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Volume 29 Number 2 April 2016 The peer-reviewed journal of Baylor Scott & White Health Scott & White Medical Center – Temple Baylor Scott & White Medical Center - Marble Falls Baylor All Saints Medical Center at Fort Worth Baylor Medical Center at McKinney Baylor Scott & White Hospital - Hillcrest Baylor Scott & White Medical Center - Round Rock Baylor University Medical Center Proceedings Baylor University Medical Center at Dallas Volume 29, Number 2 • April 2016 Pages 117–260 www.BaylorScottandWhite.com Review Article 131 Review of behavioral health integration in primary care at Baylor Scott and White Healthcare, Central Region by J. B. Jolly et al 137 Invited commentary by C. Couch Historical Article 138 Medical and surgical care during the American Civil War, 1861–1865 by R. F. Reilly Baylor Regional Medical Center at Grapevine The largest not-for-profit health care system in Texas, and one of the largest in the United States, Baylor Scott & White Health was born from the 2013 combination of Baylor Health Care System and Scott & White Healthcare. For more information on our 43 hospitals and more than 500 patient care sites, please visit www.BaylorHealth.com and www.sw.org. Original Research 119 The characteristics of Mohs surgery performed by dermatologists who learned the procedure during residency training or through postgraduate courses and observational preceptorships by H. K. Steinman et al 124 Virtual reality and brain computer interface in neurorehabilitation by D. B. Salisbury et al 128 Safety and efficacy of packed red blood cell transfusions at different doses in very low birth weight infants by L. H. Mallett et al Case Studies 143 Exercise-induced acute compartment syndrome in a young man, occurring after a short race by B. Basnet et al 145 Table tipping and a near-miss fall after unlocking a surgical table holding a morbidly obese patient by R. T. Booth et al 147 Use of ultrasound guidance to remove entrapped stimulating popliteal catheters by R. K. McAllister et al 150 Baclofen-responsive hiccups after esophageal stenting for malignancy-related dysphagia by V. Sharma et al 151 Specificity of testing in a cardiac rehabilitation setting resulting in a patient’s return to high-intensity outdoor activity following aortic dissection repair by S. Bartee et al 154 Invited commentary: Simulated performance testing to determine the aortic dissection patient’s potential for vigorous physical activity by B. A. Franklin 157 Cardiovascular autonomic neuropathy by N. McCarty and B. Silverman 160 Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2) by L. R. Phillipp and F. H. Rodriguez III 163 Holter monitor recordings in a man who snores by D. L. Glancy and P. Vijitbenjaronk 165 An interesting electrocardiogram by H. H. McClure Jr. 166 Takotsubo cardiomyopathy after administration of norepinephrine by K. Sherif et al 168 Acute myocardial infarction with isolated congenitally corrected transposition of the great arteries by J. Zimmerman et al 171 Isolated congenitally corrected transposition of the great arteries with dextroversion discovered incidentally in a patient with cocaine-induced acute myocardial infarction by A. Tandon et al 174 Invited commentary: The specialty of adult congenital heart disease by A. Cedars 176 Surgical considerations for the explantation of the Parachute left ventricular partitioning device and the implantation of the HeartMate II left ventricular assist device by Y. Ravi et al 178 Intracranial aneurysm and sildenafil by A. Adiga et al 181 Infective endocarditis caused by Klebsiella oxytoca in an intravenous drug user with cancer by A. Mohamed et al 183 Rapidly enlarging neck mass in a neonate causing airway compromise by K. Schmidt et al 185 Serendipitous discovery of peritoneal mesothelioma by A. Jaster and J. Wachsmann 188 Pneumomediastinum, pneumorrhachis, and subcutaneous emphysema in Pneumocystis jiroveci pneumonia in AIDS by N. Saleem et al 191 Multiple dural-based hemangiopericytomas by E. Stroberg et al 194 Colorectal cancer implant in an external hemorrhoidal skin tag by L. Liasis and H. T. Papaconstantinou 196 Bilateral synchronous plasmacytoma of the testis by G. Narayanan et al 198 Presentation of epidermolytic acanthomas as multiple tan papules on the vulva by J. W. Fletcher et al 200 Rumpel-Leede phenomenon presenting as a hypertensive urgency by D. Varela et al 202 Arm pain and erythema by B. M. Barth and A. L. Juergens 204 Rheumatoid meningitis associated with infliximab by S. Seago et al 207 Cryptococcal meningitis in a patient with sarcoidosis by T. N. Adams and M. Gibson 209 Thyroid hormone resistance and its management by A. M. Rivas et al 212 The price of a 15-year delay in diagnosis of Sheehan’s syndrome by R. Parikh et al 214 Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists by J. Sutton et al Editorial and Book Review 220 On John Keats and Blue Zones by J. D. Cantwell 224 Book review: In Vitro Fertilization Comes to America by S. P. Marynick From the Editor 230 Facts and ideas from anywhere by W. C. Roberts Miscellany 118 Clinical research studies enrolling patients 164 In memoriam 187 Avocations: Photograph by R. Solis 216 Baylor news 226 Reader comments: Hearts considered for transplantation and takotsubo syndrome by J. E. Madias, S. Y-Hassan, author reply by Y. Ravi; Electronic medical records by L. Hughes; Facts and ideas by T. Gore, J. Woods; Cuba by S. P. Marynick 238 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff 259 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 Scott & White Health Volume 29, Number 2 • April 2016 Editor in Chief William C. Roberts, MD Associate Editor Michael A. E. Ramsay, MD Founding Editor George J. Race, MD, PhD [email protected] Editorial Board Jenny Adams, PhD W. Mark Armstrong, MD Raul Benavides Jr., MD Mezgebe G. Berhe, MD Joanne L. Blum, MD, PhD C. Richard Boland Jr., MD Jennifer Clay Cather, MD James W. Choi, MD Cristie Columbus, MD Barry Cooper, MD Gregory J. Dehmer, MD R. D. Dignan, MD Gregory G. Dimijian, MD Michael Emmett, MD Andrew Z. Fenves, MD Giovanni Filardo, PhD James W. Fleshman, MD Editorial Staff Managing Editor Cynthia D. Orticio, MA, ELS Steven M. Frost, MD Dennis R. Gable, MD D. 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Weprin, MD F. David Winter Jr., MD Larry M. Wolford, DMD Scott W. Yates, MD, MBA, MS Residents/Fellows Aasim Afzal, MD Timothy Ball, MD Philip M. Edmundson, MD Design and Production Aptara, Inc. [email protected] 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 Baylor Scott & White Health. Funding for the journal is provided by the Baylor Health Care System Foundation. Funding is also provided by donations made by the medical staff and subscribers. These donations are acknowledged each year in a journal issue. 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Acceptance of advertising does not imply endorsement by Baylor Scott & White Health. For information, contact Cindy Orticio at [email protected]. Permission is granted to students and teachers to copy material herein for educational purposes. Authors also have permission to reproduce their own articles. Written permission is required for other uses and can be obtained through Copyright.com. Copyright © 2016, Baylor University Medical Center. All rights reserved. Printed in the United States of America on acid-free paper. Press date: March 8, 2016. To access Baylor’s physicians, clinical services, or educational programs, contact the Baylor Physician ConsultLine: 1-800-9BAYLOR (1-800-922-9567). 117 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. Research area Specific disease/condition Contact information (name, phone number, and e-mail address) Asthma and pulmonary disease Chronic obstructive pulmonary disease, asthma (adult) Jana Holloway, RRT, CRC Courtney Patenaude, BS Horacio Martinez 214-818-9495 214-818-7899 214-820-0338 [email protected] [email protected] [email protected] 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; bone marrow transplant Grace Townsend 214-818-8472 [email protected] Type 1 and type 2 diabetes, cardiovascular events Lorie Estrada 214-820-3416 [email protected] Pancreatic islet cell transplantation for type I diabetics, who either have or have not had a kidney transplant Kerri Purcell, RN 817-922-4640 [email protected] Type 2; cardiac events Trista Bachand, RN 817-922-2587 [email protected] Pancreatic islet cell transplantation for type I diabetics, who either have or have not had a kidney transplant; high cholesterol Kerri Purcell, RN 817-922-4640 [email protected] Diabetes (Dallas) Diabetes (Fort Worth) Gastroenterology Heart and vascular disease (Dallas) Inflammatory bowel disease Dr. Themistocles Dassopoulos 469-800-7180 [email protected] Aortic aneurysms, coronary artery disease, hypertension, poor leg circulation, heart attack, heart disease, congestive heart failure, angina, carotid artery disease, familial hypercholesterolemia, renal denervation for hypertension, diabetes in heart disease, cholesterol disorders, heart valves, thoracotomy pain, stem cells, critical limb ischemia, cardiac surgery associated with kidney injury, pulmonary hypertension Merielle Boatman 214-820-2273 [email protected] Heart and lung transplant, mechanical assist device such as LVAD Elizabeth Owens, BA, CCRP 214-820-4015 [email protected] Heart and vascular disease (Fort Worth) Atrial fibrillation, atrial fibrillation post PCI Meagan King 817-922-2583 [email protected] Heart and vascular disease (Legacy Heart) At risk for heart attack/stroke; previous heart attack/stroke/PAD; cholesterol disorders; atrial fibrillation; overweight/obese; other heart-related conditions Angela Germany 469-800-6409 [email protected] Heart and vascular disease (Plano) Aortic aneurysm; coronary artery disease; renal stent for uncontrolled hypertension; poor leg circulation; heart attack; heart disease; heart valve repair and replacement; critical limb ischemia; repair of aortic dissections with endografts; surgical leak repair; atrial fibrillation; heart rhythm disorders; carotid artery disease; congestive heart failure; gene profiling Tina Worley 469-814-4712 [email protected] Hepatology Infectious disease Nephrology Neurology Liver disease Jonnie Edwards 214-820-6243 [email protected] HIV/AIDS Bryan King, LVN 214-823-2533 [email protected] Hepatitis C, hepatitis B Jonnie Edwards 214-820-6243 [email protected] Type 2 diabetes with chronic kidney disease Lisa Mamo, RN Dr. Harold Szerlip 214-818-2526 214-358-2300 [email protected] [email protected] Stroke, migraine Quynh Lan Doan 214-818-2522 [email protected] Multiple sclerosis, stroke Portland Pleasant, RN 214-820-7903 [email protected] Cerebral aneurysms Kennith Layton, MD 214-827-1600 [email protected] Interventional stroke therapy Tomica Harrison 214-820-2615 [email protected] Rheumatology (9900 N. Central Expressway) Rheumatoid arthritis, psoriatic arthritis, lupus, gout, ankylosing spondylitis Giselle Huet 214-987-1253 [email protected] Surgery Chronic limb ischemia, pain management with chest tubes, colon polyps, diaphragm stimulators, and surgery as it pertains to GERD, breast cancer, esophagus, colon, colon cancer, pancreas, lung, hernias, dialysis access, per-oral endoscopic myology (POEM), thoracic outlet syndrome Tammy Fisher 214-820-7221 [email protected] Bone marrow, blood stem cells Grace Townsend Gabrielle Ethington 214-818-8472 214-818-8326 [email protected] [email protected] Solid organs Jonnie Edwards 214-820-6243 [email protected] Obesity Lorie Estrada 214-820-3416 [email protected] Neurosurgery Transplantation Weight management 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 [email protected]. 118 Proc (Bayl Univ Med Cent) 2016;29(2):118 The characteristics of Mohs surgery performed by dermatologists who learned the procedure during residency training or through postgraduate courses and observational preceptorships Howard. K. Steinman, MD, Henry Clever, MD, and Anthony Dixon, PhD, MBBS Little is known about the practice characteristics of Mohs surgery performed by physicians who learned the procedure during their dermatology residency training or through postresidency courses and observational preceptorships. All published reports have investigated Mohs surgeons trained in postresidency fellowships. This report presents the results of a multicenter prospective cohort study evaluating 1834 consecutive Mohs surgery cases performed during the same 6-month period by 9 Mohs surgeons who learned the technique in residency or in postresidency courses and observational preceptorships. One major complication was reported, a hematoma requiring outpatient drainage in an emergency room. There were 54 (2.9%) short-term complications, including 20 (1.1%) infections, 17 (0.9%) wound dehiscences, 9 (0.5%) cases of skin flap necrosis, and 8 (0.4%) hematomas or postoperative bleeding episodes. These complication rates and the data evaluating tumor type, anatomic location, primary vs. recurrent tumor status, tumor size, postoperative wound size, number of Mohs surgery stages, and repair type compare favorably to previously published reports. M ohs micrographic surgery (MMS) is a widely practiced skin cancer treatment that is safe, tissue sparing, effective, and economical (1–11). All published reports supporting these conclusions evaluated Mohs surgeons trained in postresidency fellowships. Many physicians receive their MMS training outside of postresidency fellowships (3). No published studies could be found assessing the practice characteristics of MMS performed by non–fellowship-trained Mohs surgeons. This study reports the results of a 6-month prospective cohort study of 1834 consecutive MMS cases performed by 9 non–fellowship-trained Mohs surgeons at nine locations. The practice characteristics of these Mohs surgeons are analyzed and compared with previously published reports. METHODS Study approval was obtained from the Scott & White institutional review board and exempted from further oversight. STROBE guidelines for patient series were adhered to. Nine non–fellowship-trained Mohs surgeons with differing methods of MMS training and levels of experience volunteered to submit all cases they performed between August 1, 2012, and January 31, 2013. No cases were excluded. They received MMS training Proc (Bayl Univ Med Cent) 2016;29(2):119–123 in residency, postresidency courses followed by observational preceptorships, or postresidency courses alone. Each Mohs surgeon provided his or her date of birth, gender, residency completion year, MMS training method, practice setting, geographic location, years of MMS experience, and total number of MMS cases performed. Cases performed in residency and before course and preceptorship training were excluded. Each Mohs surgeon submitted a case log documenting tumor type, anatomic location, primary vs. recurrent tumor status, tumor size, postoperative wound size, number of MMS stages, and repair type. All identifiable patient data were removed, and the institutional review board required no study consent forms. Participants reported all major complications, defined as adverse events requiring an emergency room visit or hospital admission within 48 hours of the procedure. All short-term, minor postoperative complications were reported, including wound infections (defined as a postoperative wound the Mohs surgeon felt required oral antibiotic therapy), wound dehiscence (partial or complete), bleeding, hematoma, seroma, and flap necrosis. Participants were not asked to track long-term adverse sequelae, including scars requiring revision, permanent sensory or motor nerve damage, or tumor recurrence. RESULTS Nine dermatologists with different forms of MMS training and levels of experience submitted 1834 MMS cases. Six (66%) received their training in residency, 2 (22%) through courses followed by observational preceptorships, and 1 (11%) from course training alone. Ages ranged from 38 to 64 years (average, 52 years). Eight were male and one was female. All were board-certified dermatologists practicing in the United States: three (38%) from the Midwest, three (38%) from the Southwest, two (25%) from the West, and one (13%) from the Southeast. Participants completed their MMS training an From Texas A&M Health Science Center College of Medicine and DermOne Dermatology Clinics, Irving, Texas (Steinman); First Capitol Dermatology, St. Charles, Missouri (Clever); and Australasian College of Cutaneous Oncology, Victoria, Australia (Dixon). Corresponding author: Howard K. Steinman, MD, Chief of Mohs Surgery and Dermatologic Surgery, DermOne Dermatology Clinics, 2021 N. MacArthur Blvd., Suite 300, Irving, TX 75056 (e-mail: [email protected]). 119 Table 1. The training method, practice setting, career and case experience, and number and percentage of cases submitted by each Mohs surgeon Surgeon Training method* Practice setting Career cases Career experience (years) Cases submitted (n = 1834) Percent of cases 1 R Solo practice >5000 20 97 5.3% 2 R Academic group >5000 20 54 3.0% 3 CP Solo practice 1000–2500 8 311 16.9% 4 R Dermatology group >5000 16 328 17.9% 5 CP Solo practice >5000 8 394 21.5% 6 R Multispecialty group 500–1000 2 147 8.0% 7 R Solo practice 500–1000 12 129 7.0% 8 C Solo practice >5000 3 300 16.3% 9 R Solo practice 250–500 15 Practice setting 74 4.0% 1305 71% Dermatology group (11%) 328 18% Multispecialty group (11%) 147 8% University/academic (11%) 54 3% Solo practice (67%) Career case experience >5000 1173 64% 1000–2500 311 17% 500–1000 276 15% 250–500 74 4% *CP indicates course followed by preceptorship; C, Course; R, Residency. average of 11.6 years (range, 2–20 years) before the onset of the study. The training method, practice setting, career experience, and number and percentage of cases submitted by each Mohs surgeon are shown in Table 1. Of the 1834 tumors treated, 1207 (65.8%) were basal cell carcinoma, 503 (27.4%) were squamous cell carcinoma, and 116 (6.3%) were squamous cell carcinoma in situ. Thirteen (0.7%) basosquamous cell carcinomas were categorized as squamous cell carcinomas. Four tumors (0.2%) were atypical fibroxanthomas, and four (0.2%) were other rare tumors. None of the participants treated melanocytic tumors with MMS. Overall, 96.4% of tumors were primary and 3.6% were recurrent. In terms of location, 1509 (82.2%) tumors were located on the face, 100 (5.5%) on the scalp, 82 (4.5%) on the extremities, 58 (3.2%) on the neck, 42 (2.3%) on the trunk, 40 (2.2%) on the hands, and 3 (0.2%) on the feet. The mean tumor size was 1.22 cm² (standard deviation [SD] 1.71 cm²), with a median of 0.8 cm². The mean final wound size was 3.77 cm² (SD 5.68 cm²) with a median of 2.25 cm². The average number of MMS stages to obtain clear margins was 1.66 (SD 0.82); 909 (49.6%) cases were cleared after 1 stage, 718 (39.1%) after 2 stages, 140 (7.6%) after 3 stages, 49 (2.7%) after 4 stages, and 18 (0.9%) after 5 or more stages. Of the surgical defects, 1029 (56.1%) were repaired linearly, 512 (27.9%) with local cutaneous flaps, 123 (6.7%) by secondary intention, 85 (4.6%) with skin grafts, 6 (0.3%) with partial repairs, 6 (0.3%) with a combination of techniques, and 1 with 120 a porcine xenograft. A total of 72 cases (3.9%) were referred to other surgeons for repair. Fifty-five (3.0%) adverse events were reported. One (0.05%) major complication was reported in a patient with a hematoma requiring drainage in an emergency room. The 54 (2.9%) shortterm complications included 20 (1.1%) infections, 17 (0.9%) wound dehiscences, 9 (0.5%) cases of skin flap necrosis, and 8 (0.4%) hematomas or bleeding episodes. The anatomic distribution of infections was face (70%), scalp (15%), neck (5%), and extremities (15%); 86% of the wound dehiscences were on the head or neck. DISCUSSION Physicians receive various forms of MMS training (3). Previously published MMS case series evaluated only fellowshiptrained Mohs surgeons. To our knowledge, this is the first report assessing non–fellowship-trained Mohs surgeons. Our study involved 1834 cases from 9 non–fellowshiptrained Mohs surgeons from the same 6-month period. Merritt et al (2) studied 1792 cases from 13 fellowship-trained Mohs surgeons with the same general design and scope. Alam et al (1) conducted a comprehensive study of 20,821 cases from 36 Mohs surgeons, focusing primarily on adverse effects. Recurrence rates were not evaluated in any of these studies, as 5-year follow-up data are considered the minimum duration necessary for accurate recurrence assessment (12, 13). All three studies were conducted before current MMS appropriate use criteria were published (14). Thus, clinical data permitting a Baylor University Medical Center Proceedings Volume 29, Number 2 Table 2. Tumors treated with Mohs surgery: study data versus previous reports Table 4. Number of Mohs surgery stages to obtain clear margins: study data vs. previous reports Tumor types First author, year (ref) BCC SCC SCCis 6.3% Number of Mohs surgery stages Other Total cases 0.4% 1834 7.5% 400 First author, year (ref) 1 2 3 4 >5 Average Study data 50% 39% 7.6% 2.7% 0.9% 1.7 Cook, 1998 (20) 67% 23% 4.0% 3.5% 3.0% 1.5 Study data 66% 27% Cook, 1998 (20) 77% 16% Cook, 2003 (9) 68% 29% 1343 Kimyai-Asadi, 2005* (7) 1.7 Bialy, 2004 (21) 68% 32% 98 Casey, 2009* (8) 1.8 Kimyai-Asadi, 2005 (7) 72% 21% 6.7% 3937 Alam, 2010 (22) Casey, 2009 (8) 76% 22% 2.0% Alam, 2010 (22) 73% 27% Martin, 2010 (15) 64% 28% 8.0% Merritt, 2012 (2) 61% 31% 8.3% 1792 Alam, 2013 (1) 63% 35% 2.4% 20,821 42% 41% 12% 4.0% 1.8% 1.9 N/A Martin, 2010* (15) 1.4 2000 Rogers, 2010* (16) 1.4 950 Merritt, 2012* (2) 1.6 Lilly, 2012* (19) 1.3 * Only average of total stages reported. BCC indicates basal cell carcinoma; SCC, squamous cell carcinoma; SCCis, squamous cell carcinoma in situ. determination of whether study cases complied with these criteria were not obtained. Of the 9 Mohs surgeons evaluated, 6 (55%) were in solo practice and 1 each (11%) were in academic, dermatology group, and multispecialty group practices (Table 1). Campbell (13) surveyed 303 fellowship-trained Mohs surgeons and reported a distribution of 30% in solo practice, 21% in academic practice, 39% in dermatology group practice, 9% in multispecialty group practice, and 1% listed as “other.” The differences in practice setting distribution may reflect a sampling bias or that more non–fellowship-trained Mohs surgeons are in solo practice. The percentage and distribution of tumor types treated in this study is very similar to that of previous reports (Table 2) (1, 2, 7–9, 15, 20–22). Fewer recurrent tumors (4%) were treated than in previous reports. Ravitskiy et al (11) reported on 379 tumors and found that 10% were recurrent. Cook and Zitelli (20) analyzed 400 consecutive cases and found that 16% were recurrent. These differences possibly suggest that non–fellowship-trained Mohs surgeons receive fewer outside referrals for treatment of recurrent cancers. This study data showed a low percentage of tumors (0.4%) that were not basal cell carcinoma, squamous cell carcinoma, or squamous cell carcinoma in situ. Other studies have reported ranges of 2% to 8% of rarer tumor types (Table 2). This may indicate that fellowship-trained Mohs surgeons are more prepared to manage rarer tumor types with MMS. The anatomic distribution of tumors treated in the study is also similar to that of previously published series (Table 3) (2, 7, 8, 16, 19, 20, 22). The average number of MMS stages required to achieve tumor clearance was 1.66. This value and the distribution of required stages is very similar to previous reports (Table 4) (2, 7, 8, 15, 16, 19, 20, 22). This study's mean preoperative tumor size of 1.2 cm2 is similar to that reported by Kimyai-Asadi (1.0 cm2) (7) and Merritt (1.1 cm2) (2). The average postoperative wound size (3.8 cm2) was between the values reported by Kimyai-Asadi Table 3. Anatomic distribution of tumors treated with Mohs surgery: study data versus previous reports First author, year (ref) Face Scalp Neck Study data 82% 5.5% 3.2% Cook, 1998 (20) Kimyai-Asadi, 2005* 87% 76% 5.6% 3.7% Casey, 2009*† (8) 83% 4.5% 3.4% Alam, 2010* (22) 80% 5.4% 2.2% 68% 7.0% 4.0% Rogers, 2010* (7) (16) Merritt, 2012* (2) Head & neck Ext. 2.3% 4.5% Trunk & ext. Ext. & genitalia 3.6% Genitalia Other 2.4% 5.5% 7.6% 1.8% 8.0% 86% Hands & feet 8.0% 4.8% 73% Lilly, 2012 (19) Trunk 0.2% 2.0% 7.5% 9.3% 17% 8.0% 10% 4.0% 10% 1.0% 3.0% 0.2% Ext. indicates extremities. *Data for some anatomic areas combined. †2000–2006 data only. April 2016 The characteristics of Mohs surgery performed by non–fellowship-trained dermatologists 121 Table 5. Surgical repair methods after Mohs surgery: study data versus previous reports Surgical repair methods First author, year (ref) 2nd intention Linear Flaps Graft Referred Study data 6.7% 56.1% Futoryan, 1995 (18) 3.4% 53.0% 27.9% 4.6% 3.9% 26.0% 17.0% Other Number of cases 0.6% 1834 0.1% 530 Cook, 1998 (20) 39.0% 37.0% 10.0% 13.0% Kimyai-Asadi, 2005 (7) 11.0% 69.0% 14.0% 6.2% 6.8% 53.0% 27.0% 14.0% Casey, 2009 (8) 18.0% 44.0% 19.0% 9.0% 10.0% N/A Alam, 2010 (22) 10.0% 50.0% 21.0% 8.7% 10.3% 20,821 Martin, 2010 (15) 3.0% 62.0% 18.0% 7.0% 6.0% Maragh, 2008* (17) 0.8% 0.4% 400 3937 1115 Rogers, 2010 (16) 10.0% 74.0% 13.0% 2.9% Merritt, 2012 (2) 18.0% 54.0% 9.3% 12%† 6.5% Lilly, 2012 (19) 6.4% 65.0% 14.0% 6.1% 5.7% 4.0% 950 0.7% 1204 1792 2.3% 670 *Includes 32 cases treated with “slow-Mohs” (permanent section margin control) for melanoma in situ. †Includes 0.7% that were porcine xenografts. (7) (4.3 cm2) and Merritt (2) (1.9 cm2) and similar to other reports (15, 19). The types and distribution of wound repairs are summarized in Table 5 and are in line with the results of multiple previous reports (2, 7, 8, 15–20, 22). Of the cases reported, 116 (6.3%) were squamous cell carcinoma in situ. The authors could find no other prospective multicenter cohort MMS studies distinguishing squamous cell carcinoma in situ from other tumor types treated. Of these, 97% were primary tumors, 80% were on the face or scalp, and 9% were on the extremities. Leibovitch et al (23) reported a 9-year prospective multicenter case series of all squamous cell carcinoma in situ treated with MMS. Of 270 cases, 49.2% were primary and 93.4% were on the head and neck. Chuang et al (24) reported a single center prospective study of consecutive squamous cell carcinoma in situ tumors treated with MMS. Of 29 cases, 79.3% were on the head and neck and 20.6% were on the extremities. Unlike squamous cell carcinoma and basal cell carcinoma, it is generally recognized that squamous cell carcinoma in situ can often be managed by surgical and nonsurgical modalities other than MMS (25). Several MMS studies have focused on the frequency of adverse events (1, 2, 4, 9, 15–19). This study's results compare favorably with those of previous reports (Table 6). The study's one major complication is comparable to previous reports (1, 2, 7). The study's low infection rate (1.1%) is in line with previous series (Table 6) (4, 9, 15, 17–19). The anatomic distribution of infections of face (70%), scalp (15%), neck (5%) and extremities (15%) is similar to other large series (16–18). Tumors >2.1 cm in diameter had a higher infection rate than lesions <1.25 cm Table 6. Complication rates associated with Mohs surgery: study data versus previous reports Complications First author, date (ref) Hematoma Bleeding Study data Hematoma/ bleeding Necrosis Infection Dehiscence 0.40% 0.50% 1.10% 0.93% Futoryan, 1995 (18) Cook, 2003 (9) Impaired healing 1834 2.45% 0.50% 0.15% 0.82% Maragh, 2008* (17) 0.07% Number of cases 530 0.10% 1343 0.07% 1115 Martin, 2010 (15) 0.90% 950 Rogers, 2010 (16) 0.91% 1204 Merritt, 2012 (2) 0.17% 1.23% 0.29% 0.94% 0.33% 1792 Elliott, 2012 (4) 0.21% 954 Lilly, 2012 (19) 1.49% 670 Alam, 2013 (1) 0.10% 0.40% 0.14% 20,821 *Mohs surgery and “slow-Mohs” (permanent section margin control) procedures. 122 Baylor University Medical Center Proceedings Volume 29, Number 2 (P = 0.01). Merritt (2) reported a greater overall complication rate (not only infections) for tumors >1.6 cm vs. 1.12 cm (P = 0.0001). A nonsignificant trend in increased wound infections in this study was noted with increasing number of MMS stages performed from 2 through 4 stages, yet no cases requiring ≥5 stages developed infections. This may be due to a small sample size of 17 of 1834 cases (0.9%) requiring five or more stages. No data were collected on the use of prophylactic postoperative antibiotics, which might have been used more frequently with tumors requiring ≥5 MMS stages. The overall dehiscence rate of 0.93% was higher than that reported by Cook (0.10%) (9) and Merritt (0.33%) (2). Limitations in the study include the fact that only 9 Mohs surgeons were evaluated, there was a gender bias with eight males and one female, and there was a bias towards participants in private solo practice. A disproportionate number of cases was submitted by Mohs surgeons with >5000 cases of career experience, and the number of cases submitted by participants varied significantly. Compliance with appropriate use criteria was not assessed. The determination of an infection was left to each surgeon's clinical assessment without the requirement of bacterial culture confirmation. Acknowledgments The authors wish to thank the following individuals for their contributions to this study: Robert Aylesworth, David Butler, Igor Chaplik, Carlos Garcia, John Hamill, Alex Miller, Joseph Schneider, Shannon Setzer, Juhee Song, Donald Tillman, and Edward Yob. 1. 2. 3. 4. 5. 6. 7. Alam M, Ibrahim O, Nodzenski M, Strasswimmer JM, Jiang S, Cohen JL, Albano BJ, Batra P, Behshad R, Benedetto AV, Chan CS, Chilukuri S, Crocker C, Crystal HW, Dhir A, Faulconer VA, Goldberg LH, Goodman C, Greenbaum SS, Hale EK, Hanke CW, Hruza GJ, Jacobson L, Jones J, Kimyai-Asadi A, Kouba D, Lahti J, Macias K, Miller SJ, Monk E, Nguyen TH, Oganesyan G, Pennie M, Pontius K, Posten W, Reichel JL, Rohrer TE, Rooney JA, Tran HT, Poon E, Bolotin D, Dubina M, Pace N, Kim N, Disphanurat W, Kathawalla U, Kakar R, West DP, Veledar E, Yoo S. Adverse events associated with Mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers. JAMA Dermatol 2013;149(12):1378–1385. Merritt BG, Lee NY, Brodland DG, Zitelli JA, Cook J. The safety of Mohs surgery: a prospective multicenter cohort study. J Am Acad Dermatol 2012;67(6):1302–1309. Shriner DL, McCoy DK, Goldberg DJ, Wagner RF Jr. Mohs micrographic surgery. J Am Acad Dermatol 1998;39(1):79–97. Elliott TG, Thom GA, Litterick KA. Office based dermatological surgery and Mohs surgery: a prospective audit of surgical procedures and complications in a procedural dermatology practice. Australas J Dermatol 2012;53(4):264–271. Tierney EP, Hanke CW. Cost effectiveness of Mohs micrographic surgery: review of the literature. J Drugs Dermatol 2009;8(10):914–922. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 2013;133(5):1188–1196. Kimyai-Asadi A, Goldberg LH, Peterson SR, Silapint S, Jih MH. The incidence of major complications from Mohs micrographic surgery performed in office-based and hospital-based settings. J Am Acad Dermatol 2005;53(4):628–634. April 2016 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Casey AS, Kennedy CE, Goldman GD. Mohs micrographic surgery: how ACMS fellowship directors practice. Dermatol Surg 2009;35(5):747–756. Cook JL, Perone JB. A prospective evaluation of the incidence of complications associated with Mohs micrographic surgery. Arch Dermatol 2003;139(2):143–152. Mosterd K, Krekels GA, Nieman FH, Ostertag JU, Essers BA, Dirksen CD, Steijlen PM, Vermeulen A, Neumann H, Kelleners-Smeets NW. Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008;9(12):1149–1156. Ravitskiy L, Brodland DG, Zitelli JA. Cost analysis: Mohs micrographic surgery. Dermatol Surg 2012;38(4):585–594. Smeets NW, Kuijpers DI, Nelemans P, Ostertag JU, Verhaegh ME, Krekels GA, Neumann HA. Mohs’ micrographic surgery for treatment of basal cell carcinoma of the face—results of a retrospective study and review of the literature. Br J Dermatol 2004;151(1):141–147. Campbell RM, Perlis CS, Malik MK, Dufresne RG Jr. Characteristics of Mohs practices in the United States: a recall survey of ACMS surgeons. Dermatol Surg 2007;33(12):1413–1418. Ad Hoc Task Force, Connolly SM, Baker DR, Coldiron BM, Fazio MJ, Storrs PA, Vidimos AT, Zalla MJ, Brewer JD, Smith Begolka W; Ratings Panel, Berger TG, Bigby M, Bolognia JL, Brodland DG, Collins S, Cronin TA Jr, Dahl MV, Grant-Kels JM, Hanke CW, Hruza GJ, James WD, Lober CW, McBurney EI, Norton SA, Roenigk RK, Wheeland RG, Wisco OJ. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol 2012;67(4):531–550. Martin JE, Speyer LA, Schmults CD. Heightened infection-control practices are associated with significantly lower infection rates in office-based Mohs surgery. Dermatol Surg 2010;36(10):1529–1536. Rogers HD, Desciak EB, Marcus RP, Wang S, MacKay-Wiggan J, Eliezri YD. Prospective study of wound infections in Mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. J Am Acad Dermatol 2010;63(5):842–851. Maragh SL, Brown MD. Prospective evaluation of surgical site infection rate among patients with Mohs micrographic surgery without the use of prophylactic antibiotics. J Am Acad Dermatol 2008;59(2):275–278. Futoryan T, Grande D. Postoperative wound infection rates in dermatologic surgery. Dermatol Surg 1995;21(6):509–514. Lilly E, Schmults CD. A comparison of high- and low-cost infection-control practices in dermatologic surgery. Arch Dermatol 2012;148(7):859– 861. Cook J, Zitelli JA. Mohs micrographic surgery: a cost analysis. J Am Acad Dermatol 1998;39(5 Pt 1):698–703. Bialy TL, Whalen J, Veledar E, Lafreniere D, Spiro J, Chartier T, Chen SC. Mohs micrographic surgery vs traditional surgical excision: a cost comparison analysis Arch Dermatol 2004;140(6):736–742. Alam M, Berg D, Bhatia A, Cohen JL, Hale EK, Herman AR, Huang CC, Jiang SI, Kimyai-Asadi A, Lee KK, Levy R, Rademaker AW, White LE, Yoo SS. Association between number of stages in Mohs micrographic surgery and surgeon-, patient-, and tumor-specific features: a cross-sectional study of practice patterns of 20 early- and mid-career Mohs surgeons. Dermatol Surg 2010;36(12):1915–1920. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Cutaneous squamous carcinoma in situ (Bowen's disease): treatment with Mohs micrographic surgery. J Am Acad Dermatol 2005;52(6):997–1002. Chuang GS, Lu LK, Cummins DL, Wu H, Finn D, Rogers GS, Lee D. Incidence of invasive squamous cell carcinomas in biopsy-proven squamous cell carcinomas in situ sent for Mohs micrographic surgery. Dermatol Surg 2012;38(9):1456–1460. Morton CA, Birnie AJ, Eedy DJ. British Association of Dermatologists’ guidelines for the management of squamous cell carcinoma in situ (Bowen’s disease) 2014. Br J Dermatol 2014;170(2):245–260. The characteristics of Mohs surgery performed by non–fellowship-trained dermatologists 123 Virtual reality and brain computer interface in neurorehabilitation David B. Salisbury, PsyD, ABPP, Marie Dahdah, PhD, Simon Driver, PhD, Thomas D. Parsons, PhD, and Kathleen M. Richter, MBA, MS The potential benefit of technology to enhance recovery after central nervous system injuries is an area of increasing interest and exploration. The primary emphasis to date has been motor recovery/augmentation and communication. This paper introduces two original studies to demonstrate how advanced technology may be integrated into subacute rehabilitation. The first study addresses the feasibility of brain computer interface with patients on an inpatient spinal cord injury unit. The second study explores the validity of two virtual environments with acquired brain injury as part of an intensive outpatient neurorehabilitation program. These preliminary studies support the feasibility of advanced technologies in the subacute stage of neurorehabilitation. These modalities were well tolerated by participants and could be incorporated into patients’ inpatient and outpatient rehabilitation regimens without schedule disruptions. This paper expands the limited literature base regarding the use of advanced technologies in the early stages of recovery for neurorehabilitation populations and speaks favorably to the potential integration of brain computer interface and virtual reality technologies as part of a multidisciplinary treatment program. T he yearly incidence of traumatic brain injury (TBI) (∼1.7 million), acquired brain injury (∼900,000), and spinal cord injury (SCI) (∼12,000) in the US fails to adequately reflect the long-term impact and annual societal cost, which may exceed $100 billion a year (1–5). As advances in medical care are improving survival rates in these populations, the need for a multidisciplinary approach focusing on long-term outcomes, secondary complications, and quality of life is magnified (3, 6). This multidisciplinary approach strongly aligns with key aspects of the World Health Organization’s International Classification of Functioning, Disability, and Health Model, where the primary health conditions must be conceptualized in relation to environmental and contextual factors with emphasis upon improving function (7) (Figure 1). Advanced technologies such as brain computer interface (BCI), which uses brain patterns to help patients bypass injuries that impede motor or verbal responses, and virtual reality (VR) have shown potential as viable treatment tools in the rehabilitation setting (8–11); however, the application of advanced technologies in neurorehabilitation is not systematic, and studies to support their use in clinical settings remain limited (12–14). This prompted our 124 Figure 1. The International Classification of Functioning, Disability, and Health model. Source: World Health Organization (7). group to begin exploratory studies into the feasibility and utility of off-the-shelf BCI and VR technologies with neurorehabilitation populations. This paper introduces two original studies to demonstrate how advanced technology may be integrated into the subacute phase of central nervous system recovery. Approval to complete the studies was obtained from the hospital’s institutional review board. FEASIBILITY STUDY AND PILOT STUDY On the SCI rehabilitation treatment unit at the Baylor Institute for Rehabilitation, 25 medically stable patients without severe cognitive or psychiatric impairment were included in the first study. Most participants had sustained cervical-level (48%) or thoracic-level (44%) SCIs and had residual tetraplegia (52%). At initial contact, an extensive screening was completed, including neuropsychological tests, formal questionnaires of mood, pain, and physical status, and qualitative, study-specific questions. Select measures were repeated immediately before the off-the-shelf BCI paradigm and at the final contact. The From the Baylor Institute for Rehabilitation, Dallas, Texas (Salisbury, Dahdah, Driver); Baylor Regional Medical Center at Plano, Plano, Texas (Dahdah); the Department of Psychology, the University of North Texas, Denton, Texas (Parsons); and the Center for Clinical Effectiveness, Baylor Scott & White Health, Dallas, Texas (Richter). Corresponding author: David B. Salisbury, PsyD, ABPP, Department of Neuropsychology, Director of Clinical Training, Baylor Institute for Rehabilitation, 411 N. Washington Avenue, Dallas, TX 75246 (e-mail: dsalisbury@bir-rehab. com). Proc (Bayl Univ Med Cent) 2016;29(2):124–127 BCI paradigm involved a cube rotation task using the EPOC headset (Emotiv, San Francisco, CA). This device was originally developed for gaming, but has been increasingly used in research studies (15–17). Although this off-the shelf BCI is less sensitive in its capture of electroencephalographic data when compared with traditional medical devices (18), its portability, ease of use, and cost made it an attractive option for an inpatient hospital setting. This device allows for wireless 14-channel electroencephalographic recording based on the international 10 to 20 locations (AF3, F7, F3, FC5, T7, P7, O1, O2, P8, T8, FC6, F4, F8, AF4) along with two reference electrodes (P3, P4). After a brief training session for each increasingly complex BCI task (push cube, move left, move right, and cube disappearance), each participant performed three trials, lasting 8 seconds each. A MATLAB scoring program was employed for data acquisition, to log stimulus presentation, and for psychophysiological monitoring (19). The results of the feasibility study suggested that the technology was easily learned (92% of trials were successful) and mastery of the paradigm was not significantly related to prior technology proficiency, current cognitive functioning, pain level, or emotional distress. Equally important, the participants enjoyed the experience and had no reported adverse effects from the headset. The encouraging findings of the small feasibility study open the door for future work among inpatient SCI populations during rehabilitation. This is an ideal time to provide initial exposure and training for such technology if clinical paradigms can be developed. The daunting next step entails the development of paradigms specific to SCI treatment targets. On our SCI treatment team, key psychological treatment goals revolve around psychological adjustment, pain management, and educational interventions that often incorporate aspects of social skills training. Future use of BCI paradigms will be dependent on the ability to integrate VR paradigms that are linked to this triad of clinical priorities. Of particular interest within the rehabilitation psychology field is programming based on frequent challenges and emotionally laden scenarios after SCI. These scenarios could touch upon addressing disability with family/friends, navigating public areas with limited access, and addressing intimacy concerns. One could envision a preventive approach using virtual social simulations to promote more adaptive skills in early stages of rehabilitation. BCI could also be linked to biofeedback-like paradigms to further address pain, anxiety, and emotional regulation, which can complicate outcomes after SCI. The emphasis on clinically relevant and generalizable treatment environments may be in part addressed via immersive environments. A second pilot study was conducted to validate the cognitive rehabilitation efficacy of two virtual environments following central nervous system insult. Participants included individuals with acquired TBI, stroke, brain neoplasm, and anoxic injury. A key focus was treatment outcomes associated with VR training of specific executive functions: cognitive flexibility, working memory, complex attentional processes, and cognitive and motor inhibition, in addition to processing speed. April 2016 Individuals who consented to participate in this study were enrolled in a multidisciplinary outpatient day neurorehabilitation program at the Baylor Institute for Rehabilitation. The only deviation in programming was the introduction of the two VR programs as a supplementary cognitive rehabilitation intervention. The laptop-presented virtual apartment (ClinicaVR: Apartment Stroop [20]) and virtual classroom settings (VR Classroom [21–24]) were selected because they simulate demands and distractions found in real-world settings. While in the immersive environments, participants performed two conditions of a response inhibition task in the face of distractions. Task difficulty increased across sessions with respect to the quantity and type of distractions the participant was exposed to, with a total of 8 training sessions completed biweekly (4-week treatment duration). A Z800 3DVisor head-mounted display (HMD) was used to create a 3D-like effect, and the built in 3-axis head-tracker allowed patients to look 360 degrees around themselves by turning their head. During baseline testing (session 1) and the final session (session 8), patients were additionally administered the Automated Neuropsychological Assessment Metrics Stroop and Go-No Go computerized tests, Woodcock-Johnson 3rd Edition Pair Cancellation subtest, and Delis-Kaplan Executive Functions System Color-Word Interference test (25–27). These tests were used to compare VR treatment outcomes with performance on unimodal Stroop/executive testing and paper-pencil tests. Patients also completed the Simulator Sickness Questionnaire upon conclusion of sessions 1 and 8 to document any symptoms associated with the HMD. Twenty-one brain injury patients participated in the pilot study: 9 diagnosed with stroke (43%), 6 with TBI (29%), 2 with anoxic injury (10%), 3 with brain tumor (14%), and 1 with amyloid angiopathy (5%). Preliminary analyses were conducted using the performance of the group with stroke, which accounted for the largest diagnostic category. The smaller groups comprising patients with anoxic injury and brain tumor demonstrated such profound variability that a combined analysis would have been minimally informative. When comparing the stroke subgroup with 9 demographically matched healthy controls on the ClinicaVR: Apartment Stroop, there were no significant group differences in reaction time on conditions with distractions (F(1,16) 3.418, P = 0.062) or without distractions (F(1,16) 1.793, P = 0.200) employing analysis of covariance and adjusting for age. However, response time was significantly slower for stroke patients than for controls (F(1,16) 17.109, P < .01). The former may be due to the fact that the stroke subgroup included some relatively young patients, ranging in age from 22 to 65 (mean age = 47). It may also be that the stroke group was relatively higher functioning cognitively, given that patients with significantly impaired comprehension, bimanual apraxia, and attention (e.g., patients with attention span < 10 minutes) that could potentially confound cognitive performance outcomes on the VR programs were excluded from the study. However, two of the stroke patients were noted to respond with errors on all items of the incongruent word-color stimulus trial of the Stroop task, indicating variation in severity level within this group. Virtual reality and brain computer interface in neurorehabilitation 125 Qualitatively, across all acquired brain injury patient groups treated in this pilot study (TBI, stroke, anoxic injury, etc.), those exhibiting overt impulsivity or anxiety appeared to exhibit impulsive responding on the VR-based executive measures. Patients with reported or observable fatigue demonstrated reduced attention and self-monitoring, committing omission errors due to fluctuations in engagement. As additional quantitative error analysis is completed, it will be interesting to learn whether results parallel qualitative observations. Six of the 21 patients initially endorsed slight or moderate fatigue, headache, eye strain, difficulty focusing, perspiring, and blurred vision on the Simulator Sickness Questionnaire, which assesses the occurrence, nature, and severity of sickness symptoms induced by virtual environments (28). By the fourth session, the number of patients reporting HMD-related symptoms declined to four. No adverse events occurred, and no patients volitionally withdrew from the study. Six of the 21 patients partially completed the study, but failed to complete all 8 intervention sessions. Two patients were medically withdrawn from the day neurorehabilitation program due to refractory medical complications, two patients self-discharged from the program against medical advice, and four patients’ rehabilitation regimens were concluded prior to their projected discharge dates when insurance or state-assisted benefits were not extended. With regard to feasibility, similar to the BCI apparatus described above, the portability, ease of use, and cost of the devices used to administer the VR programs made them amenable to this setting. Scheduling of the VR intervention sessions and space required constant and effective communication between the research team and the day neurorehabilitation teams, due to the variability in patient schedules, modifications in length of stay, and unplanned events (e.g., illness, external medical appointments, impact of payer source on rehabilitation days). The day neurorehabilitation team was positively responsive to integration of the VR intervention in the rehabilitation program. Due to built-in demonstrations paired with verbal instructions from the research team members administering the VR interventions, patients found the technology user-friendly. Some patients provided unsolicited feedback, stating that the virtual environments and internal distractions in the programs were realistic. In fact, patients spontaneously commented on the improvement in their performance from initial to later sessions. One patient specifically attributed an observable subjective improvement in reaction time to the VR intervention. The efforts to replicate home and school settings using VR in the pilot study allow for potentially highly relevant information to guide discharge planning. It is hoped that findings from this pilot study will encourage ongoing study to validate VR technologies in neurological populations for the purpose of enhancing cognitive intervention and rehabilitation. lack of adverse effects even with patients in the subacute stage of recovery, were quite encouraging. Still, the clear enthusiasm for technology must be tempered by an acknowledgment of potential barriers. The key concerns involve issues surrounding the utility of BCI and VR, management of technological problems, and financial feasibility. The virtual environments used in these pilot studies are not commercially available, and only a few research labs have access to them. Further, a number of VR systems use arrays of screens to allow for full-body interactions, costing many thousands of dollars. From a utility standpoint, our projects ranged from simple visual stimuli to more advanced depictions of real-world settings. Still, there may be a need for more realistic visual paradigms. Studies are needed to assess the impact and potential clinical efficacy of varying levels of stimulus fidelity and immersion. Our studies involved collaboration with experts in the area of technology and psychology who could provide any needed assistance in a timely manner. The presence of an information technology support staff was also readily available as part of our hospital system. Still, occasions arose where technology did not work properly, resulting in delayed intervention or the need to reschedule. Such complications speak to the challenges of implementing interventions dependent upon technology within inpatient and outpatient rehabilitation settings. Any delays in these fast-paced settings, requiring the coordination of various disciplines, can be quite disruptive to the milieu. Finally, the financial feasibility of VR and BCI will largely be determined by future outcomes research. Unless there is support for clinical gain in the form of improved outcomes, decreased complications, or secondary decline in medical costs (e.g., decreased length of stay, less use of future medical services), cost concerns may prohibit adoption of such technologies. Mainstream implementation in rehabilitation would be a financial challenge considering the trend of declining reimbursement for clinical services and emphasis on bundled services with recent health care changes. The initial cost must be coupled with the need for staff training and statistician support by individuals trained to analyze the data formats associated with this technology. Additionally, BCI and VR require a private space that limits distractions that are all too frequent in rehabilitation settings. Private rooms or dedicated areas for such interventions would be ideal, yet allocation of such space was a challenge in our studies. 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Beeram, MD This double-blinded, randomized, crossover study evaluated the safety and effectiveness of 20 mL/kg aliquots of packed red blood cell (PRBC) transfusions versus 15 mL/kg aliquot transfusions in very low birth weight (VLBW) infants with anemia. The study enrolled 22 hemodynamically stable VLBW infants requiring PRBC transfusions, with a mean gestational age of 25.7 ± 2.2 weeks and birth weight of 804 ± 261 g. Each infant was randomized to receive one of two treatment sequences: 15 mL/kg followed by 20 mL/kg or 20 mL/kg followed by 15 mL/kg. The infants were monitored during and after transfusions, and the efficacy and safety of the treatments were evaluated. Infants had higher posttransfusion hemoglobin (13.2 g/dL vs 11.8 g/dL, P < 0.01) and hematocrit levels (38.6 g/dL vs 34.4 g/dL, P < 0.01) following 20 mL/kg PRBC transfusions when compared to 15 mL/kg transfusions. There were no differences in the incidence of tachypnea, hepatomegaly, edema, hypoxia, necrotizing enterocolitis, or vital sign instability between groups. In conclusion, high-volume PRBC transfusions (20 mL/kg) were associated with higher posttransfusion hemoglobin and hematocrit levels but no adverse effects. Higher-volume transfusions may reduce the need for multiple transfusions and therefore the number of donors the infant is exposed to. A nnually, more than 60,000 infants are born in the United States with a birth weight ≤1500 g. These very low birth weight (VLBW) infants are at risk of serious complications, including anemia of prematurity. Anemia of prematurity is caused by ineffective hematopoiesis and iatrogenic blood loss through frequent phlebotomy and is exacerbated by low iron stores. Anemia leads to inadequate oxygen delivery to tissues and poor growth. As a result, VLBW infants are a heavily transfused population, accounting for nearly three-quarters of neonatal red blood cell transfusions (1–3). Although blood transfusions are considered essential, there are concerns related to infection risk, the safety of directed donations, and refusal based on religious beliefs (4). Limiting packed red blood cell (PRBC) transfusions may reduce transfusion-associated infection and iron overload (5). Transfusion guidelines are based on expert opinion, rather than evidence, and therefore vary among hospitals, with some units favoring restrictive guidelines and others more liberal guidelines (6–8). Although the traditional volume of PRBC transfusions ranges from 10 to 20 mL/kg (9), there is still considerable debate 128 regarding the optimal volume of transfusion. In a systematic review, only four trials, with 146 infants, compared transfusion volumes of 10 versus 20 mL/kg (3). These studies showed no differences in neonatal outcomes, but the number of patients in each study was small and markedly limited the power of these studies to detect a difference. The purpose of this study was to evaluate the safety and effectiveness of using larger-volume aliquots for PRBC transfusions in preterm VLBW infants. METHODS This study was conducted at McLane Children’s Hospital, Baylor Scott & White Health, in Temple, Texas. VLBW infants admitted to the neonatal intensive care unit that were expected to require at least two PRBC transfusions after 48 hours of life were eligible for enrollment. Patients with any of the following were excluded: birth weight <500 g, congenital heart defects, or hemodynamic instability (defined as pulse >180 beats/min and capillary refill >3 sec). This was a randomized, double-blind, crossover study. Informed parental consent was obtained for eligible patients and then each infant was randomized, using a random number generator, to one of the two treatment sequences: 15 mL/kg transfusion followed by 20 mL/kg transfusion or 20 mL/kg transfusion followed by 15 mL/kg transfusion. For both treatment groups, the blood was transfused intravenously over 3 hours. The blood product utilized for this study consisted of component aliquot bags with a hematocrit of 60%, stored in Nutricel AS-3 (Haemonetics, Pittsburgh, PA), which contains dextrose, adenine, monobasic sodium phosphate, and sodium chloride transfused via sterile tubing. All PRBC transfusions were cytomegalovirus negative, leukocyte reduced, O-type with the same Rh type as the infant. Patients were enrolled over a 24-month period (January 2000–December 2002). Clinical and demographic information, including the Score for Neonatal Acute Physiology (SNAP-II), From the Department of Pediatrics, McLane Children’s Hospital, Baylor Scott & White Health/Texas A&M Health Science Center College of Medicine, Temple, Texas. Corresponding author: Lea H. Mallett, PhD, Department of Pediatrics, McLane Children’s Hospital, Baylor Scott & White Health, 1901 SW H. K. Dodgen Loop, Building 300, MS-CK-100, Temple, TX 76502 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):128–130 was collected (10). The need for transfusion was based on current transfusion guidelines but ultimately determined by the attending neonatologist. Before transfusion, the following specific parameters were assessed among both treatment groups: 1) respiratory distress employing the Silverman Score (11); 2) presence of edema or hepatomegaly; and 3) vital signs (heart rate, respiratory rate, blood pressure, and oxygen saturations). Vital signs were monitored hourly during and up to 6 hours after transfusion. Hematocrit, hemoglobin, and red blood cell counts were also collected 1 hour before transfusion and for 3 hours after transfusion. The primary outcome was posttransfusion change in hemoglobin and hematocrit in infants following both PRBC transfusion treatment sequences. Secondary outcomes included vital sign instability, edema or hepatomegaly, and respiratory distress. Statistical analyses were performed using SAS Version 8.2 (SAS Institute, Cary, NC). All data were compared using analysis of variance for a crossover design (12). The traditional definition of a P value of 0.05 or less for statistical significance was applied (13). Table 1. Demographic and clinical characteristics by treatment group Treatment sequence 15, 20 mL/kg (n = 10) 20, 15 mL/kg (n = 12) Gestational age (wk, mean ± SD) 25.6 ± 2.2 26.4 ± 2.2 Birthweight (g, mean ± SD) 773 ± 258 830 ± 272 White 6 5 Black 2 5 Hispanic 2 2 Vaginal 4 4 Routine C-section 5 7 Emergency C-section 1 1 26 ± 6 28 ± 6 1 0 Mother’s race or ethnic group Delivery route Maternal age (yr, mean ± SD) Gravida 1 RESULTS 2 3 8 Twenty-four infants were enrolled in the study; 2 parents 3 2 3 withdrew consent prior to randomization, and the remain4 1 4+ ing 22 patients were randomized into one of the two treatment sequences: 15 mL/kg transfusion followed by 20 mL/kg Prenatal care 10 12 transfusion or 20 mL/kg transfusion followed by 15 mL/kg Antepartum complications 10 11 transfusion. Seven patients were discharged after receiving only Arterial line 1 1 the first transfusion and 15 patients received 2 transfusions. Apgar scores (mean ± SD) Demographic and clinical characteristics of study infants by 1 min 4.8 ± 2.8 6.2 ± 2.4 treatment group are presented in Table 1. The median number 5 min 7.9 ± 1.3 8.1 ±1.3 of days between the first and second transfusion for all patients was 8 days (range, 1–22). Cord pH (mean ± SD) As shown in Table 2, infants from both sequence groups Arterial 7.2 ± 0.1 7.3 ± 0.1 had higher posttransfusion hemoglobin (13.2 vs 11.8 g/dL, Venous 7.3 ± 0.2 7.3 ± 0.1 P < 0.01) and hematocrit levels (38.6 vs 34.4 g/dL, P < 0.01) SNAP score (mean ± SD) 22.5 ± 7.3 21.6 ± 7.1 following 20 mL/kg PRBC transfusions when compared to SNAP indicates Score for Neonatal Acute Physiology. 15 mL/kg transfusions. There were no significant differences in the incidence of hepatomegaly, edema, respiratory distress, or abnormal vital signs during the 20 mL/kg transfusions comhigher hemoglobin and hematocrit values when compared to pared to the 15 mL/kg transfusions. One patient (5%) had hep15 mL/kg transfusions. Infants tolerated the higher volumes atomegaly following a transfusion of 15 mL/kg. Four patients well, with no significant differences in the incidence of re(18%) had edema following transfusion, one after 15 mL/kg spiratory distress, hepatomegaly, peripheral edema, hypoxia, and three after 20 mL/kg transfusions. Necrotizing enterocolitis developed in one patient (5%), who received 20 mL/kg followed by 15 mL/kg 2 days after the two transfusions were Table 2. Pre- and posttransfusion treatment effects by dose completed, requiring surgical interven15 mL/kg 20 mL/kg tion. The infant survived to discharge. Variable DISCUSSION Our findings support the efficacy and safety of higher-volume (20 mL/kg) PRBC transfusions, currently supported by four similar studies. The larger transfusion volumes resulted in significantly April 2016 Hemoglobin (g/dL) Hematocrit (g/dL) Pre Post 9.0 ± 1.2 11.8 ± 1.4 Pre Post P value 9.1 ± 1.0 13.2 ± 1.2 <.01 26.2 ± 3.4 34.4 ± 3.8 26.8 ± 2.8 38.6 ± 3.6 <.01 Red blood cells (M/μL) 2.8 ± 0.4 3.8 ± 0.4 2.8 ± 0.3 4.2 ± 0.4 <.01 Respiratory distress (Silverman score) 2.1 ± 1.1 2.2 ± 1.0 2.2 ± 1.3 2.2 ± 1.2 .31 Safety and efficacy of packed red blood cell transfusions at different doses in very low birth weight infants 129 necrotizing enterocolitis, or vital sign insatiability. These findings are consistent with a previous study by Wong et al in 2005 comparing 20 mL/kg with 15 mL/kg PRBC transfusions. The randomized crossover design and the addition of the SNAP-II score were strengths of this study. By randomizing the sequence and having each infant serve as his or her own control, the observed changes in hemoglobin and hematocrit were not biased by order of transfusion or by infant idiosyncrasies. However, our study had several limitations. First, our study had a limited sample size, which may have impacted our ability to detect safety signal. However, our findings add to the paucity of data in this area. Second, our results may not be generalizable to other centers with different transfusion practices. Finally, the Silverman score is subject to ascertainment bias. Therefore, further study in this area may address some of these limitations and expand its scope. Our findings suggest that higher-volume PRBC transfusions lead to higher posttransfusion hemoglobin and hematocrit volumes without increasing acute complications. These results suggest a way to potentially decrease or eliminate the need for multiple transfusions and the number of donors the infant is exposed to, thereby decreasing risk. Prospective validation of this practice, with larger studies, is needed to determine long-term benefits, safety profile, and cost-effectiveness. 1. 2. 130 Maier RF, Sonntag J, Walka MM, Liu G, Metze BC, Obladen M. Changing practices of red blood cell transfusions in infants with birth weights less than 1000 g. J Pediatr 2000;136(2):220–224. Franz AR, Pohlandt F. Red blood cell transfusions in very and extremely low birthweight infants under restrictive transfusion guidelines: is exogenous erythropoietin necessary? Arch Dis Child Fetal Neonatal Ed 2001;84(2):F96–F100. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Venkatesh V, Khan R, Curley A, Hopewell S, Doree C, Stanworth S. The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials. Br J Haematol 2012;158(3):370– 385. Wong H, Connelly R, Day A, Flavin MP. A comparison of high and standard blood transfusion volumes in premature infants. Acta Paediatr 2005;94(5):624–625. Luban NL. Review of neonatal red cell transfusion practices. Blood Rev 1994;8(3):148–153. Strauss RG. Transfusion therapy in neonates. Am J Dis Child 1991;145(8):904–911. Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, Cress GA, Johnson KJ, Kromer IJ, Zimmerman MB. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics 2005;115(6):1685–1691. Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, Peliowski A, Rios A, LaCorte M, Connelly R, Barrington K, Roberts RS. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr 2006;149(3):301–307. Simon TL, Alverson DC, AuBuchon J, Cooper ES, DeChristopher PJ, Glenn GC, Gould SA, Harrison CR, Milam JD, Moise KJ Jr, Rodwig FR Jr, Sherman LA, Shulman IA, Stehling L. Practice parameter for the use of red blood cell transfusions: developed by the Red Blood Cell Administration Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1998;122(2):130– 138. Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J Pediatr 2001;138(1):92–100. Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics 1956;17(1):1–10. Fleiss JL. The Design and Analysis of Clinical Experiments. New York: Wiley, 1986. Fisher R. The Design of Experiments. Edinburgh: Oliver and Boyd, 1953. Baylor University Medical Center Proceedings Volume 29, Number 2 Review of behavioral health integration in primary care at Baylor Scott and White Healthcare, Central Region John B. Jolly, PsyD, Norman R. Fluet, PsyD, Michael D. Reis, MD, Charles H. Stern, MD, Alexander W. Thompson, MD, and Gillian A. Jolly, BS The integration of behavioral health services in primary care has been referred to in many ways, but ultimately refers to common structures and processes. Behavioral health is integrated into primary care because it increases the effectiveness and efficiency of providing care and reduces costs in the care of primary care patients. Reimbursement is one factor, if not the main factor, that determines the level of integration that can be achieved. The federal health reform agenda supports changes that will eventually permit behavioral health to be fully integrated and will allow the health of the population to be the primary target of intervention. In an effort to develop more integrated services at Baylor Scott and White Healthcare, models of integration are reviewed and the advantages and disadvantages of each model are discussed. Recommendations to increase integration include adopting a disease management model with care management, planned guideline-based stepped care, followup, and treatment monitoring. Population-based interventions can be completed at the pace of the development of alternative reimbursement methods. The program should be based upon patient-centered medical home standards, and research is needed throughout the program development process. T he Agency for Healthcare Research and Quality defined integrated care as follows: A practice team of primary care and behavioral health clinicians working together with patients and families, using a systematic and cost-effective approach to provide patientcentered care for a defined population. This care may address mental health and substance abuse conditions, health behaviors (including their contribution to chronic medical illnesses), life stressors and crises, stress-related physical symptoms, and ineffective patterns of health care utilization (1). C. J. Peek, a national leader in care system development, reported that a variety of terms are encountered within research and conceptual writings of this emerging area, such as integrated care, patient-centered care, coordinated care, shared care, collaborative care, colocated care, and integrated primary care or primary care behavioral health (1). Kwan and Nease reported that certain structural features and clinical processes are typical of integrated behavioral health models (2). The common structural features are a care delivery team, a physical space onsite for Proc (Bayl Univ Med Cent) 2016;29(2):131–136 behavioral health, information technology, clinical and office management policies and protocols, and education and training. Common processes include access, detection, treatment, practice improvement, and cost containment and sustainability. They stated, “Ultimately, it may not matter what exactly this infrastructure looks like as long as it enables the provision of certain services” (2). THE PURPOSE OF INTEGRATING BEHAVIORAL HEALTH WITH PRIMARY CARE There are a variety of forces demanding a change and redesign in how health care is delivered in the United States. These forces include problems in the delivery of health care to patients and their families, financial pressures (including spiraling health costs), and political forces—all pushing to support such changes by delivery and payment reform. Primary care continues to be the primary setting in which individuals seek mental health treatment, yet treatment is often deficient. Wang and his colleagues reported that based upon findings from the National Comorbidity Survey Replication data, 41.1% of individuals with mental disorders had received treatment in the previous 12 months; 56% of those individuals received treatment within the primary care setting, compared with 44% who received treatment within mental health settings (3, 4). Consistent with a previous epidemiological study, primary care is the “de facto” setting for mental health services in the United States (5). However, Wang et al also found that only 12.7% of individuals who were treated in primary care received even minimally adequate treatment (3). In addition to the need to become more clinically effective, health care demands financial redesign to “bend the curve” of costs but also to support more effective, efficient, coordinated care. Health care costs are spiraling, and the “sick and disabled consume almost all health dollars” (6). Changes are particularly From private practice, Jackson, Mississippi (J. B. Jolly); the Departments of Family Medicine (Fluet, Reis, Stern) and Psychiatry (Thompson), Baylor Scott and White Healthcare, Waco and Temple, Texas; and Baylor University, Waco, Texas (G. A. Jolly). Corresponding author: John B. Jolly, PsyD, 620 N. State Street, Suite 202, Jackson, MS 39202 (e-mail: [email protected]). 131 needed to reduce costs of the chronically medically ill patient with comorbid behavioral health concerns. Gaipa and colleagues described a recent insurance report that demonstrated a significant increase of cost when the particular medical condition had comorbid behavioral health problems (7, 8). The authors of the Air Force’s Behavioral Health Optimization Program stated that focusing only on the chronically sick “does nothing for the large pipeline that keeps fueling this fire, and it has little effect on the population’s health as a whole” (6). They proposed a combination of addressing not only the sick and comorbid but also the larger, healthier population. Health care reform is supporting changes in not only clinical delivery systems, but also payment and reimbursement systems. Health care is moving from fee-for-service models to bundled/ global payments for populations of patients. The Patient Protection and Affordable Care Act (PPACA) and the Health Care and Education Reconciliation Act of 2010 demonstrate this intent with the federal health reform agenda. Fabius and colleagues reported that the most significant problem in health care reform is the fee-for-service payment model (9). They noted that feefor-service deincentivizes the changes needed in delivery and argued for bundling related costs. Under a fee-for-service model, each provider bills separately and “has no incentive to manage their use efficiently” (9). By bundling or receiving global payments, providers are compensated based upon the combined performance of all involved. The PPACA supports the testing of this payment reform model to “determine if providers can be incentivized to manage costs by taking responsibility for the costs of both acute conditions/procedures and chronic conditions” (9). Medicare, Medicaid, and commercial insurance programs are in the process of creating and releasing innovative bundled and global payment plans to support models that are clinically and cost-effective (10). CONCEPTUAL DIMENSIONS USEFUL FOR INTEGRATION In an effort to guide our process of behavioral integration at Baylor Scott & White Central Region, we considered important conceptual dimensions in this emerging field. Examining efforts in terms of an integration continuum, patient populations (whether in terms of level of pathology or even insurance status), or conceptual models of collaborative activities provided a direction (11–14). Doherty described five levels of integration: minimal collaboration, collaboration at a distance, basic collaboration on site, close collaboration in a partly integrated system, and a fully integrated system (11). The first two integration levels suffer from a lack of communication, particularly involving comorbid mental health and physical health problems, while a fully integrated system requires a change in reimbursement methods that is currently unavailable. Basic collaboration on site occurs when behavioral health providers (BHP) and primary care providers (PCP) have separate systems but share the same facility. Proximity allows for more communication, but each provider remains in his or her own professional culture. In the fourth level of integration, some organizations have close collaboration in a partly integrated system; BHPs and PCPs share 132 the same facility and have some systems in common, such as scheduling appointments or medical records. They have regular face-to-face communication. There is a sense of being part of the larger team. The fifth level of integration is a close collaboration in a fully integrated system. The BHP and PCP are part of the same team. The patient experiences the mental health treatment as part of his or her regular primary care. There is a population-based focus with primary prevention in addition to integrative case management. Another conceptual dimension that affects integration efforts considers the importance of patient populations. Mauer proposed the four-quadrant model (12), which divides patients into four categories based upon behavioral and physical “needs” and “risks.” Patients with low behavioral health needs/risks and low physical health needs/risks are typically served in primary care. Patients who have high behavioral health needs and low physical health needs are typically served in specialty behavioral health programs with linkages to primary care. Patients who have low behavioral health needs and high physical health needs are served in primary care and in the medical specialty system. Finally, patients who have high behavioral health needs and high physical health needs are typically served in both specialty behavioral health settings and primary care. Another patient population model places integration in the context of behavioral health reform to determine what type of model of care best financially incentivizes integration for particular patient populations. Bao et al discussed grouping patients based upon severity of mental health problems and insurance status (13). If a patient’s behavioral/mental health is paid by Medicaid, access is poorer, there is typically a greater need for social and human services, and coordination and collaboration between primary and behavioral health care is traditionally lacking. The Affordable Care Act’s health home provisions incentivize coordinated care for Medicaid patients who have chronic and comorbid clinical conditions. For patients, regardless of health status, whose health is paid for by commercial insurance and Medicare programs, patientcentered medical homes (PCMHs) and accountable care organizations best incentivize integration efforts (15). The Agency for Healthcare Research and Quality reported that a PCMH has five functions and attributes: providing care that is a) comprehensive, b) patient-centered, c) coordinated, d) accessible, and e) has a commitment to quality improvement (16). Bao et al reported that PCMHs have the greatest potential to serve patients with mild to moderate behavioral health conditions (13). The Patient-Centered Primary Care Collaborative Payment Reform Task Force has offered a range of payment plans with fidelity to the PCMH model; at the highest level, global payments with bonuses are proposed to lessen the need for patient volume and incentivize value creation (17, 18). Accountable care organizations have shared savings for coordinating medical and behavioral health care but are payer-specific; they lack incentives to improve quality and reduce costs for Medicaid patients (13). A particularly useful framework to guide integration efforts was provided by Collins and his colleagues (14). They discussed Baylor University Medical Center Proceedings Volume 29, Number 2 eight models of behavioral health integration that described nonintegrated to fully integrated services. The “colocation,” “disease management,” and “primary care behavioral health” models appear to be particularly relevant in discussions of the current status and future transitions of behavioral integration at Baylor Scott and White Healthcare. The colocation model occurs when PCPs and BHPs are at the same site, but have distinct services. This arrangement has the primary advantage of providing better communication. Foy and colleagues suggested that better interactive communication, defined as “collaborative arrangements that enable primary care physicians and specialists to converse,” improves outcomes (19). The colocation model is less stigmatizing and provides better access to behavioral healthcare for PCPs and their patients. One disadvantage is that patients referred to mental health for physical complaints may interpret symptoms as being “all in my head.” Additionally, if the behavioral service location is separate from the primary care treatment setting, e.g., a different wing of the building, there may be fewer opportunities for interactions and education of PCPs and “warm hand-offs.” These difficulties are intensified if BHP therapeutic hours are not modified for the primary care 15- to 20-minute appointments. Caseloads can quickly become overloaded, and access problems increase. The disease management model is “an integrated system of interventions to optimize functioning of patients and to impact the overall cost of the disease burden” (14). The chronic care or disease management model is based on Wagner, Austin, and Von Korff’s chronic care model (CCM) (20). Wagner et al suggested that the components of high-quality chronic care consist of the use of explicit plans and protocols, practice redesign, patient change processes, expert input, and information system support (20). Common elements of chronic care include collaboration between service providers and patients, care plans, self-management education, follow-up, treatment monitoring, targeted use of specialty referral, and “stepped care” (21, 22). The disease management model has advantages over the colocation model. In addition to having all the strengths of being on site, patients are screened for psychological problems in an empirical manner and closely monitored throughout the treatment process; this allows for modification and personalization of the intervention process and results in stepped care. Empirical