insulin administration. Diabetes Management 2012;2(5):395–404. Roe ED, Yoo JS, Raskin P. In search of improved glucose control: helping the patient decide between insulin injections and infusion pump therapy. Diabetes Management 2012;2(5):405–417. Vora J, Bain SC, Damci T, Dzida G, Hollander P, Meneghini LF, Ross SA. Incretin-based therapy in combination with basal insulin: A promising tactic for the treatment of type 2 diabetes. Diabetes Metab 2012 Sep 26 [Epub ahead of print]. GASTROENTEROLOGY Note: See also Oncology for research on colon cancer. 139. American Association for Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association Institute; American Society for Gastrointestinal Endoscopy; Society for Gastroenterology Nurses and Associates, Vargo JJ, DeLegge MH, Feld AD, Gerstenberger PD, Kwo PY, Lightdale JR, Nuccio S, Rex DK, Schiller LR. Multisociety sedation curriculum for gastrointestinal endoscopy. Gastrointest Endosc 2012;76(1):e1–e25. Also published in Gastroenterology 2012;143(1):e18–e41. 140. Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res 2012;26(11):1719–1725. 141. Evans TH, Schiller LR. Chronic vestibular dysfunction as an unappreciated cause of chronic nausea and vomiting. Proc (Bayl Univ Med Cent) 2012;25(3):214–217. 142. Hogan RB 3rd, Brill JV, Littenberg G, Demarco DC. Predict, resect, and discard . . . really? Gastrointest Endosc 2012;75(3):503–505. 143. Quigley EM, Abdel-Hamid H, Barbara G, Bhatia SJ, Boeckxstaens G, De Giorgio R, Delvaux M, Drossman DA, Foxx-Orenstein AE, Guarner F, Gwee KA, Harris LA, Hungin AP, Hunt RH, Kellow JE, Khalif IL, Kruis W, Lindberg G, Olano C, Moraes-Filho JP, Schiller LR, Schmulson M, Simrén M, Tzeuton C. A global perspective on irritable bowel syndrome: a consensus statement of the World Gastroenterology Organisation Summit Task Force on irritable bowel syndrome. J Clin Gastroenterol 2012;46(5):356–366. 144. Sayuk GS, Hirano I, Fitzgerald JT, Stansfield RB, Armbruster BA, Jones TN, Akinyi J, Willis CE; AGA Institute’s GTE Subcommittee. AGA Gastroenterology Training Exam (GTE): a progress report. Gastroenterology 2012;142(2):201–204.e1-2. 145. Siersema PD, Rastogi A, Leufkens AM, Akerman PA, Azzouzi K, Rothstein RI, Vleggaar FP, Repici A, Rando G, Okolo PI, Dewit O, Ignjatovic A, Odstrcil E, East J, Deprez PH, Saunders BP, Kalloo AN, Creel B, Singh V, Lennon AM, DeMarco DC. Retrograde-viewing device improves adenoma detection rate in colonoscopies for surveillance and diagnostic workup. World J Gastroenterol 2012;18(26):3400–3408. 146. Steffer KJ, Santa Ana CA, Cole JA, Fordtran JS. The practical value of comprehensive stool analysis in detecting the cause of idiopathic chronic diarrhea. Gastroenterol Clin North Am 2012;41(3):539–560. April 2013 147. Vargo JJ, Delegge MH, Feld AD, Gerstenberger PD, Kwo PY, Lightdale JR, Nuccio S, Rex DK, Schiller LR. Multisociety Sedation Curriculum for Gastrointestinal Endoscopy. Am J Gastroenterol 2012 May 22 [Epub ahead of print]. GYNECOLOGY/CLINICAL GENETICS 148. Shavell VI, Diamond MP, Senter JP, Kruger ML, Johns DA. Hysterectomy subsequent to endometrial ablation. J Minim Invasive Gynecol 2012;19(4):459–464. 149. Schaaf CP, Boone PM, Sampath S, Williams C, Bader PI, Mueller JM, Shchelochkov OA, Brown CW, Crawford HP, Phalen JA, Tartaglia NR, Evans P, Campbell WM, Tsai AC, Parsley L, Grayson SW, Scheuerle A, Luzzi CD, Thomas SK, Eng PA, Kang SH, Patel A, Stankiewicz P, Cheung SW. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet 2012;20(12):1240–1247. HEALTH CARE RESEARCH AND IMPROVEMENT Note: This section represents primarily the publications of the IHCRI staff, although some of those publications are included under Trauma and other areas. 150. Ballard DJ. The potential of Medicare accountable care organizations to transform the American health care marketplace: rhetoric and reality. Mayo Clin Proc 2012;87(8):707–709. 151. Ballard DJ, Filardo G, da Graca B, Powell JT. Clinical practice change requires more than comparative effectiveness evidence: abdominal aortic management in the USA. J Comparative Effect Res 2012;1(1):31–44. 152. Brouwer ES, West SL, Kluckman M, Wallace D, Masica AL, Ewen E, Kudyakov R, Cheng D, Bowen J, Fleming NS. Initial and subsequent therapy for newly diagnosed type 2 diabetes patients treated in primary care using data from a vendor-based electronic health record. Pharmacoepidemiol Drug Saf 2012;21(9):920–928. 153. Cheng D, Branscum AJ, Johnson WO. Sample size calculations for ROC studies: parametric robustness and Bayesian nonparametrics. Stat Med 2012;31(2):131–142. 154. Compton J, Copeland K, Flanders S, Cassity C, Spetman M, Xiao Y, Kennerly D. Implementing SBAR across a large multihospital health system. Jt Comm J Qual Patient Saf 2012;38(6):261–268. 155. Convery P, Couch C, Luquire R. Training physician and nursing leaders for performance improvement. In From Front Office to Front Line: Essential Issues for Health Care Leaders. Oakbrook Terrace, IL: The Joint Commission, 2012. 156. Couch CE. Why Baylor Health Care System would like to file for Medicare shared savings accountable care organization designation but cannot. Mayo Clin Proc 2012;87(8):723–726. 157. Dolor RJ, Masica AL, Touchette DR, Smith SR, Schumock GT. Patient safety-focused medication therapy management: challenges affecting future implementation. Am J Manag Care 2012;18(7):e238–244. 158. Filardo G, Powell JT, Martinez MA, Ballard DJ. Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst Rev 2012;3:CD001835. 159. Herrin J, da Graca B, Nicewander D, Fullerton C, Aponte P, Stanek G, Cowling T, Collinsworth A, Fleming NS, Ballard DJ. The effectiveness of implementing an electronic health record on diabetes care and outcomes. Health Serv Res 2012;47(4):1522–1540. 160. Johnson ES, Bartman B, Briesacher B, Fleming N, Gerhard T, Kornegay C, Nourjah P, Sauer B, Schumock G, Sedrakyan A, Stürmer T, West S, Schneeweiss S. The incident user design in comparative effectiveness research. Pharmacoepidemiol Drug Saf Epub 2012 Oct 1. 161. Johnson ES, Bartman BA, Briesacher BA, Fleming NS, Gerhard T, Kornegay CJ, Nourjah P, Sauer B, Schumock GT, Sedrakyan A, Stürmer T, West SL, Schneeweiss S. The Incident User Design in Comparative Effectiveness Research. Effective Health Care Program Research Report No. 32 (AHRQ Publication No. 11(12)-EHC054-EF). Rockville, MD: Agency for Healthcare Research and Quality, May 2012. 162. Kudyakov R, Bowen J, Ewen E, West SL, Daoud Y, Fleming N, Masica A. Electronic health record use to classify patients with newly diagnosed versus preexisting type 2 diabetes: infrastructure for comparative effectiveness 2012 publications of the Baylor Health Care System medical and scientific staff 219 163. 164. 165. 166. 167. research and population health management. Popul Health Manag 2012;15(1):3–11. Readhead AC, Gordon DE, Wang Z, Anderson BJ, Brousseau KS, Kouznetsova MA, Forgione LA, Smith LC, Torian LV. Transmitted antiretroviral drug resistance in New York State, 2006–2008: results from a new surveillance system. PLoS One 2012;7(8):e40533. Rice D, Bain TM, Collinsworth A, Boyer K, Fleming NS, Miller E. Effective strategies to improve the management of diabetes: case illustration from the Diabetes Health and Wellness Institute. Prim Care 2012;39(2):363–379. Touchette DR, Masica AL, Dolor RJ, Schumock GT, Choi YK, Kim Y, Smith SR. Safety-focused medication therapy management: a randomized controlled trial. J Am Pharm Assoc 2012;52(5):603–612. Walton JW, Snead CA, Collinsworth AW, Schmidt KL. Reducing diabetes disparities through the implementation of a community health worker-led diabetes self-management education program. Fam Community Health 2012;35(2):161–171. Zhang B, Youngblood L, Murphy GD, Ramsay M, Xiao Y. System engineering approach to documentation: an evaluation of the documentation process in a gastroenterology laboratory. J Biomed Inform 2012;45(3):591–597. HEPATOLOGY Note: See also Transplantation. 168. Asrani SK, Asrani NS, Freese DK, Phillips SD, Warnes CA, Heimbach J, Kamath PS. Congenital heart disease and the liver. Hepatology 2012;56(3):1160–1169. 169. Asrani SK, LaRusso NF. Fibrolamellar hepatocellular carcinoma presenting with Budd-Chiari syndrome, right atrial thrombus, and pulmonary emboli. Hepatology 2012;55(3):977–978. 170. Bajaj JS, O’Leary JG, Reddy KR, Wong F, Olson JC, Subramanian RM, Brown G, Noble NA, Thacker LR, Kamath PS; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012;56(6):2328–2335. 171. Bajaj JS, O’Leary JG, Wong F, Reddy KR, Kamath PS. Bacterial infections in end-stage liver disease: current challenges and future directions. Gut 2012;61(8):1219–1225. 172. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A; OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13(1):e11–e22. 173. Corey KE, Zheng H, Mendez-Navarro J, Delgado-Borrego A, Dienstag JL, Chung RT; HALT-C Trial Group. Serum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis. PLoS One 2012;7(2):e27144. 174. Dasher K, Trotter JF. Intensive care unit management of liver-related coagulation disorders. Crit Care Clin 2012;28(3):389–398, vi. 175. Davis GL, O’Leary JG. Use of protease inhibitors in liver transplant recipients. Gastroenterol Hepatol (N Y) 2012;8(3):183–184. 176. Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, Lauriski S, Curto TM, Stoddard A, Wright EC; HALT-C Trial Group. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. Hepatology 2012;55(4):1019–1029. 177. Gonzalez SA. Acute liver failure: diagnosis and management. In British Medical Journal Point of Care, 3rd ed. June 15, 2012. Available at https:// online.epocrates.com/home. 178. Gonzalez SA. Hepatitis B virus. In Yu VL, ed. Antimicrobial Therapy and Vaccines, vol. 1, 3rd ed. Pittsburgh, PA: ESun Technologies, 2012. 179. Gonzalez SA. Rare indications for liver transplantation. In Clavien P, Trotter J, Mullhaupt B, eds. Medical Care of the Liver Transplant Patient, 4th ed. Oxford: Wiley-Blackwell, 2012:145–154. 180. Gonzalez SA, Davis GL. The demographics of hepatitis C virus today. Clin Liver Dis 2012;1(1):2–5. 220 181. Gonzalez SA, Keeffe EB. Risk assessment for hepatocellular carcinoma in chronic hepatitis B: scores and surveillance. Int J Clin Pract 2012;66(1): 7–10. 182. Kim JY, Asrani SK, Shah ND, Kim WR, Schneekloth TD. Hospitalization for underage drinkers in the United States. J Adolesc Health 2012;50(6):648–650. 183. Lai JC, O’Leary JG, Trotter JF, Verna EC, Brown RS Jr, Stravitz RT, Duman JD, Forman LM, Terrault NA; Consortium to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C). Risk of advanced fibrosis with grafts from hepatitis C antibody-positive donors: a multicenter cohort study. Liver Transpl 2012;18(5):532–538. 184. Lok AS, Ward JW, Perrillo RP, McMahon BJ, Liang TJ. Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable. Ann Intern Med 2012;156(10):743–745. 185. McGarry LJ, Pawar VS, Panchmatia HR, Rubin JL, Davis GL, Younossi ZM, Capretta JC, O’Grady MJ, Weinstein MC. Economic model of a birth cohort screening program for hepatitis C virus. Hepatology 2012;55(5):1344–1355. 186. McMahon BJ, Block J, Haber B, London T, McHugh JA, Perrillo R, Neubauer R. Internist diagnosis and management of chronic hepatitis B virus infection. Am J Med 2012;125(11):1063–1067. 187. Moreland A, Trotter JF. Acute liver failure due to disseminated herpes simplex virus following thymectomy. Transpl Infect Dis 2012;14(5):E124–E125. 188. O’Connor JK, Trotter J, Davis GL, Dempster J, Klintmalm GB, Goldstein RM. Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl 2012;18(8):949–954. 189. O’Leary JG, Neri MA, Trotter JF, Davis GL, Klintmalm GB. Utilization of hepatitis C antibody-positive livers: genotype dominance is virally determined. Transpl Int 2012;25(8):825–829. 190. Trotter JF. Living donor liver transplantation for hepatocellular carcinoma: through the looking glass. Am J Transplant 2012;12(11):2873–2874. 191. Trotter J, Kahn B. Renal dysfunction and the liver transplant recipient: novel strategies for determination of reversibility and renal protective therapies pretransplant and posttransplant. Curr Opin Organ Transplant 2012;17(3):225–229. 192. Trotter JF, Everhart JE. Outcomes among living liver donors. Gastroenterology 2012;142(2):207–210. IMMUNOLOGY Note: Some publications of the BRI/BIIR staff are listed under Neurology, Dermatology, and Transplantation. 