guidelines are emphasized, saving scarce psychiatric resources to be used more efficiently. One primary disadvantage of this model is the current fee-for-service payment method, which does not reimburse case management services. The primary care behavioral model is based upon population-based care. Strosahl reported that population-based care is grounded in public health concepts (23). Further, primary care behavioral health is consistent with “the philosophy, goals and strategies of primary care medicine. Specifically, there is an emphasis on early identification and treatment, long-term prevention, and ‘wellness’” (24). Collins et al indicated that the entire primary care patient population is the target of assessment, intervention, and consultative services (14). The primary “customer” is the PCP, then the patient. The goals are to April 2016 support providers, improve their effectiveness, prevent chronic problems from occurring, and improve the overall health of the population. The most critical issue in utilizing this model is associated again with reimbursement. While there appear to be new efforts at paying for such population-based services as consultation, case management, and primary prevention, currently medical “offset” savings for this model have not been clearly demonstrated. CLINICAL EFFECTIVENESS OF BEHAVIORAL HEALTH INTEGRATION Metaanalyses of behavioral health integration studies have demonstrated the clinical effectiveness of collaborative care models with a variety of clinical conditions. In the most comprehensive metaanalysis completed to date, Woltmann and colleagues examined the clinical effectiveness of collaborative CCMs for mental health conditions across different settings, particularly for depression but also including bipolar disorder, anxiety, and other mental health problems (25). They compared CCMs to usual care for 57 experimental trials across 78 articles, with 140 clinical outcome analyses. To be included in the study, each CCM had to have six components consistent with the CCM: patient self-management support, delivery system redesign, use of clinical information systems, provider decision support (guidelines), health care organization support, and linkage to community resources (25). Of 133 study analyses that reported statistical comparisons, 66 analyses (49.6%) favored the CCMs, 1 favored the control condition, and 66 (49.6%) had no statistically significant differences in the comparisons. The overall findings suggested that there were small to medium effects of CCMs across multiple disorders for clinical outcome (symptoms), mental and physical quality of life, and social role functioning. The authors reported that at this point, we still do not know which components are most important, which are necessary, and what works better for whom. Most metaanalyses have cited the contribution of care management in the treatment of mental health problems, particularly for depression. Butler and her colleagues conducted a metaanalysis of 33 clinical trials from 145 articles on the integration of behavioral health and primary care in the treatment of depression (26). They specifically examined integration based upon the use of care managers, the process of care, and the degree that the studies integrated the roles of clinicians. The authors concluded that most studies demonstrated positive outcomes for treatment response and remission rates. However, the level of integration was unrelated to outcomes. Gilbody and colleagues completed a cumulative metaanalysis of 37 randomized collaborative care studies treating depression (27); all studies utilized case managers. They found a significant positive treatment effect, when compared to standard of care, at 6 months. Eleven studies examined effects beyond 6 months; significant treatment effects were found at 12 months, 18 months, and 5 years. Case management supervision and mental health background were found to be significantly related to the size of positive treatment outcome. Gilbody et al Review of behavioral health integration in primary care at Baylor Scott and White Healthcare, Central Region 133 also reported that studies that had a case manager, a PCP, and access to specialist input, consistent with Katon and colleagues’ collaborative care model (22), tended to be more effective than other models (27). Williams et al completed a systematic review of 28 studies that used care management and interventions treating depression within primary care settings (28). Consistent with Wagner and colleagues’ CCM, most studies included patient education and self-management, monitoring of symptoms, decision support, registries, and mental health supervision of care managers (20). The authors found that almost all multifaceted interventions led to significant improvements in depression outcomes within 1 year. Gensichen et al found case management to be the primary positive factor in depression outcomes in a metaanalysis of 13 studies within primary care settings (29). Instead of a specific focus on care management, Foy and colleagues suggested that the important factor in patient success is “interactive” communication of PCPs and specialists (19). In a metaanalysis of 18 depression studies that excluded care managers but incorporated direct communication between PCPs and psychiatrists, the authors found significant reductions in patients’ depression. They concluded that collaboration that allows for direct communication between the PCP and specialist improves patient outcomes. In sum, collaborative care, based upon a CCM, demonstrates clear evidence for effectiveness. The most effective studies consist of care management, a PCP, and some form of specialist consultation and supervision. BAYLOR SCOTT AND WHITE CLINICS Clinic patient characteristics Baylor Scott and White Healthcare-Central Region, Department of Family Medicine, has two primary care clinics that have BHPs. The Waco Clinic (WC) is located in Waco, Texas, a city of 127,000 within a county of 238,000. The Killeen Clinic (KC) is located within a city of 134,000 in a county of 323,000. Fort Hood, one of the largest military installations in the world, is located in Killeen. WC, which has had a psychology presence for the past 20 years, has four providers: three licensed psychologists and one licensed professional counselor. WC has always functioned with an annual profit margin while maintaining traditional 50-minute therapeutic hours. Contrary to Strosahl’s concern about therapists being “swamped,” WC functions without a long waiting list. In comparison to a non-colocated clinic, WC demonstrated a statistically significant shorter time from PCP referral to first BHP appointment for older patients, with approximately 77% of all patients attending their initial appointment after being referred by the PCP (31). KC hired two licensed psychologists within the past year. The Table shows the Table. The mental health patient populations of two primary care clinics with behavioral health providers in Baylor Scott & White Central Region, calendar year 2013 Killeen Clinic Waco Clinic Clinic population 28,000 17,000 Female 74% 63% Caucasian 59% 85% African American 17% 7% 44 42 Anxiety 83% 76% Depression 68% 59% Substance abuse 12% 8% Conduct disorders 7% 16% Obesity 23% 47% Demographics COST-EFFECTIVENESS OF BEHAVIORAL HEALTH INTEGRATION Behavioral health integration is clinically effective. Is it also cost-effective? Woltmann et al argued, “The major focus of health care cost reduction efforts must be in reducing avoidable complications of chronic illnesses, which account for up to 22% of all health care expenditures. Reducing these complications could realistically result in a $40-billion per-year savings” (25). Strosahl stated, “While improving clinical outcomes in healthcare is obviously an important goal, the ‘straw that stirs the drink’ is the huge medical offset potential of integrated care” (23). He suggested that integrated care has the potential for cost offset of approximately 20% to 40%. Woltmann and colleagues examined health care costs in their metaanalysis of collaborative CCMs for mental health conditions (25). They found that among the 21 economic analyses (among 57 clinical effectiveness trials examined), only 10 could be compared; 9 (90%) found no statistically signifi cant diff erence in costs between the CCM and the control condition. One study found the control condition less expensive. Van Steenbergen-Weijenburg and colleagues found eight studies that met quality criteria examining the cost-effectiveness of collaborative care for major depression (30). They found that all studies demonstrated that collaborative care is effective but, in most cases, more expensive. They concluded that while collaborative care seems promising, “the economic information is insufficient for policy decisions” (30). 134 Median age (years) Psychiatric diagnoses (overlapping) Comorbid chronic health conditions Diabetes 17% 7% Asthma 14% 9% Other problems <5% <5% 91% 61% Referrals From clinic PCPs From other BSW-CR clinics 20% Reimbursement Commercial insurance 48% 30% Scott & White Plan 16% 31% Medicare 18% 14% Medicaid 10% 10% PCP indicates primary care physician; BSW-CR, Baylor Scott & White Central Region. Baylor University Medical Center Proceedings Volume 29, Number 2 similarities and differences in the clinics’ mental health patient populations. Clinic structural and process features Both clinics have a close collaboration within a partly integrated system (11). Both clinics appear to be composed largely of patients with low behavioral health needs/risks and low physical health needs (12). While the clinics use a fee-for-service model of reimbursement, 90% of the payers for both clinics are non-Medicaid; PCMHs and accountable care organizations best incentivize integration efforts (13). At this time, both clinics fit the colocation model with integration enhancements (14). The Patient-Centered Integrated Behavioral Health Care Principles and Tasks, a qualitative assessment of our adherence to principles and tasks considered important for behavioral health integration, was completed (32). The major strengths of both clinics are that PCPs and BHPs are colocated, they offer evidence-based treatments for their patients and families, and they systematically identify problems for most patients. Advantages of colocated services include easy, nonstigmatizing access for primary care patients, “curbside” consultations and improved communication with PCPs, and shared electronic medical records. Consultations to PCPs are limited, however, by the 50-minute hour; BHPs are not easily accessible except when suicidal/homicidal ideation is prominent. While KC providers share treatment space, WC providers are in separate wings of the clinic. There are many advantages to shared space, but also disadvantages; administrative issues appear less complicated with services in separate wings. Both clinics have a goal of educating PCPs concerning psychological/behavioral issues, given that behavioral health plays such an important role in primary care (3). In both clinics, the PCPs and BHPs collaborate using care plans within the shared electronic medical records. While both clinics use measurement-based identification of behavioral and emotional problems, and develop and modify treatment plans based upon this data, these efforts are not completed systematically at this point. Both clinics use valid measurement tools to screen, diagnose, and even document baseline symptom severity. WC and KC provide initial evaluations that rely primarily on interview and self-report measures, such as the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder 7-item scale (33, 34). WC BHPs offer general psychopharmacology consultation, within their scope of practice, comfort level, and training, and based upon ethical guidelines. Among KC and WC behavioral health care patients, 48% and 31%, respectively, are treated with psychotropic medications. For those patients who have severe mental illness and/or need more complicated psychopharmacological intervention, referrals are made to psychiatrists at Baylor Scott and White in Temple, Texas. This service is located 30 or more miles from WC and KC and has a 2- to 3-month waiting list for nonemergency patients. Less than 5% of behavioral health patients for both clinics were referred to psychiatrists. While there is active communication among PCPs and BHPs in both clinics, particularly with the shared electronic medical record, there is no formal care coordination or case April 2016 management. The lack of case management clearly sets limits on being responsive to patients’ changing needs. The clinics’ newest electronic medical record has a registry, which will allow both clinics to track and monitor patients who are not improving; neither clinic has begun this process yet. Providers are formally assessed for patient satisfaction, and, while accountable, providers are not reimbursed for quality of care and patient outcomes. Integration recommendations for Baylor Scott and White-Central Region Based upon a review of current concepts and models of behavioral health integration with primary care, the efficacy of certain structures and processes, and the cost-effectiveness of programs in use, the following recommendations are offered. First, research studies on the efficacy and cost-efficiency of collaborative care clearly support the need and role for a care manager who is responsible for patient education and involving the patient in the treatment process. After initial assessment, patients may be triaged to simple monitoring with education; discussion of guideline-based PCP-provided medication or therapy options; possible initiation of short-term, problemsolving, or cognitive-behavioral treatment; or close continual monitoring. The registry will permit close monitoring and a treatment-responsive approach to care. Patients who are not progressing may be moved to the next level of “stepped care.” The primary goal is patient progress for lower cost. Second, the program should adhere to PCMH standards, which require certain types of tasks to be completed with the majority of patients to ensure that care is patient-centered, coordinated, effective, and efficient (15). Finally, research is needed to assess and monitor the efficacy and cost-efficiency of Baylor Scott and White’s behavioral health integration program. Assessment needs to be completed with empirically based measures that are sensitive to change. Important questions include, for example, whether the program demonstrates greater effectiveness and efficiency than “previous” care. In sum, there is a need for research to assess and guide program changes in order to be more clinically and cost-effective. 1. 2. 3. 4. 5. 6. Peek CJ, The National Integration Academy Council. Lexicon for Behavioral Health and Primary Care Integration: Concepts and Definitions Developed by Expert Consensus [AHRQ Publication No. 13-IP001-EF]. Rockville, MD: Agency for Healthcare Research and Quality, 2013. Available at http://integrationacademy.ahrq.gov/sites/default/files/Lexicon.pdf. Kwan B, Nease D, Talen M, Valeras A, eds. Integrated Behavioral Health in Primary Care. New York, NY: Springer, 2013. Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelvemonth use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62(6):629–640. Kessler RC, Merikangas KR. The National Comorbidity Survey Replication (NCS-R): background and aims. Int J Methods Psychiatr Res 2004;13(2):60–68. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. 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Health and cost impact of comorbidity and integrated care. In Gaipa M, Pathy V, Sonn E, eds. Paying for Integrated Primary Care and Behavioral Health: Identifying Barriers and Developing Strategies to Overcome Them. Denver, CO: Center for Improving Value in Health Care, 2013. Fabius R, Maccracken L, Pritts J. Vocabulary of Healthcare Reform Glossary. Ann Arbor, MI: Truven Health Analytics, 2012. Available at http:// truvenhealth.com/portals/0/assets/VocabHealthReformGlossary.pdf. Druss BG, Mauer BJ. Health care reform and care at the behavioral health–primary care interface. Psychiatr Serv 2010;61(11):1087–1092. Doherty WJ. The why’s and levels of collaborative family healthcare. Fam Syst Med 1995;13(3–4):275–281. Mauer BJ. Behavioral Health/Primary Care Integration: Finance, Policy and Integration of Services. Rockville, MD: National Council for Community Behavioral Healthcare, 2013. Available at http://www.integration.samhsa. gov/BehavioralHealthandPrimaryCareIntegrationandthePCHM-2006. pdf. Bao Y, Casalino LP, Pincus HA. Behavioral health and health care reform models: patient-centered medical home, health home, and accountable care organization. J Behav Health Serv Res 2013;40(1):121–132. Collins C, Hewson DL, Munger R, Wade T. Evolving Models of Behavioral Health Integration in Primary Care. New York, NY: Milbank Memorial Fund, 2010. Available at http://dx.doi.org/10.1599/EvolvingCare2010. National Committee for Quality Assurance. Accreditation. Available at http://www.ncqa.org/Programs/Accreditation.aspx. Agency for Health Care Research and Quality. Defining the PCMH. Available at http://pcmh.ahrq.gov/page/defining-pcmh. Goroll AH, Bagley B, Harbrecht M, Kirschner N, Kenkeremath N. Payment Reform to Support High-Performing Practice: Report of the Payment Reform Task Force. Washington, DC: Patient-Centered Primary Care Collaborative, 2010. Available at https://www.pcpcc.org/sites/default/files/ media/paymentreformpub.pdf. Levey SM, Miller BF, Degruy FV III. Behavioral health integration: an essential element of population-based healthcare redesign. Transl Behav Med 2012;2(3):364–371. Foy R, Hempel S, Rubenstein L, Suttorp M, Seelig M, Shanman R, Shekelle PG. Meta-analysis: effect of interactive communication between collaborating primary care physicians and specialists. Ann Intern Med 2010;152(4):247–258. 20. Wagner EH, Austin BT, Von Korff M. Organizing care for patients with chronic illness. Milbank Q 1996;74(4):511–544. 21. Von Korff M, Glasgow RE, Sharpe M. Organising care for chronic illness. BMJ 2002;325(7355):92–94. 22. Katon W, Von Korff M, Lin E, Simon G. Rethinking practitioner roles in chronic illness: the specialist, primary care physician, and the practice nurse. Gen Hosp Psychiatry 2001;23(3):138–144. 23. Strosahl K. Mind and body primary mental healthcare: new model for integrated services. Behav Healthc Tomorrow 1996;5(5):93–96. 24. Strosahl K. The integration of primary care and behavioral health: type II changes in the era of managed care. In Cummings N, O’Donohue W, Hayes S, Follette V, eds. Integrated Behavioral Healthcare: Positioning Mental Health Practice with Medical/Surgical Practice. New York: Academic Press, 2001. 25. Woltmann E, Grogan-Kaylor A, Perron B, Georges H, Kilbourne AM, Bauer MS. Comparative effectiveness of collaborative chronic care models for mental health conditions across primary, specialty, and behavioral health care settings: systematic review and meta-analysis. Am J Psychiatry 2012;169(8):790–804. 26. Butler M, Kane RL, McAlpine D, Kathol R, Fu SS, Hagedorn H, Wilt T. Does integrated care improve treatment for depression? A systematic review. J Ambul Care Manage 2011;34(2):113–125. 27. Gilbody S, Bower P, Fletcher J, Richards D, Sutton AJ. Collaborative care for depression: a cumulative meta-analysis and review of longer-term outcomes. Arch Intern Med 2006;166(21):2314–2321. 28. Williams JW Jr, Gerrity M, Holsinger T, Dobscha S, Gaynes B, Dietrich A. Systematic review of multifaceted interventions to improve depression care. Gen Hosp Psychiatry 2007;29(2):91–116. 29. Gensichen J, Beyer M, Muth C, Gerlach FM, Von Korff M, Ormel J. Case management to improve major depression in primary health care: a systematic review. Psychol Med 2006;36(1):7–14. 30. van Steenbergen-Weijenburg KM, van der Feltz-Cornelis CM, Horn EK, van Marwijk HW, Beekman AT, Rutten FF, Hakkaart-van Roijen L. Cost-effectiveness of collaborative care for the treatment of major depressive disorder in primary care. A systematic review. BMC Health Serv Res 2010;10:19. 31. Basu R, Phillip KM, Stevens AB. Psychology in Primary Care: An Examination of Best Practices. Available at http://www.slideshare.net/hmorn/ psychology-in-primary-care-an-evaluation-of-best-practices-basu. 32. Advancing Integrative Mental Health Solutions. Patient-Centered Integrated Health Care Principles and Tasks. Seattle, WA: AIMS Center, 2012. Available at http://uwaims.org/files/AIMS_Principles_Checklist_final.pdf. 33. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16(9):606–613. 34. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006;166(10):1092–1097. Baylor University Medical Center Proceedings Volume 29, Number 2 Invited Commentary I f you turn over your commercial health insurance card, it is likely to state in small print that “for behavioral health coverage call 1-800-xxx.” In the US, behavioral health has for at least the last 20 years been largely carved out to behavioral managed care provider organizations. As a practicing family physician, I was often frustrated to direct my patient needing counseling or additional behavioral intervention to such obscure and nonintegrated resources. When the patient did access the resource, there was no exchange of data between me and the behavioralist—no reports, no dialogue, no discussion of comorbid conditions. Unless the patient came back to me and self-reported the behavioral therapy or psychotropic medications, there was a complete separation between his/her health care and behavioral care. But carved-out managed behavioral care is changing (1), and as Jolly et al indicate in their well-researched article (2), there is growing recognition of the value of integrating behavioral care with general health care. Virtually all physicians realize that psychological and behavioral factors are involved in clinical outcomes of both acute and chronic diseases (diabetes, asthma, heart failure), lifestylemodifiable conditions (obesity, smoking cessation), as well as primary behavioral illnesses (depression, anxiety). Extensive literature has clearly shown that inadequately addressed behavioral conditions add great cost to population health and fail to produce needed outcomes. Staggering sums of direct and indirect costs of mental illness have been described (3). Insel considered the entire field of mental health to be ripe for clinically effective and cost-effective intervention (3). As we described in our recently published Baylor Scott & White book, true accountable clinical integration can knit complex polymorbid patient care into improved outcomes, and simultaneously decrease costs (4). One key success factor will surely be reintegrating behavioral care into the general health care setting. The authors propose several levels of integration, which for most patients other than those with severe mental Proc (Bayl Univ Med Cent) 2016;29(2):137 illness are ideally delivered in coordination with primary care. The greatest barrier seems to be payment. Fee-for-service payment poorly supports the integrated care coordination and multilevel behavioral therapy structure that can produce best outcomes when integrated with the individual’s medical home. Primary care physicians are trained to be comprehensivists (5), yet that model of payment produces transactionalists who are better remunerated to treat episodes and to avoid probing into the behavioral components that underlie outcomes of illness and population health. Models such as the colocation and more ideally the disease management approach utilizing the structure of the patientcentered medical home are needed. Collecting outcome data for both quality and cost-effectiveness will be extremely important. Baylor Scott & White’s leadership in population health will support exploration and determination of more ideal approaches to behavioral care. —Carl Couch, MD Baylor Scott & White Health, Dallas, Texas E-mail: [email protected] 1. 2. 3. 4. 5. Dalzell M. Mental health: under ACA is it better to carve in or to carve out? Managed Care, December 2012. Available at http://www.managedcaremag.com/archives/1212/1212.mental_health_carve.html; accessed January 25, 2016. Jolly JB, Fluet NR, Reis MD, Stern CH, Thompson AW, Jolly GA. Review of behavioral health integration in primary care at Baylor Scott and White Healthcare, Central Region. Proc (Bayl Univ Med Cent) 2016;29(2):131–136. Insel T. The global cost of mental illness [Director’s blog entry, National Institute of Mental Health, September 28, 2011]. Available at http://www. nimh.nih.gov/about/director/2011/the-global-cost-of-mental-illness.shtml; accessed January 25, 2016. Couch C. Accountable: The Baylor Scott & White Quality Alliance Accountable Care Journey. Boca Raton, FL: CRC Press, 2016:19–21. Couch, Accountable: 116–118. 137 Medical and surgical care during the American Civil War, 1861–1865 Robert F. Reilly, MD This review describes medical and surgical care during the American Civil War. This era is often referred to in a negative way as the Middle Ages of medicine in the United States. Many misconceptions exist regarding the quality of care during the war. It is commonly believed that surgery was often done without anesthesia, that many unnecessary amputations were done, and that care was not state of the art for the times. None of these assertions is true. Physicians were practicing in an era before the germ theory of disease was established, before sterile technique and antisepsis were known, with very few effective medications, and often operating 48 to 72 hours with no sleep. Each side was woefully unprepared, in all aspects, for the extent of the war and misjudged the degree to which each would fight for their cause. Despite this, many medical advances and discoveries occurred as a result of the work of dedicated physicians on both sides of the conflict. Table 1. Medical and surgical advances during the war Type Medical Advances Use of quinine for the prevention of malaria Use of quarantine, which virtually eliminated yellow fever Successful treatment of hospital gangrene with bromine and isolation Development of an ambulance system for evacuation of the wounded Use of trains and boats to transport patients Establishment of large general hospitals Creation of specialty hospitals Surgical Safe use of anesthetics Performance of rudimentary neurosurgery Development of techniques for arterial ligation T he Civil War was fought in over 10,000 places and was the bloodiest war in the history of the United States. Two percent of the population at the time (approximately 620,000) died during the conflict (1). More Americans died in the Civil War than in all other wars combined. As hard as it is to believe, these numbers may actually be an underestimate of the death toll, given that much of the data regarding deaths of Confederate soldiers was destroyed when Richmond burned on April 2, 1865. More recent estimates based on comparative census data put the figure closer to 752,000 (2). Countless other soldiers were left disabled. The year after the war ended, the state of Mississippi spent 20% of its annual budget on artificial limbs for its veterans (3). Many misconceptions exist regarding medicine during the Civil War era, and this period is commonly referred to as the Middle Ages of American medicine. Medical care was heavily criticized in the press throughout the war. It was stated that surgery was often done without anesthesia, many unnecessary amputations were done, and that care was not state of the art for the times. None of these assertions is true. Actually, during the Civil War, there were many medical advances and discoveries (Table 1). Twice as many soldiers died of disease during the war than in combat (3). This was a marked improvement compared with the Mexican War (1846–1848), where there were 7 to 10 deaths 138 Performance of the first plastic surgery from disease for every death in battle. It was not until World War II that weapons killed more Americans than disease. The war left about 1 in 10 able-bodied Union soldiers dead or incapacitated, versus 1 in 4 in the Confederate Army (3). WHY DID SO MANY DIE? Soldiers died from two general causes: battlefield injuries and disease. Contributing factors to combat-related deaths were inexperienced surgeons; the lack of a coordinated system to get the injured off the battlefield quickly; wound infections, since sterile technique was not yet recognized as important; and battlefield tactics that did not keep pace with advances in weaponry. Contributing factors to disease-related deaths included poor sanitation and overcrowded camps; the ignoring of sanitation by line officers; inadequate pre-enlistment screening From the Division of Nephrology, Medical Service, Veterans Affairs North Texas Health Care System, Dallas, Texas, and the Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Robert F. Reilly, MD, Veterans Affairs North Texas Health Care System, Nephrology Section, MC 111G1, 4500 South Lancaster Road, Dallas, TX 75216-7167 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):138–142 of recruits; poor diet; lack of immunity to childhood diseases; and few specific treatments for disease. Army Regulation 1297 set out criteria for preinduction physical exams: In passing a recruit the medical officer is to examine him stripped; to see that he has free use of all his limbs; that his chest is ample; that his hearing, vision and speech are perfect; that he has no tumors, or ulcerated or extensively cicatrized legs; no rupture or chronic cutaneous affection; that he has not received any contusion, or wound of the head, that may impair his faculties; that he is not a drunkard; is not subject to convulsions; and has no infectious disorder; nor any other that may unfit him for military service (4). That was the requirement; however, the reality was that many exams early in the war were of poor quality. Governors needed to fill quotas, and examining physicians were paid per recruit. If you could walk, carry a gun, and had front teeth and a trigger finger, you could enlist. Front teeth were needed in order to tear open the cartridge containing gunpowder and the bullet. Dental care was poor in the 1860s, and this was a frequent cause of rejecting a recruit. It was the origin of the term 4F (missing 4 front teeth). The system was so poor that it is estimated that about 250 women served as soldiers during the war (5). The quality of physical exams improved with the Civil War Military Draft Act of 1863, when fines and prison sentences were put in place for physicians who were derelict in their duties, resulting in many more recruits being rejected from service. To better comprehend medical care delivered during this period, it is important to understand the medical infrastructure at the time. The first medical school was established in the United States in Philadelphia in 1765. There was no prerequisite preparation for admission, no entrance exam, and no state medical licensing boards. Medical school was 2 years in duration. In the first year, lectures were given in two 4-month semesters. The second year was a repetition of the first. Students did not have any clinical experience prior to graduation. Medical schools at the time were more like proprietary schools. There was a large entrance fee and as a result very few students ever failed (6). The Flexner Report was still 50 years in the future, which required 2 or more years of college and a 4-year curriculum. In 1862, there were only six colleges of pharmacy in the US. Most doctors prescribed, compounded, and dispensed their own medications. The germ theory of disease would not be established until 1870 and Koch’s postulates in 1890. Disease was thought to be a result of either direct or indirect inflammation (7). Indirect inflammation was thought to be caused by excess blood flow to a tissue, a theory promulgated by a prominent 18th-century physician, Benjamin Rush. This led to the concept that bloodletting might be beneficial. By the time of the Civil War, bloodletting had largely fallen out of fashion. Before the war, the United States had a peace time army of 16,000 soldiers. There were 113 doctors in the army. At the start of the war, 24 went south and 3 were dismissed for disloyalty (8). At the end of the war, there were over 12,000 doctors in the Union Army and over 3000 in the Confederate Army. Before April 2016 the war, the largest military hospital was at Fort Leavenworth, which had 40 beds. The only hospital in Washington, DC, before the war was a two-story six-room building used to isolate smallpox patients. The first major battle of the war fought at Bull Run in Manassas, Virginia, on July 21, 1861, illustrates how woefully unprepared the Union was from a medical standpoint at the start of the war. Fortunately, at Bull Run, casualty figures were not large compared with future battles (North, 481 killed, 1011 wounded; South, 387 killed, 1582 wounded) (9). Despite this, many problems were encountered. There was no military ambulance corps. Ambulances were driven by civilians who fled when the first shots were fired. If they left the ambulances behind, healthy soldiers stole them to flee back to Washington, DC. Not a single wounded soldier returned to Washington, DC, in an ambulance (10). Tragically, wounded soldiers remained on the battlefield for days, the first two spent in the rain. Incredibly, Surgeon General Finley did not order medical supplies until after the battle was over. ORGANIZATION OF BATTLEFIELD MEDICAL CARE How medical care was delivered on and off the battlefield changed during the war. Early on, stretcher bearers were members of the regimental band, and many fled when the battle started. Soldiers acting as stretcher bearers rarely returned to the front lines. As the war evolved, stretcher bearers became part of the medical corps. At the battle of Antietam, there were 71 Union field hospitals. As the war went on, these were consolidated. There were ambulances here that were used to bring the wounded to temporary battlefield hospitals, which were larger, often under tents, and out of artillery range. Later in the war, patients were transported to large general hospitals by train or ship in urban centers. These did not exist when the war began. There was no military ambulance corps in the Union Army until August of 1862. Until that time, civilians drove the ambulances. Initially the ambulance corps was under the Quartermaster corps, which meant that ambulances were often commandeered to deliver supplies and ammunition to the front. Jonathan Letterman set up his own ambulance corps in the East under General George McClellan. Medical directors chose all the soldiers for their services. Ambulances could not be used for other purposes, and only the ambulance corps was allowed to remove wounded from the battlefield. Letterman was responsible for a number of organizational improvements within the Army of the Potomac and was given a free hand by McClellan to implement them. Large general hospitals were established by September of 1862 (11). These were in large cities, and soldiers were transported there by train or ship. At the end of the war, there were about 400 hospitals with about 400,000 beds. There were 2 million admissions to these hospitals with an overall mortality of 8%. In the South, the largest general hospital, Chimborazo, was in Richmond, Virginia. It was built out of tobacco crates on 40 acres. It contained five separate hospitals, each made up of 30 buildings. There were 150 wards with 40 to 60 patients per ward. The census was as high as 4000. They treated about 76,000 patients with a 9% mortality (12). Medical and surgical care during the American Civil War, 1861–1865 139 Table 2. Types of weapons and number of wounds treated* Type of weapon Number % of recorded cases Conoidal (Minié) ball 108,049 76.0% Round or musket ball 16,742 12.0% Fragment of shell 12,520 9.0% Pistol or buckshot 3,008 2.0% Grape, canister, etc. 1,153 1.0% 359 0.3% 139 0.1% Solid shot Explosive musket ball Unknown missile 103,829 – *From Bollet AJ, Civil War Medicine: Challenges and Triumphs, Table 3.1, p. 84. Copyright 2002 by Galen Press, Ltd. All rights reserved. Reprinted with permission of Galen Press, Ltd., Tucson, AZ. COMBAT-RELATED INJURIES Before interpreting the data regarding combat-related injuries, it is important to recognize limitations in the reporting. In order to be reported, a soldier had to be either transported to or make it back to a field hospital, and this may have resulted in an underreporting of deaths from cannon fire. As shown in Table 2, most injuries resulted from the Minié ball invented by the French officer Claude-Etienne Minié in 1849. The Minié ball is a 0.58-caliber bullet that is slow moving and is made from soft lead. It flattens on impact and creates a wound that grows larger as the bullet moves deeper into tissues. It shatters bone above and below impact and usually does not exit. Because of its relatively slow muzzle velocity, it brought bits of clothing, skin, and bacteria into the wound. The majority of gunshot wounds occurred in the upper and lower extremities, but the fatality rate from these wounds was low (Table 3). Only 18% of wounds were to the abdomen, but these were more often fatal from intestinal perforation in the preantibiotic era. Commanders in the field were also slow to adjust their tactics in keeping with advances in weaponry. In the Revolutionary War era, smooth bore muskets were accurate only up to about 50 yards and were difficult to reload quickly, making rapid repetitive firing difficult. However, newer rifled muskets in use after the first year of the war were accurate up to 500 yards, Table 3. Distribution of wounds among those listed as killed in battle or admitted to hospitals* Site Killed in battle Wounded Trunk 51% 18% Head and neck 42% 11% Lower extremities 5% 35% Upper extremities 3% 36% *From Bollet AJ, Civil War Medicine: Challenges and Triumphs, Table 3.2, p. 88. Copyright 2002 by Galen Press, Ltd. All rights reserved. Reprinted with permission of Galen Press, Ltd., Tucson, AZ. Compiled from data in Medical and Surgical History, Surgical Section, vol. 3, p. 692. 