193. Banchereau J, Pascual V, O’Garra A. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 2012;13(10): 925–931. 194. Banchereau J, Thompson-Snipes L, Zurawski S, Blanck JP, Cao Y, Clayton S, Gorvel JP, Zurawski G, Klechevsky E. The differential production of cytokines by human Langerhans cells and dermal CD14+ DCs controls CTL priming. Blood 2012;119(24):5742–5749. 195. Banchereau J, Zurawski S, Thompson-Snipes L, Blanck JP, Clayton S, Munk A, Cao Y, Wang Z, Khandelwal S, Hu J, McCoy WH 4th, Palucka KA, Reiter Y, Fremont DH, Zurawski G, Colonna M, Shaw AS, Klechevsky E. Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming. Proc Natl Acad Sci U S A 2012;109(46):18885–18890. 196. Banchereau R, Jordan-Villegas A, Ardura M, Mejias A, Baldwin N, Xu H, Saye E, Rossello-Urgell J, Nguyen P, Blankenship D, Creech CB, Pascual V, Banchereau J, Chaussabel D, Ramilo O. Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PLoS One 2012;7(4):e34390. 197. Bao M, Hanabuchi S, Facchinetti V, Du Q, Bover L, Plumas J, Chaperot L, Cao W, Qin J, Sun SC, Liu YJ. CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J Immunol 2012;189(2):786–792. 198. Bloom CI, Graham CM, Berry MP, Wilkinson KA, Oni T, Rozakeas F, Xu Z, Rossello-Urgell J, Chaussabel D, Banchereau J, Pascual V, Lipman Baylor University Medical Center Proceedings Volume 26, Number 2 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. M, Wilkinson RJ, O’Garra A. Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy. PLoS One 2012;7(10):e46191. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, Abhyankar A, Israël L, Trevejo-Nunez G, Bogunovic D, Cepika AM, MacDuff D, Chrabieh M, Hubeau M, Bajolle F, Debré M, Mazzolari E, Vairo D, Agou F, Virgin HW, Bossuyt X, Rambaud C, Facchetti F, Bonnet D, Quartier P, Fournet JC, Pascual V, Chaussabel D, Notarangelo LD, Puel A, Israël A, Casanova JL, Picard C. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 2012;13(12):1178–1186. Caielli S, Banchereau J, Pascual V. Neutrophils come of age in chronic inflammation. Curr Opin Immunol 2012;24(6):671–677. Chang HH, Soderberg K, Skinner JA, Banchereau J, Chaussabel D, Haynes BF, Ramoni M, Letvin NL. Transcriptional network predicts viral set point during acute HIV-1 infection. J Am Med Inform Assoc 2012;19(6):1103–1109. Chau BN, Xin C, Hartner J, Ren S, Castano AP, Linn G, Li J, Tran PT, Kaimal V, Huang X, Chang AN, Li S, Kalra A, Grafals M, Portilla D, MacKenna DA, Orkin SH, Duffield JS. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 2012;4(121):121ra18. Conrad C, Gregorio J, Wang YH, Ito T, Meller S, Hanabuchi S, Anderson S, Atkinson N, Ramirez PT, Liu YJ, Freedman R, Gilliet M. Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3+ T-regulatory cells. Cancer Res 2012;72(20):5240–5249. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR. Landscape of transcription in human cells. Nature 2012;489(7414):101–108. Duluc D, Gannevat J, Anguiano E, Zurawski S, Carley M, Boreham M, Stecher J, Dullaers M, Banchereau J, Oh S. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol 2012 Nov 7 [Epub ahead of print]. Duluc D, Gannevat J, Joo H, Ni L, Upchurch K, Boreham M, Carley M, Stecher J, Zurawski G, Oh S. Dendritic cells and vaccine design for sexually-transmitted diseases. Microb Pathog 2012 Nov 29 [Epub ahead of print]. Esashi E, Bao M, Wang YH, Cao W, Liu YJ. PACSIN1 regulates the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells. Eur J Immunol 2012;42(3):573–579. Flamar AL, Zurawski S, Scholz F, Gayet I, Ni L, Li XH, Klechevsky E, Quinn J, Oh S, Kaplan DH, Banchereau J, Zurawski G. Noncovalent assembly of anti-dendritic cell antibodies and antigens for evoking immune responses in vitro and in vivo. J Immunol 2012;189(5):2645–2655. Hanabuchi S, Watanabe N, Liu YJ. TSLP and immune homeostasis. Allergol Int 2012;61(1):19–25. Jahan-Tigh RR, Ryan C, Obermoser G, Schwarzenberger K. Flow cytometry. J Invest Dermatol 2012;132(10):e1. Joo H, Coquery C, Xue Y, Gayet I, Dillon SR, Punaro M, Zurawski G, Banchereau J, Pascual V, Oh S. Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J Exp Med 2012;209(7):1335–1348. Kim TW, Yu M, Zhou H, Cui W, Wang J, DiCorleto P, Fox P, Xiao H, Li X. Pellino 2 is critical for Toll-like receptor/interleukin-1 recep- April 2013 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. tor (TLR/IL-1R)-mediated post-transcriptional control. J Biol Chem 2012;287(30):25686–25695. Li D, Romain G, Flamar AL, Duluc D, Dullaers M, Li XH, Zurawski S, Bosquet N, Palucka AK, Le Grand R, O’Garra A, Zurawski G, Banchereau J, Oh S. Targeting self- and foreign antigens to dendritic cells via DCASGPR generates IL-10-producing suppressive CD4+ T cells. J Exp Med 2012;209(1):109–121. Lin W, Piskol R, Tan MH, Li JB. Comment on “Widespread RNA and DNA sequence differences in the human transcriptome.” Science 2012;335(6074):1302. Martirosyan A, Pérez-Gutierrez C, Banchereau R, Dutartre H, Lecine P, Dullaers M, Mello M, Pinto Salcedo S, Muller A, Leserman L, Levy Y, Zurawski G, Zurawski S, Moreno E, Moriyón I, Klechevsky E, Banchereau J, Oh S, Gorvel JP. Brucella ␤ 1,2 cyclic glucan is an activator of human and mouse dendritic cells. PLoS Pathog 2012;8(11):e1002983. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer 2012;12(4):265–277. Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, Zaver SA, Schenk M, Zeng S, Zhong W, Liu ZJ, Modlin RL, Liu YJ, Cheng G. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 2012;13(12):1155–1161. Pascual V, Banchereau J. Tracking interferon in autoimmunity. Immunity 2012;36(1):7–9. Ramaswami G, Lin W, Piskol R, Tan MH, Davis C, Li JB. Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods 2012;9(6):579–581. Romain G, van Gulck E, Epaulard O, Oh S, Li D, Zurawski G, Zurawski S, Cosma A, Adam L, Chapon C, Todorova B, Banchereau J, DereuddreBosquet N, Vanham G, Le Grand R, Martinon F. CD34-derived dendritic cells transfected ex vivo with HIV-Gag mRNA induce polyfunctional T-cell responses in nonhuman primates. Eur J Immunol 2012;42(8): 2019–2030. Schwingshackl P, Obermoser G, Nguyen VA, Fritsch P, Sepp N, Romani N. Distribution and maturation of skin dendritic cell subsets in two forms of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Acta Derm Venereol 2012;92(3):269–275. Simonini G, Xu Z, Caputo R, De Libero C, Pagnini I, Pascual V, Cimaz R. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum 2013;65(2):513–518. Tattermusch S, Skinner JA, Chaussabel D, Banchereau J, Berry MP, McNab FW, O’Garra A, Taylor GP, Bangham CR. Systems biology approaches reveal a specific interferon-inducible signature in HTLV-1 associated myelopathy. PLoS Pathog 2012;8(1):e1002480. Toyoshima M, Howie HL, Imakura M, Walsh RM, Annis JE, Chang AN, Frazier J, Chau BN, Loboda A, Linsley PS, Cleary MA, Park JR, Grandori C. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci U S A 2012;109(24):9545–9550. Xu W, Joo H, Clayton S, Dullaers M, Herve MC, Blankenship D, De La Morena MT, Balderas R, Picard C, Casanova JL, Pascual V, Oh S, Banchereau J. Macrophages induce differentiation of plasma cells through CXCL10/IP-10. J Exp Med 2012;209(10):1813–1823, S1–S2. Zhang Z, Bao M, Lu N, Weng L, Yuan B, Liu YJ. The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat Immunol 2012;14(2):172–178. INTERNAL MEDICINE AND FAMILY MEDICINE Note: Most family medicine and internal medicine articles are subclassified by specialty, even if generalists were first authors or coauthors. 227. Graves RC, Oehler K, Tingle LE. Febrile seizures: risks, evaluation, and prognosis. Am Fam Physician 2012;85(2):149–153. 228. Kuo VC. Hepatitis E infection. Proc (Bayl Univ Med Cent) 2012;25(2): 119–120. 229. Vrček I, Gummelt KL. Diagnosis and treatment of a red, swollen eye. Proc (Bayl Univ Med Cent) 2012;25(4):378–380. 2012 publications of the Baylor Health Care System medical and scientific staff 221 METABOLIC DISEASES 230. Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O’Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafé L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenço CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet 2012;44(3):338–342. 231. Bottiglieri T, Arning E, Wasek B, Nunbhakdi-Craig V, Sontag JM, Sontag E. Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain. J Neurosci 2012;32(27):9173–9181. 232. Brown KJ, Vanderver A, Hoffman EP, Schiffmann R, Hathout Y. Characterization of transferrin glycopeptide structures in human cerebrospinal fluid. Int J Mass Spectrom 2012;312:97–106. 233. Fogli A, Merle C, Roussel V, Schiffmann R, Ughetto S, Theisen M, Boespflug-Tanguy O. CSF N-glycan profiles to investigate biomarkers in brain developmental disorders: application to leukodystrophies related to eIF2B mutations. PLoS One 2012;7(8):e42688. 234. Huyghe A, Horzinski L, Hénaut A, Gaillard M, Bertini E, Schiffmann R, Rodriguez D, Dantal Y, Boespflug-Tanguy O, Fogli A. Developmental splicing deregulation in leukodystrophies related to EIF2B mutations. PLoS One 2012;7(6):e38264. 235. Inoue-Choi M, Nelson HH, Robien K, Arning E, Bottiglieri T, Koh WP, Yuan JM. One-carbon metabolism nutrient status and plasma Sadenosylmethionine concentrations in middle-aged and older Chinese in Singapore. Int J Mol Epidemiol Genet 2012;3(2):160–173. 236. Marin-Valencia I, Good LB, Ma Q, Duarte J, Bottiglieri T, Sinton CM, Heilig CW, Pascual JM. Glut1 deficiency (G1D): epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype. Neurobiol Dis 2012;48(1):92–101. 237. Mercimek-Mahmutoglu S, Sinclair G, van Dooren SJ, Kanhai W, Ashcraft P, Michel OJ, Nelson J, Betsalel OT, Sweetman L, Jakobs C, Salomons GS. Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease. Mol Genet Metab 2012;107(3):433–437. 238. Mischoulon D, Alpert JE, Arning E, Bottiglieri T, Fava M, Papakostas GI. Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. J Clin Psychiatry 2012;73(6):843–848. 239. Mochel F, Durant B, Meng X, O’Callaghan J, Yu H, Brouillet E, Wheeler VC, Humbert S, Schiffmann R, Durr A. Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 2012;287(2):1361–1370. 240. Mochel F, Schiffmann R, Steenweg ME, Akman HO, Wallace M, Sedel F, Laforêt P, Levy R, Powers JM, Demeret S, Maisonobe T, Froissart R, Da Nobrega BB, Fogel BL, Natowicz MR, Lubetzki C, Durr A, Brice A, Rosenmann H, Barash V, Kakhlon O, Gomori JM, van der Knaap MS, Lossos A. Adult polyglucosan body disease: natural history and key magnetic resonance imaging findings. Ann Neurol 2012;72(3):433–441. 241. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 2012;338(6105):394–397. 242. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, 222 243. 244. 245. 246. 247. 248. Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012;169(12):1267–1274. Potic A, Brais B, Choquet K, Schiffmann R, Bernard G. 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. Arch Neurol 2012;69(7):920–923. Ramos-Roman MA, Sweetman L, Valdez MJ, Parks EJ. Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. Metabolism 2012;61(2):202–212. Segal MM, Schiffmann R. Decision support for diagnosis: co-evolution of tools and resources. Neurology 2012;78(20):1546–1547. Tétreault M, Putorti ML, Thiffault I, Sylvain M, Venderver A, Schiffmann R, Brais B, Bernard G. TACH leukodystrophy: locus refinement to chromosome 10q22.3-23.1. Can J Neurol Sci 2012;39(1):122–123. Thomas NK, Willis S, Sweetman L, Borges K. Triheptanoin in acute mouse seizure models. Epilepsy Res 2012;99(3):312–317. Vogel KR, Arning E, Wasek BL, Bottiglieri T, Gibson KM. Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAH (ENU2) mice. J Inherit Metab Dis 2012 Sep 14 [Epub ahead of print]. NEPHROLOGY Note: See also Transplantation. 249. Aggarwal N, Porter AC, Tang IY, Becker BN, Akkina SK. Creatininebased estimations of kidney function are unreliable in obese kidney donors. J Transplant 2012;2012:872894. 250. Akkina SK, Ricardo AC, Patel A, Das A, Bazzano LA, Brecklin C, Fischer MJ, Lash JP. Illicit drug use, hypertension, and chronic kidney disease in the US adult population. Transl Res 2012;160(6):391–398. 251. Colbert G, Richey D, Schwartz JC. Widespread tuberculosis including renal involvement. Proc (Bayl Univ Med Cent) 2012;25(3):236–239. 