140 and troops could easily fire them at a rate of 3 times a minute and sometimes faster. In the Revolutionary War, men could charge a fixed entrenched position with the possibility of success, whereas in the Civil War this same tactic was sure to fail. This was evidenced by the catastrophic failures of Picket’s charge at Gettysburg in the East, and Hood’s charge at Franklin, Tennessee, in the West. Six high-ranking Confederate generals were killed at the battle of Franklin, where over 1750 men died in a 5-hour period, with another 5500 wounded or captured (13). Perhaps the most famous example of a lack of appreciation for the improvement in weaponry by those in high command occurred at the Battle of Spotsylvania Courthouse. John Sedgwick was the highest ranking Union general killed in the war. While directing troop movements at Spotsylvania Courthouse, he scolded his men for dodging bullets from sharpshooters concealed in the distant woods. “I am ashamed of you dodging that way. They couldn’t hit an elephant at this distance” (14). Moments later a bullet fired from more than 500 yards struck him in the head, killing him instantly. SURGICAL PROCEDURES Three of every four surgical procedures performed during the war were amputations. Each amputation took about 2 to 10 minutes to complete. There were 175,000 extremity wounds to Union soldiers, and about 30,000 of these underwent amputation with a 26.3% mortality. The further from the torso the amputation was carried out, the greater the survival (Table 4). As the war went on, it was noticed that if amputation was done within 24 hours, mortality was lower than if performed Table 4. Deaths from amputation for the British Army in the Crimean War and the Confederate Army of Northern Virginia, 1863* Amputation site British Army in the Crimea: Deaths (%) Hip† 100% Confederate Army of Northern Virginia: Deaths (%) based on timing of amputation Under 48 hours After 48 hours 66% — Thigh† 56% 38% 73% Shoulder joint 33% 31% 71% Lower leg 30% 30% 49% Arm 26% 14% 37% Foot 23% 3% 12% 5% 12% 22% Forearm *From Bollet AJ, Civil War Medicine: Challenges and Triumphs, Table 5.5, p. 156. Copyright 2002 by Galen Press, Ltd. All rights reserved. Reprinted with permission of Galen Press, Ltd., Tucson, AZ. Crimean War data: Cantlie N, A History of the Army Medical Department, Vol. 2. Edinburgh: Churchill Livingston, 1973. Confederate Army of Northern Virginia data: Sorrel P, Gun-shot wounds—Army of Northern Virginia. Conf States Med Surg J 1864;1(10):153 and Chisolm JJ, A Manual of Military Surgery for Use of the Surgeons in the Confederate Army, 3rd ed., 1864; republished: Dayton, OH: Morningside Press, 1992, p. 361. †“Hip” meant an amputation high on the femur, near the hip joint. “Thigh” usually meant an amputation near the middle of the femur, although sometimes the location was specifically described as “upper third” or “lower third.” Baylor University Medical Center Proceedings Volume 29, Number 2 after more than 48 hours. Only about 1 in 15 Union physicians was allowed to amputate. Only the most senior and experienced surgeons performed amputations. These changes were put into effect because of the public perception that too many amputations were being performed. Amputations were not carried out using sterile technique, given that Lister’s classic paper on antisepsis did not appear until after the war in 1867 (15). Anesthesia was first introduced in the United States in the 1840s. During the Civil War, it was used in over 80,000 cases. Chloroform was preferred because it had a quicker onset of action, could be used in small volumes, and was nonflammable. During the war there were only 43 anesthesia-related deaths. Anesthesia was fairly light (stage II) leading to the misperception that it was not being used. Postoperative wound infections, when they developed, were a serious problem in the preantibiotic era. Laudable pus was thick and creamy (thought to be due to Staphylococcal infection) and associated with a better prognosis than malignant pus, which was thin and bloody (thought to be due to Streptococcal infection). Hospital gangrene was a peculiar type of necrotizing fasciitis that was first seen in the larger general hospitals. It was probably a result of a Streptococcal infection since nurses taking care of these patients occasionally developed erysipelas, but the exact organism remains unknown. A large percentage of patients with it died (45%) (8). Treatment was to dissect away dead tissue and inject the wound margins with bromine under anesthesia. The wound was then packed with a bromine-soaked dressing and the patients isolated in separate tents with a separate bandage supply. Nurses dressed these patients’ wounds last and washed their hands in chlorinated soda between patients. NONCOMBAT-RELATED DEATH AND ILLNESS A variety of factors contributed to a high rate of noncombatrelated illness, including overcrowded and filthy camps. Latrines were often not used or were drained into drinking water supplies or not covered daily. Food quality was poor from several standpoints. It was poorly stored, poorly cooked, and lacked enough vitamin C to prevent scurvy. The Army of the Potomac eventually added a number of rules: camps had be pitched on new ground and drained by ditches 18 inches deep, tents had to be struck twice a week to sun their floors, cooking had to be done only by company cooks, all refuse had to be burned or buried daily, soldiers had to bathe twice a week and change clothing at least once a week, and latrines had to be 8 feet deep and covered by 6 inches of dirt daily. There were few useful medications at the time, and about two thirds of all drugs were botanicals. In 1860 Oliver Wendell Holmes stated at the annual meeting of the Massachusetts Medical Society, “I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind,—and all the worse for the fishes” (16). Medications that were helpful included quinine for malaria, morphine, chloroform, and ether, as well as paregoric. Many others were harmful. Fowler’s solution was used to treat fevers and contained arsenic. Calomel (mercurous chloride) was used April 2016 for diarrhea. Mercury is excreted in high concentration in saliva. This led to excessive salivation, loss of teeth, and gangrene of the mouth and cheeks in some patients. There were several famous cases of calomel toxicity. One involved Louisa May Alcott, the author of Little Women, and the second Carleton Burgan. He was one of the first people to undergo plastic surgery in the United States. Dr. Gurdon Buck performed a series of five operations using skin from his forehead to rebuild his cheek and side of his nose. Physicians at the time had an extraordinary workload. The following was excerpted from a letter Dr. Daniel Holt wrote to his wife, Euphrasia: You cannot imagine the amount of labor I have to perform. As an instance of what almost daily occurs, I will give you an account of day-before-yesterday’s duty. At early dawn, while you, I hope, were quietly sleeping, I was up at Surgeon’s call and before breakfast prescribed for 86 patients at the door of my tent. After meal I visited the hospitals and a barn where our sick are lying, and dealt medicines and write prescriptions for one hundred more; in all visited and prescribed for, one hundred and eighty-six men. I had no dinner. At 4 o’clock this labor was completed and a cold bite was eaten. After this, in the rain, I started for Sharpsburg, four miles distant, for medical supplies (17). The soldier’s diet consisted of fresh or pickled beef. It was heavily salted and frequently needed to be soaked prior to cooking and was often spoiled. Salt-cured pork was often rancid and mostly fat. Coffee and hard tack were staples of the diet. Hard tack was a large biscuit that was often dipped in coffee to make it more palatable. There was very little in the way of fresh fruits or vegetables. Desiccated vegetables were often substituted, but the process led to the loss of biologic activity of vitamin C and unfortunately to many potentially preventable cases of scurvy. Scurvy had been known to result from lack of fresh foods and greens in the diet based on an observation made by Johann Bachstrom in 1734. The case fatality rate of many diseases worsened as the war went on, perhaps as a result of malnutrition and dietary deficiencies. The most common sickness among soldiers was gastrointestinal disorders. There were 711 cases per 1000 soldiers per year (18). The rate was higher in the West, where sanitation was worse. The mortality rate of acute diarrhea and dysentery was 3 to 17 per 1000 per year, while that of chronic diarrhea and dysentery was 126 to 162 per 1000 per year (19). There were no cholera outbreaks. Malaria was also frequent: 224 of every 1000 Union soldiers seeking medical treatment were diagnosed with the disease (20). It was particularly common in southern states such as Arkansas and Mississippi. William H. Van Buren discovered in 1861 that quinine could be used prophylactically to prevent malaria. Southern states did not have a large enough supply to use it in this way. Although the cause of malaria was unknown at the time, it was known that its incidence could be reduced by locating camps away from stagnant water, sleeping in closed rooms, and sleeping on elevated ground or upper floors of buildings. Medical and surgical care during the American Civil War, 1861–1865 141 Digging ditches or canals and sleeping outdoors were known to increase risk. Yellow fever was a major problem in the South, killing over 10,000 people (21). There were more outbreaks in Texas during the war than in any other state. Epidemics occurred in summer and autumn months. It was known as the stranger’s disease since it often affected newcomers to the area. Those that were infected and survived acquired lifelong immunity. Outbreaks would often occur after a ship arrived from a Caribbean port. It could be prevented by quarantining newly arrived ships in most cases. Attempts at its prevention by Benjamin Butler in New Orleans may have been the first example of a medical incentive plan. Butler, with urging from his superior officer Rear Admiral David Farragut, told Dr. Jonathan M. Foltz: “In this matter your orders shall be absolute. Order off all you may think proper [ships to quarantine], and so long as you keep yellow fever away from New Orleans your salary shall be one thousand dollars per month. When yellow fever appears in this city your pay shall cease.” Dr. Foltz quarantined all ships for 40 days 70 miles below the city, and this virtually eliminated yellow fever in New Orleans (22). There were over 75,000 cases of typhoid fever in the Union Army during the war. It resulted from exposure to fecally contaminated food and water, as well as flies. It killed 17% of affected soldiers in 1861 and 56% by 1865 (23). Typhoid fever was especially common in Washington, DC, where it claimed the life of Abraham Lincoln’s son Willie. Measles outbreaks were also common. There were at least 67,000 cases in the Union Army, with more than 4000 deaths. Of the 1200 soldiers in the 12th North Carolina, 800 developed measles during a 4-month period in 1861 after arriving in a West Virginia camp (24). Farmers made up 48% of the Union Army, and rural populations often had very little immunity to childhood diseases. Epidemics were common at the time of an influx of new troops, especially early in the war. The death rate was almost twice as high in African Americans as in whites, 11% versus 6%. A smallpox vaccine had been invented by Edward Jenner 70 years before the war, but a large percentage of the population was not vaccinated. The annual incidence of smallpox was 5.2 cases per 1000 in whites and 35.1 per 1000 in African Americans (25). Cases were quarantined. Because vaccine material was in short supply during the war, material was aspirated from the pustules of vaccinated people. This unfortunately resulted in the transmission of many cases of syphilis. 142 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Civil War Trust. Civil war casualties. Available at http://www.civilwar. org/education/civil-war-casualties.html. Hacker JD. A census-based count of the Civil War dead. Civ War Hist 2011;57:307–348. Foote S. The Civil War: A Narrative, vol. 3. New York: Random House, 1958:1040–1041. Grace W. The Army Surgeon’s Manual: For the Use of Medical Officers, Cadets, Chaplains, and Hospital Stewards: Containing the Regulations of the Medical Department, All General Orders from the War Department, and Circulars from the Surgeon-Generals Office from January 1st, 1861 to April 1st, 1865. New York: Bailliere Brothers, 1865. Available at http:archive. org/stream/62510310R.nlm.nih.gov/62510310R_djvu.txt. Blanton D, Cook LM. They Fought Like Demons: Women Soldiers in the Civil War. New York: Random House, 2002:7. Freeman FR. Gangrene and Glory: Medical Care During the American Civil War. Urbana, IL: University of Illinois Press, 1998:28–29. Wilbur CK. Civil War Medicine. Guilford, CT: Global Pequot Press, 1998:3. Mitchell SW. On the medical department in the Civil War. JAMA 1914;62:1445–1450. Rutkow IM. Bleeding Blue and Gray: Civil War Surgery and the Evolution of American Medicine. New York: Random House, 2005:21–28. Adams GW. Doctors in Blue: The Medical History of the Union Army in the Civil War. Baton Rouge, LA: Louisiana State University Press, 1952:26. Beller SP. Medical Practices in the Civil War. Charlotte, VT: OurStory, 1998:57–62. Bollet AJ. Civil War Medicine: Challenges and Triumphs. Tucson, AZ: Galen Press, 2002:223. McDonough JL, Connelly TL. Five Tragic Hours: The Battle of Franklin. Knoxville, TN: University of Tennessee Press, 1983:3. McMahon MT. The death of General John Sedgwick. Available at http:// www.civilwarhome.com/sedgwickdeath.htm Lister J. On the antiseptic principle in the practice of surgery. Br Med J 1867;2:246–248. Holmes OW. Currents and Counter-Currents in Medical Science with Other Addresses and Essays. An Address Delivered Before the Massachusetts Medical Society at the Annual Meeting, May 30, 1860. Cambridge, MA, University Press, 1861:39. Holt DM. A Surgeon’s Civil War: The Letters and Diary of Daniel M Holt, M.D. Kent, OH: Kent State University Press, 1994:34. Adams GW: 226. Bollet AJ: 284–285. Adams GW: 227. Bell AM. Mosquito Soldiers: Malaria, Yellow Fever and the Course of the American Civil War. Baton Rouge, LA: Louisiana State University Press, 2010:41–44. Foltz CS. Surgeon of the Seas: The Adventurous Life of Surgeon General Jonathan M. Foltz in the Days of the Wooden Ships. Indianapolis, IN: BobbsMerrill, 1931:253. Bollet AJ: 272–274. Buist JR. Some items of my medical and surgical experience in the Confederate Army. Southern Practitioner 1903;25:574–581. Bollet AJ: 290. Baylor University Medical Center Proceedings Volume 29, Number 2 Exercise-induced acute compartment syndrome in a young man, occurring after a short race Bibhusan Basnet, MD, Mousa Matar, MD, Siddharthan Vaitilingham, MD, Shyam Chalise, MD, Nkem Irooegbu, MD, MPH, and Jane Bang, MD We describe a case of exercise-induced acute compartment syndrome (ACS) in a 23-year-old man who presented to his primary care physician 48 hours after he attempted to run a 5K race. He noticed searing pain in his left leg after the first half mile but had no other symptoms. He was referred to the emergency department and diagnosed with ACS, and a fasciotomy was done. A presentation of limb pain that is out of proportion to a known or suspected injury should prompt consideration of ACS. Early recognition and surgical management are essential to achieving the best possible outcome. A cute compartment syndrome (ACS) is an emergency requiring immediate surgical decompression (1). Because it can progress rapidly, urgent diagnosis and treatment are necessary to prevent subsequent tissue ischemia and necrosis. The syndrome is typically a consequence of trauma (2). Chronic compartment syndrome is a common problem among athletes, while an acute presentation after exercise is rare (3–7). Our case demonstrates delayed presentation of exercise-induced ACS. CASE PRESENTATION A 23-year-old man with no significant medical history presented to his primary care physician with severe pain in the left lower leg. Two days earlier, he attempted to run a 5K race but had to stop after the first half mile. He complained of searing pain associated with numbness in his left lower extremity. He described some pain in his right leg as well, but of a less severe nature. He stopped running with the onset of pain and attempted to resume after stretching but was unable to do so due to his pain. Rest, warm and cold compresses, acetaminophen, and nonsteroidal antiinflammatory drugs did not alleviate the pain. On examination, he had significant swelling and tenderness in the anterior and lateral aspects of his left leg. Distal pulses were palpable in both legs. He was sent to the emergency department for further evaluation. Radiographs taken in the emergency department showed no bony injury or other abnormality. Doppler venous ultrasound revealed no evidence of deep vein thrombosis. His serum creatine kinase was 15,988 U/L (normal range, 30–233); aspartate aminotransferase, 348 U/L (normal range, 13–59); Proc (Bayl Univ Med Cent) 2016;29(2):143–144 alanine aminotransferase, 164 U/L (normal range, 7–53); and creatinine, 1.19 mg/dL (normal range, 0.7–1.3). Compartment pressures in the leg were obtained using a commercially available intracompartmental pressure monitor system and found to be 50 in the anterior and lateral compartment with a delta pressure of <30. A left anterior and lateral fasciotomy was performed within 6 hours of initial presentation. No muscle rupture was found intraoperatively. Aggressive intravenous fluid therapy was initiated to treat his rhabdomyolysis. Postoperatively, the patient's symptoms improved rapidly and his serum creatine kinase quickly improved. Two days later, secondary closure of the skin overlying the fascial releases was performed. The patient was discharged home after a 3-day stay. DISCUSSION ACS is a limb-threatening and occasionally life-threatening condition characterized by increased interstitial pressure within an osteofascial compartment, exceeding a critical point and resulting in reduced tissue perfusion and myoneural ischemia (8). ACS has been reported after heavy exercise, weight lifting, military training, and marathons (8–10). Our patient had leg pain after a very short run. The differential diagnosis included compartment syndrome, muscle group rupture, stress fracture, and ligament injury. We used a noninvasive test to determine compartment pressure. A recent metaanalysis suggested use of intracompartmental pressure measurement to confirm the diagnosis in patients in whom ACS is suspected (11). Magnetic resonance imaging of the leg would have helped with the preliminary differentials, but with an elevated delta pressure of the lower extremity, ACS was considered and emergency fasciotomy was done. ACS should be especially suspected in the presence of one or more of the following symptoms: pain out of proportion to a known or suspected injury (with or without pain on passive stretch), sensory changes, and a loss of motor power (12). In our patient, ACS is likely to have occurred secondary to exercise-induced rhabdomyolysis resulting in tissue edema From the Presence St. Joseph Hospital, Chicago, Illinois. Corresponding author: Bibhusan Basnet, MD, Department of Internal Medicine, Presence St. Joseph Hospital, 2900 N. Lakeshore Drive, Chicago, IL 60657 (e-mail: [email protected]). 143 with subsequent muscle injury and tissue damage. Some cases of exercise-induced compartment syndrome may evolve over a prolonged period of time, with slow but progressive muscle tissue injury. The fascia that delineates the compartments prevents expansion, causing a rise in the intracompartmental pressures (13).This can cause further elevations in creatine kinase, which can lead to severe acute kidney injury, electrolyte abnormalities, and permanent muscle damage. In our patient, the creatine kinase level was elevated to >10,000 without evidence of acute kidney injury or myoglobin in urine. Rhabdomyolysis must be considered in patients presenting with ACS so that early compartment release surgery and vigorous fluid resuscitation can be initiated. Elevated serum transaminases were also noted at presentation, a finding that improved in parallel to the creatine kinase levels. The patient had no high-risk behavior, and serology for hepatitis viruses was negative. Skeletal muscle injury is believed to be the most likely source of the elevated transaminases. ACS is diagnosed on the basis of clinical findings. In highrisk patients, surgical consultation, possibly including the measurement of compartment pressures, should not be delayed in order to obtain laboratory test results. A delta pressure (compartment pressure subtracted from diastolic blood pressure) of <30 mm Hg indicates a need for fasciotomy (14). Serial or continuous measurements are essential when patient risk or clinical suspicion is high. 1. 144 Finkelstein JA, Hunter GA, Hu RW. Lower limb compartment syndrome: course after delayed fasciotomy. J Trauma 1996;40(3):342–344. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Mubarak SJ, Hargens AR. Acute compartment syndromes. Surg Clin North Am 1983;63(3):539–565. Archbold HA, Wilson L, Barr RJ. Acute exertional compartment syndrome of the leg: consequences of a delay in diagnosis: a report of 2 cases. Clin J Sport Med 2004;14(2):98–100. Hill CE, Modi CS, Baraza N, Mosleh-Shirazi MS, Dhukaram V. Spontaneous compartment syndrome of the foot. J Bone Joint Surg Br 2011;93(9):1282–1284. Hope MJ, McQueen MM. Acute compartment syndrome in the absence of fracture. J Orthop Trauma 2004;18(4):220–224. Nau T, Menth-Chiari WA, Seitz H, Vécsei V. Acute compartment syndrome of the thigh associated with exercise. Am J Sports Med 2000;28(1):120–122. Sinikumpu JJ, Lepojärvi S, Serlo W, Orava S. Atraumatic compartment syndrome of the foot in a 15-year-old female. J Foot Ankle Surg 2013;52(1):72–75. Waterman BR, Liu J, Newcomb R, Schoenfeld AJ, Orr JD, Belmont PJ. Risk factors for chronic exertional compartment syndrome in a physically active military population. Am J Sports Med 2013;41(11):2545–2549. Blasier D, Barry RJ, Weaver T. Forced march-induced peroneal compartment syndrome. A report of two cases. Clin Orthop Relat Res 1992;(284):189–192. Miozzari HH, Gerard R, Stern R, Toman J, Assal M. Acute exertional medial compartment syndrome of the foot in a high-level athlete: a case report. Am J Sports Med 2008;36(5):983–986. Shadgan B, Menon M, O’Brien PJ, Reid WD. Diagnostic techniques in acute compartment syndrome of the leg. J Orthop Trauma 2008;22(8):581–587. Shadgan B, Menon M, Sanders D, Berry G, Martin Jr C, Duffy P, Stephen D, O’Brien PJ. Current thinking about acute compartment syndrome of the lower extremity. Can J Surg 2010;53(5):329–334. King TW, Lerman OZ, Carter JJ, Warren SM. Exertional compartment syndrome of the thigh: a rare diagnosis and literature review. J Emerg Med 2010;39(2):e93–e99. McQueen MM, Gaston P. Acute compartment syndrome. Who is at risk? J Bone Joint Surg Br 2000;82(2):200–203. Baylor University Medical Center Proceedings Volume 29, Number 2 Table tipping and a near-miss fall after unlocking a surgical table holding a morbidly obese patient Robert T. Booth, MD, Russell K. McAllister, MD, and Timothy M. Bittenbinder, MD Presented is a case report of a morbidly obese patient who experienced a near-miss fall in the operating room due to several factors. We present the importance of recognizing the change in fulcrum location on a Steris 4085 operating table when the bed is in the unlocked versus the locked position. This small change, in the presence of morbid obesity and reverse orientation of the table, can lead to an unsafe situation in which the patient's weight can cause the table to tip. We present potential ways to avoid this complication. T he prevalence of obesity for adults in the United States more than doubled from 1960 to 2010. In addition, the prevalence of those qualifying as extremely obese increased sixfold in that same time period (1). Not only have we experienced a significant increase in patient weight, but caring for an increasingly obese population has led to a worsening of the economic burden. The medical cost of obesity nearly doubled over the 10-year period from 1998 to 2008, rising from $78.5 billion to $147 billion (2). Obese patients are not only susceptible to the physiologic and pathological risks associated with their body habitus, but approach the limits of the safe use of operating room (OR) equipment, further increasing their risk of morbidity and mortality in the operative suite. We present a case of a near-miss fall of a morbidly obese patient occurring when the OR table tipped after unlocking stabilizing pistons in order to move the table position. CASE DESCRIPTION A 41-year-old man with chronic sinusitis presented to the operative suite for endoscopic nasal surgery. He was 6′3″ (1.9 m) and 417 lbs (189 kg), with a body mass index (BMI) of 52.4, placing him in the superobese category of obesity (BMI >49.9). The patient was transferred to the Steris 4085 (Steris Corporation, Mentor, OH) OR table, with the OR table in reverse orientation and the full articulation slide of the tabletop away from the base toward the direction of the patient’s head (Figure 1). General anesthesia was induced, and the patient was endotracheally intubated uneventfully. The surgeon then requested that the OR table be turned 90 degrees to the patient’s left to improve access to the operative site and enable use of image guidance equipment. The circuit was disconnected from the Proc (Bayl Univ Med Cent) 2016;29(2):145–146 Figure 1. Steris 4085 operating room table in the reverse position. endotracheal tube, and the operating table was unlocked. The table began to abruptly tip downward with the patient's head rapidly approaching the floor in a Trendelenburg-like trajectory. Fortunately, the resident was at the head of the table and was able to slow the table from tilting further, while another person provided counterweight at the foot of the table to level and stabilize it. The table was then turned with an adjustable height stool under the head of the table and additional staff placing counterweight at the foot of the table to maintain a level position. Once the OR table was relocked, the stool was kept in place to safeguard against a subsequent tipping. The patient did not experience any adverse effects from the event and the decision was made to proceed with the surgery as planned. The rest of the case was completed without incident or complication. DISCUSSION Unfortunately, it isn’t difficult to find examples in the news of patient falls in the OR leading to tragic, and sometimes lethal, results (3, 4). Often, these falls are a result of lack of attentiveness by OR staff during at-risk times, such as after the security belt has been removed during emergence from anesthesia From the Department of Anesthesiology, Baylor Scott & White Health, Temple, Texas. Corresponding author: Russell K. McAllister, MD, Department of Anesthesiology, Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508 (e-mail: [email protected]). 145 (4). Additionally, a case similar to ours described a morbidly obese patient presenting for nasal surgery, who nearly fell from a tipping OR table after it was unlocked (5). An inquiry of the Anesthesia Closed Claims Project Database since the year 2000 revealed 21 claims in which a patient fell from the OR or procedure table. Fifteen of the scenarios were related to general anesthesia; four involved scenarios of regional anesthesia, and two, monitored anesthesia care (2). Most of the falls resulted in temporary and nondisabling injuries, but two resulted in permanent and severe injury. Among the 21 patient falls, half resulted in payment to the plaintiff ranging from $18,000 to $925,000, with a median payment of $49,000 (personal correspondence, Karen Posner, PhD, December 10, 2015). The Steris 4085 OR table allows the tabletop to slide away from the base, thereby freeing space underneath the patient for radiologic imaging equipment. Examination of the product specification sticker on the OR table regarding weight limits by table position could easily lull a provider into a false sense of security. The stickers reveal a diagram of the OR table in normal orientation with the slide mechanism fully articulated toward the head with a stated weight limit of 600 lbs. Further investigation of the manufacturer’s sales literature reveals that the weight parameters are accurate in the normal orientation, without specifying limits in the reverse orientation position (6). It is important to note the manufacturer’s warning to not release the floor locks while the patient is on the table. One factor behind this warning is the shifting of the fulcrum once the leveling floor lock pistons are raised to lower the OR table onto the wheels in order to mobilize the table. In the case of the Steris 4085, unlocking the OR table shifts the fulcrum 4.75 inches toward the feet, effectively shortening the base when the floor lock pistons are withdrawn (Figure 2). Education of OR personnel and vigilance by all OR staff can decrease the risk of an OR table-tipping injury. OR personnel should be aware of 146 Figure 2. Close-up view of the base of the Steris 4085. Note the distance between the wheels and the floor locking pistons and how it will affect the fulcrum when the bed is unlocked and the wheels are engaged with the floor. the potential dangers, and care should be taken to have needed personnel readily available if the table needs to be unlocked when a high-risk situation exists. 1. 2. 3. 4. 5. 6. Fryar CD, Carroll MD, Ogden CL. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960–1962 through 2009–2010. NCHS Health E-Stat. Available at http://www.cdc. gov/nchs/data/hestat/obesity_adult_09_10/obesity_adult_09_10.htm; accessed January 2, 2016. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Aff (Millwood) 2009;28(5):w822–w831. Suit TD. Woman hurt after falling off operating table. Stamford Advocate, May 22, 2012. Irons ME. Family, hospital settle after mother’s fatal fall in operating room. Boston Globe, October 14, 2009. Razavian S, Thurn J. On the tipping point of disaster: operating room surgical table with obese patients. APSF Newsletter, 2013;28 23–24. Steris Corporation Steris 4085 Surgical Table: A Smart Investment in Surgical Versatility. Mentor, OH: Steris, 2010. Available at http://webapi. steris.com/api/salesconnection/getdocumentbynumber?id=M3309EN& fileName=STERIS%204085%20SURGICAL%20TABLE:%20A%20 SMART%20INVESTMENT%20IN%20SURGICAL%20VERSATILITY. pdf; accessed January 2, 2016. Baylor University Medical Center Proceedings Volume 29, Number 2 Use of ultrasound guidance to remove entrapped stimulating popliteal catheters Russell K. McAllister, MD, James B. Hulin, DO, and Don J. Daniels, MD Peripheral nerve catheters are beneficial for continuous pain relief following surgery or trauma to an extremity. However, spring-loaded peripheral nerve catheters can become uncoiled and entrapped, resulting in difficulty in catheter removal. We present two cases where ultrasound guidance provided significant assistance in the safe removal of entrapped peripheral nerve catheters without neurologic sequelae. One of the catheters was adhered to nearby tissue, and one had become uncoiled and anchored in place by the distal tip. Guidelines for the safe management of entrapped catheters are suggested, including the use of saline injections through the catheter under ultrasound guidance to assist in the evaluation and removal of the catheters. Figure 1. Distal tip configuration of Arrow StimuCath. P eripheral nerve catheters are typically easily removed when the need for nerve blockade has ended. However, spring-loaded peripheral nerve catheters are at risk for uncoiling with entrapment of the catheter and wire in nearby structures. We report two cases of entrapped catheters following popliteal nerve block utilizing a 20-gauge catheter (Arrow StimuCath, Teleflex Medical Germany, Kernen, Germany) with a coiled omni-port end with a hemispherical distal tip (Figure 1). Identification and removal of the catheters was facilitated by the use of ultrasound. We report on the assessment and management of entrapped continuous peripheral nerve catheters. CASE 1 A 24-year-old American Society of Anesthesiologists class I woman underwent a left tibiotalar arthrodesis under general anesthesia. The plan for postoperative analgesia included the placement of a continuous popliteal nerve block. In the postanesthesia care unit, a continuous popliteal catheter was placed utilizing a lateral approach and ultrasound guidance. A 17-gauge insulated needle was used to place a 19-gauge 60 cm StimuCath continuous nerve block catheter after obtaining nerve stimulation with dorsiflexion at 0.55 milliamperes. The catheter was secured with tape and attached to an elastomeric pump prior to discharging the patient home. On postoperative day 3, the patient was unable to remove the catheter and presented for further evaluation. She denied any radicular pain. The catheter insertion site was clean and dry, and the Proc (Bayl Univ Med Cent) 2016;29(2):147–149 patient had a normal lower extremity neurologic examination. An attempt to withdraw the catheter under ultrasound visualization demonstrated lateral movement of the common peroneal and tibial nerves. Injection of 10 mL of preservativefree normal saline through the catheter failed to relieve the apparent adhesion. Lateral and anteroposterior x-rays of the knee did not reveal a knot or kinking of the catheter (Figure 2). A second attempt of injecting 20 mL of saline through the catheter under ultrasound guidance successfully loosened the catheter, resulting in its easy removal. CASE 2 A 28-year-old man sustained a traumatic injury to his right foot, requiring multiple surgeries including external fixation and washouts. Ultimately, the patient underwent a transmetatarsal amputation and opted for a continuous popliteal nerve block for postoperative analgesia. In the preoperative holding area, a popliteal nerve block was placed utilizing a posterior approach and ultrasound guidance. A From Baylor Scott & White Health and Texas A&M College of Medicine, Temple, Texas (McAllister, Daniels); and Integris Southwest Hospital, Oklahoma City, Oklahoma (Hulin). Corresponding author: Russell K. McAllister, MD, Assistant Dean, Quality and Patient Safety and Residency Program Director, Department of Anesthesiology, Baylor Scott & White Health, 2401 S. 31st Street, Temple, TX 76508 (e-mail: [email protected]). 147 Figure 2. Lateral knee radiograph revealing no obvious kinking or knotting of the catheter. 17-gauge insulated needle was used to place a 19-gauge 60 cm StimuCath continuous nerve block catheter after obtaining nerve stimulation with dorsiflexion at 0.50 milliamperes. The catheter was secured and connected to an elastomeric pump prior to discharge. On postoperative day 5, the patient was unable to remove the catheter and returned for further evaluation. The catheter site was clean and dry with minimal erythema, and the right lower extremity neurologic exam revealed no deficits in sensory or motor function. Ultrasound examination of the popliteal fossa did not reveal movement of the neurovascular structures when traction was placed on the catheter. However, traction on the catheter did produce tenting under the skin at the location of the distal tip of the catheter. This area was prepped and draped in sterile fashion, and the skin was anesthetized with 3 mL of 1% lidocaine. Blunt dissection exposed the metallic tip of the catheter, which was acting as an anchor. Traction on the catheter had produced uncoiling of the distal end. The hemispherical tip was cut from the end of the catheter and removed through the incision site. Once the anchoring tip was removed, the remaining portion of the catheter was easily removed through the initial insertion site (Figure 3). Figure 3. StimuCath catheter following removal in two parts reveals the uncoiled distal end. 148 DISCUSSION Complications from peripheral nerve catheters are rare but important (1–3). These two cases demonstrate potential problems that may be encountered when using the Arrow StimuCath system. Both cases resulted in entrapped peripheral nerve catheters. Wiesmann et al reported two similar cases of entrapped stimulating catheters (4). In one of the cases, when the catheter was unable to be removed with forceful traction, a surgical removal was planned under general anesthesia. Once muscle relaxation occurred, additional forceful traction on the catheter allowed it to be removed intact without neurologic sequelae. In the second case, additional force was used and the catheter was removed intact. In both cases, the coiled ends of each catheter had become uncoiled, as described in our patients. To aid in the removal of entrapped peripheral nerve catheters, we recommend the following approach: • Prior to attempting to remove the catheter, ensure full sensation has returned to the limb. • Use ultrasound to identify the neurovascular bundle. If traction on the catheter produces displacement of the neurovascular structures, withhold traction. • Inject preservative-free normal saline through the catheter (hydrodissection) to loosen adhesions and reattempt removal of the catheter under ultrasound visualization. • Inject contrast media through the catheter to rule out catheter kinking or coiling. • Contact a surgeon for evaluation and possible surgical removal. The proposed mechanism for catheter entrapment in the first case was adhesions. Buckenmaier et al found that the manufactured design of a continuous peripheral nerve block tip can contribute to adhesions in a rat model (5). They postulated that removal of an adhered catheter could potentially cause neural damage or injury to adjacent structures, including blood vessels. The proposed mechanism of entrapment in the second case was uncoiling of the spring-wound distal tip. Damage to the spring-wound catheter tip during placement, most commonly by shearing forces if the catheter is withdrawn back into the needle, may increase the risk of uncoiling during removal, resulting in damage to nearby structures. Ultrasound was used to evaluate the neurovascular bundle and revealed no evidence of movement of the nerve complex when traction was placed on the catheter. However, skin tenting by the uncoiled wire catheter tip was noted within the tunnel site when traction on the catheter was released. We propose that ultrasound evaluation may offer advantages over plain x-ray in management of entrapped catheters. Ultrasound allows visualization of the neurovascular structures, whereas x-rays do not. In addition, the stimulating catheters with the coil tips are visible with ultrasound, allowing identification of catheter tip location. Most importantly, ultrasound visualization of these structures and their relationship to the catheter tip during gentle traction and “hydrodissection” is not only diagnostic, but in some cases may be therapeutic in relieving adhesions. A similar technique has also been used to facilitate removal of a knotted femoral nerve catheter that had become Baylor University Medical Center Proceedings Volume 29, Number 2 entrapped, theoretically by expanding the area just below the fascia iliaca with 10 mL of saline. This increased area allowed for easy removal of the knotted catheter (6). In addition, the portability and simplicity of most ultrasound machines allows for additional flexibility. Ultrasound evaluation would also offer a more feasible solution in patients with an allergy to intravenous contrast agents. There have been no case reports to date revealing damage to neurovascular structures upon removal of a continuous peripheral nerve catheter. However, the potential exists for damage, and further study of the diagnosis and management of these types of problems would be beneficial. 1. Borgeat A, Blumenthal S, Lambert M, Theodorou P, Vienne P. The feasibility and complications of the continuous popliteal nerve block: a 1001-case survey. Anesth Analg 2006;103(1):229–233. April 2016 2. 3. 4. 5. 