252. Patel T, Fenves A, Colbert G. The de novo diagnosis of systemic lupus erythematosus and lupus nephritis during pregnancy. Proc (Bayl Univ Med Cent) 2012;25(2):129–131. 253. Sanchez C, Fenves A, Schwartz J. Focal segmental glomerulosclerosis and parvovirus B19. Proc (Bayl Univ Med Cent) 2012;25(1):20–22. 254. Saxena R, Fenves A, Yu XQ, Vaziri ND, Silva FG, Zhou XJ. Renal function and disease in the aging kidney. In Schrier RW, ed. Schrier’s Diseases of the Kidney and Urinary Tract, 9th ed. Baltimore: Lippincott Williams & Wilkins, 2012. 255. Shroff GR, Akkina SK, Miedema MD, Madlon-Kay R, Herzog CA, Kasiske BL. Troponin I levels and postoperative myocardial infarction following renal transplantation. Am J Nephrol 2012;35(2):175–180. NEUROLOGY/NEUROSURGERY 256. Black SB, Evans RW. Economic credentialing of physicians by insurance companies and headache medicine. Headache 2012;52(6):1037–1040. 257. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367(12):1087–1097. 258. Freitag FG. Headache: advances in understanding and treatment. Lancet Neurol 2012;11(1):10–12. 259. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78(17):1346–1353. 260. Hostin R, McCarthy I, O’Brien M, Bess S, Line B, Boachi-Adjei O, Burton D, Gupta M, Ames C, Deviren V, Kebaish K, Shaffrey C, Wood K, Hart R; International Spine Study Group. Incidence, mode, and location of acute proximal junctional failure following surgical treatment for adult spinal deformity. Spine (Phila Pa 1976) 2012 Sept 13 [Epub ahead of print]. 261. Khan O, Miller A, Tornatore C, Phillips J, Barnes C. Practice patterns of US neurologists in secondary progressive and primary progressive Baylor University Medical Center Proceedings Volume 26, Number 2 262. 263. 264. 265. 266. multiple sclerosis: a modified Delphi consensus study. Neurol Clin Pract 2012;2(1):58–66. Phillips JT. Consensus statements from a panel of U.S. managed care pharmacists and physicians for management of multiple sclerosis agents. J Manag Care Pharm 2012;18(3):277. Phillips J, Stone L. Use of MRI in the clinical management of multiple sclerosis. In Cohen J, Rudick R, eds. Multiple Sclerosis Therapeutics, 4th ed. Cambridge: Cambridge University Press, 2012:645–653. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78(17):1337–1345. Tornatore C, Phillips J, Khan O, Miller AE, Barnes CJ. Practice patterns of US neurologists in patients with CIS, RRMS, or RIS: a consensus study. Neurol Clin Pract 2012;2(1):48–57. Weinstock-Guttman B, Galetta SL, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, O’Connor PW, Phillips JT, Polman C, Stuart WH, Lynn F, Hotermans C. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. J Neurol 2012;259(5):898–905. 284. 285. 286. NURSING/ALLIED HEALTH 267. Ashmore JA, Frierson G, Blair SN. The role of physical activity in weight loss and weight loss maintenance. In Akabas SR, Lederman SA, Moore BJ, eds. Textbook of Obesity: Biological, Psychological and Cultural Implications. New York: John Wiley & Sons, 2012:344–353. 268. Cochran VY, Blair B, Wissinger L, Nuss TD. Lessons learned from implementation of postdischarge telephone calls at Baylor Health Care System. J Nurs Adm 2012;42(1):40–46. 269. Custer JW, White E, Fackler JC, Xiao Y, Tien A, Lehmann H, Nichols DG. A qualitative study of expert and team cognition on complex patients in the pediatric intensive care unit. Pediatr Crit Care Med 2012;13(3):278–284. 270. Hasse JM. Diet linked to cancer. Nutr Clin Pract 2012;27(5):581. 271. Hasse JM. Nutrition support safe practices. Nutr Clin Pract 2012;27(6): 713–714. 272. Hasse JM. Pre- and probiotics. Nutr Clin Pract 2012;27(2):149. 273. Houston S, Leveille M, Luquire R, Fike A, Ogola GO, Chando S. Decisional involvement in Magnet®, Magnet-aspiring, and non-Magnet hospitals. J Nurs Adm 2012;42(12):586–591. 274. Leeper B, Centeno M. Disparities in cardiac care for patients with complex cardiovascular care needs. J Cardiovasc Nurs 2012;27(2):114–119. 275. Pilcher J. Growing dendrites and brain-based learning. Neonatal Net 2012;31(3):191–194. 276. Pilcher J. Owning your professional development. Neonatal Netw 2012;31(6): 401–406. 277. Pilcher J. Toolkit for NICU nurse preceptors. Neonatal Netw 2012;31(1): 39–44. 278. Pilcher J, Goodall H, Jensen C, Huwe V, Jewell C, Reynolds R, Karlsen KA. Special focus on simulation: educational strategies in the NICU: simulation-based learning: it’s not just for NRP. Neonatal Netw 2012;31(5):281–287. 279. Poskey GA, Hersch G. Listening to their voices: parents’ perspective on infant crying. J Occup Ther Schools Early Intervent 2012;5(2):114–125. 280. Smith NZ. Treating metastatic breast cancer with systemic chemotherapies: current trends and future perspectives. Clin J Oncol Nurs 2012;16(2):E33–E43. 281. Tjiong L, Cyr A, Fox J. Comparison of manual compression alone versus with hemostatic patch in achieving hemostasis after femoral catheter removal. J Perianesth Nurs 2012;27(2):88–93. 282. Wyatt C, Jumper J. The human touch: learning that the job is about more than machines. Biomed Instrum Technol 2012;46(3):181–183. ONCOLOGY/HEMATOLOGY/SURGICAL ONCOLOGY 283. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston April 2013 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network [Agura E]. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012;367(16): 1487–1496. Antelo M, Balaguer F, Shia J, Shen Y, Hur K, Moreira L, Cuatrecasas M, Bujanda L, Giraldez MD, Takahashi M, Cabanne A, Barugel ME, Arnold M, Roca EL, Andreu M, Castellvi-Bel S, Llor X, Jover R, Castells A, Boland CR, Goel A. A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS One 2012;7(9):e45357. Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, Waller EK, Litzow MR, Liesveld JL, Lazarus HM, Artz AS, Gupta V, Savani BN, McCarthy PL, Cahn JY, Schouten HC, Finke J, Ball ED, Aljurf MD, Cutler CS, Rowe JM, Antin JH, Isola LM, Di Bartolomeo P, Camitta BM, Miller AM, et al. Classifying cytogenetics in patients with AML in complete remission undergoing allogeneic transplantation: a CIBMTR study. Biol Blood Marrow Transplant 2012;18(2):280–288. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 2012;30(21):2585–2592. Blum JL, Barrios CH, Feldman N, Verma S, McKenna EF, Lee LF, Scotto N, Gralow J. Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2012;136(3):777–788. Boland CR. Lynch syndrome: new tales from the crypt. Lancet Oncol 2012;13(6):562–564. Boland CR. Taking the starch out of hereditary colorectal cancer. Lancet Oncol 2012;13(12):1179–1180. Bouvard V, Baan RA, Grosse Y, Lauby-Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Straif K; WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of malaria and of some polyomaviruses. Lancet Oncol 2012;13(4):339–340. Bracarda S, Hutson TE, Porta C, Figlin RA, Calvo E, Grünwald V, Ravaud A, Motzer R, Kim D, Anak O, Panneerselvam A, Escudier B. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br J Cancer 2012;106(9):1475–1480. Brim H, Lee E, Abu-Asab MS, Chaouchi M, Razjouyan H, Namin H, Goel A, Schäffer AA, Ashktorab H. Genomic aberrations in an African American colorectal cancer cohort reveals a MSI-specific profile and chromosome X amplification in male patients. PLoS One 2012;7(8):e40392. Burch M, Cooper B. Fondaparinux-associated heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent) 2012;25(1):13–15. Buzdar AU, Xu B, Digumarti R, Goedhals L, Hu X, Semiglazov V, Cheporov S, Gotovkin E, Hoersch S, Rittweger K, Miles DW, O’Shaughnessy J, Tjulandin S; on behalf of the NO16853 trial group. Randomized phase II non-inferiority study (NO16853) of two different doses of capecitabine in combination with docetaxel for locally advanced/metastatic breast cancer. Ann Oncol 2012;23(3):589–597. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 2012 Oct 15 [Epub ahead of print]. Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Ravaud A, Kim D, Panneerselvam A, Anak O, Figlin RA. Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer 2012;48(3):333–339. Cao Y, Panos L, Graham RL, Parker TH 3rd, Mennel R. Primary cutaneous angiosarcoma of the breast after breast trauma. Proc (Bayl Univ Med Cent) 2012;25(1):70–72. 2012 publications of the Baylor Health Care System medical and scientific staff 223 298. Cho DC, Hutson TE, Samlowski W, Sportelli P, Somer B, Richards P, Sosman JA, Puzanov I, Michaelson MD, Flaherty KT, Figlin RA, Vogelzang NJ. Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy. Cancer 2012 Jun 6 [Epub ahead of print]. 299. Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol 2012;30(5): 507–512. 300. Collea RP, Kruter FW, Cantrell JE, George TK, Kruger S, Favret AM, Lindquist DL, Melnyk AM, Pluenneke RE, Shao SH, Crockett MW, Asmar L, O’Shaughnessy J. Pegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II study. Ann Oncol 2012;23(10):2599–2605. 301. Cortes J, Calvo V, Ramírez-Merino N, O’Shaughnessy J, Brufsky A, Robert N, Vidal M, Muñoz E, Perez J, Dawood S, Saura C, Di Cosimo S, González-Martín A, Bellet M, Silva OE, Miles D, Llombart A, Baselga J. Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis. Ann Oncol 2012;23(5):1130–1137. 302. Craig DW, O’Shaughnessy JA, Kiefer JA, Aldrich J, Sinari S, Moses TM, Wong S, Dinh J, Christoforides A, Blum JL, Aitelli CL, Osborne CR, Izatt T, Kurdoglu A, Baker A, Koeman J, Barbacioru C, Sakarya O, De La Vega FM, Siddiqui A, Hoang L, Billings PR, Salhia B, Tolcher AW, Trent JM, Mousses S, Von Hoff DD, Carpten JD. Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 2012 Nov 19 [Epub ahead of print]. 303. Crown J, O’Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol 2012;23(Suppl 6):vi56–vi65. 304. Ding YC, McGuffog L, Healey S, Friedman E, Laitman Y, ShimonPaluch S, Kaufman B, Liljegren A, Lindblom A, Olsson H, Kristoffersson U, Stenmark Askmalm M, Melin B, Domchek SM, Nathanson KL, Rebbeck TR, Jakubowska A, Lubinski J, Jaworska K, Durda K, Gronwald J, Huzarski T, Cybulski C, Byrski T, Osorio A, Ramony Cajal T, Stavropoulou AV, Benítez J, Hamann U, Rookus MA, Aalfs CM, de Lange J, Meijers-Heijboer HE, Oosterwijk JC, van Asperen CJ, GomezGarcia EB, Hoogerbrugge N, Jager A, van der Luijt RB, Easton DF, Peock S, Frost D, Ellis SD, Platte R, Fineberg E, Evans DG, Lalloo F, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles DM, Cole T, Cook J, Brewer C, Tischkowitz M, Godwin AK, Pathak HB, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Barjhoux L, Leone M, Gauthier-Villars M, Caux-Moncoutier V, de Pauw A, Hardouin A, Berthet P, Dreyfus H, Fert Ferrer S, Collonge-Rame MA, Sokolowska J, Buys SS, Daly MB, Miron A, Terry MB, Chung WK, John EM, Southey MC, Goldgar DE, Singer CF, Tea Maria MK, Gschwantler-Kaulich D, Fink-Retter A, Hansen TV, Ejlertsen B, Johannsson OT, Offit K, Sarrel K, Gaudet MM, Vijai J, Robson ME, Piedmonte M, Andrews L, Cohn DE, Demars LR, Disilvestro P, Rodriguez GC, Toland AE, Montagna M, Agata S, Imyanitov EN, Isaacs C, Janavicius R, Lazaro C, Blanco I, Ramus SJ, Sucheston LE, Karlan BY, Gross J, Ganz PA, Beattie MS, Schmutzler RK, Wappenschmidt B, Meindl A, Arnold N, Niederacher D, PreislerAdams S, Gadzicki D, Varon-Mateeva R, Deissler H, Gehrig A, Sutter C, Kast K, Nevanlinna H, Aittomäki K, Simard J, Spurdle AB, Beesley J, Chen X, Tomlinson GE, Weitzel JN, Garber JE, Olopade FI, Rubinstein WS, Tung N, Blum JL, Narod SA, Brummel S, Gillen DL, Lindor NM, Fredericksen Z, Pankratz VS, Couch FJ, Radice P, Peterlongo P, Greene MH, Loud JT, Mai PL, Andrulis IL, Glendon G, Ozcelik H, Gerdes AM, Thomassen M, Jensen UB, Skytte AB, Caligo MA, Lee A, Chenevix-Trench G, Antoniou AC, Neuhausen SL. A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012;21(8):1362–1370. 224 305. Finkelman BS, Rubinstein WS, Friedman S, Friebel TM, Dubitsky S, Schonberger NS, Shoretz R, Singer CF, Blum JL, Tung N, Olopade OI, Weitzel JN, Lynch HT, Snyder C, Garber JE, Schildkraut J, Daly MB, Isaacs C, Pichert G, Neuhausen SL, Couch FJ, Van’t Veer L, Eeles R, Bancroft E, Evans DG, Ganz PA, Tomlinson GE, Narod SA, Matloff E, Domchek S, Rebbeck TR. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol 2012;30(12):1321–1328. 306. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COUAA-301 Investigators [Hutson T]. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;13(10):983–992. 307. Fleming MT, Sonpavde G, Kolodziej M, Awasthi S, Hutson TE, Martincic D, Rastogi A, Rousey SR, Weinstein RE, Galsky MD, Berry WR, Wang Y, Boehm KA, Asmar L, Rauch MA, Beer TM. Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castrationresistant prostate cancer. Clin Genitourin Cancer 2012;10(1):6–14. 308. Freytes CO, Zhang MJ, Carreras J, Burns LJ, Gale RP, Isola L, Perales MA, Seftel M, Vose JM, Miller AM, Gibson J, Gross TG, Rowlings PA, Inwards DJ, Pavlovsky S, Martino R, Marks DI, Hale GA, Smith SM, Schouten HC, Slavin S, Klumpp TR, Lazarus HM, van Besien K, Hari PN. Outcome of lower-intensity allogeneic transplantation in non-Hodgkin lymphoma after autologous transplantation failure. Biol Blood Marrow Transplant 2012;18(8):1255–1264. 309. Galsky MD, Hahn NM, Powles T, Hellerstedt BA, Lerner SP, Gardner TA, Yu M, O’Rourke M, Vogelzang NJ, Kocs D, McKenney SA, Melnyk AM Jr, Hutson TE, Rauch M, Wang Y, Asmar L, Sonpavde G. Gemcitabine, cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer. Clin Genitourin Cancer 2012 Dec 7 [Epub ahead of print]. 310. Garcia M, Choi C, Kim HR, Daoud Y, Toiyama Y, Takahashi M, Goel A, Boland CR, Koi M. Association between recurrent metastasis from stage II and III primary colorectal tumors and moderate microsatellite instability. Gastroenterology 2012;143(1):48–50.e1. 311. Gasche JA, Goel A. Epigenetic mechanisms in oral carcinogenesis. Future Oncol 2012;8(11):1407–1425. 312. Goel A. Colorectal cancer: sailing with a T-cell EMAST. Dig Dis Sci 2012;57(1):1–3. 313. Goel A, Arnold CN. Biology and genetics of colorectal cancer and polyps and polyposis. In Hawkey C, Richter J, Bosch J, Garcia-Tsao G, Chan F, eds. Textbook of Clinical Gastroenterology and Hepatology. Chichester, UK: Wiley Blackwell, 2012:428–437. 314. Goel A, Boland CR. Epigenetics of colorectal cancer. Gastroenterology 2012 143(6):1442–1460.e1. 315. Gopal AK, Ramchandren R, O’Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 2012;120(3):560–568. 316. Hinson SA, Silva EG, Pinto K. Ovarian serous cystadenofibromas associated with a low-grade serous carcinoma of the peritoneum. Ann Diagn Pathol 2012;31(6):547–555. 317. Hur K, Han TS, Jung EJ, Yu J, Lee HJ, Kim WH, Goel A, Yang HK. Up-regulated expression of sulfatases (SULF1 and SULF2) as prognostic and metastasis predictive markers in human gastric cancer. J Pathol 2012;228(1):88–98. 318. Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, Hemmi H, Koi M, Boland CR, Goel A. MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut 2012 Jul 10 [Epub ahead of print]. 319. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, Demarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le Baylor University Medical Center Proceedings Volume 26, Number 2 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 doseescalation trial. Lancet Oncol 2012;13(8):773–781. Jennings AW, Preskitt JT, Vallera RD. Extraadrenal pheochromocytoma and vagal paraganglioma. Proc (Bayl Univ Med Cent) 2012;25(2): 152–154. Jones G, Arthurs B, Kaya H, Macdonald K, Qin R, Fairbanks RK, Lamoreaux WT, Jawed I, Tward JD, Martincic D, Shivnani AT, Lee CM. Overall survival analysis of adjuvant radiation versus observation in stage I testicular seminoma: a Surveillance, Epidemiology, and End Results (SEER) analysis. Am J Clin Oncol 2012 Jul 9 [Epub ahead of print]. Kathiria AS, Butcher LD, Feagins LA, Souza RF, Boland CR, Theiss AL. Prohibitin 1 modulates mitochondrial stress-related autophagy in human colonic epithelial cells. PLoS One 2012;7(2):e31231. Kathiria AS, Neumann WL, Rhees J, Hotchkiss E, Cheng Y, Genta RM, Meltzer SJ, Souza RF, Theiss AL. Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses. Cancer Res 2012;72(22):5778–5789. Khandani AH, Cowey CL, Moore DT, Gohil H, Rathmell WK. Primary renal cell carcinoma: relationship between 18F-FDG uptake and response to neoadjuvant sorafenib. Nucl Med Commun 2012;33(9):967–973. Kotsopoulos J, Lubinski J, Lynch HT, Kim-Sing C, Neuhausen S, Demsky R, Foulkes WD, Ghadirian P, Tung N, Ainsworth P, Senter L, Karlan B, Eisen A, Eng C, Weitzel J, Gilchrist DM, Blum JL, Zakalik D, Singer C, Fallen T, Ginsburg O, Huzarski T, Sun P, Narod SA. Oophorectomy after menopause and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012;21(7): 1089–1096. Kroeker TR, O’Brien JC. Outcomes of combined oncologic resection and carotid endarterectomy in patients with head and neck cancer. Head Neck 2012 Jan 20 [Epub ahead of print]. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, O’Shaughnessy J, Kinzler KW, Parmigiani G, Vogelstein B, Diaz LA Jr, Velculescu VE. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 2012;4(162):162ra154. Li J, Koike J, Kugoh H, Arita M, Ohhira T, Kikuchi Y, Funahashi K, Takamatsu K, Boland CR, Koi M, Hemmi H. Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancer. Biochim Biophys Acta 2012;1823(4):889–899. Lin TL, Levy MY. Acute myeloid leukemia: focus on novel therapeutic strategies. Clin Med Insights Oncol 2012;6:205–217. Link A, Becker V, Goel A, Wex T, Malfertheiner P. Feasibility of fecal microRNAs as novel biomarkers for pancreatic cancer. PLoS One 2012;7(8):e42933. Mann S, Patel P, Matthews CM, Pinto K, O’Connor J. Malignant transformation of endometriosis within the urinary bladder. Proc (Bayl Univ Med Cent) 2012;25(3):293–295. Martins FC, De S, Almendro V, Gönen M, Park SY, Blum JL, Herlihy W, Ethington G, Schnitt SJ, Tung N, Garber JE, Fetten K, Michor F, Polyak K. Evolutionary pathways in BRCA1-associated breast tumors. Cancer Discov 2012;2(6):503–511. McGee J, Kotsopoulos J, Lubinski J, Lynch HT, Rosen B, Tung N, KimSing C, Karlan B, Foulkes WD, Ainsworth P, Ghadirian P, Senter L, Eisen A, Sun P, Narod SA; Hereditary Breast Cancer Clinical Study Group. Anthropometric measures and risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. Obesity (Silver Spring) 2012;20(6):1288–1292. Moinpour CM, Donaldson GW, Liepa AM, Melemed AS, O’Shaughnessy J, Albain KS. Evaluating health-related quality-of-life therapeutic effectiveness in a clinical trial with extensive nonignorable missing data and heterogeneous response: results from a phase III randomized trial of gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer. Qual Life Res 2012;21(5):765–775. Morgan C, Shah ZA, Hamilton R, Wang J, Spigel J, DeLeon W, DeLeon P, Leete T, Fulmer JM. The radial scar of the breast diagnosed at core needle biopsy. Proc (Bayl Univ Med Cent) 2012;25(1):3–5. April 2013 336. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, Wilding G, Agarwal N, Thompson JA, Cella D, Bello A, Korytowsky B, Yuan J, Valota O, Martell B, Hariharan S, Figlin RA. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30(12):1371–1377. 337. Nadler E, Forsyth M, Satram-Hoang S, Reyes C. Costs and clinical outcomes among patients with second-line non-small cell lung cancer in the outpatient community setting. J Thorac Oncol 2012;7(1):212–218. 338. Nishida N, Kudo M, Nagasaka T, Ikai I, Goel A. Characteristic patterns of altered DNA methylation predict emergence of human hepatocellular carcinoma. Hepatology 2012;56(3):994–1003. 339. O’Shaughnessy JA. Breast cancer in focus: treatment options for triple-negative metastatic breast cancer. Clin Adv Hematol Oncol 2012;10(1):43–45. 340. O’Shaughnessy JA, Kaufmann M, Siedentopf F, Dalivoust P, Debled M, Robert NJ, Harbeck N. Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer. Oncologist 2012;17(4):476–484. 341. Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, Garcia-Sanz R, Ocio EM, Morra E, Morel P, Anderson KC, Patterson CJ, Munshi NC, Tedeschi A, Joshua DE, Kastritis E, Terpos E, Ghobrial IM, Leleu X, Gertz MA, Ansell SM, Morice WG, Kimby E, Treon SP. Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 2012 Nov 15 [Epub ahead of print]. 342. Patil S, Figlin RA, Hutson TE, Michaelson MD, Negrier S, Kim ST, Huang X, Motzer RJ. Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-ş . Br J Cancer 2012;106(10):1587–1590. 343. Porta C, Calvo E, Climent MA, Vaishampayan U, Osanto S, Ravaud A, Bracarda S, Hutson TE, Escudier B, Grünwald V, Kim D, Panneerselvam A, Anak O, Motzer RJ. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 trial. Eur Urol 2012;61(4):826–833. 344. Powles T, Hutson TE. Difficulty in predicting survival in metastatic renal cancer. Lancet Oncol 2012;13(9):859–860. 345. Santarpia L, Qi Y, Stemke-Hale K, Wang B, Young EJ, Booser DJ, Holmes FA, O’Shaughnessy J, Hellerstedt B, Pippen J, Vidaurre T, Gomez H, Valero V, Hortobagyi GN, Symmans WF, Bottai G, Di Leo A, GonzalezAngulo AM, Pusztai L. Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. Breast Cancer Res Treat 2012;134(1):333–343. 346. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators [Hutson T]. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367(13):1187–1197. 347. Shahriar R, Alexander CT, Quirk CR, Keglovits L, Van Vrancken M. Numb chin syndrome as the initial presentation of posttransplant lymphoproliferative disorder. Proc (Bayl Univ Med Cent) 2012;25(3): 243–245. 348. Shen K, Qi Y, Song N, Tian C, Rice SD, Gabrin MJ, Brower SL, Symmans WF, O’Shaughnessy JA, Holmes FA, Asmar L, Pusztai L. Cell line derived multi-gene predictor of pathologic response to neoadjuvant chemotherapy in breast cancer: a validation study on US Oncology 02103 clinical trial. BMC Med Genomics 2012 Nov 16;5:51. 349. Shen Y, Takahashi M, Byun HM, Link A, Sharma N, Balaguer F, Leung HC, Boland CR, Goel A. Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells. Cancer Biol Ther 2012;13(7):542–552. 350. Shia J, Zhang L, Shike M, Guo M, Stadler Z, Xiong X, Tang LH, Vakiani E, Katabi N, Wang H, Bacares R, Ruggeri J, Boland CR, Ladanyi M, Klimstra DS. Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/ PMS2 deficiency. Mod Pathol 2012 Aug 24 [Epub ahead of print]. 2012 publications of the Baylor Health Care System medical and scientific staff 225 351. Silva EG. The stromal origin of some epithelial ovarian neoplasms: “Fere ex nihilo.” Int J Gynecol Cancer 2012;22(6):906–907. 352. Sonpavde G, Choueiri TK, Escudier B, Ficarra V, Hutson TE, Mulders PF, Patard JJ, Rini BI, Staehler M, Sternberg CN, Stief CG. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol 2012;61(2):307–316. 353. Sonpavde G, Matveev V, Burke JM, Caton JR, Fleming MT, Hutson TE, Galsky MD, Berry WR, Karlov P, Holmlund JT, Wood BA, Brookes M, Leopold L. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol 2012;23(7):1803–1808. 354. Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE, Zhan F, Vogelzang NJ. Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer 2012;10(1):1–5. 355. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366(8):707–714. 356. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood 2012;119(10):2205–2208. 357. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, NiculescuDuvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366(3):207–215. 358. Takahashi M, Cuatrecasas M, Balaguer F, Hur K, Toiyama Y, Castells A, Boland CR, Goel A. The clinical significance of MiR-148a as a predictive biomarker in patients with advanced colorectal cancer. PLoS One 2012;7(10):e46684. 359. Takahashi M, Sung B, Shen Y, Hur K, Link A, Boland CR, Aggarwal BB, Goel A. Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family. Carcinogenesis 2012;33(12):2441–2449. 360. Thomas VT, Hinson S, Konduri K. Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. Ther Adv Med Oncol 2012;4(1):31–37. 361. Thompson P, Roe DJ, Fales L, Buckmeier J, Wang F, Hamilton SR, Bhattacharyya A, Green S, Hsu CH, Chow HH, Ahnen DJ, Boland CR, Heigh RI, Fay DE, Martinez ME, Jacobs E, Ashbeck EL, Alberts DS, Lance P. Design and baseline characteristics of participants in a phase III randomized trial of celecoxib and selenium for colorectal adenoma prevention. Cancer Prev Res (Phila) 2012;5(12):1381–1393. 362. Toiyama Y, Goel A. The diagnostic, prognostic and predictive potential of microRNA biomarkers in colorectal cancer. Current Colorectal Cancer Reports 2012;8(1):22–31. 363. Toiyama Y, Yasuda H, Saigusa S, Matushita K, Fujikawa H, Tanaka K, Mohri Y, Inoue Y, Goel A, Kusunoki M. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int J Cancer 2012;130(12):2912–2921. 364. Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol 2012;13(8):827–837. 