6. De Tran QH, De La Cuadra-Fontaine JC, Chan SY, Kovarik G, Asenjo JF, Finlayson R. Coiling of stimulating perineural catheters. Anesthesiology 2007;106(1):189–190. Cuvillon P, Ripart J, Lalourcey L, Veyrat E, L’Hermite J, Boisson C, Thouabtia E, Jacques Eledjam J. The continuous femoral nerve block catheter for postoperative analgesia: bacterial colonization, infectious rate and adverse effects. Anesth Analg 2001;93(4):1045–1049. Wiesmann T, Wallot P, Nentwig L, Beermann AV, Wulf H, Zoremba M, Al-Dahna T, Eschbach D, Steinfeldt T. Separation of stimulating catheters for continuous peripheral regional anesthesia during their removal—two case reports and a critical appraisal of the use of steel-coil containing stimulating catheters. Local Reg Anesth 2015;8 15–19. Buckenmaier CCIII, Auton AA, Flournoy WS. Continuous peripheral nerve block catheter tip adhesion in a rat model. Acta Anaesthesiol Scand 2006;50(6):694–698. Kendall MC, Nader A, Maniker RB, McCarthy RJ. Removal of a knotted stimulating femoral nerve catheter using a saline bolus injection. Local Reg Anesth 2010;3 31–34. Use of ultrasound guidance to remove entrapped stimulating popliteal catheters 149 Baclofen-responsive hiccups after esophageal stenting for malignancy-related dysphagia Vishal Sharma, DM, Arka De, MD, Sandeep Lamoria, MD, and Brinder Mohan Singh Lamba, MD Hiccups can have multiple causes, including esophageal lesions. Hiccups after insertion of self-expanding metallic stents have been reported occasionally following stenting for lesions of the gastroesophageal junction. We report a patient who developed hiccups after insertion of a stent for squamous cell carcinoma of the proximal esophagus. The hiccups responded only to the initiation of baclofen therapy. H iccups or singultus refers to the sound produced by abrupt closure of the glottis after repeated involuntary, spastic contractions of the respiratory muscles. Hiccups are usually self-limited. The treatment options for persistent or intractable hiccups are both pharmacological and nonpharmacological. Drugs reported to be useful include baclofen, gabapentin, pregabalin, metoclopramide, domperidone, chlorpromazine, nifedipine, amitriptyline, valproate, carbamazepine, and phenytoin (1). Nonpharmacologic treatments include hypnosis, acupuncture, nerve stimulation, and nerve blocks for vagus and phrenic nerves (1). Hiccups related to placement of self-expanding metallic stent (SEMS) have been reported rarely in the literature (2, 3). We report a case of persistent hiccups following placement of an esophageal stent which responded to baclofen. CASE REPORT A 75-year-old man presented with progressively increasing dysphagia to solid foods and weight loss for 3 months. Upper endoscopy showed an ulceroproliferative mass about 20 cm from the incisors, and the endoscope could not be negotiated beyond the lesion. Biopsy revealed squamous cell carcinoma. Chest computed tomography showed asymmetrical mural thickening of the middle esophagus and loss of fat planes, with the aorta and lesion abutting the carina. Using an ultrathin endoscope, the lesion length was assessed and an Ultraflex partially covered stent (15 cm) was placed across the lesion for palliation of dysphagia. The immediate postendoscopic period was unremarkable. However, 12 hours after stent placement, the patient developed hiccups that did not respond to physical maneuvers, proton pump inhibitors, or chlorpromazine. His metabolic parameters, including liver and kidney function tests, creatinine, and serum electrolytes, were normal. Chest radiographs confirmed the proper positioning of the stent and the absence of pneumothorax or gas under the diaphragm. Repeat endoscopy showed the stent in place and above the gastroesophageal junction. The patient was started on baclofen 5 mg three times daily 150 with good clinical response. Baclofen was given for 3 days and then was stopped, with no recurrence of hiccups. DISCUSSION There are several known causes of persistent hiccups, including lesions of the reflex arc, uremia, bronchoscopy, central line placement, and cardiac pacing, as well as gastroesophageal reflux and esophageal obstruction or distension (1, 4–6). Expansion of SEMS may lead to hiccups by producing esophageal distension, or, in cases in which the gastroesophageal junction is stented, through reflux or diaphragmatic irritation (1–3). Chlorpromazine is the only agent approved by the US Food and Drug Administration for the treatment of persistent hiccups (7). Although not approved specifically for this indication, baclofen, a centrally acting GABAB agonist, has been found to be effective in persistent hiccups and may be considered in patients not responding to chlorpromazine (8, 9). This is the first report of a case in which the esophageal stent produced baclofen-responsive hiccups, despite the stent not crossing the gastroesophageal junction. We suggest that stent-related hiccups may be treated with baclofen if they fail to respond to physical maneuvers and chlorpromazine. 1. 2. 3. 4. 5. 6. 7. 8. 9. Steger M, Schneemann M, Fox M. The pathogenesis and pharmacological treatment of hiccups. Aliment Pharmacol Ther 2015;42(9):1037–1050. Katsinelos P, Pilpilidis J, Xiarchos P, Christodoulou K, Papagianis A, Amperiadis P, Eugenidis N. Baclofen therapy for intractable hiccups induced by Ultraflex esophageal endoprosthesis. Am J Gastroenterol 2000;95(10):2986–2987. Turkyilmaz A, Eroglu A. Use of baclofen in the treatment of esophageal stent-related hiccups. Ann Thorac Surg 2008;85(1):328–330. Fisher MJ, Mittal RK. Hiccups and gastroesophageal reflux: cause and effect? Dig Dis Sci 1989;34(8):1277–1280. Kaufmann HJ. Hiccups: an occasional sign of esophageal obstruction. Gastroenterology 1982;82(6):1443–1445. Fass R, Higa L, Kodner A, Mayer EA. Stimulus and site specific induction of hiccups in the oesophagus of normal subjects. Gut 1997;41(5):590–593. Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil 2012;18(2):123–130. Walker P, Watanabe S, Bruera E. Baclofen, a treatment for chronic hiccup. J Pain Symptom Manage 1998;16(2):125–132. Ramírez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. Am J Gastroenterol 1992;87(12):1789–1791. From the Department of Gastroenterology, PGIMER and DR RML Hospital, Delhi, India. Corresponding author: Vishal Sharma, DM, Department of Gastroenterology, PGIMER and Dr RML Hospital, Delhi, India (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):150 Specificity of testing in a cardiac rehabilitation setting resulting in a patient’s return to high-intensity outdoor activity following aortic dissection repair Sparky Bartee, BS, Sanjay Shrestha, BS, Beatriz Ramos, BS, Tim Bilbrey, MBA, Pasquale Carbone, MS, Jeffrey M. Schussler, MD, Rick Deutsch, MS, MBA, and Jenny Adams, PhD A 66-year-old man who had undergone aortic dissection repair a year earlier sought to assess the feasibility of returning to the high-intensity outdoor activities he had long enjoyed. In response to his inquiry, the cardiac rehabilitation staff at Baylor Hamilton Heart and Vascular Hospital designed a comprehensive testing plan that simulated the specific movements and anticipated cardiac requirements associated with his goal activities. The activities included 1) lifting and manipulating a 50-pound suitcase, 2) hiking to the top of Half Dome in California’s Yosemite National Park, and 3) scuba diving. To illustrate our approach, we describe some of the tests that were performed and report the results. After analyzing the detailed physiological data collected during testing, we provided the patient with an exercise prescription and specific guidelines that he could use to gauge his level of physical exertion during his outdoor adventures. Within approximately 6 months of testing, he successfully performed the goal activities without adverse symptoms. A year after undergoing successful repair of an acute ascending aortic dissection, a 66-year-old man asked his physician about returning to the high-intensity outdoor activities he had long enjoyed prior to the surgery. The patient, who wanted information about the feasibility of his goals, sought out the testing laboratory within the Cardiac Rehabilitation Department at Baylor Hamilton Heart and Vascular Hospital. CASE REPORT The patient had a history of hypertension, but he never used tobacco, alcohol, or drugs and had no family history of aortic dissection. He presented to his physician at the age of 64 with a type A dissection (involving the innominate and left common carotid arteries) in the setting of ascending aortic aneurysm. Relevant medications upon arrival at our testing laboratory 2 years later included metoprolol, hydrochlorothiazide, aspirin, and lisinopril. His body mass index was 23.8 kg/m2, and his waist circumference was 35.5 inches. His preoperative ascending aorta measured 5.1 cm, and his postoperative aortic root diameter measured 3.9 cm (normal range, 2.5–4.0 cm). The patient posed a unique testing challenge for the staff because he had three very different activity goals: 1) lifting and manipulating a 50-pound suitcase, 2) hiking to the top of Half Proc (Bayl Univ Med Cent) 2016;29(2):151–153 Dome in California’s Yosemite National Park, and 3) scuba diving. Utilizing our facility’s specialized equipment, we designed and implemented a comprehensive testing plan that would simulate the anticipated movements, force, and cardiac requirements associated with these activities, enabling us to collect detailed physiologic data. To illustrate our approach, we describe some of the tests that were performed and the associated results. In keeping with the standard protocol of our cardiac rehabilitation facility, we used telemetry (TeleRehab VersaCare, ScottCare Corp, Cleveland, OH) to monitor the patient’s electrocardiogram. His blood pressure was recorded at the beginning and end of each session (before warm-up walking and after cooldown walking) and at peak exertion during the individual tests. Testing was symptom limited, meaning that no specific blood pressure or heart rate limits were used to restrict the patient’s exercise intensity. We monitored him for elevated rate-pressure product (systolic blood pressure × heart rate ≥ 36,000) (1), angina pectoris, dizziness, pain, arrhythmias, and shortness of breath. Goal 1: Lifting and manipulating a 50-pound suitcase. To simulate lifting a suitcase and raising it overhead, the patient performed a deadlift and military press maneuver using a static force gauge that was attached to a multidimensional strength assessment system (IsoTrack Pro, JTECH Medical, Midvale, UT) that measures static lifting, pulling, and pushing strength. To simulate manipulation of the suitcase, the patient performed the upright row, the bicep curl, and the military press while wearing a noninvasive, continuous blood pressure From the Department of Kinesiology, University of Texas at Arlington, Arlington, Texas (Bartee, Shrestha, Ramos); the Cardiac Rehabilitation Department, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas (Bilbrey, Carbone, Schussler, Adams); and the Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center at Dallas and Baylor Hamilton Heart and Vascular Hospital, and Texas A&M College of Medicine, Dallas, Texas (Schussler). Mr. Deutsch is a consultant in San Jose, California. Mr. Shrestha is now with the Carter Rehabilitation and Fitness Center at Baylor All Saints Medical Center, Fort Worth, Texas; Mr. Bartee is with the Food and Nutritional Supplement Division of the US Food and Drug Administration, San Diego, California; and Ms. Ramos is with the Cancer Foundation for Life, Dallas, Texas. Corresponding author: Jenny Adams, PhD, Cardiac Rehabilitation Department, Baylor Heart and Vascular Hospital, 411 N. Washington, Suite 3100, Dallas, TX 75246 (e-mail: [email protected]). 151 a b c Figure 1. Half Dome hiking tests and outcome: (a) a 45-degree cable pull to measure strength; (b) the stair-climber metabolic stress test, designed to simulate the cable ascent to the summit of Half Dome in Yosemite National Park, California; and (c) the patient nearing the summit approximately 6 months after testing. monitor (Finometer MIDI, Finapres Medical Systems B.V., Amsterdam, the Netherlands). Goal 2: Hiking to the top of Half Dome (Figure 1). The hike is 15 miles round trip with an elevation gain of 4737 feet; the summit is 8842 feet above sea level. The final 400 vertical feet to the summit is a 600-foot stretch of smooth granite that has a 45-degree incline and features waist-high cables that hikers pull to move vertically. To confirm the patient’s physiologic response to simulated hiking, we had him complete a peak treadmill stress test while wearing a calibrated desktop metabolic system (Fitmate MED, Cosmed USA Inc., Chicago, IL) that directly measured his oxygen consumption. An additional metabolic stress test was needed to simulate the incline, duration, and difficulty of the cable ascent to the summit of Half Dome. We used a stairclimbing machine (StairMaster StepMill SM916, Nautilus Inc., Vancouver, WA) that had a built-in 45-degree slope and placed it directly in front of resistance training equipment that had a cable pull-down station. This set-up enabled the patient to perform one-hand cable pulls while performing vertical stepping movements. To ensure that the test accurately covered the goal distance of 400 vertical feet, we measured the height of each step a and calculated the step rate accordingly. The protocol involved 2-minute stages that increased incrementally. The initial setting was 24 steps per minute, and the patient ended the test at 71 steps per minute. He achieved 9 metabolic equivalents (METs, defined as the energy cost of exercise, where 1 MET = 3.4 mL O2 per kg of body weight per minute). Goal 3: Scuba diving (Figure 2). We designed a series of maneuvers to simulate a boat dive (i.e., walking to exit the boat, entering the water, diving, and climbing back into the boat). While wearing diving gear (a 35-pound tank and a 20-pound weight belt), the patient completed five repetitions of the following sequence: walking 15 feet toward a swimming pool, stepping off to enter the water, swimming 164 feet, and climbing a ladder to exit the pool. We measured his blood pressure, heart rate, and breathing frequency immediately after each sequence. Because systolic and diastolic pressures return to normal approximately 10 seconds after the last repetition of a resistance training set (2), we placed the blood pressure cuff on the patient’s arm immediately after he exited the pool. Peak heart rate, systolic blood pressure, and rate-pressure product data obtained during tests corresponding to each of the patient’s goals are shown in the Table. The peak breathing b c Figure 2. Scuba diving tests and outcome: (a) exiting the pool after a simulated diving sequence; (b) staff members measuring vital signs; and (c) the patient diving in Cozumel, Mexico, approximately 5 months after testing. 152 Baylor University Medical Center Proceedings Volume 29, Number 2 Table. Peak heart rate, systolic blood pressure, and rate-pressure product data from selected tests designed to simulate the physiologic exertion of the patient’s goal activities Test and related goal activity HR (bpm) SBP (mm Hg) RPP Static strength exercises* For suitcase manipulation: Upright row 94 147† 13,818 Bicep curl 92 155† 14,260 74 154† 11,396 178 170† 30,260 Stair-climber metabolic stress test for Half Dome hiking 131 158 20,698 Pool simulation of scuba diving with tank and belt (55-lb load) 105 138 14,490 Military press For Half Dome cable: 45-degree pull *Data shown for right arm. †Measured with a continuous blood pressure monitor instead of a cuff. HR indicates heart rate; SBP, systolic blood pressure; RPP, rate-pressure product. frequency during the Half Dome and scuba diving tests was 36 breaths per minute, and the peak rating of perceived exertion was 7 on a scale of 1 to 10, signifying “really hard” effort. During the 3 days of exercise testing, the patient had no adverse signs or symptoms that required him to discontinue any session. DISCUSSION Aortic dissection has been linked with severe physical exertion (3), and disproportionate mean arterial blood pressure responses (320/250 mm Hg) have been associated with heavy resistance training and the Valsalva maneuver (4). Individuals who have survived aortic dissection often struggle with functional independence (5), and they may fear reaching the intensity that would be required for their return to strenuous activities. The reality, however, is that patients who are physically active before their cardiovascular event or surgery want to resume performing exercise at the intensity levels they are accustomed to. Exercise guidelines for those who have had aortic dissection repair are vague and inconsistent (3, 5–8). The patient in this case, for example, was given the following recommendations: aerobic exercise is permissible, but lifting anything over 30 pounds is not; systolic blood pressure should not exceed 160 mm Hg; and resistance training should be limited to low amounts of weight and high numbers of repetitions. Furthermore, he was advised to avoid straining by breath holding (the Valsalva maneuver), as during bowel movements. The drawback to any limited prescription for exercise after surgery is that it is based on little, if any, scientific data. At our specificity of testing laboratory, we develop physical performance tests that are designed to simulate the patient’s activity goals. We then use the physiologic data collected during testing to create a biofeedback model through which we are able to provide specific exercise guidelines. In this case, we provided April 2016 data about his breathing frequency, heart rate, and rating of perceived exertion that he could use to more accurately gauge the intensity level of physical exertion during his activities. Although our simulated testing approach provides no guarantee against future cardiovascular events, our goal was to provide this patient research-based objective exercise recommendations, which are clearly needed in this at-risk population. Nevertheless, the fact that no cardiovascular event occurred during the simulated testing does not substantiate that the activities are safe. Simulated testing also has an inherent limitation that must be noted. Additional stressors (emotional, environmental, altitude, etc.) that cannot be effectively replicated in a laboratory may result in increased cardiac demand when patients perform the goal activities in their routine environmental setting. Approximately 18 months after undergoing aortic dissection repair, the patient reached his goals without cardiovascular symptoms. He uneventfully carried his 50-pound suitcase on a trip to Cozumel, Mexico, where he performed 16 dives. A month later, he hiked to the top of Half Dome. Acknowledgments Grant support was provided by an anonymous foundation 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 Cardiovascular Research Review 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. 2. 3. 4. 5. 6. 7. 8. Adams J, Cline MJ, Hubbard M, McCullough T, Hartman J. A new paradigm for post-cardiac event resistance exercise guidelines. Am J Cardiol 2006;97(2):281–286. MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58(3):785–790. Hatzaras I, Tranquilli M, Coady M, Barrett PM, Bible J, Elefteriades JA. Weight lifting and aortic dissection: more evidence for a connection. Cardiology 2007;107(2):103–106. MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58(3):785–790. Chaddha A, Kline-Rogers E, Woznicki EM, Brook R, Housholder-Hughes S, Braverman AC, Pitler L, Hirsch AT, Eagle KA. Cardiology patient page. Activity recommendations for postaortic dissection patients. Circulation 2014;130(16):e140–142. Williams MA, Haskell WL, Ades PA, Amsterdam EA, Bittner V, Franklin BA, Gulanick M, Laing ST, Stewart KJ; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Resistance exercise in individuals with and without cardiovascular disease: 2007 update. Circulation 2007;116(5):572–584. Chaddha A, Eagle KA, Braverman AC, Kline-Rogers E, Hirsch AT, Brook R, Jackson EA, Woznicki EM, Housholder-Hughes S, Pitler L, Franklin BA. Exercise and physical activity for the post-aortic dissection patient: the clinician’s conundrum. Clin Cardiol 2015;38(11):647–651. Chaddha A, Kline-Rogers E, Eagle KA, Braverman AC, Erickson SR, Jackson EA, Franklin BA, Woznicki EM, Jabara JT, Montgomery DG, Eagle KA. Survivors of aortic dissection: activity, mental health, and sexual function. Clin Cardiol 2015;38(11):652–659. Specificity of testing in a cardiac rehabilitation setting resulting in a patient’s return to high-intensity outdoor activity 153 Invited Commentary Simulated performance testing to determine the aortic dissection patient’s potential for vigorous physical activity A cute aortic dissection (AD) is a life-threatening emergency that involves a tear in the intimal-medial wall and occurs predominantly in adults with systemic hypertension (1‒3). The hypothesized mechanisms responsible for the development and triggering of AD are shown in Figure 1 (3). Despite recent advances in the acute treatment and medical management of AD, in-hospital mortality for patients with AD remains high, regardless of the type of dissection (i.e., involving Figure 1. Schematic of hypothesized mechanism of acute aortic dissection. the ascending aorta [type A] or distal to the left subclavian artery MMPs indicates matrix metalloproteinases; SBP, systolic blood pressure. Adapted [type B]) (4). Nevertheless, survival rates in patients presenting from Hatzaras et al., 2007 (3). with type A AD treated with surgery approximate 96% and 91% at 1 and 3 years versus 89% and 69% for those managed medically (5). except at the highest levels of exertion, at which SBPs between Although progressive acute management has contributed 180 and 220 mm Hg may be achieved in some persons (8). to the improved prognosis, survivors of acute AD maintain In contrast, heavy weight lifting, which may transiently evoke a heightened risk of aortopathy and associated cardiovascular excessive increases in SBP (>300 mm Hg) (10‒13), has been events that may be favorably or unfavorably modulated by carsuggested as the trigger for AD in numerous reports (14‒16). dioprotective interventions and selected triggers, respectively Consequently, it seems reasonable for post-AD patients to avoid (Figure 2) (6). Because few data are available regarding the spestrenuous weightlifting performed to failure or lifting heavy cific types and intensities of exercise that may be both safe and objects to decrease the risk for future aortic dilation, dissecbeneficial for this escalating patient population, this void poses a tion, and/or aortic rupture (6). For individuals with known conundrum for patients with a prior AD, as well as for clinicians aortic dilation, it appears that lifting up to 50% of their body caring for and counseling them. Consequently, following AD, weight during the bench press or an equivalent level of perceived physical inactivity and depression/anxiety generally increase, exertion for other strength exercises is relatively safe, provided which further reduce functional capacity and/or quality of life that the peak SBP remains below 200 mm Hg (8, 16). For in AD survivors (7). Understanding the hemodynamic responses to varied types of physical activity (8), as well as the role of commonly prescribed antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers), to attenuate average and peak systolic blood pressures (SBP) during physical exertion, potentially allowing the AD survivor to more safely tolerate greater intensities of exercise, is crucial to preventing recurrent cardiac events in this high-risk patient population while simultaneously maintaining or improving their functional capacity, self-efficacy, and psychosocial well-being (6, 9). Aerobic exer- Figure 2. Potential triggers and cardioprotective interventions for acute aortic dissection. ACE indicates cise elicits only a modest rise in SBP (∼10 angiotensin-converting enzyme; ARB, angiotensin receptor blocker. Reprinted with permission from Chaddha mm Hg/metabolic equivalent [MET]), et al, 2015 (6). Copyright © Wiley Periodicals, Inc. 154 Proc (Bayl Univ Med Cent) 2016;29(2):154–156 post-AD patients, even more conservative SBP upper limits (e.g., 160‒170 mm Hg) would appear prudent. Because structured aerobic exercise lowers the product of the heart rate (HR) and SBP at rest and at any given level of submaximal exercise, signifying a reduction in the rate-pressure product, a key determinant of myocardial oxygen consumption (r = 0.92) (17, 18), it is feasible that exercise regimens might lower lifelong recurrent aortic risk during exertion-related and nonexertion (e.g., emotional) stresses. Since β-blockers are associated with improved survival in patients with prior AD, presumably by reducing HR, myocardial contractility, and abrupt increases in ventricular pressure (9), it is plausible that regular exercise may also serve as a cardioprotective intervention for the AD patient (6). Moreover, the associated increase in cardiorespiratory fitness has also been shown to be a strong prognostic indicator, inversely related to cardiovascular and allcause mortality in patients with and without heart disease (19). The prognosis of the AD patient has considerably improved over the last decade by advances in rapid diagnosis, medical therapies, and emergency surgery. To counter the adverse sequelae associated with the surgical approach, including deconditioning, reduced functional capacity, and decreased quality of life, cardiologists and cardiovascular surgeons increasingly refer these patients to medically supervised, exercise-based cardiac rehabilitation programs. These centers are designed to rehabilitate patients through electrocardiographically (ECG) monitored exercise therapy and complementary counseling and education, simultaneously providing referring physicians with valuable serial surveillance data to potentially enhance their ongoing medical management. In a cohort of 33 French patients (25 men, 8 women) with AD (mean ± SD age = 55.1 ± 9.3 years), moderate-intensity rehabilitative exercise sessions (18 ± 10) were carried out on a cycle ergometer at 11.3 ± 1.5 (“fairly light”) using the 6 to 20 category Borg scale, with blood pressure monitoring during training (<160 mm Hg in 75% of patients). Physical work capacity during cycle ergometer testing increased from 62.7 ± 11.8 to 91.6 ± 16.5 watts (P = 0.002). Follow-up was for 1 year and included 3 complications in 2 patients that required additional thoracic surgery, although no deaths, cerebrovascular accidents, or myocardial infarctions were recorded. Ten of the 19 patients (53%) of working age were able to return to work (20). These data substantiate the feasibility, relative safety, and effectiveness of exercise-based cardiac rehabilitation in post-AD survivors. For selected AD patients, returning to former occupational and leisure-time activities is an important objective and may also be psychologically therapeutic. Unfortunately, many of these patients fail to return to specific activities, including sexual activity (7), because they lack the medical assurance that they can resume these activities safely. Because advising the post-AD patient to return to high-volume, high-intensity activities is complex, it is important for physicians (and patients) to have as much information as possible about the associated myocardial and aerobic requirements. The underlying assumption for a safe return to activity is that the AD patient should work below April 2016 loads that evoke abnormal clinical signs or symptoms, including ischemic ST-segment depression, angina pectoris, serious arrhythmias, or excessive HR and/or SBP responses. Moreover, the associated energy expenditure should be considerably less than the patient’s peak or symptom-limited functional capacity. Several noninvasive procedures can be used in formulating a prescription for activity resumption. These may involve a clinical assessment of the patient and activity simulation, including an analysis of the type of work, cardiac demands, and energy requirements. Testing may include weight carrying, repetitive weight lifting, arm wrench work, machine operation, or combinations thereof, using ambulatory ECG and blood pressure monitoring. Although conventional exercise testing is still the most widely used technique to evaluate exertion-related hemodynamic responses, aerobic capacity, and associated ECG changes during progressive physical activity, standard lower extremity exercise may not necessarily reflect the requirements for lifting and carrying. In the current issue of the Baylor University Medical Center Proceedings, Bartee et al (21) provide an interesting case report on a 66-year-old man who underwent AD (type A) repair 18 months earlier and, by undergoing a series of simulated physical performance tests designed to mimic the vigorous to high intensity physical activities that he wanted to return to, he was able to accomplish these uneventfully. The patient’s activity goals were varied and included lifting and manipulating a 50-pound suitcase, hiking to the top of Half Dome in California’s Yosemite National Park, and scuba diving. Cardiac rehabilitation staff developed an ingenious, comprehensive series of tests that simulated the anticipated physical, static, aerobic, and myocardial requirements of these activities, as illustrated and described (21). Testing was symptom-limited, and no specific HR or SBP limits were used to restrict the patient’s exercise intensity. The HR responses during the 6-test battery averaged 112 bpm, corresponding to 73% of the patient’s agepredicted HR max, whereas SBPs were generally compatible with conventional endurance training regimens, ranging from 138 to 170 mm Hg. Clearly, the 45-degree cable pull-down station, associated with the stair climber metabolic stress test to simulate Half Dome hiking, elicited the highest rate-pressure product, 30,260 mm Hg × bpm. Nevertheless, these attenuated hemodynamic responses were most likely attributed to the patient’s aggressive medical management, including β-blocker, diuretic, and angiotensin-converting enzyme inhibitor therapy. The patient completed the entire test battery without adverse symptoms, and the objective data obtained, including perceived exertion, were used to provide specific exercise guidelines that enabled him to safely achieve his ‘real-life’ activity goals. The authors acknowledged that uneventful simulated testing does not substantiate that such activities are invariably safe, and that additional unaccounted for superimposed stressors, including environmental factors, altitude, and the hyperadrenergic response associated with competition, could further exacerbate the associated cardiac demands. Despite these limitations, the present case report underscores the importance of Simulated performance testing to determine the aortic dissection patient’s potential for vigorous physical activity 155 further defining and expanding the exertional parameters of the post-AD patient, using activity simulation to help rectify the current vagaries in the prescriptive process. —Barry A. Franklin, PhD Department of Preventive Cardiology and Cardiac Rehabilitation William Beaumont Hospital, Royal Oak, Michigan Oakland University William Beaumont School of Medicine, Rochester, Michigan E-mail: [email protected] 1. 2. 3. 4. 5. 6. 7. 156 de Virgilio C, Nelson RJ, Milliken J, Snyder R, Chiang F, MacDonald WD, Robertson JM. Ascending aortic dissection in weight lifters with cystic medial degeneration. Ann Thorac Surg 1990;49(4):638–642. Roberts WC, Vowels TJ, Kitchens BL, Ko JM, Filardo G, Henry AC, Hamman BL, Matter GJ, Hebeler RF Jr. Aortic medial elastic fiber loss in acute ascending aortic dissection. Am J Cardiol 2011;108(11):1639–1644. Hatzaras IS, Bible JE, Koullias GJ, Tranquilli M, Singh M, Elefteriades JA. Role of exertion or emotion as inciting events for acute aortic dissection. Am J Cardiol 2007;100(9):1470–1472. Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, Evangelista A, Fattori R, Suzuki T, Oh JK, Moore AG, Malouf JF, Pape LA, Gaca C, Sechtem U, Lenferink S, Deutsch HJ, Diedrichs H, Marcos y Robles J, Llovet A, Gilon D, Das SK, Armstrong WF, Deeb GM, Eagle KA. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA 2000;283(7):897–903. Tsai TT, Evangelista A, Nienaber CA, Trimarchi S, Sechtem U, Fattori R, Myrmel T, Pape L, Cooper JV, Smith DE, Fang J, Isselbacher E, Eagle KA; on behalf of the International Registry of Acute Aortic Dissection (IRAD). Long-term survival in patients presenting with type A acute aortic dissection. Circulation 2006;114(Suppl I):I350–I356. Chaddha A, Eagle KA, Braverman AC, Kline-Rogers E, Hirsch AT, Brook R, Jackson EA, Woznicki EM, Housholder-Hughes S, Pitler L, Franklin BA. Exercise and physical activity for the post-aortic dissection patient: the clinician’s conundrum. Clin Cardiol 2015;38(11):647–651. Chaddha A, Kline-Rogers E, Braverman AC, Erickson SR, Jackson EA, Franklin BA, Woznicki EM, Jabara JT, Montgomery DG, Eagle KA. Survivors of aortic dissection: activity, mental health, and sexual function. Clin Cardiol 2015;38(11):652–659. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Mayerick C, Carré F, Elefteriades J. Aortic dissection and sport: physiologic and clinical understanding provide an opportunity to save young lives. J Cardiovasc Surg (Torino) 2010;51(5):669–681. Melby SJ, Zierer A, Damiano RJ Jr, Moon MR. Importance of blood pressure control after repair of acute type A aortic dissection: 25-year follow-up in 252 patients. J Clin Hypertens (Greenwich) 2013;15(1):63–68. Seals DR, Washburn RA, Hanson PG, Painter PL, Nagle FJ. Increased cardiovascular response to static contraction of larger muscle groups. J Appl Physiol Respir Environ Exerc Physiol 1983;54(2):434–437. MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58(3):785–790. Palatini P, Mos L, Munari L, Valle F, Del Torre M, Rossi A, Varotto L, Macor F, Martina S, Pessina AC, Dal Palù C. Blood pressure changes during heavy-resistance exercise. J Hypertens Suppl 1989;7(6):S72–S73. Narloch JA, Brandstater ME. Influence of breathing technique on arterial blood pressure during heavy weight lifting. Arch Phys Med Rehabil 1995;76(5):457–462. Schor JS, Horowitz MD, Livingstone AS. Recreational weight lifting and aortic dissection: case report. J Vasc Surg 1993;17(4):774–776. Ragucci MV, Thistle HG. Weight lifting and type II aortic dissection. A case report. J Sports Med Phys Fitness 2004;44(4):424–427. Hatzaras I, Tranquilli M, Coady M, Barrett PM, Bible J, Elefteriades JA. Weight lifting and aortic dissection: more evidence for a connection. Cardiology 2007;107(2):103–106. Kitamura K, Jorgensen CR, Gobel FL, Taylor HL, Wang Y. Hemodynamic correlates of myocardial oxygen consumption during upright exercise. J Appl Physiol 1972;32(4):516–522. Nelson RR, Gobel FL, Jorgensen CR, Wang K, Wang Y, Taylor HL. Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 1974;50(6):1179–1189. Franklin BA. Survival of the fittest: evidence for high-risk and cardioprotective fitness levels. Curr Sports Med Rep 2002;1(5):257–259. Corone S, Iliou MC, Pierre B, Feige JM, Odjinkem D, Farrokhi T, Bechraoui F, Hardy S, Meurin P; Cardiac Rehabilitation Working Group of the French Society of Cardiology. French registry of cases of type I acute aortic dissection admitted to a cardiac rehabilitation center after surgery. Eur J Cardiovasc Prev Rehabil 2009;16(1):91–95. Bartee S, Shrestha S, Ramos B, Bilbrey T, Carbone P, Schussler JM, Deutsch R, Adams J. Specificity of testing in a cardiac rehabilitation setting resulting in a patient’s return to high-intensity outdoor activity following aortic dissection repair. Proc Bayl Univ Med Cent 2016;29(2):151-153. Baylor University Medical Center Proceedings Volume 29, Number 2 Cardiovascular autonomic neuropathy Niamh McCarty and Barry Silverman, MD Cardiovascular autonomic neuropathy often goes unrecognized. We present a case of a 22-year-old man with multiple manifestations of this disease, including weakness, dizziness, fatigue, tachycardia, abnormal QTc, and orthostasis, which occurred 2 years after his type 1 diabetes diagnosis. He exhibited parasympathetic denervation with resting tachycardia and exercise intolerance but also had evidence of orthostatic hypotension, which suggests sympathetic denervation. He did not have complete cardiovascular autonomic reflex testing, which would have been helpful, but improved with aggressive diabetes treatment and the increase of beta-blockade. It is important to identify these patients to understand their signs and symptoms and consider appropriate therapies. C ardiovascular autonomic neuropathy (CAN) is a serious and common complication of diabetes mellitus (DM) that is often not recognized. Diabetes mellitus affects more than 26 million people in the United States. Prevalence rates of CAN increase with age and duration of DM. The Diabetes Control and Complication Trial reported rates as high as 35% in type 1 DM and 44% in type 2 DM, with a prevalence rate of up to 60% in longstanding diabetics (1). The presence of CAN is associated with increased cardiovascular mortality and is the cause of cardiac dysfunction and multiple clinical symptoms, including resting tachycardia, exercise intolerance, postural hypotension, silent ischemia, cardiomyopathy, and perioperative instability (1–4). CASE REPORT A 22-year-old African American man with a 2-year history of type 1 DM presented to the clinic with complaints of fatigue, decreased exercise tolerance, palpitations, and persistent tachycardia. He was 6' tall and 147 lb. His blood pressure and heart rate recorded supine, sitting, and standing after 3 minutes were 138/80 mm Hg/105 beats per minute (bpm), 130/88 mm Hg/122 bpm, and 98/72 mm Hg/126 bpm, respectively. His exam revealed the presence of peripheral neuropathy with numbness and tingling extending bilaterally to the shin. A Holter monitor recorded a marked decrease in his heart rate variability (HRV), with HRV of 20 bpm over each hour and an average of 118 bpm with no dipping during sleep. His thyroid function was normal. An electrocardiogram exhibited sinus Proc (Bayl Univ Med Cent) 2016;29(2):157–159 tachycardia, a borderline abnormal QTc interval of 448 ms, a QT of 324 ms, ST elevation in all leads, and 38 mm voltage in V5. The echocardiogram demonstrated an ejection fraction of 45% to 50%, mild septal bounce, and left ventricular diastolic abnormality. A cardiac nuclear study reported an ejection fraction of 37% with global hypokinesis. His hemoglobin A1c level was 10.7%, with a history of poorly controlled blood sugars. His medications at the time of the clinic visit included metoprolol succinate 50 mg daily, insulin therapy, and gabapentin. Once CAN was diagnosed, the patient improved with aggressive treatment of his diabetes, which lowered his hemoglobin A1c to <7, and the increase of beta-blockade. DISCUSSION CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. Ewing et al (5) recommend five simple tests, the cardiac autonomic reflex tests, to establish the diagnosis: 1) HRV with deep breathing; 2) HRV lying to standing; 3) the Valsalva maneuver; 4) postural fall in blood pressure; and 5) blood pressure response to sustained handgrip. A single abnormal test may indicate early CAN, and three positive tests are recommended for a definite diagnosis (3). In early subclinical CAN, the cardiovascular autonomic reflex tests may not be able to detect any abnormalities; however, CAN is also detected by abnormal plasma catecholamine and cardiac imaging (1, 6, 7). Scintigraphy has been vital in diagnosing subclinical CAN (3). Diastolic dysfunction is observed with the echocardiogram, while cardiac magnetic resonance imaging can detect early stages of CAN via myocardial torsion (8). Pappachan et al found a connection between CAN and prolongation of QTc and suggested that QTc can be used to diagnose CAN (9). However, Valensi et al found that QTc was not significantly different between diabetic patients with and without CAN and control patients (10). The progression of CAN usually begins with parasympathetic denervation, followed by sympathetic tone enhancement From the Division of Cardiovascular Medicine, Northside Hospital, Atlanta, Georgia. Corresponding author: Barry Silverman, MD, Northside Heart, 5670 PeachtreeDunwoody Road, Atlanta, GA 30342 (e-mail: [email protected]) 157 and eventually sympathetic denervation (1, 11, 12); therefore, resting tachycardia is often the presenting sign (ranging from 100 to 130 bpm). As CAN progresses in severity, there is a decrease in heart rate. Patients with subclinical CAN will have abnormalities in HRV, which is followed by changes in baroreflex sensitivity (3, 13). With advanced CAN, sympathetic denervation along with impaired baroreflex sensitivity and decreased norepinephrine response to change in posture will result in orthostasis (3). The pathological mechanism of CAN remains uncertain but is likely multifactorial (14). What seems to be fundamental in the development and progression of CAN is hyperglycemia and its activation of multiple metabolic and/or redox pathways. This, in conjunction with reduced blood flow to nerve fibers, contributes to the disorder (1). Myocardial blood flow activity in response to sympathetic stimulation is significantly impaired after longstanding type 1 DM and may contribute to the eventual development of myocardial injury (15). CAN prevalence increases with age and a longer duration of diabetes. However, in select patients, it occurs in youth early in the course of the disease (15). CAN is linked to mortality risk, as shown by a metaanalysis of 15 different studies (16). In the EURODIAB Prospective Complications Study, albuminuria and peripheral and autonomic neuropathy had a strong association with mortality in patients with type 1 DM (17). There are limited therapeutic approaches to prevent or reverse CAN, and this may be due to the fact that the exact mechanisms behind the development of CAN are not understood. Lifestyle modifications have improved moderate CAN (1). Weight loss in obese diabetics and aerobic exercise for patients with both type 1 and type 2 DM improved HRV and cardiac autonomic functionality (1, 3). Early and comprehensive glycemic control is thought to prevent diabetic complications and potentially reverse CAN symptoms (1, 3). One therapy that may be effective in the management of CAN is the beta-blocker bisoprolol, which was shown to increase HRV related to parasympathetic activity in heart failure (18). Gottlieb et al noted that post–myocardial infarction diabetic patients had a 36% reduction in mortality with the use of beta-blockers (19). The use of angiotensin-converting enzyme inhibitors hinders downstream sympathetic outflow; 1-year use of quinapril resulted in some benefit for treating CAN (20), while a year of trandolapril resulted in no benefits of autonomic function or neuropathy symptoms in patients with CAN (21). Diabetic patients with neuropathy were treated for a year with an aldose reductase inhibitor (zopolrestat) and showed improved resting and exercise left ventricular ejection fractions, cardiac output, and stroke volume (22). Orthostasis can be treated both pharmacologically and with lifestyle changes. Midodrine and 9-alpha-flourohydrocortisone improved systolic blood pressure upon standing (23, 24). Somatostatin and somatostatin analogues (octreotide) increased blood pressure in patients with autonomic neuropathy (25). Pyridostigmine bromide improved symptoms without worsening supine hypertension (26). 158 CAN is underrecognized in diabetic patients. Autonomic testing is a helpful and cost-effective aid to diagnosis. CAN is a common disorder that is not only associated with DM but also occurs in patients with malignancy, autoimmune disorders, Parkinson’s disease, and a number of other neurologic and medical disorders. It is important to identify these patients to understand their signs and symptoms and consider appropriate therapies. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes? J Cardiovasc Transl Res 2012;5:463– 468. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26(5):1553-1579. Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014;5(1):17–39. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27(7):639–653. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985;8(5):491–498. Bernardi L, Spallone V, Stevens M, Hilsted J, Frontoni S, Pop-Busui R. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev 2011;27(7):654–664. Stevens MJ. New imaging techniques for cardiovascular autonomic neuropathy: a window on the heart. Diabetes Technol Ther 2001;3(1):9–22. Vanninen E, Mustonen J, Vainio P, Länsimies E, Uusitupa M. Left ventricular function and dimensions in newly diagnosed non-insulin-dependent diabetes mellitus. Am J Cardiol 1992;70(3):371–378. Pappachan JM, Sebastian J, Bino BC, Jayaprakash K, Vijayakumar K, Sujathan P, Adinegara LA. Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis. Postgrad Med J 2008;84(990):205–210. Valensi PE, Johnson NB, Maison-Blanche P, Extramania F, Motte G, Coumel P. Influence of cardiac autonomic neuropathy on heart rate dependence of ventricular repolarization in diabetic patients. Diabetes Care 2002;25(5):918–923. Schönauer M, Thomas A, Morbach S, Niebauer J, Schönauer U, Thiele H. Cardiac autonomic diabetic neuropathy. Diab Vasc Dis Res 2008;5(4):336– 344. Jordan J, Tank J. Complexity of impaired parasympathetic heart rate regulation in diabetes. Diabetes 2014;63(6):1847–1849. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115(3):387–397. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther 2008;120(1):1–34. Schnell O, Cappuccio F, Genovese S, Standl E, Valensi P, Ceriello A. Type 1 diabetes and cardiovascular disease. Cardiovasc Diabetol 2013;12(1):156– 166. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003;26(6):1895–1901. Soedamah-Muthu SS, Chaturvedi N, Witte DR, Stevens LK, Porta M, Fuller JH. EURODIAB Prospective Complications Study Group. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care 2008;31(7):1360–1366. Pousset F, Copie X, Lechat P, Jaillon P, Boissel JP, Hetzel M, Fillette F, Remme W, Guize L, Le Heuzey JY. Effects of bisoprolol on heart rate variability in heart failure. Am J Cardiol 1996;77(8):612–617. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998;339(8):489–497. Baylor University Medical Center Proceedings Volume 29, Number 2 20. Athyros VG, Didangelos TP, Karamitsos DT, Papageorgiou AA, Boudoulas H, Kontopoulos AG. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 1998;53(4):201–209. 21. Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J, Schady W, Boulton AJ. Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 1998;352(9145):1978–1981. 22. Johnson B, Nesto R, Pfeifer MA, Slater WR, Vinic AI, Chyun DA, Law G, Wackers F, Young L. Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration. Diabetes Care 2004;27(2):448–454. April 2016 23. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a doubleblind, placebo-controlled study with midodrine. Am J Med 1993;95(1):38–48. 24. Campbell IW, Ewing DJ, Clarke BF. 9-Alpha-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes 1975;24(4):381–384. 25. Hoeldtke RD, Bryner KD, Hoeldtke ME, Hobbs G. Treatment of autonomic neuropathy, postural tachycardia and orthostatic syncope with octreotide LAR. Clin Auton Res 2007;17(6):334–340. 26. Singer W, Sandroni P, Opfer-Gehrking TL, Suarez GA, Klein CM, Hines S, O’Brien PC, Slezak J, Low PA. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 2006;63(4):513– 518. Cardiovascular autonomic neuropathy 159 Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2) Lucas R. Philipp, BA, and Fred H. Rodriguez III, MD Timothy syndrome (TS) is a rare, multisystem disorder most commonly associated with profound QTc prolongation and cutaneous dysmorphia arising from mutations of the L-type calcium channel. We present a case of a 12-day-old newborn who presented with respiratory distress and cyanosis. Diagnostic workup was notable for multiple cardiac abnormalities, and genetic analysis was consistent with an exon 8 mutation of the CACNA1C gene, which is diagnostic for TS type 2 (atypical TS). This patient presented with a novel constellation of symptoms, without dysmorphic features, and with a more moderate QTc interval. The heterogeneity of phenotypes suggests that this disorder may be characterized by variable expressivity or a spectrum of disease rather than a clearly defined syndrome. T imothy syndrome (TS) is a rare, multisystem disorder associated with profound QTc prolongation and syndactyly, formally described by Splawski and Timothy et al (1–3). Also known as long-QT syndrome type 8 (LQTS8), TS is caused by gain of function mutations affecting the L-type calcium channel CACNA1C gene. Additional syndromic features include facial dysmorphia, cardiac anomalies, and cognitive impairment (1–3). TS has been described in less than 50 patients, 5 of whom were noted to have phenotypic/ genotypic variations known as atypical TS (4–6). These patients lack syndactyly and have demonstrated a greater frequency and severity of cardiac symptoms (5). The paucity of atypical TS cases denotes clear limitations in our ability to produce generalizable conclusions with respect to genotype-phenotype interactions. We describe the youngest documented case of atypical TS in a 12-day-old infant with clinical findings unique from prior cases. CASE REPORT Within the patient’s first 5 days of life, she experienced intermittent hypoglycemia and hypocalcemia, an episode of bradycardia, desaturation, and abnormal findings on electrocardiography (Figure 1). The echocardiogram showed a patent ductus arteriosus with normal left ventricular systolic function. The infant developed severe shortness of breath and episodic fainting spells at 12 days postdelivery. Arterial blood gas showed a pH of 6.9 with lactic acidosis (20.16 mmol/L). Calcium and 160 bicarbonate were given. The patient’s chest x-ray, lumbar puncture, and all cultures were unremarkable. The electrocardiogram showed 2:1 AV conduction (ventricular rate 69 bpm) and a QTc of 636 ms (Figure 1). The brain natriuretic peptide level was 21,000 pg/mL. An echocardiogram showed biventricular systolic dysfunction (Figure 2). Milrinone and esmolol drips were initiated. The patient underwent patent ductus arteriosus ligation, and temporary A/V pacing wires were placed. A dual-chamber permanent pacemaker was later implanted via a subxiphoid approach with epicardial right atrial and left ventricular leads. The initial mode was DDD 80-210 (activation rate–upper limit of detection), but was revised to DDD 90-210. The results of the GeneDX long QT gene panel were positive for a heterozygous mutation of the CACNA1C gene, demonstrating the Gly406Arg (G406R) mutation—a c.1216 G>A in exon 8. This patient had no syndactyly or facial dysmorphia. Her family history was negative for congenital and genetic defects. The patient was discharged on day 25 in good condition. The child returned with cardiac arrest with metabolic acidosis (pH 6.78, lactic acid 11.26) 2.5 weeks later. She developed ventricular fibrillation, was defibrillated to resume sinus rhythm, and received magnesium and calcium. She was then bolused with lidocaine and started on a lidocaine drip. Ventricular ectopy and intermittent ventricular tachycardia persisted. Esmolol was started. She had significant hypotension (systolic pressure 30–50 mm Hg) requiring vasopressor support. A repeat echocardiogram showed persistence of her severely depressed biventricular systolic function, and milrinone was added. She continued to have neurologic problems, and a computed tomography scan showed extensive hypoxic ischemic brain injury. After discussion with her parents, care was withdrawn, and the infant died on her 52nd day of life. DISCUSSION TS type 1 accounts for most TS cases and is associated with a 100% incidence of cutaneous syndactyly (2). Severe cardiac From Emory University School of Medicine (Philipp, Rodriguez) and Sibley Heart Center Cardiology (Rodriguez), Atlanta, Georgia. Corresponding author: Lucas R. Philipp, 12180 S. Solomon Road, Olathe, KS 66061 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):160–162 a c b Figure 1. Characteristic electrocardiographic findings in this patient from lead II tracings at various times during hospitalization: (a) the most frequent finding in this patient, showing 2:1 AV block (ventricular rate = 69 bpm; atrial rate = 138 bpm) and a prolonged QTc (622 ms); (b) 1:1 AV conduction (heart rate = 119 bpm), QTc = 558 ms, with T-wave alternans; (c) QTc = 659 ms with 2:1 AV conduction (ventricular rate = 82 bpm; atrial rate = 164 bpm). symptoms underlie nearly every diagnosis of TS, including repolarization abnormalities such as a QTc of 480 to 700 ms, 2:1 AV block, and T wave alternans. Structural defects are also common (4). The leading cause of death is ventricular tachyarrhythmia, which is present in 80% of individuals. TS type 1 is an autosomal dominant condition, arising from de novo mutations in exon 8a of CACNA1C, which codes for the CaV1.2 protein (4, 7). This results in a Gly406Arg substitution that alters calcium channel inactivation, leading to excess calcium influx and action potential prolongation. Rare cases have described inheritance patterns of somatic mosaicism, a which is associated with a milder phenotype (2, 5, 8). The G406R mutation in the CACNA1C gene has also been associated with atypical TS (2, 9, 10). However, atypical TS (TS types 2 and 3) arises from mutations in exon 8 of CACNA1C. Exon 8 is mutually exclusive with exon 8a, exon 8 mRNA being the predominant isoform in most tissues (7). In the context of this current understanding of the disorder, the present patient was genotype positive for atypical TS; however, her phenotype was unique. Although a greater incidence and severity of facial dysmorphia has been noted in atypical TS (2), this infant had normal facial features. c b Figure 2. Key echocardiogram findings on the first hospital readmission after birth. (a) Apical four-chamber view illustrating left ventricular noncompaction and biventricular hypertrophy. (b) Parasternal long-axis image showing left ventricular hypertrophy and left ventricular noncompaction. (c) M-mode image showing moderately to severely depressed left ventricular systolic function. Fractional shortening 17.9%. April 2016 Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2) 161 Previous studies have suggested that CACNA1C exon 8 TS genotypes are associated with a more extreme prolongation of QTc in affected individuals, ranging between 620 and 730 ms (4, 5, 9). A proposed explanation is the predominance of exon 8 mRNA products in the heart (80%) relative to those of 8a (5). The QTc of our patient ranged from 487 to 660 ms, with a mean of approximately 550 ms. This range falls short of the originally described features of atypical TS (2), but exceeds the normal rate-corrected ranges by a large margin. Since our patient was diagnosed at such a young age, we were initially optimistic about her prognosis. We had hoped that with early medical intervention, we would have been able to effectively treat potentially lethal heart rhythms in a prophylactic manner. However, although we successfully placed a cardiac pacemaker in this patient, its function does not address the underlying abnormal cellular pathology within the cardiomyocytes of atypical TS patients. It is of substantial importance to consider the sharp juxtaposition the present case poses to prior reports (11). Our patient received standard, evidence-based treatment at an exceptionally early time in the course of her disease. In spite of this, these interventions were not successful. This patient presented with a novel constellation of symptoms, including a more moderate QTc interval and a lack of the facial dysmorphia that has accompanied all prior cases of atypical TS. The heterogeneity of phenotypes observed in atypical TS may suggest that the disorder is characterized by variable expressivity or is a spectrum of disease rather than a clearly defined syndrome. Most importantly, it has been previously suggested that early medical intervention may be pivotal in preventing early cardiac fatalities in atypical TS. However, pacemaker implantation did not prevent ventricular dysrhythmias in our patient. The extent to which this channelopathy disrupts normal electrical activity of the heart may have been previously underestimated, and other potential therapies need to be explored. 162 1. Reichenbach H, Meister EM, Theile H. The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet. Kinderarztl Prax 1992;60(2):54– 56. 2. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119(1):19–31. 3. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol 1995;25(1):59– 64. 4. Yazawa M, Dolmetsch RE. Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res 2013;6(1):1–9. 5. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 2005;102(23):8089–8096. 6. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo T-P. Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet A 2015;167A(3):629–634. 7. Tang ZZ, Sharma S, Zheng S, Chawla G, Nikolic J, Black DL. Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein. J Biol Chem 2011;286(12):10007–10016. 8. Etheridge SP, Bowles NE, Arrington CB, Pilcher T, Rope A, Wilde AA, Alders M, Saarel EV, Tavernier R, Timothy KW, Tristani-Firouzi M. Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet A 2011;155A(10):2578–2583. 9. Yarotskyy V, Gao G, Peterson BZ, Elmslie KS. The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol 2009;587(Pt 3):551–565. 10. Dufendach KA, Giudicessi JR, Boczek NJ, Ackerman MJ. Maternal mosaicism confounds the neonatal diagnosis of type 1 Timothy syndrome. Pediatrics 2013;131(6):e1991–e1995. 11. Diep V, Seaver LH. Long QT syndrome with craniofacial, digital, and neurologic features: is it useful to distinguish between Timothy syndrome types 1 and 2? Am J Med Genet A 2015;167(11):2780–2785. Baylor University Medical Center Proceedings Volume 29, Number 2 Holter monitor recordings in a man who snores D. Luke Glancy, MD, and Prasert Vijitbenjaronk, MD E lectrocardiographic a rhythm strips were recorded over a 24-hour period in a 49-year-old man who snored but had no prior b cardiac history and no rhythm disturbances while awake. A modified lead II strip recorded at 4:06 am showed marked sinus arrhythmia and c second-degree AV block (Figure 1a). The AV block increased when the sinus rate slowed, suggesting increased vagal tone affecting both the sinus and the AV nodes. The fourth QRS was slightly wider than the others and may have been junctional escape complex; its T wave was considerably wider Figure 1. Electrocardiograms over a 24-hour period. Modified lead II strips showing (a) marked sinus arrhythmia and secondthan the others and prob- degree AV block at 4:06 AM and (b) normal sinus rhythm at 4:09 AM. (c) Continuous modified V1 rhythm strips recorded at ably contained a sinus P 11:52 PM showing marked slowing of the sinus rate accompanied by sudden high-grade AV block. wave. A modified lead II strip recorded 3 minutes later showed normal sinus rhythm occur predominantly or, as in this patient, exclusively during throughout (Figure 1b). Modified V1 rhythm strips recorded sleep. Relief of the upper airway obstruction has reduced the at 11:52 pm showed marked slowing of the sinus rate accompafrequency and severity of rhythm disturbances (1). Continunied by sudden high-grade AV block with ventricular asystole ous positive airway pressure (CPAP) reduces the arrhythmia of 5.46 seconds that was terminated by a ventricular escape recurrence rate following pulmonary vein isolation for atrial complex (with a sinus P wave in its ST segment). Afterwards, fibrillation in patients with obstructive sleep apnea and inthere was a slight increase in the sinus rate accompanied by creases atrial fibrillation-free survival off antiarrhythmic drugs marked first-degree AV block. Again, sudden, transient highor repeat ablation. Pulmonary vein isolation appears to offer grade AV block accompanying slowing of the sinus rate suglimited value to patients with obstructive sleep apnea not gested increased vagal tone (Figure 1c). treated with CPAP (5). In addition to its association with bradyarrhythmias, obstructive sleep apnea has been associated with ventricular From the Sections of Cardiology, Louisiana State University Health Sciences ectopy, including nonsustained ventricular tachycardia, atrial Center and the Touro Infirmary, New Orleans, Louisiana. fibrillation, and atrial flutter (1–3). Obstructive sleep apnea is Corresponding author: D. Luke Glancy, MD, 1203 West Cherry Hill Loop, Folsom, also associated with sudden cardiac death (4). The arrhythmias LA 70437 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):163–164 163 1. 2. 3. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52(5):490–494. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97(21):2154–2159. Mehra R, Stone KL, Varosy PD, Hoffman AR, Marcus GM, Blackwell T, Ibrahim OA, Salem R, Redline S. Nocturnal arrhythmias across a spectrum 4. 5. of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169(12):1147–1155. Gami AS, Howard DE, Olson EJ, Somers VK. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005;352(12):1206–1214. Fein AS, Shvilkin A, Shah D, Haffajee CI, Das S, Kumar K, Kramer DB, Zimetbaum PJ, Buxton AE, Josephson ME, Anter E. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013;62(4):300–305. In memoriam CHARLES DALE COLN, MD Author: Department of Pediatric Surgery, Baylor University Medical Center at Dallas Dr. Dale Coln, who served as the first chief of pediatric surgery at Baylor University Medical Center (BUMC), died January 5, 2016, from complications of Alzheimer’s disease. He was 81 years old. Dr. Coln grew up in Dallas, attending Arlington Heights High School. He received his bachelor’s degree from Baylor University, followed by a medical degree from Baylor University College of Medicine in 1961. After medical school, he married Dr. Shirley Kindberg, a pediatrician who later directed BUMC’s newborn nursery. Dr. Coln completed a research fellowship with Dr. G. Tom Shires in Dallas and a surgery residency at Parkland Hospital. He was in the Parkland emergency room when Lee Harvey Oswald was brought in 2 days after Kennedy’s assassination. Several years after beginning his surgical practice, Dr. Coln completed a fellowship in pediatric surgery in Cape Town, South Africa, and in 1972, he was named chairman of pediatric surgery at Parkland. One of his legacies there was establishing a pediatric trauma unit. He became chairman at BUMC in 1987. For decades, until his retirement in 2005, he treated children both in Dallas and in his nine mission trips to Guatamela. He was especially known for the Nuss procedure, used for correcting congenital chest wall abnormalities. Recognized throughout his career for his compassionate care of children, Dr. Coln’s many honors include the American Academy of Pediatrics’ 164 Special Achievement Award in 2001 and the Children’s Medical Center’s Distinguished Service Award in 2002. Tributes to Dr. Coln were published on his retirement and are available at http://www.baylorhealth.edu/Documents/BUMC%20Proceedings/2005%20Vol%2018/No.%204/18_4_tributes_coln.pdf. GLENN WELDON TILLERY, MD Department of Pathology, Baylor University Medical Center Dr. Glenn Weldon Tillery was born on December 29, 1932, and died on January 13, 2016, at the age of 83. Born in Lubbock, Texas, Dr. Tillery attended Lubbock High School, the University of New Mexico, and the University of Texas Southwestern Medical School. During medical school, he married Mary Swan, who was working as a laboratory technician at Baylor Hospital. He competed an internship in internal medicine at the Dallas VA Hospital from 1959 to 1960 and served as a flight surgeon in the US Air Force in San Antonio. Dr. Tillery then pursued a pathology residency at BUMC under the direction of Dr. George Race. Early in his pathology career, he was recruited by Arabian American Oil Co. and served as chief of pathology services in Dhahran, Saudi Arabia. He then returned to BUMC’s pathology department and was chief of the department from 1986 to 1999. His influence at the medical center through the years was considerable, and he was a major force in building the Department of Pathology at BUMC. He retired in 2012. Baylor University Medical Center Proceedings Volume 29, Number 2 An interesting electrocardiogram Howard H. McClure Jr., MD H aving spent years collecting electrocardiograms (ECGs), I found this one the most intriguing (Figure). Try to solve it. Two hints: (1) don’t be seduced by the top row; and (2) a caliper is useful. SOLUTION At first blush, the strip across the top appears to be 2:1 block. On more careful inspection, it appears the PR is shortening, suggesting the possibility of an ectopic pacer. If one takes that cycle length (RR interval), it can be identified elsewhere in the record. This is a junctional escape Figure. An interesting electrocardiogram. pacemaker; all the other beats are sinus capture with a variety of PR intervals. These intervals the atrioventricular node and not conduct. Every component are determined by the preceding RP (i.e., recovery time of the of the record has a rational explanation. atrioventricular node; Henry Marriott’s famous “RP-dependent One of the confusing features of this tracing is that coPR”). The last two beats in the third strip have the longest and incidentally, the sinus rate of 76 is almost a multiple of the shortest PRs. They also have the shortest and longest RPs. If the independent junctional rate of 39. This may lead to confusion RP is too short, it may fall in the absolute refractory period of that a P and a QR are related when they are not! From Baylor University Medical Center at Dallas. Corresponding author: Howard H. McClure Jr., MD, 1519 Marseille Place, Dallas, TX 75204 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):165 165 Takotsubo cardiomyopathy after administration of norepinephrine Khaled Sherif, MD, Sharmila Sehli, MD, and Leigh A. Jenkins, MD Stress-induced cardiomyopathy is a syndrome of transient cardiac dysfunction with no clear pathophysiology. It is thought to be secondary to catecholamine surge. The mechanism by which catecholamine can induce transient cardiac dysfunction is unknown. We present a case of a patient who developed stressinduced cardiomyopathy after she was administered norepinephrine due to a nursing error. S tress-induced Figure 1. ECG showing ST segment and T wave changes. cardiomyopathy (also known as takotsubo cardiomyopathy, TC) is of packed red blood cells with furosemide were ordered. After the a syndrome of transient cardiac dysfunction precipitated patient received blood, norepinephrine (Levophed) 4 mg intraveby intense emotional or physical stress. It has been recognized nously was given instead of furosemide 40 mg due to a nursing in Japan since 1991 (1). The prevalence of TC in the general error. Soon after that, the patient started complaining of chest pain population is estimated to be between 1.7% and 2.2% in pawith dyspnea and was in acute distress with tachypnea and expiratients who present with suspected acute coronary syndrome. It is tory wheezing. An electrocardiogram showed new ST segment characterized by acute chest pain, electrocardiographic changes, and T wave changes in the precordial leads (Figure 1). Her tropoand elevated cardiac biomarkers in the absence of obstructive nin T level was 0.44 ng/mL; creatinine kinase, 131 ng/mL; and coronary artery disease. It can be classified into a left ventricucreatinine kinase–myocardial band, 6.9 ng/mL. A transthoracic lar apical ballooning variant (most common), an inverted or echocardiogram showed severely depressed left ventricular systolic reverse variant (basal akinesis with hyperdynamic apex), and function with an ejection fraction of 25% to 29% with apical wall a midventricular variant. We present a patient who developed akinesis and hypokinesis of anterior, anteroseptal, and anterolateral TC after receiving a norepinephrine injection. CASE REPORT A 76-year-old woman with hypertension, type 2 diabetes mellitus, and diverticulosis presented with bright red rectal bleeding. On admission, she was hemodynamically stable. She was found to have normocytic anemia with a hemoglobin of 7.8 g/dL. Two units 166 From the Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Corresponding author: Khaled A. Sherif, MD, Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9410, Lubbock, TX 79430 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):166–167 Figure 2. Left ventriculogram showing apical ballooning. walls. Coronary angiography showed no evidence of significant obstructive coronary artery disease. A left ventriculogram showed mildly depressed left ventricular systolic function and an ejection fraction of 45%, with evidence of apical ballooning (Figure 2). The diagnosis of takotsubo cardiomyopathy was made. The patient was treated with beta-blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonist for heart failure symptoms. She improved over time and was discharged home. A transthoracic echocardiogram after 6 months showed an ejection fraction of 50% to 55%. DISCUSSION The left ventricular dysfunction that occurs with stressinduced cardiomyopathy is thought to be secondary to catecholamine surge brought on by intense psychological or physical stress. Much of the evidence for this comes from observational and case-control studies that have found an association between elevated catecholamine levels and disease onset. The mechanism by which catecholamine can induce transient left ventricular dysfunction is unclear. It is possible that high doses of catecholamine are directly toxic to myocardial cells. This is supported by histological findings from animal studies and autopsy findings from TC patients that document myofibril degeneration, contraction band necrosis, and leukocyte infiltration (2). Molecular studies in cultured cardiocytes have shown that high doses of epinephrine April 2016 are directly toxic to the cells. This results in a significant rise in cyclic adenosine monophosphate and calcium levels that trigger the formation of free oxygen radicals, initiation of expression of stress response genes, and induction of apoptosis in a subset of cells (3, 4). Myocardial necrosis cannot explain the entire picture because most patients with TC regain full recovery of left ventricular function. It has been proposed that epinephrine may cause damage by inducing spasm of coronary macro- and microvasculature and/or stunning of cardiocytes directly because of cyclic adenosine monophosphate–mediated calcium overload (5). About 80% of TC cases occur in postmenopausal women. Studies have shown that estrogen plays an important role in protecting the myocardium (6), possibly by downregulating beta-adrenergic receptors. Postmenopausal women lose this protection and are more vulnerable to the catecholamine surge that is associated with stress. There is a predominance of the apical ballooning variant. It was previously suggested that the apex of the heart is more sensitive to epinephrine due to a higher density of beta-adrenergic receptors in the cardiac apex versus the base (4). In our case, the patient accidentally received a high dose of norepinephrine, which stimulates alpha and beta-1 adrenergic receptors and produces both positive ionotropic and vasodepressor effects. The patient developed the classic form of TC, and this case confirms the direct causal role of catecholamine in the pathophysiology of TC. In the past, several cases of iatrogenically induced TC have been reported. To the best of our knowledge, this is the first report of stress-induced cardiomyopathy secondary to iatrogenic norepinephrine injection. 1. 2. 3. 4. 5. 6. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. J Cardiol 1991;21(2):203–214. Movahed A, Reeves WC, Mehta PM, Gilliland MG, Mozingo SL, Jolly SR. Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs. Int J Cardiol 1994;45(1):23–33. Mann DL, Kent RL, Parsons B, Cooper G IV. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85(2):790– 804. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5(1):22–29. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352(6):539–548. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y, Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of tako-tsubo (ampulla) cardiomyopathy. J Cardiovasc Pharmacol 2003;42(Suppl 1):S117–S119. Takotsubo cardiomyopathy after administration of norepinephrine 167 Acute myocardial infarction with isolated congenitally corrected transposition of the great arteries Jeremy Zimmermann, DO, J. Ryan Altman, MD, and D. Scott Gantt, DO Congenital cardiac abnormalities diagnosed at the time of acute coronary syndrome are rare. A 43-year-old man presented to the emergency department complaining of recurring, severe chest pain. Subsequent emergent coronary angiography demonstrated unusual coronary anatomy: 1) one small caliber bifurcating vessel originating from the right sinus of Valsalva; 2) one very large vessel arising from the posterior sinus; and 3) no coronary artery from the normal left sinus of Valsalva. The large vessel from the posterior sinus was totally occluded in its midportion and was treated with intravascular ultrasound-guided percutaneous coronary intervention. Further diagnostic workup, including twodimensional transthoracic echocardiogram and computed tomographic coronary angiography, demonstrated isolated corrected transposition of the great arteries with a dilated systemic ventricle and systolic dysfunction with an ejection fraction of 30%. The patient’s clinical course was complicated by recurrent nonsustained ventricular tachycardia, treated with medical therapy and a dual-chamber implantable cardioverter defibrillator. This case is an example of a common clinical presentation with a very uncommon congenital heart disorder. Similar cases may become more frequent as the number of adult congenital heart patients increases in the population. D e novo diagnosis of congenital cardiac abnormalities is uncommon in the average adult cardiology practice. Th ese patients can present a signifi cant diagnostic challenge when they develop acute coronary syndrome. Described below is an example of a common clinical presentation with a very uncommon congenital heart disorder. CASE REPORT A 43-year-old white man presented to the emergency department complaining of chest pain. He was known to have hypertension, tobacco abuse, antisocial personality disorder, and chronic obstructive pulmonary disease. His chest pain began the night prior to presentation while watching television and lasted several hours. The pain was substernal, with radiation to his back, and was alleviated by lying prone, allowing the patient to sleep through the night. The following day, he developed recurrent pain and after 2 hours was convinced by his girlfriend 168 to seek medical attention. The patient had maintained a normal active lifestyle throughout childhood into his fourth decade of life, developing mild dyspnea with exertion over the 6 months prior to his presentation. His initial electrocardiogram (ECG) demonstrated sinus tachycardia, left axis deviation, nonspecific intraventricular conduction delay, left atrial enlargement, and old anteroseptal infarct, without dextrocardia (Figure 1). A portable chest radiograph demonstrated increased central vascular prominence with cephalization, mild cardiomegaly, and no dextroversion (Figure 2). Emergent coronary angiography revealed a relatively small caliber vessel arising from an anterior cusp, bifurcating into small caliber branches without stenosis (Figure 3). A second coronary artery was found originating from the posterior cusp supplying much of the inferior lateral region. This vessel was large caliber and was occluded in its midportion. Percutaneous coronary intervention with a 5 × 16 mm Veriflex bare-metal stent was performed with subsequent intravascular ultrasound demonstrating severe fibrocalcific plaque at the stenotic region and good stent strut apposition. At the time of transfer to the coronary care unit, the patient was free of chest pain and hemodynamically stable. A transthoracic echocardiogram in the coronary care unit demonstrated congenitally corrected transposition of the great arteries (CTGA) with systemic ventricular dilatation and systolic dysfunction with an ejection fraction of <30%. A computed tomographic angiogram of the coronary arteries revealed a dominant coronary artery originating from the posteriorly positioned right sinus of Valsalva with a configuration most typical of a morphologic right coronary artery (Figure 3e, 3f ). The stent in the midportion of the main branch was widely patent. The coronary artery originating from the rightward rotated left cusp demonstrated a configuration most typical of a morphologic left coronary artery. From Baylor Scott & White Health and Texas A&M Health Science Center, Temple, Texas. Corresponding author: Jeremy Zimmermann, DO, Baylor Scott & White Health, 2401 S. 31st Street, Temple, TX 76508 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):168–170 pulmonary artery and right atrium, while the morphologic right ventricle and tricuspid valve are connected to the left atrium and aorta, committing the right ventricle to systemic pressure demands. CTGA is rare and represents <1% of congenital heart abnormalities (1). Up to 90% of patients with CTGA have additional cardiac defects such as ventricular septal defect, pulmonary artery stenosis, tricuspid valve abnormalities, and mitral valve abnormalities (1). The clinical impact of Figure 1. Initial presenting electrocardiogram showing sinus tachycardia, anterior Q waves, and a nonspecific ST segment these associated defects typically leads to diagnosis in the elevation concerning for injury pattern. first few decades of life. In the absence of these defects, termed isolated CTGA, the diagnosis The patient’s clinical course was complicated by multiple may be delayed into the fourth decade of life or later. These episodes of symptomatic bradycardia with junctional rhythm patients often present with worsening tricuspid regurgitation, and several episodes of nonsustained ventricular tachycardia systemic ventricular failure, and ventricular arrhythmias, cul>48 hours after his myocardial infarction. Along with iniminating in clinical congestive heart failure and the potential tiation of medical therapy, a dual-chamber implantable carneed for cardiac transplantation (2–4). Ventricular arrhythdioverter defibrillator was placed into the morphologic left mias related to systolic heart failure and conduction system ventricle, followed by discharge on hospital day 7. At followdisease with bradycardia and heart block are common. The up 1 week later, the patient was asymptomatic with a benign risk of developing complete heart block increases by 2% anexamination. nually and is thought to be related to intrinsic conduction system fibrosis (1). DISCUSSION In terms of the coronary artery anatomy, most patients CTGA is associated with atrioventricular discordance and with CTGA have coronary artery ventricular concordance, ventriculoarterial discordance. The morphologic left ventricle with the morphologic left ventricle supplied by a branching and mitral valve are transposed to the right, attached to the vessel similar to the left anterior descending and circumflex vessels, and the right ventricle supplied by a vessel similar to a right coronary artery. Depending on the specific location of the aorta and pulmonary artery, spatial orientation of the coronary ostia can be challenging with standard angiography. One case series from 1988 found that 11 out of 18 CTGA patients had normal coronary artery ventricular concordance, whereas the other 7 had significant anomalies such as a single coronary ostium or hypoplasia of the left anterior descending artery (4). This case is an example of a typical presentation of acute coronary syndrome in a patient with a complex and rare congenital heart condition. During “routine” emergent coronary angiography, the origin of the culprit vessel in the posterior sinus of Valsalva was particularly challenging to engage. Advancing modern medical therapy and surgical techniques inevitably will result in a larger population of adult patients with congenital heart conditions presenting for both routine preventive care as well as emergency care. A thorough understanding of their Figure 2. A portable chest radiograph obtained in the emergency department pathology is becoming more important, as is the need for speshowing increased central vascular prominence with cephalization, mild cardiocialists in adult congenital heart disease. megaly, and no dextroversion. April 2016 Acute myocardial infarction with isolated congenitally corrected transposition of the great arteries 169 a b d e c f Figure 3. (a) Diagnostic invasive coronary angiography with a femoral approach demonstrates occlusion (arrow) of the large anomalous coronary branch that descends down the posterior aspect of the heart. (b) The distal portion of the occluded artery can be seen filling in after a wire was passed across the lesion. (c) The patent vessel demonstrates good flow after deploying a bare-metal stent. (d) There was anomalous coronary circulation supplying the anterior wall of the pulmonary ventricle. (e) Coronary CT angiogram demonstrates anterior displacement of the aortic root as well as the anomalous anterior coronary arteries. (f) Posterior view of the coronary CT angiogram shows the large posterior descending branch and its large segment in the midportion where the stent was deployed (arrow). 