226 365. Ubel PA, Berry SR, Nadler E, Bell CM, Kozminski MA, Palmer JA, Evans WK, Strevel EL, Neumann PJ. In a survey, marked inconsistency in how oncologists judged value of high-cost cancer drugs in relation to gains in survival. Health Aff (Millwood) 2012;31(4):709–717. 366. Vogelzang NJ, Bhor M, Liu Z, Dhanda R, Hutson TE. Everolimus vs. temsirolimus for advanced renal cell carcinoma: use and use of resources in the US Oncology network. Clin Genitourin Cancer 2012 Oct 11 [Epub ahead of print]. 367. Williams JC, Hamilton JK, Shiller M, Fischer L, Deprisco G, Boland CR. Combined juvenile polyposis and hereditary hemorrhagic telangiectasia. Proc (Bayl Univ Med Cent) 2012;25(4):360–364. 368. Witta SE, Jotte RM, Konduri K, Neubauer MA, Spira AI, Ruxer RL, Varella-Garcia M, Bunn PA Jr, Hirsch FR. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced nonsmall-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol 2012;30(18):2248–2255. 369. Yurgelun MB, Goel A, Hornick JL, Sen A, Turgeon DK, Ruffin MT 4th, Marcon NE, Baron JA, Bresalier RS, Syngal S, Brenner DE, Boland CR, Stoffel EM. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 2012;5(4):574–582. 370. Zurita AJ, George DJ, Shore ND, Liu G, Wilding G, Hutson TE, Kozloff M, Mathew P, Harmon CS, Wang SL, Chen I, Chow Maneval E, Logothetis CJ. Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Ann Oncol 2012;23(3):688–694. ORAL AND MAXILLOFACIAL SURGERY 371. Wolford LM. Mandibular asymmetry: temporomandibular joint degeneration. In Bagheri SC, Bell RB, Khan HA, eds. Current Therapy in Oral and Maxillofacial Surgery. St. Louis: Elsevier Saunders, 2012:696–725. 372. Wolford LM, Bourland TC, Rodrigues D, Perez DE, Limoeiro E. Successful reconstruction of nongrowing hemifacial microsomia patients with unilateral temporomandibular joint total joint prosthesis and orthognathic surgery. J Oral Maxillofac Surg 2012;70(12):2835–2853. 373. Wolford LM, Perez D, Stevao E, Perez E. Airway space changes after nasopharyngeal adenoidectomy in conjunction with Le Fort I osteotomy. J Oral Maxillofac Surg 2012;70(3):665–671. 374. Wolford LM, Rodrigues DB. Orthognathic considerations in the young patient and effects on facial growth. In Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer, 2012:1789–1808. 375. Wolford LM, Rodrigues DB. Temporomandibular joint (TMJ) pathologies in growing patients: effects on facial growth and development. In Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer, 2012:1809–1828. 376. Wolford LM, Stevo ELL, Alexander CM, Goncalves JR, Rodrigues DB. Orthodontics for orthognathic surgery. In Miloro M, Ghali GE, Larsen P, Waite P, eds. Peterson’s Principles of Oral and Maxillofacial Surgery. Shelton, CT: People’s Medical Publishing House-USA, 2012:1263–1294. ORTHOPAEDIC SURGERY 377. Atesok K, Mabrey JD, Jazrawi LM, Egol KA. Surgical simulation in orthopaedic skills training. J Am Acad Orthop Surg 2012;20(7):410–422. 378. Brodsky JW, Brajtbord J, Coleman SC, Raut S, Polo FE. Effect of heating on the mechanical properties of insole materials. Foot Ankle Int 2012;33(9):772–778. 379. Brodsky JW, Toppins A. Postsurgical imaging of the peroneal tendons. Semin Musculoskelet Radiol 2012;16(3):233–240. 380. Daoud AI, Geissler GJ, Wang F, Saretsky J, Daoud YA, Lieberman DE. Foot strike and injury rates in endurance runners: a retrospective study. Med Sci Sports Exerc 2012;44(7):1325–1334. 381. Smith SM, Coleman SC, Bacon SA, Polo FE, Brodsky JW. Improved ankle push-off power following cheilectomy for hallux rigidus: a prospective gait analysis study. Foot Ankle Int 2012;33(6):457–461. Baylor University Medical Center Proceedings Volume 26, Number 2 OTOLARYNGOLOGY 382. Arosarena O, Ducic Y, Tollefson TT. Mandible fractures: discussion and debate. Facial Plast Surg Clin North Am 2012;20(3):347–363. 383. Inman J, Ducic Y. Intracranial free tissue transfer for massive cerebrospinal fluid leaks of the anterior cranial fossa. J Oral Maxillofac Surg 2012;70(5):1114–1118. PATHOLOGY 384. Chen J, Matzuk MM, Zhou XJ, Lu CY. Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury. Kidney Int 2012;82(11):1195–1207. 385. Du Y, An S, Liu L, Li L, Zhou XJ, Mason RP, Mohan C. Serial noninvasive monitoring of renal disease following immune-mediated injury using near-infrared optical imaging. PLoS One 2012;7(9):e43941. 386. Harbour LN, Koch MS, Louis TH, Fulmer JM, Guileyardo JM. Abdominal apoplexy: two unusual cases of hemoperitoneum. Proc (Bayl Univ Med Cent) 2012;25(1):16–19. 387. Hutcheson J, Vanarsa K, Bashmakov A, Grewal S, Sajitharan D, Chang BY, Buggy JJ, Zhou XJ, Du Y, Satterthwaite AB, Mohan C. Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. Arthritis Res Ther 2012;14(6):R243. 388. Hwang SH, Lee H, Yamamoto M, Jones LA, Dayalan J, Hopkins R, Zhou XJ, Yarovinsky F, Connolly JE, Curotto de Lafaille MA, Wakeland EK, Fairhurst AM. B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosusprone mice. J Immunol 2012;189(12):5786–5796. 389. Kiani AN, Wu T, Fang H, Zhou XJ, Ahn CW, Magder LS, Mohan C, Petri M. Urinary vascular cell adhesion molecule, but not neutrophil gelatinase-associated lipocalin, is associated with lupus nephritis. J Rheumatol 2012;39(6):1231–1237. 390. Singh S, Wu T, Xie C, Vanarsa K, Han J, Mahajan T, Oei HB, Ahn C, Zhou XJ, Putterman C, Saxena R, Mohan C. Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis. Arthritis Res Ther 2012;14(4):R164. 391. Van Buren P, Velez RL, Vaziri ND, Zhou XJ. Iron overdose: a contributor to adverse outcomes in randomized trials of anemia correction in CKD. Int Urol Nephrol 2012;44(2):499–507. 392. Van Vrancken MJ, Guileyardo J. Vertebral artery thrombosis and subsequent stroke following attempted internal jugular central venous catheterization. Proc (Bayl Univ Med Cent) 2012;25(3):240–242. PHYSICAL MEDICINE AND REHABILITATION 393. Bombardier CH, Fann JR, Tate DG, Richards JS, Wilson CS, Warren AM, Temkin NR, Heinemann AW; PRISMS Investigators. An exploration of modifiable risk factors for depression after spinal cord injury: which factors should we target? Arch Phys Med Rehabil 2012;93(5):775–781. 394. Driver S, Ede A, Dodd Z, Stevens L, Warren AM. What barriers to physical activity do individuals with a recent brain injury face? Disabil Health J 2012;5(2):117–125. 395. Kelley E, Sullivan C, Loughlin JK, Hutson L, Dahdah MN, Long MK, Schwab KA, Poole JH. Self-awareness and neurobehavioral outcomes, 5 years or more after moderate to severe brain injury. J Head Trauma Rehabil 2012 Dec 15 [Epub ahead of print]. 396. Srinivasan R. Patient safety in the rehabilitation of children with traumatic brain injury and cerebral palsy. Phys Med Rehabil Clin N Am 2012;23(2): 393–400. 397. Stiers W, Hanson S, Turner AP, Stucky K, Barisa M, Brownsberger M, Van Tubbergen M, Ashman T, Kuemmel A. Guidelines for postdoctoral training in rehabilitation psychology. Rehabil Psychol 2012;57(4):267–29. 398. Warren AM, Williamson M, Erosa NA, Elliott TR. Spinal cord injury. In The Handbook of Psychology, Volume 9: Health Psychology, 2nd ed. New York: Wiley, 2012. PLASTIC SURGERY 399. Beale EW, Rasko Y, Rohrich RJ. A twenty year experience with secondary rhytidectomy: a review of technique, longevity and outcomes. Plast Reconstr Surg 2012 Nov 8 [Epub ahead of print]. April 2013 400. Bidic SM, Dauwe PB, Heller J, Brown S, Rohrich RJ. Reconstructing large keloids with neodermis: a systematic review. Plast Reconstr Surg 2012;129(2):380e–382e. 401. Chang S, Lehrman C, Itani K, Rohrich RJ. A systematic review of comparison of upper eyelid involutional ptosis repair techniques: efficacy and complication rates. Plast Reconstr Surg 2012;129(1):149–157. 402. Cruz RS, O’Reilly EB, Rohrich RJ. The platysma window: an anatomically safe, efficient, and easily reproducible approach to neck contour in the face lift. Plast Reconstr Surg 2012;129(5):1169–1172. 403. Del Vecchio D, Rohrich RJ. A classification of clinical fat grafting: different problems, different solutions. Plast Reconstr Surg 2012;130(3): 511–522. 404. Eaves FF 3rd, Haeck PC, Rohrich RJ. ASAPS/ASPS position statement on stem cells and fat grafting. Plast Reconstr Surg 2012;129(1): 285–287. 405. Gir P, Brown SA, Oni G, Kashefi N, Mojallal A, Rohrich RJ. Fat grafting: evidence-based review on autologous fat harvesting, processing, reinjection, and storage. Plast Reconstr Surg 2012;130(1):249–258. 406. Gir P, Oni G, Brown SA, Mojallal A, Rohrich RJ. Human adipose stem cells: current clinical applications. Plast Reconstr Surg 2012;129(6): 1277–1290. 407. Nguyen AT, Ahmad J, Fagien S, Rohrich RJ. Cosmetic medicine: facial resurfacing and injectables. Plast Reconstr Surg 2012;129(1):142e–153e. 408. Pessa JE, Rohrich RJ. Aging changes of the midfacial fat compartments: a computed tomographic study. Plast Reconstr Surg 2012;129(1): 274–275. 409. Rasko YM, Beale E, Rohrich RJ. Secondary rhytidectomy: comprehensive review and current concepts. Plast Reconstr Surg 2012;130(6): 1370–1378. 410. Rifkin LH, Stojadinovic S, Stewart CH, Song KH, Maxted MC, Bell MH, Kashefi NS, Speiser MP, Saint-Cyr M, Story MD, Rohrich RJ, Brown SA, Solberg TD. An athymic rat model of cutaneous radiation injury designed to study human tissue-based wound therapy. Radiat Oncol 2012;7:68. 411. Rohrich RJ. Current concepts in the use of acellular dermal matrices in surgery. Plast Reconstr Surg 2012;130(5 Suppl 2):1S–3S. 412. Rohrich RJ, Hoxworth RE, Kurkjian TJ. The role of the columellar strut in rhinoplasty: indications and rationale. Plast Reconstr Surg 2012;129(1):118e–125e. 413. Rohrich RJ, Kurkjian TJ, Hoxworth RE, Stephan PJ, Mojallal A. The effect of the columellar strut graft on nasal tip position in primary rhinoplasty. Plast Reconstr Surg 2012;130(4):926–932. 414. Rohrich RJ, Liu JH. Defining the infratip lobule in rhinoplasty: anatomy, pathogenesis of abnormalities, and correction using an algorithmic approach. Plast Reconstr Surg 2012;130(5):1148–1158. 415. Saint-Cyr M, Wong C, Oni G, Maia M, Trussler A, Mojallal A, Rohrich RJ. Modifications to extend the transverse upper gracilis flap in breast reconstruction: clinical series and results. Plast Reconstr Surg 2012;129(1):24e–36e. 416. Song EH, Shirazian A, Binns B, Fleming Y, Ferreira LM, Rohrich RJ, Azari K. Benchmarking academic plastic surgery services in the United States. Plast Reconstr Surg 2012;129(6):1407–1418. 417. Unger JG, Lee MR, Kwon RK, Rohrich RJ. A multivariate analysis of nasal tip deprojection. Plast Reconstr Surg 2012;129(5):1163–1167. PULMONOLOGY/SLEEP MEDICINE 418. Gower RG, Lumry WR, Davis-Lorton MA, Johnston DT, Busse PJ. Current options for prophylactic treatment of hereditary angioedema in the United States: patient-based considerations. Allergy Asthma Proc 2012;33(3):235–240. 419. Grant JA, White MV, Li HH, Fitts D, Kalfus IN, Uknis ME, Lumry WR. Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks. Allergy Asthma Proc 2012;33(4):348–353. 420. Henry D, Rosenthal L. “Listening for his breath”: The significance of gender and partner reporting on the diagnosis, management, and treatment of obstructive sleep apnea. Soc Sci Med 2012 Jun 16 [EPub ahead of print]. 2012 publications of the Baylor Health Care System medical and scientific staff 227 421. Kalfus IN, Gower RG, Riedl M, Bernstein JA, Lumry WR, Frank MM. Hereditary angioedema: implications of treating a rare disease. Ann Allergy Asthma Immunol 2012;109(2):150–151. 422. Rosenthal L: Got CPAP? Use it in the hospital! Sleep Breath 2012;16: 945–946. RADIOLOGY Note: See also Oncology and other departments in which radiologists were first authors or coauthors. 423. Barry S, Ha KY, Laurie L. Carcinoma of the breast in men. Proc (Bayl Univ Med Cent) 2012;25(4):367–368. 424. Barry S, Savage C, Layton KF. Combined endovascular thrombolysis and uterine fibroid embolization in a patient with dural venous sinus thrombosis and severe metrorrhagia. J Vasc Interv Radiol 2012;23(3):424–426. 425. Barry SK, Schucany WG. Dracunculiasis of the breast: radiological manifestations of a rare disease. J Radiol Case Rep 2012;6(11):29–33. 426. Carter BW. Hermansky-Pudlak syndrome complicated by pulmonary fibrosis. Proc (Bayl Univ Med Cent) 2012;25(1):76–77. 427. Fitzpatrick MC, Carter BW. Pulmonary mucormycosis complicating cutaneous blastic plasmacytoid dendritic cell neoplasm. Proc (Bayl Univ Med Cent) 2012;25(3):287–288. 428. Gibbs WN, Opatowsky MJ, Burton EC. AIRP best cases in radiologicpathologic correlation: cerebral fat embolism syndrome in sickle cell ␤-thalassemia. Radiographics 2012;32(5):1301–1306. 429. Henderson JB, Zarghouni M, Hise JH, Opatowsky MJ, Layton KF. Dementia caused by dural arteriovenous fistulas reversed following endovascular therapy. Proc (Bayl Univ Med Cent) 2012;25(4):338–340. 430. Islam S, Schucany WG, Hurst DC, Lepe-Suastegui MR. Echinococcus granulosus infection presenting as right upper-quadrant abdominal pain. Proc (Bayl Univ Med Cent) 2012;25(1):80–82. 431. Kershen LM, Schucany WG, Gilbert NF. Nora’s lesion: bizarre parosteal osteochondromatous proliferation of the tibia. Proc (Bayl Univ Med Cent) 2012;25(4):369–371. 432. Layton KJ, Gallichan D, Testud F, Cocosco CA, Welz AM, Barmet C, Pruessmann KP, Hennig J, Zaitsev M. Single shot trajectory design for region-specific imaging using linear and nonlinear magnetic encoding fields. Magn Reson Med 2012 Oct 5 [Epub ahead of print]. 433. Layton KJ, Morelande M, Farrell PM, Moran B, Johnston LA. Performance analysis for magnetic resonance imaging with nonlinear encoding fields. IEEE Trans Med Imaging 2012;31(2):391–404. 434. Levine HR, Ha K, O’Rourke B, Barnett D, Opatowsky MJ. A pictorial review of complications of acute coalescent mastoiditis. Proc (Bayl Univ Med Cent) 2012;25(4):372–373. 435. Levine HR, O’Connor J, dePrisco G. Obstetrical emergency: an unusual case of an ectopic pregnancy. Proc (Bayl Univ Med Cent) 2012;25(1):73–75. 436. McDonald JS, Carter RE, Layton KF, Mocco J, Madigan JB, Tawk RG, Hanel RA, Roy SS, Cloft HJ, Klunder AM, Suh SH, Kallmes DF. Interobserver variability in retreatment decisions of recurrent and residual aneurysms. AJNR Am J Neuroradiol 2012 Oct 25 [Epub ahead of print]. 437. McQuillan B, Carter B, Millard-Hasting B, Ayotte K, Jesinger R, Lichtenberger J. The interventricular septum: a multimodality review of anatomy and pathology. Am J Roentgen 2012;198(5 Suppl). 438. Patel P, Fischer L, O’Connor J. Retroperitoneal ganglioneuroma incidentally found in a patient presenting with renal colic. Proc (Bayl Univ Med Cent) 2012;25(3):291–292. 439. Patel P, Schucany G, Wood PB, Hurst D. Paget’s disease of the calcaneus causing right foot pain. Proc (Bayl Univ Med Cent) 2012;25(2):161–162. 440. Patel P, Schucany WG, Toye L, Ortinau E. Flexor tendon pulley injury in a bowler. Proc (Bayl Univ Med Cent) 2012;25(3):282–284. 441. Patel P, Schucany WG. A rare case of intraneural ganglion cyst involving the tibial nerve. Proc (Bayl Univ Med Cent) 2012;25(2):132–135. 442. Ray MJ, Barnett DW, Snipes GJ, Layton KF, Opatowsky MJ. Ruptured intracranial dermoid cyst. Proc (Bayl Univ Med Cent) 2012;25(1): 23–25. 443. Ray MJ, Savage C, Klintmalm GB, Rees CR. Endovascular caudal retraction of the cranial end of a misplaced Viatorr TIPS prior to liver transplantation. Proc (Bayl Univ Med Cent) 2012;25(4):341–343. 228 444. Saad AF, Opatowsky MJ, Nixon AY, Gilbert SC, Thacker IC. Ruptured cerebral arteriovenous malformation presenting as intraventricular hemorrhage. Proc (Bayl Univ Med Cent) 2012;25(2):163–164. 445. Sacks J, Ray MJ, Williams S, Opatowsky MJ. Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E (“Europa”). Proc (Bayl Univ Med Cent) 2012;25(4):374–376. 446. Schucany WG. Echinococcal infection of the liver causing Budd-Chiari syndrome. Proc (Bayl Univ Med Cent) 2012;25(1):83–84. 447. Taylor WB III, Lloyd MD, Mendeloff EN, Laird WP, Dockery WD, Carter BW. Anomalous origin of the right coronary artery from the pulmonary trunk demonstrated by electrocardiographically gated computed tomography coronary angiography. Proc (Bayl Univ Med Cent) 2012;25(3):289–290. 448. Taylor WB III, Vandergriff CL, Opatowsky MJ, Layton KF. Bowhunter’s syndrome diagnosed with provocative digital subtraction cerebral angiography. Proc (Bayl Univ Med Cent) 2012;25(1):26–27. 449. Vandergriff C, Opatowsky M, O’Rourke B, Layton K. Papillary tumor of the pineal region. Proc (Bayl Univ Med Cent) 2012;25(1):78–79. 450. Zarghouni M, Levine H, Layton KF. Intracranial Nocardia in the setting of AIDS. Proc (Bayl Univ Med Cent) 2012;25(4):381–382. 451. Zarghouni M, Seale TM IV, Ogden E, Savage CM, Carter BW. Benign endobronchial granular cell tumor resulting in right middle lobe collapse. Proc (Bayl Univ Med Cent) 2012;25(4):365–366. 452. Zarghouni M, Vandergriff C, Layton KF, McGowan JB, Coimbra C, Bhakti A, Opatowsky MJ. Chordoid glioma of the third ventricle. Proc (Bayl Univ Med Cent) 2012;25(3):285–286. RHEUMATOLOGY 453. Cush JJ, Dao KH. Malignancy risks with biologic therapies. Rheum Dis Clin North Am 2012;38(4):761–770. 454. Cush JJ, Dao KH. Refining drug safety in rheumatology. Rheum Dis Clin North Am 2012;38(4):xi–xiv. 455. Dao KH, Herbert M, Habal N, Cush JJ. Nonserious infections: should there be cause for serious concerns? Rheum Dis Clin North Am 2012;38(4):707–725. 456. Hsia EC, Schluger N, Cush JJ, Chaisson RE, Matteson EL, Xu S, Beutler A, Doyle MK, Hsu B, Rahman MU. Interferon-␥ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Arthritis Rheum 2012;64(7):2068–2077. 457. Kavanaugh A, Martin G, Cush JJ, Bergman MJ, Fleischmann R, Troum OM, Strand V, Ruderman EM, Wells AF. Proceedings of the 2012 Rheumatology Winter Clinical Symposia. Semin Arthritis Rheum 2012;41(6):923–926. 458. Petryna O, Cush JJ, Efthimiou P. IL-1 Trap rilonacept in refractory adult onset Still’s disease. Ann Rheum Dis 2012;71(12):2056–2057. SURGERY Note: Most surgery articles are subclassified by specialty, even if general surgeons were first authors or coauthors. 459. Culp BL, Cedillo VE, Arnold DT. Single-incision laparoscopic cholecystectomy versus traditional four-port cholecystectomy. Proc (Bayl Univ Med Cent) 2012;25(4):319–323. 460. Stillsmoking K, Jones RC. The changing face of health care education: a new surgical simulation center at Baylor University Medical Center. Proc (Bayl Univ Med Cent) 2012;25(1):37–40. TRANSPLANTATION (ORGAN AND PANCREATIC CELLS) 461. Abouljoud M, Klintmalm G, Whitehouse S. Transplant organizational structures: viewpoints from established centers. Am J Transplant 2012;12(10):2623–2629. 462. Akkina SK, Asrani SK, Peng Y, Stock P, Kim WR, Israni AK. Development of organ-specific donor risk indices. Liver Transpl 2012;18(4):395–404. 463. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, Pattou F, Berney T, Baylor University Medical Center Proceedings Volume 26, Number 2 464. 465. 466. 467. 468. 469. 470. 471. 472. 473. 474. 475. 476. 477. 478. 479. 480. Secchi A, Messinger S, Senior PA, Maffi P, Posselt A, Stock PG, Kaufman DB, Luo X, Kandeel F, Cagliero E, Turgeon NA, Witkowski P, Naji A, O’Connell PJ, Greenbaum C, Kudva YC, Brayman KL, Aull MJ, Larsen C, Kay TW, Fernandez LA, Vantyghem MC, Bellin M, Shapiro AM. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 2012;35(7):1436–1445. Carlisle EM, Testa G. Adult to adult living related liver transplantation: where do we currently stand? World J Gastroenterol 2012;18(46): 6729–6736. Chen S, Shimoda M, Chen J, Matsumoto S, Grayburn PA. Ectopic transgenic expression of NKX2.2 induces differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle 2012;11(8): 1544–1553. Chen S, Shimoda M, Chen J, Matsumoto S, Grayburn PA. Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle 2012;11(4):695–705. Chujo D, Foucat E, Takita M, Itoh T, Sugimoto K, Shimoda M, Yagi K, Yamagishi M, Tamura Y, Yu L, Naziruddin B, Levy MF, Ueno H, Matsumoto S. Emergence of a broad repertoire of GAD65-specific T-cells in type 1 diabetes patients with graft dysfunction after allogeneic islet transplantation. Cell Transplant 2012;21(12):2783–2795. Chujo D, Takita M, Tekin Z, Matsumoto S. Chronic graft dysfunction in allogenic islet cell transplantation. In Berhardt LV, ed. Advances in Medicine and Biology. New York: Nova Science Publishers, 2012:183–201. Feng S, Trotter JF. Can we stop waiting for Godot? Establishing selection criteria for simultaneous liver-kidney transplantation. Am J Transplant 2012;12(11):2869–2870. Itoh T, Iwahashi S, Kanak MA, Shimoda M, Takita M, Chujo D, Tamura Y, Rahman AM, Chung WY, Onaca N, Coates PT, Dennison AR, Naziruddin B, Levy MF, Matsumoto S. Elevation of high-mobility group box 1 after clinical autologous islet transplantation and its inverse correlation with outcomes. Cell Transplant 2012 Dec 4. [Epub ahead of print]. Itoh T, Sugimoto K, Takita M, Shimoda M, Chujo D, Sorelle JA, Naziruddin B, Levy MF, Matsumoto S. Low temperature condition prevents hypoxia induced islet cell damage and HMGB1 release in a mouse model. Cell Transplant 2012 Apr 10 [Epub ahead of print]. Itoh T, Takita M, Sorelle JA, Shimoda M, Sugimoto K, Chujo D, Qin H, Naziruddin B, Levy MF, Matsumoto S. Correlation of released HMGB1 levels with the degree of islet damage in mice and humans and with the outcomes of islet transplantation in mice. Cell Transplant 2012 Apr 26 [Epub ahead of print]. Jackson AM, Kanak MA, Grishman EK, Chaussabel D, Levy MF, Naziruddin B. Gene expression changes in human islets exposed to type 1 diabetic serum. Islets 2012;4(4):312–319. Kaneku H, O’Leary JG, Taniguchi M, Susskind BM, Terasaki PI, Klintmalm GB. Donor-specific human leukocyte antigen antibodies of the immunoglobulin G3 subclass are associated with chronic rejection and graft loss after liver transplantation. Liver Transpl 2012;18(8):984–992. Klintmalm GB. Treat patients, not statistics. Am J Transplant 2012; 12(3):794. Matsumoto S, Takita M, Shimoda M, Sugimoto K, Itoh T, Chujo D, Sorelle JA, Tamura Y, Rahman AM, Onaca N, Naziruddin B, Levy MF. Impact of tissue volume and purification on clinical autologous islet transplantation for the treatment of chronic pancreatitis. Cell Transplant 2012;21(4):625–632. McKenna GJ, Trotter JF. Sirolimus conversion for renal dysfunction in liver transplant recipients: the devil really is in the details. . . . Am J Transplant 2012;12(3):521–522. McKenna GJ, Trotter JF. Sirolimus—it doesn’t deserve its bad Rap(a). J Hepatol 2012;56(1):285–287. Naziruddin B, Matsumoto S, Noguchi H, Takita M, Shimoda M, Fujita Y, Chujo D, Tate C, Onaca N, Lamont J, Kobayashi N, Levy MF. Improved pancreatic islet isolation outcome in autologous transplantation for chronic pancreatitis. Cell Transplant 2012;21(2–3):553–558. Naziruddin B, Wease S, Stablein D, Barton FB, Berney T, Rickels MR, Alejandro R. HLA class I sensitization in islet transplant recipients: re- April 2013 481. 482. 483. 484. 485. 486. 487. 488. 489. 490. 491. 492. 493. 494. 495. 496. 497. port from the Collaborative Islet Transplant Registry. Cell Transplant 2012;21(5):901–908. Noguchi H, Naziruddin B, Jackson A, Shimoda M, Fujita Y, Chujo D, Takita M, Peng H, Sugimoto K, Itoh T, Kobayashi N, Ueda M, Okitsu T, Iwanaga Y, Nagata H, Liu X, Kamiya H, Onaca N, Levy MF, Matsumoto S. Comparison of ulinastatin, gabexate mesilate, and nafamostat mesilate in preservation solution for islet isolation. Cell Transplant 2012;21(2–3):509–516. Noguchi H, Naziruddin B, Jackson A, Shimoda M, Ikemoto T, Fujita Y, Chujo D, Takita M, Peng H, Sugimoto K, Itoh T, Kobayashi N, Onaca N, Levy MF, Matsumoto S. Fresh islets are more effective for islet transplantation than cultured islets. Cell Transplant 2012;21(2–3):517–523. Noguchi H, Naziruddin B, Shimoda M, Chujo D, Takita M, Sugimoto K, Itoh T, Onaca N, Levy MF, Matsumoto S. A combined continuous density/osmolality gradient for supplemental purification of human islets. Cell Med 2012;3(1):33–41. Noguchi H, Naziruddin B, Shimoda M, Fujita Y, Chujo D, Takita M, Peng H, Sugimoto K, Itoh T, Kobayashi N, Onaca N, Levy MF, Matsumoto S. Evaluation of osmolality of density gradient for human islet purification. Cell Transplant 2012;21(2–3):493–500. O’Connor JK, Trotter J, Davis GL, Dempster J, Klintmalm GB, Goldstein RM. Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl 2012;18(8):949–954. O’Leary JG, Neri MA, Trotter JF, Davis GL, Klintmalm GB. Utilization of hepatitis C antibody-positive livers: genotype dominance is virally determined. Transpl Int 2012;25(8):825–829. Paterno F, Shiller M, Tillery G, O’Leary JG, Susskind B, Trotter J, Klintmalm GB. Bortezomib for acute antibody-mediated rejection in liver transplantation. Am J Transplant 2012;12(9):2526–2531. Ruiz R, Klintmalm GB. Renal-sparing regimens employing new agents. Curr Opin Organ Transplant 2012;17(6):619–625. Ruiz R, Tomiyama K, Campsen J, Goldstein RM, Levy MF, McKenna GJ, Onaca N, Susskind B, Tillery GW, Klintmalm GB. Implications of a positive crossmatch in liver transplantation: a 20-year review. Liver Transpl 2012;18(4):455–460. Saxena V, Lai JC, O’Leary JG, Verna EC, Brown RS Jr, Stravitz RT, Trotter JF, Krishnan K, Terrault NA; Consortium to Study Health Outcomes in HCV Liver Transplant Recipients. Recipient-donor race mismatch for African American liver transplant patients with chronic hepatitis C. Liver Transpl 2012;18(5):524–531. Seven N, Matsumoto S, Takita M, Qin H, De Vol E, Hollander PA. Metabolic assessment including continuous glucose monitoring for allogenic islet transplantation. Infusystems USA 2012;9(1):4–10. Sher L, Jennings L, Rudich S, Alexopoulos SP, Netto G, Teperman L, Kinkhabwala M, Brown RS Jr, Pomfret E, Klintmalm G; HCV-3 Study Group. Results of live donor liver transplantation in patients with hepatitic C virus infection: the HCV 3 trial experience. Clin Transplant 2012;26(3):502–509. Shimoda M, Itoh T, Iwahashi S, Takita M, Sugimoto K, Kanak MA, Chujo D, Naziruddin B, Levy MF, Grayburn PA, Matsumoto S. An effective purification method using large bottles for human pancreatic islet isolation. Islets 2012;4(6). Shimoda M, Itoh T, Sugimoto K, Iwahashi S, Takita M, Chujo D, Sorelle JA, Naziruddin B, Levy MF, Grayburn PA, Matsumoto S. Improvement of collagenase distribution with the ductal preservation for human islet isolation. Islets 2012;4(2):130–137. Shimoda M, Noguchi H, Fujita Y, Takita M, Ikemoto T, Chujo D, Naziruddin B, Levy MF, Kobayashi N, Grayburn PA, Matsumoto S. Islet purification method using large bottles effectively achieves high islet yield from pig pancreas. Cell Transplant 2012;21(2–3):501–508. Shimoda M, Noguchi H, Fujita Y, Takita M, Ikemoto T, Chujo D, Naziruddin B, Levy MF, Kobayashi N, Grayburn PA, Matsumoto S. Improvement of porcine islet isolation by inhibition of trypsin activity during pancreas preservation and digestion using ␣1-antitrypsin. Cell Transplant 2012;21(2–3):465–471. Takita M, Matsumoto S, Noguchi H, Shimoda M, Ikemoto T, Chujo D, Tamura Y, Olsen GS, Naziruddin B, Purcell K, Onaca N, Levy MF. 2012 publications of the Baylor Health Care System medical and scientific staff 229 498. 499. 500. 501. 502. Adverse events in clinical islet transplantation: one institutional experience. Cell Transplant 2012;21(2–3):547–551. Takita M, Matsumoto S, Qin H, Noguchi H, Shimoda M, Chujo D, Itoh T, Sugimoto K, Onaca N, Naziruddin B, Levy MF. Secretory unit of islet transplant objects (SUITO) index can predict severity of hypoglycemic episodes in clinical islet cell transplantation. Cell Transplant 2012;21(1):91–98. Takita M, Matsumoto S. SUITO index for evaluation of clinical islet transplantation. Cell Transplant 2012 Apr 2 [Epub ahead of print]. Takita M, Matsumoto S, Shimoda M, Chujo D, Itoh T, Sorelle JA, Purcell K, Onaca N, Naziruddin B, Levy MF. Safety and tolerability of the T-cell depletion protocol coupled with anakinra and etanercept for clinical islet cell transplantation. Clin Transplant 2012;26(5):E471–E484. Talukder AH, Bao M, Kim TW, Facchinetti V, Hanabuchi S, Bover L, Zal T, Liu YJ. Phospholipid scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Cell Res 2012;22(7):1129–1139. Testa G, Carlisle E, Simmerling M, Angelos P. Living donation and cosmetic surgery: a double standard in medical ethics? J Clin Ethics 2012;23(2):110–117. HISTORY 503. Fordtran JS, Prince R, Seldin DW. A Dallas doctor who spoke truth to power: three perspectives. Proc (Bayl Univ Med Cent) 2012;25(3): 254–264. 504. Urschel HC Jr, Urschel BB. Robert R. Shaw, MD: thoracic surgical hero, Afghanistan medical pioneer, champion for the patient, never a surgical society president. Ann Thorac Surg 2012;93(6):2111–2116. INTERVIEWS 505. Barry MJ, Roberts WC. Michael John Barry, MD: a conversation with the editor on shared decision-making. Proc (Bayl Univ Med Cent) 2012;25(4):383–388. 506. Boden WE, Roberts WC. William Edward Boden, MD: a conversation with the editor. Am J Cardiol 2012;110(1):145–159. 507. Grayburn PA, Benjamin MM. Paul Arthur Grayburn, MD: an interview by Mina Mecheal Benjamin, MD. Proc (Bayl Univ Med Cent) 2012;25(3):265–270. 508. Libby P, Roberts WC. Peter Libby, MD: a conversation with the editor. Am J Cardiol 2012;110(5):741–760. 509. Saucedo JF, Roberts WC. Jorge Felix Saucedo, MD, MBA: a conversation with the editor on optimizing antiplatelet and antithrombotic therapy in patients having percutaneous coronary intervention for acute coronary syndromes. Proc (Bayl Univ Med Cent) 2012;25(2):136–138. EDITORIALS, BOOK REVIEWS, AND MISCELLANEOUS 510. Allday RL, Brooks J, Hosford SL, Owen SF. Tributes to Gordon Hosford, MD. Proc (Bayl Univ Med Cent) 2012;25(3):274–275. 511. Boland CR. “Irreducible complexity” or “delightful challenge”? Proc (Bayl Univ Med Cent) 2012;25(2):169–170. 512. Boland CR, Krejs G, Emmett M, Richardson C. A birthday celebration for John S. Fordtran, MD. Proc (Bayl Univ Med Cent) 2012;25(3):250– 253. 513. Dauwe P, Heller JB, Unger JG, Graham D, Rohrich RJ. Social networks uncovered: 10 tips every plastic surgeon should know. Aesthet Surg J 2012;32(8):1010–1015. 230 514. Gurevitz SA, Stone MJ. Review of Amyloidosis: Diagnosis and Treatment. Proc (Bayl Univ Med Cent) 2012;25(2):166. 515. Hasse JM. Editor’s note. Nutr Clin Pract 2012;27(3):319. 516. Hasse JM. Editor’s note. Nutr Clin Pract 2012;27(4):439. 517. Knox S. Review of The Lump. Proc (Bayl Univ Med Cent) 2012; 25(4):399. 518. Kuhn JA. Dissecting Darwinism. Proc (Bayl Univ Med Cent) 2012;25(1):41–47; discussion, 25(2):168–173. 519. Mack MJ. If this were my last speech, what would I say? Ann Thorac Surg 2012;94(4):1044–1052. 520. Matthews CM. Exploring the obesity epidemic. Proc (Bayl Univ Med Cent) 2012;25(3):276–277. 521. Neubach P, Snoots W. Tributes to George Boswell, MD. Proc (Bayl Univ Med Cent) 2012;25(2):165. 522. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2012;25(1):98–107. 523. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2012;25(2):174–183. 524. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2012;25(3):304–313. 525. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2012;25(4):400–410. 526. Roberts WC. Formulating an answerable question, displaying data, illustrating, writing, reviewing, and editing manuscripts for publication in medical journals. Am J Cardiol 2012;110(2):290–306. 527. Roberts WC. Good books in cardiovascular disease appearing in 2011. Am J Cardiol 2012;109:1236–1237. 528. Roberts WC. How I prepare a manuscript for publication in a medical journal. Methodist Debakey Cardiovasc J 2012;8(4):53–54. 529. Roberts WC. Proceedings of the editorial board meeting of the American Journal of Cardiology on March 25, 2012. Am J Cardiol 2012;110(2):316–317. 530. Rohrich RJ, Stuzin JM. Globalization of plastic surgery: the world of plastic and reconstructive surgery in Brazil. Plast Reconstr Surg 2012;130(4):967–968. 531. Rohrich RJ, Sullivan D. So you want to be a change artist? Plast Reconstr Surg 2012;129(6):1435–1437. 532. Rohrich RJ, Sullivan D. So you want to get paid for what you do? The saga continues. Plast Reconstr Surg 2012;130(2):471–473. 533. Rohrich RJ, Weber RA. Are teachers born or do they develop over time? Plast Reconstr Surg 2012;129(5):1209–1211. 534. Rohrich RJ, Weinstein AG. Connect with plastic surgery: social media for good. Plast Reconstr Surg 2012;129(3):789–792. 535. Rohrich RJ. Logging in to the PRS iPad app: access made easy. Plast Reconstr Surg 2012;129(6):1438–1340. 536. Warren B. Review of The Top Five Regrets of the Dying. Proc (Bayl Univ Med Cent) 2012;25(3):299–300. 537. Winter FD. Review of Genius on the Edge. Proc (Bayl Univ Med Cent) 2012;25(1):95–96. 538. Yager M, Emmett M. How worms’ sex behavior can have a major impact on understanding human disease. Proc (Bayl Univ Med Cent) 2012;25(4):395–396. Note: This list (finalized on February 11, 2013) was based on submissions from medical and allied health staff and on PubMed searches. Although the list is representative of the year’s publications, some articles and book chapters were undoubtedly missed, since only a small percentage of researchers respond to the request for publications. Staff are encouraged to submit their publications each year. For more information or to submit publications for this list, please contact Cynthia Orticio (cynthiao@BaylorHealth.edu). Baylor University Medical Center Proceedings Volume 26, Number 2 Instructions for authors aylor University Medical Center Proceedings welcomes research articles, review articles, case studies, and editorials from Baylor and non-Baylor authors. Manuscripts containing Baylor data are particularly desired. Send all manuscripts and editorial correspondence to William C. Roberts, MD, Editor in Chief, Baylor Scientific Publications Office, 3500 Gaston Avenue, Dallas, Texas 75246; phone: 214-820-9996; fax: 214-820-4064; e-mail: cynthiao@BaylorHealth.edu. B MANUSCRIPT SUBMISSION Submit the word processing document by e-mail to cynthiao@BaylorHealth.edu. Large files may be sent using YouSendIt or SendNow. Cover letter and attachments: According to journal policies outlined below, list suggested reviewers and discuss potential conflicts of interest in your cover letter and provide as attachments copies of institutional review board approval or exemption, written permission for reprinting tables or figures, copies of any published material that could be considered duplicative, and release authorization forms for photographs. Schedule: Deadlines for submission are as follows: January issue, September 1; April issue, December 1; July issue, March 1; and October issue, June 1. The editorial office cannot guarantee that any manuscript submitted by these deadlines will be published in the specified issue; variables include the peer review and revision process and the number of articles already accepted. ARTICLE TYPES In addition to multipatient studies (original research articles), Proceedings publishes several other article types. Case studies: Include an abstract, a single-paragraph introduction (optional with short reports), a case description of 0.5 to 2 doublespaced pages, and a discussion of 1 to 5 double-spaced pages. Up to 25 references are acceptable (although many case reports have 5 to 10). The maximum number of figures and tables (combined) is 6. Historical studies: Abstracts are recommended. There is no word limit, but most historical studies are 1500 to 3500 words. Editorials: There is no word limit, but most editorials are 800 to 1600 words. Book reviews: See past issues for format. There is no word limit, but most book reviews are 800 to 1600 words. Avocations: Submit an image file for your painting or photograph or a discussion of your hobby for a maximum of 300 words. Reader comments (letters to the editor): Both responses to previously published material and brief reports or observations are considered for this section. The limit is 1200 words. MANUSCRIPT PREPARATION Format: Type manuscripts double spaced, leaving 1-inch margins. Number all pages, including the title page. Title page: Include on the first page the article’s title; the authors’ names, highest degree(s), and affiliations; and the name, address, e-mail Proc (Bayl Univ Med Cent) 2013;26(2):231–232 address, and phone number of the corresponding author. Acknowledge any grant support. Abstract: Provide a one-paragraph double-spaced abstract of 150 to 250 words. Abstracts are required for original articles and case studies and are recommended for reviews and long historical articles. Conclusions: Conclusion paragraphs at the end of the discussion section are rarely needed and are often cut if included. References: Number references according to the order in which they are cited in the text and type them double spaced at the end of the manuscript. Do not use the footnote or endnote functions of word processing software. The numbers in the text should be on line and in parentheses, such as (14, 16, 17). The references should conform to the following style, listing all authors: Journal article: O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364(3):205–214. Book chapter: Ramsay M. Liver transplantation and portopulmonary hypertension. In Milan Z, ed. Cardiovascular Diseases and Liver Transplantation. New York: Nova Biomedical Books, 2011:83–97. Book: Gulati G, Filicko-O’Hara J, Krause JR. Case Studies in Hematology and Coagulation. Chicago, IL: American Society for Clinical Pathology Press, 2012. Authors using Endnote can access Proceedings’ reference style by downloading an EndNote style file, available at http://www.baylorhealth.edu/Research/Proceedings/SubmitaManuscript/Pages/ManuscriptPreparation.aspx. Personal communications and unpublished data should not be used as references; they should be identified in parentheses in the text. Tables and figures: Number tables and figures in the order in which they are discussed in the text. Include call-outs in the text and place the tables at the end of the document as Word files using the Word table function. Figures can be embedded in the text at the end of the document or provided as separate files, with legends in the Word file. Provide enough details in titles, footnotes, and legends so that the tables and figures can be understood apart from the text. Submit photographs as 350-ppi tiff or jpeg files. Submit graphs and diagrams as electronic files (EPS format preferred). Use of color: Color is used in articles only when clinically required (as with certain pathology and radiology images). Avoid using color when creating charts and graphs. If photographs (such as those in interviews) are originally in color, they can be converted to black and white during journal production. Articles that use color are generally grouped together in the issue to decrease overall printing expenses. Style issues: Use generic names for drugs; capitalize any trade names when they are used. Limit the number of abbreviations in a manuscript to five, and do not abbreviate single words, such as intravenous. Spell out all abbreviations on first usage. Proceedings 231 follows the style guide of the American Medical Association. As further guidance, prospective authors are encouraged to consult the “Authors’ submission toolkit” (1) and an article on medical publishing by the editor in chief (2). MANUSCRIPT PROCESSING Peer review: All manuscripts are subject to peer review by editorial board members or other selected reviewers; however, the final decision as to which articles are published will be made by the editor in chief. At the time of manuscript submission, authors are encouraged to suggest reviewers, within or outside the Baylor Health Care System, and to list any reviewers they feel should not be used because of potential bias. If a manuscript was previously reviewed by another journal, authors should submit those reviews and clearly indicate any revisions that have been made. Such manuscripts will receive expedited processing, since they usually will not be sent out for re-review. Editing: All manuscripts will be edited for clarity and conformity to Proceedings’ style. The corresponding author will have the opportunity to review editing either before or at the page proof stage. Reprints: Authors can order reprints using the form provided through an e-mail link from the printer. Reprints are delivered approximately 4 weeks after the issue comes out. All authors receive a copy of the printed journal, and PDF files of articles are freely available to the authors and the general public. JOURNAL POLICIES Duplicate publication: When submitting the manuscript, provide a copy of any published or submitted article that is similar to what is being submitted to Proceedings, so that the editor can judge whether the manuscript in question would be a duplicate publication. Once manuscripts are accepted, authors transfer copyright to Baylor University Medical Center at Dallas. Authorship: All authors listed in the manuscript must have participated in the design or analysis of the project. In addition, all authors must review the final text and be prepared to take public responsibility for its content. Ethical treatment of research subjects: For reports of experimental investigations of human or animal subjects, indicate institutional review board approval or exemption within the manuscript. Authors should also explain in the Methods section the procedures followed to obtain informed consent. Conflict of interest: Grant support for a particular study must be indicated on the title page. In addition, authors must communicate to the editor in the cover letter any affiliations that could be perceived as potential conflicts of interest. Examples include honoraria, educational grants, participation in speakers’ bureaus, expert testimony, patent licensing arrangements, consultancies, and stock ownership. 232 Use of protected health information: Authors should not refer to patients by name or initials or provide other specific identifying information, such as Social Security number or medical record number. Authors are further encouraged to avoid including extraneous social details about patients. Patient authorization forms are required for all identifying photographs. For a copy of Proceedings’ full privacy policy, contact the managing editor. Permissions: Permission is required for reproduction of any material, including figures and tables, that has been published elsewhere. When submitting manuscripts, provide written documentation that permission has been obtained or notify the editorial staff of the need to request permission (providing all necessary source information). For photographs in which the subject can be recognized, submit release authorizations at the time of manuscript submission. For additional information, please contact Cynthia Orticio, managing editor, at 214-820-9996 or cynthiao@BaylorHealth.edu. 1. 2. Chipperfield L, Citroma L, Clark J, David FS, Neck R, Evangelista M, Gonzalez J, Groves T, Magan J, Mansa B, Miller C, Mooney LA, Murphy A, Shelton J, Wilson PD, Weigl A. Authors’ submission toolkit: a practical guide to getting your research published. Cur Med Res Open 2010;26(8):1967–1982. Roberts WC. Formulating an answerable question, displaying data, illustrating, writing, reviewing, and editing manuscripts for publication in medical journals. Am J Cardiol 2012;110(2):290–306. MANUSCRIPT SUBMISSION CHECKLIST — The entire manuscript is double-spaced and in one Word file, in the following order: title page, abstract, text, references, tables, figures (either figure legends only or figures embedded plus legends). Page numbers appear on the bottom of each page. — The title page has required elements: title, authors (with full names and degrees), affiliations, and address for corresponding author. — A single-paragraph abstract of 150 to 250 words is included. — For case studies: After the abstract, the manuscript includes a single-paragraph introduction (optional), a case discussion of 0.5 to 2 double-spaced pages, and a discussion of 0.5 to 5 double-spaced pages. The manuscript does not exceed the limit of 25 references or 6 figures and tables. — Figures are high-resolution. Photographs are 350-ppi tiff or jpeg files. — References include all authors, the full article title, the journal abbreviation from Index Medicus, the volume and issue number, and inclusive page numbers. References in the text appear in parentheses, rather than in superscript or footnotes or endnotes. — All authors have approved the version to be submitted. Manuscripts that do not meet these requirements may be returned to authors before peer review is initiated. Baylor University Medical Center Proceedings Volume 26, Number 2 Volume 26 Number 2 April 2013 Baylor University Medical Center Proceedings Multipatient Studies 95 Model for the cost-efficient delivery of continuous quality cancer care: a hospital and private-practice collaboration 163 166 Thermoregulatory catheter–associated inferior vena cava thrombus 168 J. L. Gierman, W. P. Shutze Sr., G. J. Pearl, M. L. Foreman, S. E. Hohmann, and W. P. Shutze Jr. 103 Impact of sham-controlled vertebroplasty trials on referral patterns at two academic medical centers High-intensity, occupation-specific training in a series of firefighters during phase II cardiac rehabilitation J. Adams, D. Cheng, and R. F. Berbarie 109 Morphological features of temporal arteritis 116 Quality of life of HIV/AIDS patients in a secondary health care facility, Ilorin, Nigeria W. C. Roberts, S. Zafar, and J. M. Ko 120 Timing and causes of death after injuries J. Sobrino and S. Shafi Volume 26, Number 2 • April 2013 Baylor University Medical Center, Dallas, Texas 124 Facts and principles learned at the 39th Annual Williamsburg Conference on Heart Disease M. M. Benjamin and W. C. Roberts 137 177 179 182 185 Editorials, Tributes, and Book Reviews 194 146 Lymphoma in the breast Inflammatory breast cancer K. Y. Ha, S. B. Glass, and L. Laurie Pages 93–232 152 Plasmablastic lymphoma following transplantation 156 Recurrent acute inflammatory demyelinating polyradiculoneuropathy following R-CHOP treatment for non-Hodgkin lymphoma 159 Endolymphatic sac tumor and otalgia M. J. Van Vrancken, L. Keglovits, and J. Krause J. J. Liang, P. P. Singh, and T. E. Witzig M. Zarghouni, M. L. Kershen, L. Skaggs, A. Bhatki, S. C. Gilbert, C. E. Gomez, and M. J. Opatowsky To access Baylor’s physicians, clinical services, or educational programs, contact the Baylor Physician ConsultLine: 1-800-9BAYLOR (1-800-922-9567) 161 196 Tributes to Harold C. Urschel Jr., MD A. U. Goldstein and M. A. Ramsay 199 Tribute to Elgin W. Ware Jr., MD Steve Frost 200 Book review: Making Rounds with Oscar James Marroquin From the Editor 202 Facts and ideas from anywhere William C. Roberts Miscellany 94 158 165 167 187 192 193 212 215 Inguinal lymphadenopathy as the initial presentation of sarcoidosis J. George, R. Graves, and R. Meador Jr. Tributes to George E. Hurt Jr., MD B. Allison, C. H. Scheihing, and W. C. Roberts K. Y. Ha, J. C. Wang, and J. I. Gill 149 An underappreciated problem with auscultation Allen B. Weisse Charles Stewart Roberts Case Studies Diagnosis and management of delayed hemoperitoneum following therapeutic paracentesis M. J. Katz, M. N. Peters, J. D. Wysocki, and C. Chakraborti J. I. Ewing, C. A. Denham, C. R. Osborne, N. B. Green, J. Divers, and J. E. Pippen Jr. The debate on national health insurance . . . 80 years ago Hepatitis C and recurrent treatment-resistant acute ischemic stroke A. Saxsena, J. Tarsia, C. Dunn, A. Aysenne, B. Shah, and D. F. Moore Invited commentary 144 The calcium-alkali syndrome M. Arroyo, A. Z. Fenves, and M. Emmett 191 Thomas B. Gore Persistent giant U wave inversion with anoxic brain injury M. N. Peters, M. J. Katz, L. A. Howell, J. C. Moscona, T. A. Turnage, and P. Delafontaine Our experience as a Health Volunteers Overseas–sponsored team in Huế, Vietnam A forgotten landmark medical study from 1932 by the Committee on the Cost of Medical Care A 21-year-old pregnant woman with congenital heart disease D. Luke Glancy Historical Studies 142 Congenitally bicuspid aortic valve in brothers: coarctation of the aorta with a normally functioning aortic valve in one and no coarctation but severe aortic stenosis in the other S. Zafar and W. C. Roberts 174 S. I. Bello and I. K. Bello Review Articles Ascites with elevated protein content as the presenting sign of constrictive pericardial disease B. A. George, G. dePrisco, J. F. Trotter, A. C. Henry III, and R. C. Stoler 171 S. S. Lindsey, D. F. Kallmes, M. J. Opatowsky, E. A. Broyles, and K. F. Layton 106 Kayser-Fleischer rings of acute Wilson’s disease A. M. Mantas, J. Wells, and J. Trotter Y. M. Coyle, A. M. Miller, and R. S. Paulson 100 Levamisole-induced vasculitis R. Abdul-Karim, C. Ryan, C. Rangel, and M. Emmett 231 Clinical research studies enrolling patients Avocations: Photograph by Dr. Rosenthal Avocations: Photograph by Dr. Hoppenstein Avocations: Photograph by Dr. Khan Baylor news Reader comments In memoriam Selected published abstracts of Baylor researchers 2012 publications of the Baylor Health Care System medical and scientific staff Instructions for authors www.BaylorHealth.edu/Proceedings Indexed in PubMed, with full text available through PubMed Central

Volume 26 Number 2 April 2013

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