1. 2. 170 Warnes CA. Transposition of the great arteries. Circulation 2006; 114(24):2699–2709. Kaya A, Tanboga IH, Kurt M, Işik T, Ozgokce M, Topçu S, Aksakal E. Corrected transposition of the great arteries with previously unreported cardiac anomalies. Cardiovasc J Afr 2012; 23(5):e5–e7. 3. 4. Kocabay G, Akturk S, Moe AS, Boztosun B. A rare coronary artery anomaly in a patient with isolated congenitally corrected transposition of great arteries. J Am Geriatr Soc 2009;57(10):1940–1941. Dabizzi RP, Barletta GA, Caprioli G, Baldrighi G, Baldrighi V. Coronary artery anatomy in corrected transposition of the great arteries. J Am Coll Cardiol 1988;12(2):486–491. Baylor University Medical Center Proceedings Volume 29, Number 2 Isolated congenitally corrected transposition of the great arteries with dextroversion discovered incidentally in a patient with cocaine-induced acute myocardial infarction Anumeha Tandon, MD, Rahul Bose, MD, Anthony D. Yoon, MD, and Jeffrey M. Schussler, MD Complex cardiac congenital anomalies can occasionally be found in adult patients who have no knowledge of their condition. Here we present the case of a 27-year-old man with cocaine-induced acute myocardial infarction in whom an isolated congenitally corrected transposition of the great arteries with dextroversion was discovered incidentally. W hile congenital anomalies are often left to subspecialists in the adult congenital arena, familiarity with them is important for Figure 1. Electrocardiogram demonstrating a reversal of the P-wave axis (inverted P waves in leads I, AVR, and AVF; arrow) the general cardiologist. When with reversal of progression of R waves across the entire precordial leads (V1–V6). these patients present in association with other, more common conditions, evaluation can anterior descending artery, but in a conformation that would be be more challenging. considered “opposite” of normal anatomy. The opposite coronary artery appeared similar in conformation to a right coronary CASE DESCRIPTION artery, but also had an “opposite” course (Figure 3). A 27-year-old man presented with chest pain. A loud systolic A transthoracic echocardiogram (with images obtained primurmur was heard at the right sternal border, and a rightward marily from right-sided windows) revealed an aorta originating displaced point of maximal impact was noted. The admission from a morphologic right ventricle (systemic ventricle) and the electrocardiogram showed prominent R waves in V1, with an pulmonary trunk from a morphologic left ventricle (pulmonary inverted P-wave axis, and reverse R wave progression across the ventricle). These findings were confirmed by cardiac computed precordium (Figure 1). A chest radiograph demonstrated a righttomography (Figure 4). Abdominal ultrasound showed normally ward-pointed heart, prominent right-sided chambers, and the oriented viscera confirming situs solitus (normal orientation absence of the usual aortic and pulmonary contours (Figure 2). of the viscera). The patient was treated medically for cocaine The urine was positive for cocaine. The patient’s troponin level intoxication and was ultimately discharged in good condition. was 55 ng/mL. At urgent cardiac catheterization, the ventriculogram in the left anterior oblique position disclosed the heart From the Department of Internal Medicine, Division of Cardiology, Baylor University pointing toward the right hemithorax, suggesting dextrocardia Medical Center at Dallas (Tandon, Bose, Yoon, Schussler); the Jack and Jane or dextroversion. Angiography showed no coronary narrowing, Hamilton Heart and Vascular Hospital, Dallas, Texas (Tandon, Yoon, Schussler); but demonstrated “mirror image” epicardial coronary arteries. and Texas A&M College of Medicine (Schussler). The most anterior coronary artery coursed toward the right side Corresponding author: Jeffrey M. Schussler, MD, 621 N. Hall Street, Suite 400, of the body and covered a distribution similar to that of a left Dallas, TX 75226 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):171–173 171 Figure 2. Chest radiograph demonstrating a rightward-oriented heart, with the morphologic left ventricle (LV) pointed towards the right. There is loss of the normal aortopulmonary contours (arrowhead), and this area appears “flat.” The gastric bubble is noted under the left hemidiaphragm, indicative of situs solitus (normally oriented viscera). DISCUSSION Congenitally corrected transposition of the great arteries (CCTGA) is a rare (<1% of all congenital heart disease) anomaly where the great arteries are transposed and the ventricles, ventricular septum, atrioventricular valves, epicardial coronary arteries, and the conduction system are inverted. Other congenital heart defects such as ventricular septal defect, pulmonary stenosis, anomalies of the systemic atrioventricular valve (commonly, Ebstein’s anomaly), and conduction defects are present in approximately 98% of these patients. Most patients are identified in childhood, usually due to complications from the associated abnormalities. A minority of patients (particularly those without associated anomalies) may be asymptomatic for many years and present later in life due to findings on physical or radiologic exams, or if they experience systemic ventricular failure (1). Dextrocardia, or a rightward-pointing heart, is seen in up to 20% of these patients, and CCTGA should be strongly suspected when dextrocardia is observed (2). Dextrocardia with situs solitus (normally oriented viscera) and no other cardiac anomalies is rare, with an incidence of 1 live birth in 30,000 (3). a b c d Figure 3. Systemic ventriculogram (morphologic right ventricle) with a rightward-oriented apex. (a) Standard left anterior oblique imaging demonstrates a systemic ventricle that points towards the right side of the body. (b) Injection of the ascending aorta (Ao) fills the left main (LM) coronary artery. (c) Selective injection of the LM fills arteries that are equivalent to the left anterior descending (LAD) and left circumflex (LCx) arteries, in that they supply blood to the anterior and lateral portions of the systemic ventricle. (d) Injection of the posteriorly located coronary artery, equivalent to the right coronary artery (RCA), demonstrates that it supplies blood to the posterior portions of the systemic ventricle. 172 Baylor University Medical Center Proceedings Volume 29, Number 2 a b c d cardiac magnetic resonance imaging, and invasive coronary angiography can all be used in conjunction to allow for accurate diagnosis. Coronary anatomy, in particular, is variable. In up to 50% of patients, there may be associated coronary anomalies (4). Patients who present with coronary atherosclerosis or acute coronary syndromes are uncommon, as these patients usually present with systemic ventricular failure early in life. Coronary revascularization is appropriate and feasible, although it may be technically challenging due to abnormal conformation of the coronary anatomy (5, 6). 1. Wissocque L, Mondesert B, Dubart AE. Late diagnosis of isolated congenitally corrected transposition of the great arteries in a 92-year old woman. Eur J Cardiothorac Surg 2015 Nov 15 [Epub ahead of print]. 2. Warnes CA. Transposition of the great arteries. Circulation 2006;114(24):2699–2709. 3. Solzbach U, Beuter M, Hartig B, Haas H. Isolated dextrocardia Figure 4. (a) Computed tomography of the heart with 3D rendering demonstrating the course of the coronary arteries as with situs solitus (dextroversion). they supply blood to the systemic ventricle (SV). (b) A fully rendered 3D representation of the heart shows the relationship Herz 2010;35(3):207–210. between the SV and the pulmonary ventricle (PV) as well as the left anterior descending (LAD). (c) A short-axis view of the 4. Ismat FA, Baldwin HS, Karl heart demonstrates that the aorta (Ao) is positioned anterior to the pulmonary artery (PA); (d) rather than being oriented TR, Weinberg PM. Coronary 90° to each other, they are oriented in parallel. anatomy in congenitally corrected transposition of the great arteries. Int J Cardiol 2002;86(2– 3):207–216. The approach to evaluating a patient with dextrocardia, 5. Baltalarli A, Tanriverdi H, Goksin I, Onem G, Rendeci O, Sacar M. once the condition has been identified, should include idenCoronary arterial revascularization in an adult with congenitally cortification of visceral situs, atrioventricular concordance, venrected transposition of great arteries and dextrocardia. J Card Surg tricular morphology and situs, relation of the great arteries, 2006;21(3):296–297. 6. Mehrotra P, Choi JW, Flaherty J, Davidson CJ. Percutaneous coronary and finally associated abnormalities (4). Imaging modalities intervention in a patient with cardiac dextroversion. Proc (Bayl Univ Med such as echocardiography, cardiac computed tomography, Cent) 2006;19(3):226–228. April 2016 Isolated congenitally corrected transposition of the great arteries with dextroversion discovered incidentally 173 Invited Commentary The specialty of adult congenital heart disease O ver the last three decades, adults with congenital heart disease (ACHD) have become one of the fastest growing populations of adults with chronic heart disease. Despite significant progress in laying the foundations to meet the rising care needs for ACHD patients, limited access to care and suboptimal data are impediments to continued progress. The successes of pediatric cardiologists and surgeons have permitted individuals with conditions that previously would have been lethal in childhood to live and thrive well into adulthood. This fact, in combination with improvements in imaging technology permitting identification of clinically silent lesions, has led to rapid growth in the numbers of patients with ACHD in the general population (1, 2). This success, however, has created a unique challenge to the field of cardiology. Adult cardiologists are not required by the Accreditation Council for Graduate Medical Education (ACGME) to have specific training in caring for patients with congenital heart disease. As a result, most adult cardiologists lack adequate familiarity with congenital cardiac problems to provide optimal care. ACGME requirements for pediatric cardiology training, in contrast, focus on congenital heart disease and require fellows to have experience specifically in ACHD. Nevertheless, pediatric cardiologists have limited exposure to cardiologic issues common in adult patients, such as coronary vascular disease or the cardiovascular effects of cocaine abuse, for example. In recognition of the need for a uniquely trained cadre of individuals to care for this population, the ACGME has recently created a training pathway for ACHD, open to both pediatric and adult cardiologists, and ACHD is now recognized as a subspecialty of both pediatric and adult cardiology. In addition, the most recent guideline statement from the American College of Cardiology and American Heart Association on the management of patients with ACHD recommends that patients with all but the most simple of lesions be evaluated by ACHD specialists (3). The benefits of these recommendations were demonstrated in a recent population-based study from Quebec, Canada, in which referrals for ACHD specialty care resulted in decreased mortality rates (4). As rates of hospitalization and inpatient care costs among ACHD patients continue to grow and the ACHD population ages, the importance of access to ACHD-trained practitioners will increase (5–8). To meet the growing needs to serve the ACHD population, more ACHD-trained specialists are needed. In 2009, there were just over 2000 board-certified or -eligible pediatric cardiologists in the United States (9). In contrast, only approximately 200 examinees sat for the first ACHD board exam in October 2015. In the US and Canada, however, it is estimated there are now more adults than children living with congenital heart disease (2, 3). 174 In addition to meeting the growing demand for clinical care, more ACHD specialists are needed to broaden the therapeutic options available to improve outcomes in this unique population. The few well-conducted, randomized, placebocontrolled trials in ACHD have failed to demonstrate the efficacy of modern neurohumoral modulation in improving outcomes in ACHD patients (10–16). Although these failures may indicate inefficacy of the tested medications, trends present in these studies suggest that patient heterogeneity and inadequate study power may have contributed to their failure. Continued progress demands cooperation between providers to optimize patient recruitment and to identify novel ACHDspecific outcomes with greater sensitivity to clinical changes in this population. It is essential that adult cardiologists make good on the promises implied by the successes of our pediatric colleagues, to improve quality and quantity of life for ACHD patients. To achieve this goal, the cardiology community must encourage fellowship training in ACHD, increase cooperation between providers, and increase awareness of the importance of diseasespecific care. In this way we can continue to make a major difference in the lives of some of the greatest medical success stories of the last century. —Ari M. Cedars, MD Baylor University Medical Center at Dallas E-mail: [email protected] 1. 2. 3. 4. 5. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 2007;115(2):163–172. Marelli AJ, Ionescu-Ittu R, Mackie AS, Guo L, Dendukuri N, Kaouache M. Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation 2014;130(9):749–756. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, del Nido P, Fasules JW, Graham TPJr, Hijazi ZM, Hunt SA, King ME, Landzberg MJ, Miner PD, Radford MJ, Walsh EP, Webb GD, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Page RL, Riegel B, Tarkington LG, Yancy CW; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; Heart Rhythm Society; International Society for Adult Congenital Heart Disease; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease. J Am Coll Cardiol 2008;52(23):e143–e263. Mylotte D, Pilote L, Ionescu-Ittu R, Abrahamowicz M, Khairy P, Therrien J, Mackie AS, Marelli A. 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Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail 2013;15(6):690–698. Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114(1):48–54. Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sørensen KE, Søndergaard L. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation 2014;130(23):2021–2030. The specialty of adult congenital heart disease 175 Surgical considerations for the explantation of the Parachute left ventricular partitioning device and the implantation of the HeartMate II left ventricular assist device Yazhini Ravi, MD, Shelley Bansal, MD, Paola C. Rosas, MD, PhD, RPh, Ernest L. Mazzaferri Jr., MD, and Chittoor B. Sai-Sudhakar, MD Chronic heart failure is the leading cause of death in the world. With newer therapies, the burden of this disease has decreased; however, a significant number of patients remain refractive to existing therapies. Myocardial infarction often leads to ventricular remodeling and eventually contributes to heart failure. The ParachuteTM (Cardiokinetix, Menlo Park, CA) is the first device designed for percutaneous ventricular restoration therapy, which reduces left ventricular volume and minimizes the risk of open surgical procedures. For the first time, we report a case of explantation of the Parachute ventricular partitioning device and transition to a HeartMate IITM left ventricular assist device and the surgical considerations for a successful outcome. C hronic heart failure (HF) patients with previous anterolateral myocardial infarction resulting in anteroapical regional wall motion abnormality have been treated with the Cardiokinetix Parachute ventricular partitioning device (VPD), which is deployed percutaneously in the left ventricular (LV) cavity to the dysfunctional region (1). While the data from the trial demonstrate improved outcomes, a small percentage of patients continue to deteriorate symptomatically (2, 3). This necessitates consideration for advanced surgical therapies for HF, including heart transplantation and longterm mechanical circulatory support (2, 3). The presence of a VPD and the static LV chamber pose surgical challenges during placement of long-term devices. We report our experience in the successful removal of the VPD and implantation of a left ventricular assist device (LVAD). CASE REPORT A 57-year-old woman with a longstanding history of HF due to morbid obesity was not considered to be a candidate for heart transplantation. She also had hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and depression. She presented with severe chest pain, fatigue, and dizziness and a prior history of numerous percutaneous interventions on the coronary vasculature. In 2009, due to progression of HF, the patient had successful VPD placement. Postimplant, her ejection fraction improved from 15% to 25% with subjective improvement of HF symptoms. However, 24 months after VPD placement, she presented in New 176 York Heart Association class IV HF, and an echocardiogram demonstrated an ejection fraction of <15%. After stabilization with inotropic therapy, the patient underwent a sternotomy, explantation of the VPD, and implantation of an LVAD (HeartMate IITM, Thoratec, Pleasanton, CA) without any complications. A year after the LVAD was placed, it was explanted because it clotted off. The patient survived this incident. Interestingly, she did well for a period of time, but in 2014, she had multiple admissions for HF and was once again screened for the Parachute USA trial. As there were no exclusion criteria for prior LVAD, nor prior Parachute implantations, she was reenrolled (phase 3), and a Parachute device was placed successfully. This patient had the first-ever reimplant of a VPD. She has subsequently done well and is presently listed in class 2 HF. DISCUSSION The Parachute device is made of a self-expanding nitinol frame, an expanded polytetrafluoroethylene impermeable occlusive membrane, and a polymer foot. The Parachute system encompasses the device, balloon, and a delivery system consisting of the catheter and dilator (4). The frame has a conical shape, which has 16 struts, the tips of which have anchors. The anchors stabilize the device in the myocardium. However, these struts have the potential to be firmly adherent to the myocardium after deployment in the LV chamber. Moreover, it is conceivable that the excluded portion of the LV chamber between the VPD and the scarred area of the LV wall harbors a static column of blood, which could lead to thrombus formation (4). The foot is radio-opaque and aids visualization for proper placement of the device under fluoroscopy (3). A median sternotomy is performed and the patient is fully heparinized. Ascending aortic cannulation is carried From the Division of Cardiothoracic Surgery, Department of Surgery, Baylor Scott and White Health, Temple, Texas (Ravi, Sai-Sudhakar); Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, Florida (Bansal); Department of Medical Physiology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas (Rosas); and Department of Cardiology, The Ohio State University, Columbus, Ohio (Mazzaferri). Corresponding author: Yazhini Ravi, MD, 747 Brindley Circles, 2401 S. 31st Street, Temple, TX 76508 (e-mail:[email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):176–177 Figure. Outer surface of the Parachute device showing the areas of thrombus formation and the anchors (struts) with fibrous overgrowth. out by placing an Embol-X (Edwards LifeSciences, Irvine, CA) aortic cannula in the ascending aorta and a dual-stage venous cannula in the right atrium. The size of the ascending aorta is measured and the appropriately sized specialized net is selected and placed through the side port of the aortic cannula and deployed in the ascending aorta. The power source of the LVAD is disconnected and the patient is immediately placed on a full cardiopulmonary bypass circuit. The deployment of the appropriately sized net in the ascending aorta facilitates the capture of any particulate embolic debris that may potentially be dislodged from the LV cavity due to altered flow dynamics in the chamber secondary to discontinuation of LVAD support and initiation of cardiopulmonary bypass. The aorta is cross-clamped. After the patient is placed in a steep Trendelenburg position, the left ventricle is brought into the midline and the apex is cored. Care should be taken to ensure that in the process of LV wall coring, the membranous portion of the VPD is not dam- April 2016 aged by the coring device and hence the problem of distal embolization is avoided. It is imperative to perform a thorough evaluation of the LV chamber excluded by the VPD. This is the region of the LV chamber bounded by the LV scarred akinetic portion and the outer surface of the VPD. The potential for clot formation in this region is significant due to factors including the akinetic nature of the chamber walls and the absence of washout in the space excluded by the VPD (Figure). The clot is carefully evacuated through the cored out LV apex. The self-expanding nitinol frame of the VPD is tipped with pointed barbs which, after initial deployment, are firmly embedded in the LV free wall and septum with development of fibrous tissue around the end regions of the nitinol frame. A gentle inward pressure on each strut of the nitinol frame toward its center dislodges the struts from the LV points of embedment. Subsequently, the VPD is explanted through the LV apex. The outside of the LV wall and ventricular septum are carefully inspected to ensure the absence of partial or full thickness lacerations. The LVAD is then implanted, and the patient is gradually weaned off cardiopulmonary bypass and placed on LVAD support. Prior to decannulation, the net deployed through the aortic cannula is removed and evaluated for the presence of particulate debris. 1. 2. 3. 4. Abraham WT. Could the ParachuteTM ventricular partitioning device be a winner in the fight against heart failure? Expert Rev Cardiovasc Ther 2013;11(3):263–265. Costa MA, Mazzaferri EL Jr, Sievert H, Abraham WT. Percutaneous ventricular restoration using the Parachute device in patients with ischemic heart failure: three-year outcomes of the Parachute first-in-human study. Circ Heart Fail 2014;7(5):752–758. Costa MA, Pencina M, Nikolic S, Engels T, Templin B, Abraham WT. The Parachute IV trial design and rationale: percutaneous ventricular restoration using the Parachute device in patients with ischemic heart failure and dilated left ventricles. Am Heart J 2013;165(4):531–536. Sousa P, Bettencourt N, Ferreira N, de Jesus I, da Gama V. Left ventricular partitioning device (‘Parachute’): a multi-modality imaging perspective. Eur Heart J Cardiovasc Imaging 2014;15(2):225. Surgical considerations for the explantation of the Parachute left ventricular partitioning device 177 Intracranial aneurysm and sildenafil Avinash Adiga, MD, Hawa Edriss, MD, and Kenneth Nugent, MD Sildenafil is one of the most commonly used drugs for the treatment of erectile dysfunction. To date, we found five reported cases of intracerebral bleeding and two reported cases of subarachnoid hemorrhage related to sildenafil use. We report a 49-year-old hypertensive and diabetic patient who presented with acute pulmonary edema and loss of consciousness following ingestion of 100 mg of sildenafil prior to sexual intercourse. He was not previously aware of the presence of an aneurysm and had no family history of it. Computed tomography of his head revealed a subarachnoid hemorrhage due to rupture of a saccular aneurysm with subsequent repeat hemorrhage within a few hours of presentation. A sudden increase in blood pressure led to pulmonary edema. Studies have shown that sildenafil acts on phosphodiesterase-1, -2 and -5 receptors and leads to a secondary increase in intracerebral circulation and vasodilatory effects, leading to sympathetic overactivity which increases the risk for intracranial bleeding. S ildenafil, marketed as Viagra, is a widely used phosphodiesterase (PDE)-5 inhibitor to treat male sexual/erectile dysfunction and to increase libido and sexual performance. The common adverse effects of this drug include headache, flushing, indigestion, and impaired vision. Five cases of intracerebral bleeding and two cases of subarachnoid hemorrhage (SAH) due to sildenafil use have been reported (1–7). We report a 49-year-old man who presented with a hypertensive crisis and an SAH caused by rupture of a saccular intracranial aneurysm during sexual intercourse following sildenafil intake. CASE REPORT A 49-year-old man with diabetes mellitus and hypertension was brought in to the emergency department due to acute-onset shortness of breath and loss of consciousness during sexual intercourse. The patient had ingested 100 mg of sildenafil prior to the event (unknown time gap). Reportedly, he was diaphoretic and short of breath and required intubation due to a low Glasgow Coma Scale score of <7. His blood pressure was 181/105 mm Hg with a mean arterial pressure of 124 mm Hg. His chest examination revealed bibasilar crackles. A neurological examination was not completed because the patient was sedated. His pupils were round and reactive with normal deep tendon reflexes, and he could localize the pain. Routine blood counts, platelet 178 counts, and coagulation factors were normal. His chest x-ray revealed diffuse bilateral opacities consistent with pulmonary edema. An electrocardiogram showed a normal sinus rhythm. An arterial blood gas showed high anion gap (29) metabolic acidosis with respiratory acidosis: pH 7.22; partial pressure of oxygen, 68 mm Hg; partial pressure of carbon dioxide, 42.7 mm Hg; bicarbonate, 17.1 mEq/L; and lactate, 4.7 mmol/L. Bedside transthoracic echocardiography showed normal systolic function with no regional wall motion abnormality and grade II diastolic dysfunction. Computed tomography of the head showed a massive acute SAH with the largest blood collection in the area of the anterior communicating artery with mild hydrocephalus (Figure 1a). The patient was started on mannitol 100 g over 30 minutes and underwent computed tomography angiogram of intracranial vessels, which showed an aneurysm at the junction of the right anterior cerebral artery and anterior communicating artery (Figure 1b). He was urgently taken to the operating room and underwent ventriculostomy. While in the operating room, his ventricular pressures increased, his pupils dilated, suggesting brain herniation, and he underwent bilateral decompressive craniotomy and aneurysm clipping. Postoperatively, his Glasgow Coma Scale score was 3/15, and he was cooled to maintain temperature around 35°C for 48 hours. Because of his low Glasgow Coma Scale score, his chances for safe extubation seemed unlikely, and a tracheostomy and percutaneous endoscopic gastrostomy tube were placed on postoperative day 8. On postoperative day 10, he started to improve slowly, and his Glasgow Coma Scale increased to 15/15 on postoperative day 31. He continued to require a tracheostomy collar and was discharged to a neurorehabilitation institute. DISCUSSION Sildenafil inhibits PDE-5–mediated hydrolysis of cyclic guanosine monophosphate (cGMP), leading to increased intracellular cGMP levels in the vascular smooth muscle of the corpus cavernosum and resulting in smooth muscle relaxation and arterial vasodilation (8). The amount of cGMP in From Texas Tech University Health Science Center, Lubbock, Texas. Corresponding author: Avinash Adiga, MD, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):178–180 a b Figure 1. (a) Computed tomography demonstrating a subarachnoid hemorrhage. (b) Computed tomography angiography showing an anterior carotid artery aneurysm. cerebrovascular smooth muscles is affected by nitric oxide and PDE. Nitric oxide activates guanylate cyclase in the cerebral arterial cells. The activated guanylate cyclase converts guanosine triphosphate to cGMP. The latter causes relaxation of vascular smooth muscle cells in the cerebral vasculature (9, 10). The relationship between intracranial hemorrhage (ICH) and sildenafil use is likely due to increased blood flow to the intracranial vessels, which is significantly increased during sexual intercourse. Increased blood flow to the cerebral blood vessels facilitates rupture of the cerebrovascular vessels in patients with other hemorrhagic risk factors (3). Ballard et al suggested that sildenafil also acts on PDE-1 and PDE-2, which are involved in controlling cerebral circulation (11). Studies on mice have demonstrated that sildenafil decreases cerebral vasospasm by increasing and restoring cGMP levels (12). The reported adverse effects of sildenafil include headache, visual disturbances, pupil-sparing third nerve palsy, and transient hypertension, and these symptoms suggest that sildenafil also affects brain microvasculature regulation (13, 14). Unusual susceptibility to this drug could lead to abnormal vasodilatation of cerebral arteries and abnormal redistribution of arterial blood flow in the brain. The hypothetical relationship between ICH and sildenafil ingestion is not well understood (2, 5). Transcranial Doppler studies have shown that sildenafil increases cerebrovascular reactivity and causes vasodilation with increased blood flow and volume (15). The vasodilatory effect of sildenafil causes hypotension that could lead to an increase in sympathetic activity, which might be the reason for secondary hypertension leading to SAH, as occurred in our case. Ayberk et al reported a case of intracerebral bleed in a healthy 35-year-old man 3 hours after ingestion of 50 mg of sildenafil without any sexual activity (5). This supports our conclusion that sildenafil results in reactive sympathetic hyperactivity that leads to ICH regardless of the presence or absence of other risk factors, such as hypertension and sexual intercourse. Nevertheless, our known hypertensive patient had an elevated blood pressure and SAH after sildenafil use. Whether the hypertensive crisis in this patient caused by sildenafil was secondary to sympathetic hyperactivity or sexual intercourse or whether the ICH itself caused hypertension cannot be determined. Also, we do not know if there is a doserelated effect which causes ICH. All reported patients ingested 50 mg or more (Table 1). Sildenafil citrate has been shown to be safe in patients without cardiovascular disease but is contraindicated in those with acute coronary syndromes, life-threatening coronary arrhythmias, and recent stroke. The US Food and Drug Administration advises Table 1. Reported cases of subarachnoid hemorrhage after sildenafil use Variable Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Our case Age (years) 62 44 62 67 35 49 33 49 Hypertension Yes No Yes No No Unknown No Yes Dose of sildenafil (mg) 50 4 tablets (unknown strength) 50 50 50 Unknown 50 100 15/15 15/15 15/15/drowsy Deceased 15/15 15/15 15/15 15/15 12/15 15/15 Dead on arrival 3/15 Unknown Low/intubated 15/15 Thalamic and capsular Left temporal Right subthalamic Left temporal subcortical Caudate nucleus Left ACA, SAH Right basal ganglia, SAH Right ACA, SAH Glasgow Coma Scale: admission and discharge Type of bleed ACA indicates anterior cerebral artery; SAH, subarachnoid hemorrhage. Cases appear in references 1–7. April 2016 Intracranial aneurysm and sildenafil 179 cautioned use of sildenafil in patients with a history of myocardial infarction or stroke within 6 months and those with resting hypotension, severe hypertension (<170/110 mm Hg), and heart failure (16). All five previously reported intracerebral hemorrhages with sildenafil use presented with minimal volume hemorrhage in elderly patients with a risk factor of ICH, and surgical evacuation was not required (Table 1) (1–5). However, the previous two reports of SAH with sildenafil use were associated with severe bleeding (6, 7). One patient required emergency decompression due to impending herniation, and the other patient was pronounced dead on arrival (6, 7). Our patient rebled following the initial SAH and underwent ventriculostomy and bilateral decompressive craniotomy. His neurological status improved tremendously, and his Glasgow Coma Scale score was 15/15 on discharge. In conclusion, sildenafil is a relatively safe and widely used medication to treat erectile dysfunction. However, serious complications, such as severe ICH and SAH, have been reported with its use. 1. 2. 3. 4. 5. 180 Alpsan MH, Bebek N, Ciftci FD, Coban O, Bahar S, Tuncay R. Intracerebral hemorrhage associated with sildenafil use: a case report. J Neurol 2008;255(6):932–933. Buxton N, Flannery T, Wild D, Bassi S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg 2001;15(4):347–349. Martí I, Martí Massó JF. Hemiballism due to sildenafil use. Neurology 2004;63(3):534. Monastero R, Pipia C, Camarda LK, Camarda R. Intracerebral haemorrhage associated with sildenafil citrate. J Neurol 2001;248(2):141–142. Ayberk G, Ozveren MF, Yaman ME, Tosun H. Intracerebral hemorrhage after sildenafil citrate use: an incidental association? Urol J 2014;11(2):1524–1526. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Byoun HS, Lee YJ, Yi HJ. Subarachnoid hemorrhage and intracerebral hematoma due to sildenafil ingestion in a young adult. J Korean Neurosurg Soc 2010;47(3):210–212. De-Giorgio F, Arena V, Arena E, Arena E, Lodise M, Valerio L, d’Aloja E, Chiarotti M. Subarachnoid hemorrhage during sexual activity after sildenafil intake: an accidental association? Am J Forensic Med Pathol 2011;32(4):310–311. McHugh J, Cheek DJ. Nitric oxide and regulation of vascular tone: pharmacological and physiological considerations. Am J Crit Care 1998;7(2):131–140. Inoha S, Inamura T, Ikezaki K, Nakamizo A, Amano T, Fukui M. Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model. Neurol Res 2002;24(6):607– 612. Sobey CG, Quan L. Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. Am J Physiol 1999;277(5 Pt 2):H1718–H1724. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998;159(6):2164–2171. Han BH, Vellimana AK, Zhou ML, Milner E, Zipfel GJ. Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage. Neurosurgery 2012;70(1):178–186. Donahue SP, Taylor RJ. Pupil-sparing third nerve palsy associated with sildenafil citrate (Viagra). Am J Ophthalmol 1998;126(3):476–477. Vobig MA, Klotz T, Staak M, Bartz-Schmidt KU, Engelmann U, Walter P. Retinal side-effects of sildenafil. Lancet 1999;353(9150):375. Brenner S, Diomedi M, Sallustio F. Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study. Neurology 2006;66(9):1455– 1456. Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol 1999;83(4):576–582, A7. Baylor University Medical Center Proceedings Volume 29, Number 2 Infective endocarditis caused by Klebsiella oxytoca in an intravenous drug user with cancer Ashref Mohamed, MD, Connor Hall, MS, PhD, Michael Hatch, MS, Mohamed Ayan, MBBCh, and Richard Winn, MD Infective endocarditis caused by Klebsiella species is rare, with most isolates being K. pneumoniae. We report the case of a 24-year-old intravenous drug user with newly diagnosed seminoma who developed K. oxytoca endocarditis. In addition to having K. oxytoca isolated from blood culture, cultures of that species were obtained from a retroperitoneal metastasis found on original presentation. I nfective endocarditis caused by Klebsiella species is a rare event, accounting for ≤1.2% cases of native valve endocarditis and up to 4.1% cases of prosthetic valve endocarditis (1). Of these, most are caused by K. pneumoniae. K. oxytoca is implicated in a significant minority of endocarditis cases caused by Klebsiella species, with only 5 reported cases (2–6). Most cases of K. oxytoca endocarditis occur in the elderly and are nosocomial. Here we report a case of community-acquired K. oxytoca in an intravenous drug abuser coinciding with newly diagnosed testicular cancer. CASE PRESENTATION A 24-year-old man presented to the emergency department with a 1-week history of fluctuating back and flank pain associated with fever. He first presented to an outside hospital after experiencing sudden-onset fever, chills, sweats, pallor, and dyspnea. At that visit, his temperature was 102°F, and a computed tomography (CT) scan of the abdomen without contrast revealed a large perinephric mass. The patient was sent to our facility for further management. In the emergency department, his blood pressure was 107/65 mm Hg; heart rate, 116 beats/minute; respiratory rate, 16 breaths/minute; and temperature, 97.7°F. Examination revealed right upper-quadrant tenderness on deep palpation and normal heart sounds with no murmur. His electrocardiogram was unremarkable. His hemoglobin was 12.2 g/dL; white blood cell count, 21,890/uL; alkaline phosphatase, 489 IU/L; aspartate aminotransferase, 199 IU/L; and alanine aminotransferase, 223 IU/L. Blood cultures were obtained and he was started on empiric vancomycin and meropenem for concerns of abscess and sepsis. Repeat CT scan with contrast confirmed a peripherally enhancing right retroperitoneal mass measuring 6.4 × 7.5 × 9.1 cm with central hypodensity, suggestive of a necrotic lymph node and concerning for malignancy (Figure 1). A 12 French drain- Proc (Bayl Univ Med Cent) 2016;29(2):181–182 Figure 1. CT scan of the abdomen with contrast showing a retroperitoneal mass with abscess formation. age catheter was placed, and 80 mL of purulent thick fluid was aspirated and submitted for gram stain, cultures, and cytology. An additional 160 mL of fluid was drained over the next 3 days. On follow-up, he reported having a 3-month history of an enlarging testicular mass. Following ultrasound concerning for malignancy, a radical right orchiectomy was performed showing classic seminoma, and further imaging staged the cancer as stage IIIB due to involvement of retroperitoneal and mediastinal lymph nodes. Meanwhile, blood cultures obtained in the emergency department as well as the outside hospital revealed growth of K. oxytoca. Vancomycin was discontinued. On hospital day 5, the patient’s fever spiked to 102.9°F, and a holosystolic murmur most prominent over the apex was discovered. At this point, the patient admitted to injection of amphetamines diluted with tap water 1.5 weeks prior to admission. Transesophageal echocardiogram revealed 0.44 × 0.17 cm vegetation on the posterior mitral valve leaflet (Figure 2). In From the Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas (Mohamed, Hall, Hatch, Winn); and Creighton University Medical Center, Omaha, Nebraska (Ayan). Corresponding author: Ashref Mohamed, MD, Department of Internal Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430 (e-mail: [email protected]). 181 Figure 2. Transesophageal echocardiogram revealing 0.44 × 0.17 cm vegetation on the posterior mitral valve leaflet. addition, CT-guided drainage of the retroperitoneal mass grew K. oxytoca and also contained malignant cells. Repeat CT scan 4 days after drain placement showed a reduction in mass size to 5.5 × 5.0 × 8.0 cm. The patient’s fever abated, and follow-up blood cultures were negative. Intravenous meropenem was continued for 6 weeks with no complications. No follow-up echocardiogram was performed as the patient was lost to follow-up. DISCUSSION This is a rare case of infective endocarditis of the mitral valve caused by K. oxytoca in an intravenous drug user. The diagnosis of infective endocarditis is based on the modified Duke criteria: one major criterion (intracardiac mass on the mitral valve) and three minor criteria (fever, positive blood culture, and predisposing intravenous drug use) (7). K. oxytoca endocarditis is extremely rare. The five reported cases are summarized in Table 1 (2–6). Of those cases, two were community acquired, as was Table 1. Previously reported cases of infective endocarditis caused by Klebsiella oxytoca Case (ref) Age/sex Presentation Mode of entry Treatment Watanakunakorn, 87 M 1985 (2) UTI, bacteremia, IE After transurethral resection of the prostate Cefazolin, tobramycin Repiso et al, 2001 (3) 33 M Bacteremia, IE (BP PV) Intravenous drug user Cefotaxime, gentamicin Chen et al, 2006 (4) 71 F Bacteremia, IE (MV) Community acquired, unknown mode of entry Cefazolin de Escalante et al, 2007 (5) 75 M Bacteremia, IE (AV) Following AAA Imipenem, repair gentamicin Duggal et al, 2012 (6) 66 M Bacteremia, IE (BP AV) Ceftriaxone, Community gentamicin acquired, unknown mode of entry AAA indicates abdominal aortic aneurysm; AV, aortic valve; BP, bioprosthetic; IE, infective endocarditis; MV, mitral valve; PV, pulmonary valve; UTI, urinary tract infection. 182 this case (4). Fortunately, K. oxytoca endocarditis appears to have favorable outcomes, as reported cases show resolution with antibiotics alone (2, 4, 6). In contrast, K. pneumoniae endocarditis has a 49% mortality rate, and 44% of patients ultimately require valve replacement (1). K. oxytoca is an opportunistic gram-negative rod that is differentiated from K. pneumoniae by its indole positivity. Intravenous drug use is a significant risk factor for the development of infective endocarditis and a probable mode of entry in this patient, who had a history of injecting tap water-diluted intravenous drugs (8). Over 90% of infectious endocarditis cases in intravenous drug users are caused by gram-positive cocci, specifically staphylococci or streptococci, but other organisms are possible (9). In addition, neoplasia is a predisposing factor for developing K. oxytoca bacteremia (10). It is possible that this patient had prior metastatic spread of his seminoma to a retroperitoneal lymph node. He then seeded his blood with K. oxytoca through the injection of amphetamines diluted in tap water, where the bacteria then simultaneously colonized the necrotic lymph node and mitral valve, colonized the mitral valve with subsequent septic embolization to the lymph node, or colonized the necrotic lymph node with subsequent colonization of the mitral valve. Documented modes of entry for K. oxytoca in cases of bacteremia include, in descending order, the hepatobiliary tract (50%–55%), intravascular or urinary catheters (7%–16%), the urinary tract (5%–6%), skin and soft tissues (3%–5%), and the peritoneal cavity (2%–6%), while 23% to 34% of infections have no identifiable ports of entry (10, 11). Therefore, defining the precise route of entry in this patient is difficult, but intravenous drug use is strongly supported as the causal mechanism. Anderson MJ, Janoff EN. Klebsiella endocarditis: report of two cases and review. Clin Infect Dis 1998;26(2):468–474. 2. Watanakunakorn C. Klebsiella oxytoca endocarditis after transurethral resection of the prostate gland. South Med J 1985;78(3):356–357. 3. Repiso M, Castiello J, Repáraz J, Uriz J, Sola J, Elizondo MJ. Endocarditis caused by Klebsiella oxytoca: a case report. Enferm Infecc Microbiol Clin 2001;19(9):454–455. 4. Chen JY, Chen PS, Chen YP, Lee WT, Lin LJ. Community-acquired Klebsiella oxytoca endocarditis: a case report. J Infect 2006;52(5):e129–e131. 5. de Escalante Yangüela B, Aibar Arregui MA, Muñoz Villalengua M, Olivera González S. Klebsiella oxytoca nosocomial endocarditis. Med Interna 2007;24(11):563–564. 6. Duggal A, Waraich KK, Cutrona A. Klebsiella oxytoca endocarditis in a patient with a bioprosthetic aortic valve. Infect Dis Clin Pract 2012;20(3):224–225. 7. Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med 2013;368(15):1425–1433. 8. Tung MK, Light M, Giri R, Lane S, Appelbe A, Harvey C, Athan E. Evolving epidemiology of injecting drug use-associated infective endocarditis: a regional centre experience. Drug Alcohol Rev 2015;34(4):412–417. 9. Mathew J, Addai T, Anand A, Morrobel A, Maheshwari P, Freels S. Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 1995;155(15):1641–1648. 10. Lin RD, Hsueh PR, Chang SC, Chen YC, Hsieh WC, Luh KT. Bacteremia due to Klebsiella oxytoca: clinical features of patients and antimicrobial susceptibilities of the isolates. Clin Infect Dis 1997;24(6):1217–1222. 11. Kim BN, Ryu J, Kim YS, Woo JH. Retrospective analysis of clinical and microbiological aspects of Klebsiella oxytoca bacteremia over a 10-year period. Eur J Clin Microbiol Infect Dis 2002;21(6):419–426. 1. Baylor University Medical Center Proceedings Volume 29, Number 2 Rapidly enlarging neck mass in a neonate causing airway compromise Kyra Schmidt, BS, Andres Leal, MD, Thomas McGill, MD, and Roy Jacob, MD Up to 20% of all congenital pediatric head and neck masses are branchial cleft cysts. Second branchial cleft cysts account for 95% of branchial anomalies, and fourth branchial cleft cysts are the rarest type. Their typical presentations include non–life-threatening symptoms, such as drainage, skin irritations, minor swelling, and tenderness. We describe a 5-week-old neonate with increasing stridor secondary to a rapidly growing neck mass. Imaging and surgical excision confirmed the mass to be an infected fourth branchial cleft cyst. W e describe a neonate with a neck mass causing airway compromise. Branchial cleft anomalies comprise up to 20% of all congenital pediatric head and neck lesions (1). Branchial cleft anomalies form when there is an abnormality in the obliteration of the clefts in between the branchial arches (2). Of these anomalies, fourth branchial cleft anomalies are rarest and are typically found in the lower third of the neck on the left side (2, 3). Discovery often occurs after infection of the cyst and resultant suppurative thyroiditis (4). Fourth cleft cysts have been reported to occur at any age, including in utero. Typically, branchial cleft cysts have non–lifethreatening symptoms including drainage, skin irritation, minor swelling, and tenderness, but if infected can result in difficulty swallowing and breathing due to mass effect. CASE DESCRIPTION A 5-week-old neonate was brought to the emergency department with difficulty breathing and a left-sided neck mass. The mother reported that the infant had increased difficulty breathing at night and when crying for the past 1 week. He also had vomiting for 1 week with decreased appetite. The mass had been noticed 4 weeks earlier and had been progressively increasing in size. The child was alert and comfortable at rest in the mother's arms. However, when placed supine, he became agitated and exhibited stridor and respiratory distress. A 5 × 4 cm mass was identified on the left side of the neck, crossing the midline (Figure 1). An ultrasound of the neck showed a mass with heterogeneous echogenicity with predominantly solid components and minimal vascularity (Figure 2). Computed tomography (CT) of the neck with intravenous contrast demonstrated a nonenhancing mass Proc (Bayl Univ Med Cent) 2016;29(2):183–184 Figure 1. Five-week-old with mass in left side of neck and resulting rightward shift of the trachea. Figure 2. Ultrasound shows a solid mass in the left side of the neck with minimal vascularity. From the Texas Tech University Health Sciences Center School of Medicine (Schmidt); and the Departments of Surgery (Leal, McGill) and Radiology (Jacob), Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas. Corresponding author: Roy Jacob, MD, Department of Radiology, University Medical Center, Texas Tech University, 602 Indiana Avenue, Lubbock, TX 79415 (e-mail: [email protected]). 183 (5–9). In this case, CT imaging was useful in determining the extent of the mass and identified structures at risk during excision. It also showed the involvement of the left lobe of the thyroid gland. Treatment of branchial cleft cysts is complete excision after infancy, to prevent recurrent infection and abscess formation as well as mass effect on local structures (10–12). Airway compromise and respiratory distress are indications for emergent surgery. This case illustrates that fourth branchial cleft cysts can rapidly increase in size and compromise the airway and should be considered in the differential diagnosis while evaluating a neonatal neck mass. 1. Figure 3. CT of the neck shows the mass involving the left lobe of the thyroid gland along with mass effect and rightward displacement of the trachea. in the left side of the neck at the base with involvement of the left lobe of the thyroid gland as well as significant compression of the trachea (Figure 3). The mass was excised, and histologic study disclosed it to be a fourth branchial cleft cyst. DISCUSSION When presented with a neck mass in a neonate, differentials include rhabdomyosarcoma, teratoma, venolymphatic malformations, fibromatosis colli, and a branchial cleft cyst. Venolymphatic malformations are typically soft, compressible, and nonpulsatile. Clinical findings are nonspecific in the other differentials. Ultrasound and CT imaging were helpful in diagnosis. While ultrasound has a low predictive power for third or fourth branchial cleft anomalies, ultrasound imaging in this case was used to eliminate venolymphatic malformations and fibromatosis colli from the differential diagnosis (5). CT is the most common diagnostic tool for branchial anomalies, with a positive branchial anomaly identification rate as high as 64% 184 Goff CJ, Allred C, Glade RS. Current management of congenital branchial cleft cysts, sinuses, and fistulae. Curr Opin Otolaryngol Head Neck Surg 2012;20(6):533–539. 2. Waldhausen JH. Branchial cleft and arch anomalies in children. Semin Pediatr Surg 2006;15(2):64–69. 3. Nicoucar K, Giger R, Pope HG Jr, Jaecklin T, Dulguerov P. Management of congenital fourth branchial arch anomalies: a review and analysis of published cases. J Pediatr Surg 2009;44(7):1432–1439. 4. Nicollas R, Ducroz V, Garabédian EN, Triglia JM. Fourth branchial pouch anomalies: a study of six cases and review of the literature. Int J Pediatr Otorhinolaryngol 1998;44(1):5–10. 5. Nicoucar K, Giger R, Jaecklin T, Pope HG Jr, Dulguerov P. Management of congenital third branchial arch anomalies: a systematic review. Otolaryngol Head Neck Surg 2010;142:21–28; e2. 6. Schroeder JW Jr, Mohyuddin N, Maddalozzo J. Branchial anomalies in the pediatric population. Otolaryngol Head Neck Surg 2007;137(2):289–295. 7. Acierno SP, Waldhausen JH. Congenital cervical cysts, sinuses and fistulae. Otolaryngol Clin North Am 2007;40(1):161–176, vii-viii. 8. Mitroi M, Dumitrescu D, Simionescu C, Popescu C, Mogoantă C, Cioroianu L, Surlin C, Căpitănescu A, Georgescu M. Management of second branchial cleft anomalies. Rom J Morphol Embryol 2008;49(1):69–74. 9. D’Souza AR, Uppal HS, De R, Zeitoun H. Updating concepts of first branchial cleft defects: a literature review. Int J Pediatr Otorhinolaryngol 2002;62(2):103–109. 10. Choi SS, Zalzal GH. Branchial anomalies: a review of 52 cases. Laryngoscope 1995;105(9 Pt 1):909–913. 11. Reiter D. Third branchial cleft sinus: an unusual cause of neck abscess. Int J Pediatr Otorhinolaryngol 1982;4(2):181–186. 12. Ford GR, Balakrishnan A, Evans JN, Bailey CM. Branchial cleft and pouch anomalies. J Laryngol Otol 1992;106(2):137–143. Baylor University Medical Center Proceedings Volume 29, Number 2 Serendipitous discovery of peritoneal mesothelioma Adam Jaster, MD, and Jason Wachsmann, MD We present the case of a 64-year-old patient with a history of BirtHogg-Dube syndrome, polycystic kidney disease treated with renal transplantation in May 2013, and multiple types of skin cancers, including malignant melanoma. He presented for lymphoscintigraphy for sentinel lymph node identification of the melanoma. Subsequent biopsy of the right axillary sentinel lymph node yielded a diagnosis of epithelial type malignant mesothelioma without a known primary tumor. Follow-up positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose integrated with computed tomography (F-18 FDG PET/CT) demonstrated several suspicious hypermetabolic abdominal masses that were later confirmed to be epithelial-type mesothelioma via percutaneous biopsy. M alignant mesothelioma is a rare tumor that originates from the cells lining the mesothelial surfaces, including the pleura, peritoneum, pericardium, and tunica vaginalis. The most common subtype of mesothelioma is the pleural form (1). Malignant peritoneal mesothelioma (MPM) accounts for about 12.5% to 25% of malignant mesotheliomas and typically occurs in middle-aged men with a variety of abdominal symptoms (2). MPM is a very aggressive tumor that may present as either a localized or diffuse form. The diffuse form typically is more aggressive and has a worse prognosis (3). CASE REPORT A 64-year-old man presented to his dermatologist for a new skin lesion in the anterior chest wall. He had a history of Birt-Hogg-Dube syndrome, polycystic kidney disease treated with renal transplantation in May 2013, and multiple types of skin cancers, including malignant melanoma. Shave biopsy of the new lesion demonstrated melanoma. Subsequent lymphoscintigraphy performed with 55.5 Mbq of Tc99m sulfur colloid showed a right axillary sentinel lymph node. The pathologic evaluation of this lymph node unexpectedly revealed malignant mesothelioma, epithelial type. The patient then underwent computed tomography (CT) of the chest, which was negative for thoracic mesothelioma. In an attempt to locate the primary lesion, a whole body Proc (Bayl Univ Med Cent) 2016;29(2):185–187 Figure 1. Lymphoscintigraphy performed with 55.5 Mbq of Tc-99m sulfur colloid showed a right axillary sentinel lymph node (arrow). 2-deoxy-2-(fluorine-18)fluoro-D-glucose positron emission tomography (F-18 FDG PET) integrated with CT was performed. This showed abnormal radiotracer uptake within two separate regions of the anterior abdominal wall, as well as the right inguinal region. Uptake related to the excisional biopsies of the melanoma and previously described right axillary sentinel lymph node were also noted (Figure 2). After a diagnosis of MPM was made via percutaneous biopsy of an anterior abdominal wall mass, a review of prior imaging was performed. Magnetic resonance imaging (MRI) of the abdomen from November 2005 depicted an enhancing anterior periumbilical mass (Figure 3). DISCUSSION The main risk factor for MPM is asbestos exposure; however, it is believed that this association is not as strong as the one between asbestos exposure and pleural mesothelioma From the Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Jason Wachsmann, MD, Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8896 (e-mail: [email protected]). 185 a b c d Figure 2. (a) Whole-body MIP image from an F-18 FDG PET/CT demonstrates abnormal radiotracer uptake within the two separate regions of the anterior abdominal wall as well as the right inguinal region (solid red arrows). Linear uptake in the right back and axilla (blue dashed arrows) corresponds to the melanoma excision and axillary node dissection sites. (b) Sagittal whole-body image from the same patient shows abnormal focal radiotracer uptake in two separate areas of the anterior abdominal wall (white arrows). (c) Transaxial CT and (d) FDG-18 PET/CT images at the level of the superiorly located abdominal wall mass show abnormal radiotracer uptake in the midline anterior wall on FDG-18 PET/CT, which corresponds with the anterior abdominal wall mass seen on CT (orange arrow). Also shown in these images are a right renal transplant (curved arrow) and polycystic left kidney (thin arrow). a (4, 5). Other proposed risk factors include simian vacuolating virus, familial Mediterranean fever, and mesothelioma susceptibility syndrome with BRCA germline mutations. Classically this tumor has a rapidly fatal course with a median survival time of 6 to 12 months. Since the disease is rare, information regarding the exact incidence, natural history, and risk factors is limited. Our patient had a history of Birt-Hogg-Dube syndrome, which is a genetic syndrome that classically involves an increased incidence of renal carcinoma, spontaneous pneumothorax, pulmonary cysts, and various skin lesions. However, the syndrome does not have a known association with mesothelioma. The preliminary staging evaluation of peritoneal mesothelioma and subsequent follow-up imaging can be performed with CT, MRI, or FDG-PET. The evaluation of peritoneal mesothelioma by FDG-PET had an accuracy of 82% in a large study that retrospectively evaluated 60 patients with this disease. This study also demonstrated that in 15 of these patients with a posttreatment negative FDG-PET study, subsequent follow-up exams accurately detected disease recurrence or further disease absence in all cases (6). Multiple other case reports have utilized FDGPET to assist in diagnosis, staging, and monitoring of therapy (7, 8). MPM is classically a very rare and aggressive tumor involving the peritoneum. Of all documented mesotheliomas, it is second to pleural mesothelioma with an incidence of 10% to 30%. The estimated incidence of this disease is 200 to 400 cases annually. Our case did not follow the classic route in the workup of MPM. b Figure 3. (a) Precontrast and (b) postcontrast transaxial spoiled gradient echo MR images from November 2005, which depict an enhancing anterior periumbilical mass that was biopsied in September 2014 and proven to be epithelial-type peritoneal mesothelioma (red arrow). Changes of polycystic kidney disease are also shown in these images (green arrows). 186 Baylor University Medical Center Proceedings Volume 29, Number 2 1. van Meerbeeck JP, Scherpereel A, Surmont VF Baas P. Malignant pleural mesothelioma: the standard of care and challenges for future management. Crit Rev Oncol Hematol 2011;78(2):92–111. 2. Saraya T, Yokoyama T, Ishii H, Tanaka Y, Tsujimoto N, Ogawa Y, Sohara E, Nakajima A, Inui T, Sayuki H, Fujiwara M, Oka T, Kawachi R, Goya T, Takizawa H, Goto H. A case of malignant peritoneal mesothelioma revealed with limitation of PET-CT in the diagnosis of thoracic metastasis J Thorac Dis 2013;5(1):E11–E16. 3. Ozguven S , Aras M , Dede F, Ones T Turoglu HT Scrotal peritoneal mesothelioma on PET/CT. Clin Nucl Med 2014;39(12):1045– 1046. 4. 5. 6. 7. 8. Bridda A, Padoan I, Mencarelli R, Frego M. Peritoneal mesothelioma: a review. MedGenMed 2007;9(2):32. Raza A, Huang WC, Takabe K. Advances in the management of peritoneal mesothelioma. World J Gastroenterol 2014;20(33)11700–11712. Vilardell AD, Rasiej MJ, Taub RN, Ichise M. Clinical utility of 18F-FDG positron emission tomography in malignant peritoneal mesothelioma. Q J Nucl Med Mol Imaging 2014 Apr 14 [Epub ahead of print]. Cao Q, Lu M, Heath J, Hausner PF, Alexander HR, Dilsizian V, Chen W. 18F-FDG PET/CT in a recurrent diffuse malignant peritoneal mesothelioma. Clin Nucl Med 2012;37(5):492–494. Nguyen BD. PET/CT demonstration and monitoring of thoracic and abdominal wall mesothelioma. Clin Nucl Med 2014;39(1) e106–e109. Avocations Indian Paintbrush blossom. Photo by Rolando M. Solis, an interventional cardiologist at Baylor Scott and White Health Garland and The Heart Hospital Baylor Plano. He can be reached by e-mail at [email protected]. April 2016 Serendipitous discovery of peritoneal mesothelioma 187 Pneumomediastinum, pneumorrhachis, and subcutaneous emphysema in Pneumocystis jiroveci pneumonia in AIDS Nasir Saleem, MD, Sanober Parveen, MD, Chibuzo Odigwe, MD, and Nkemakolam Iroegbu, MD, MPH Pneumomediastinum, the presence of free air within the mediastinal cavity, is sometimes accompanied by subcutaneous emphysema and pneumorrhachis (air within the spinal canal). We report the case of a 28-year-old man with previously undiagnosed HIV who was diagnosed with extensive pneumomediastinum, pneumorrhachis, and subcutaneous emphysema secondary to Pneumocystis jiroveci pneumonia after presenting with chest pain, dyspnea, and central cyanosis. Surgical consultation was requested, but a conservative approach of observation proved sufficient as the free air was resorbed into the surrounding tissues. P neumocystis jiroveci pneumonia is a common opportunistic infection in patients with AIDS and low CD4 counts <200 cells/mm3. In most cases, P. jiroveci pneumonia presents with chest pain, cough, shortness of breath, and hypoxemia. It has a high mortality rate unless treated promptly with antibiotics and, if severe, steroids. Pneumatoceles that form as a complication of P. jiroveci pneumonia can rupture, allowing air to leak and spread along the peribronchial linings and facial planes of the chest, neck, and axilla to give rise to subcutaneous emphysema, pneumomediastinum, and in some severe cases pneumorrhachis (1–3). Noninvasive imaging studies such as chest x-ray and computed tomography (CT) scan of the chest are usually enough to detect these findings. Pneumomediastinum, pneumorrhachis, and subcutaneous emphysema usually resolve spontaneously, and a conservative strategy of close monitoring and observation may be sufficient. CASE REPORT A 28-year-old man with no significant past medical history presented to the emergency department with substernal chest pain, dyspnea, orthopnea, and central cyanosis of 1 week duration. The symptoms progressively worsened and became very severe the night prior to his presentation. He reported fever, malaise, fatigue, and mild cough productive of clear, whitish sputum. He denied any trauma, allergies, sick contacts, recent travels, or similar episodes in the past. He reported a weight loss of about 90 lbs over the preceding year. The patient reported that he had not been sexually active for the previous 9 months but had been sexually active with both men and women and used barrier protection inconsistently. On examination, he ap188 peared in moderate to severe distress and had central cyanosis, with a pulse of 109 beats/minute, blood pressure of 132/79 mm Hg, temperature of 97.5°F, respiratory rate of 26 breaths per minute, and oxygen saturation of 76% on room air. He was placed on a nonrebreather mask, and his oxygen saturation improved to 96% to 99%. There was minimal crepitus on palpation of the neck and chest wall and scattered crackles throughout both lungs. Chest radiographs revealed diffuse bilateral opacities, marked subcutaneous emphysema in the neck, and pneumomediastinum (Figure 1a). A subsequent CT scan of the chest confirmed these findings and also showed emphysema in the axilla and pneumorrhachis (epidural pneumatosis) in the thoracic spinal canal (Figures 2). The patient’s HIV test was positive. Given the high suspicion for pneumocystis pneumonia in the presence of HIV infection, the patient was started empirically on intravenous trimethoprim-sulphamethoxazole and prednisone. Over the following 2 days, the dyspnea and chest pain disappeared. He was transitioned to nasal cannula oxygen. Subsequent chest radiographs revealed significant improvement in the extent of subcutaneous emphysema and pneumomediastinum (Figure 1b). Once stable, the patient underwent bronchoscopy, and bronchial washings confirmed the presence of P. jiroveci pneumonia on Gomori methenamine silver staining. Direct fluorescent antibody on the bronchial washings also confirmed the presence of P. jiroveci pneumonia. The patient had an HIV viral load of 485,425/mm3 and CD4 count of 24. On day 5 of his hospitalization, he was switched to oral trimethoprimsulphamethoxazole and prednisone and was discharged in stable condition to continue outpatient follow-up for reassessment and preparation for initiating highly active antiretroviral therapy. DISCUSSION Spontaneous pneumomediastinum—the presence of free air in the mediastinum without an obvious etiology—occurs in 1 in 30,000 emergency department visits (1, 2). The co-occurrence From the Department of Medicine, Presence St. Joseph Hospital, Chicago, Illinois. Corresponding author: Chibuzo Odigwe, MD, Department of Medicine, Presence St. Joseph Hospital, 2900 N. Lakeshore Drive, Chicago, IL 60657 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):188–190 b a Figure 1. (a) Chest x-ray showing bilateral pulmonary infiltrates with prominent symmetrical pneumomediastinum (black arrow) associated with subcutaneous emphysema in the base of the neck and along both shoulders (white arrows) and axilla (white arrowhead). (b) Chest x-ray, day 3, showing decreased amount of pneumomediastinum (white arrow) and subcutaneous emphysema in the soft tissues of the neck. Air in the axillary regions is almost totally resorbed (white arrowhead). of spontaneous pneumomediastinum and pneumorrhachis is rare, and few cases have been reported (3–5). Spontaneous pneumomediastinum occurs with abrupt transalveolar pressure gradient increases like a Valsalva maneuver, violent coughing, or intense physical exertion. The pathophysiologic process was described by Macklin in 1939 (6). The Macklin effect refers to an alveolar rupture with air dissection along the interstitial sheaths toward the mediastinum, eventually leading to a pneumomediastinum (7). Alveolar rupture is responsible for more than 95% of cases and is a more frequent cause than esophageal and tracheobronchial disruptions (7). The clinical presentation of pneumomediastinum is benign and self-limiting. The most common complaints are chest pain and dyspnea; chest pain is commonly pleuritic and retrosternal. CT of the chest is the gold standard for diagnosis. If suspicion for aerodigestive tract perforation is high, a barium swallow, a esophagoscopy, or bronchoscopy may be performed. The management of patients with spontaneous pneumomediastinum is conservative, consisting of rest, analgesics, and close observation. The utility of antibiotics, oxygen therapy, and restriction of oral intake is debatable (1). Although pneumomediastinum is benign, the risk of tension pneumomediastinum or pneumothorax justifies close clinical observation. Pneumopericardium may also occur, with complications such as air tamponade and cardiac herniation (8, 9). For the management of pneumomediastinum, Okada et al (8) proposed that patients without (i) fever <38°C, (ii) oxygen desaturation <96%, (iii) progressive symptoms, (iv) vomiting at the onset, and (v) anxiety should receive ambulatory care. Pneumorrhachis is usually an asymptomatic radiologic finding (9). Pneumorrhachis can be classified into traumatic, nontraumatic, and iatrogenic types (4). Pneumorrhachis usually b Figure 2. (a) Chest CT scan and (b) mediastinal window showing bilateral ground-glass infiltrates, subcutaneous emphysema in the lateral chest wall and axillary region (white arrowhead), free air surrounding mediastinal vascular structures (blue arrow), massive pneumomediastinum (white arrow), and free air in the thoracic spinal canal (black arrow). April 2016 Pneumomediastinum, pneumorrhachis, and subcutaneous emphysema in Pneumocystis jiroveci pneumonia in AIDS 189 does not cause any symptoms and is commonly detected incidentally. Pneumorrhachis without associated trauma or intervention is rare (9, 10). There are few reports of combined pneumomediastinum and extradural pneumorrhachis not associated with trauma (9, 10). Our patient developed pneumorrhachis, pneumomediastinum, pneumothorax, and surgical emphysema in the absence of trauma. In trauma victims, these findings may suggest spinal fracture or hidden severe injuries. Pneumorrhachis can be diagnosed on a radiograph or a CT scan of the spine, with CT being preferred (4, 11). The accumulated air may cause symptoms like mild radicular pain, neurological compression, and sequelae such as paraplegia (9, 10, 12). Spontaneous pneumorrhachis does not require a specific intervention, as most cases are self-limiting. Spontaneous resorption of the air within 2 to 3 weeks commonly occurs (8–10). Surgical intervention can be considered when air acts as a space-occupying lesion, causing pressure on nervous structures and resulting in neurological deficits (8–10). Pneumomediastinum is a rare complication of P. jiroveci pneumonia and has been reported at the time of diagnosis, mechanical ventilation, and trimethoprim-sulfamethoxazole treatment (11, 13, 14). In our case, we gave antimicrobial therapy for P. jiroveci pneumonia early and adopted a conservative strategy. Our case is unique as the patient, with previously undiagnosed HIV/AIDS, presented with extensive pneumomediastinum, pneumorrhachis, and subcutaneous emphysema caused by P. jiroveci pneumonia. Although pneumomediastinum has been described in relation with P. jiroveci pneumonia, concurrent pneumorrhachis related to the same etiology has rarely been reported. 2. 1. 14. 190 Jung H, Lee SC, Lee DH. Kim G-J. Spontaneous pneumomediastinum with concurrent pneumorrhachis. Korean J Thorac Cardiovasc Surg 2014;47(6):569–571. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Newcomb AE, Clarke CP. Spontaneous pneumomediastinum: a benign curiosity or a significant problem? Chest 2005;128(5):3298–3302. Carolan PL, Wright SL, Jha V. Spontaneous pneumorrhachis. Pediatr Emerg Care 2013;29(4):508–509. Karaoglan A, Cal MA, Orki A, Arpaozu BM, Colak A. Pneumorrhachis associated with bronchial asthma, subcutaneous emphysema and pneumomediastinum. Turk Neurosurg 2011;21(4):666–668. Manden PK, Siddiqui AH. Pneumorrhachis, pneumomediastinum, pneumopericardium and subcutaneous emphysema as complications of bronchial asthma. Ann Thorac Med 2009;4(3):143–145. Chassagnon G, Favelle O, Derogis V, Cottier JP. Spontaneous pneumomediastinum due to the Macklin effect: less is more. Intern Emerg Med 2015;10(6):759–761 Sakai M, Murayama S, Gibo M, Akamine T, Nagata O. Frequent cause of the Macklin effect in spontaneous pneumomediastinum: demonstration by multidetector-row computed tomography. J Comput Assist Tomogr 2006;30(1):92–94. Okada M, Adachi H, Shibuya Y, Ishikawa S, Hamabe Y. Diagnosis and treatment of patients with spontaneous pneumomediastinum. Respir Investig 2014;52(1):36–40. Oertel MF, Korinth MC, Reinges MH, Krings T, Terbeck S, Gilsbach JM. Pathogenesis, diagnosis and management of pneumorrhachis. Eur Spine J 2006;15(Suppl 5):636–643. Okoh S, Gopal KV. Pneumothorax in Pneumocystis jirovecii pneumonia: a case report, review of clinical characteristics and management. Am J Case Rep 2008;9 120–124. Moss S, Carey PB, Hind CR. Pneumocystis carinii pneumonia presenting with pneumomediastinum in an HIV-positive patient. Postgrad Med J 1995;71(832):96–97. Teruya K, Yasuoka A, Yamaguchi M, Yasuoka C, Yamamoto Y, Genka I, Tachikawa N, Kikuchi Y, Oka S. Complications during clinical courses of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Intern Med 2001;40(3):221–226. Cho JY, Kim DM, Kwon YE, Yoon SH, Lee SI. Newly formed cystic lesions for the development of pneumomediastinum in Pneumocystis jirovecii pneumonia. BMC Infect Dis 2009;9(1):171. Kaji Y, Ohara G, Kagohashi K, Satoh H. Pneumomediastinum in a patient with Pneumocystis jirovecii pneumonia. Intern Med 2012;51(16):2251. Baylor University Medical Center Proceedings Volume 29, Number 2 Multiple dural-based hemangiopericytomas Edana Stroberg, DO, David H. Uhrbrock, MD, Frank Harris, MD, Subhakar Mutyala, MD, Pier Luigi DiPatre, MD, PhD, and Ekokobe Fonkem, DO Here we report the case of a 57-year-old man who underwent resection of a dural-based hemangiopericytoma (HPC) in the left frontoparietal region. The patient was treated with radiation therapy and remained symptomfree for 10 years. At 67 years of age, he presented with a mass in the left frontal region near the same area as the first tumor, in addition to a separate smaller mass in the right middle cranial fossa. Resection of the larger left frontal mass revealed an HPC. Follow-up imaging 9 months later showed a significant increase in size of the right middle cranial fossa mass. This third mass was resected, and histological examination also demonstrated an HPC. H emangiopericytoma (HPC) was first described in 1942 by Stout and Murray as a highly vascularized tumor arising from the pericytes of Zimmerman, the modified smooth muscle cells that surround capillaries and postcapillary venules (1). In 1954, Begg and Garret first reported a case of an HPC occurring in the nervous system (2). These are rare neoplasms representing 2.5% of all meningeal tumors and 0.4% of all intracranial tumors (3). The 2007 World Health Organization (WHO) criteria developed a two-tiered system for grading intracranial HPCs, including WHO grade II and grade III (anaplastic) (Table 1) (4). In the largest published review of meningeal HPC, including follow-up data on 277 patients, local recurrence was seen in 57% of patients and systemic metastases was seen in 27% (5). Isolated intracranial metastasis remains an unusual event. The overall literature on intracranial HPC remains limited, especially concerning long-term follow-up of patients (6, 7). CASE REPORT A 57-year-old man without any significant family history or past medical history underwent resection of an extra-axial mass in the left frontoparietal region. The pathologic diagnosis of this first tumor was HPC, WHO grade III. The patient was treated with radiation therapy and remained symptom-free for approximately 10 years. When the patient was 67 years of age, radiologic imaging showed an enhancing partially cystic extra-axial mass in the left frontal region (Figures 1a and 1b). Another smaller mass was also visualized in the right middle cranial fossa (Figure 1c). He Proc (Bayl Univ Med Cent) 2016;29(2):191–193 Table 1. 2007 World Health Organization two-tiered criteria for intracranial hemangiopericytoma Grade Features II Monomorphous cellular spindle-cell tumor with round-tooval nuclei and intratumoral staghorn vessels III (anaplastic) Necrosis and/or Mitotic activity (<5 per 10 high-power fields) Plus at least two of the following: —Hemorrhage —Moderate to high cell density —Moderate to marked nuclear atypia underwent resection of the larger left frontal mass, and histological examination revealed an HPC, WHO grade III. Follow-up imaging 9 months later revealed a significant increase in size of the right middle cranial fossa mass (Figure 1d), which did not appear to have obvious connection to the previous two masses. The decision was made to proceed with resection of this third mass due to its rapid growth rate. Histological examination again revealed an HPC, WHO grade III. Subsequent imaging ruled out systemic metastases. At 1 year postresection, the patient does not have any additional symptoms and continues to be an active rancher. The original left frontoparietal mass (the first of the three tumors) was highly cellular with a very rich vascular network (Figure 2a). The vascular channels displayed a staghorn-like appearance. Multifocal necrosis and hemorrhage were identified. The mitotic activity was up to 5 mitotic figures per 10 highpower fields. Immunohistochemical studies showed prominent From the Department of Pathology (Stroberg, DiPatre), Department of Diagnostic Radiology (Uhrbrock), Department of Neurosurgery (Harris, Fonkem), and Department of Radiation Oncology (Mutyala), Baylor Scott & White Healthcare, Temple, Texas. Corresponding author: Ekokobe Fonkem, DO, Department of Neurosurgery, Baylor Scott & White Healthcare, 2401 S. 31st Street, Temple, TX 76508 (e-mail: [email protected]). 191 C a b c d staining patterns were again diagnostic of an HPC, WHO grade III. The right middle fossa mass was resected 9 months after the second left frontal mass and was microscopically similar to the previous tumors (Figures 2d and 2e). Mitotic activity was focally brisk with up to 5 mitotic figures per 10 high-power fields. There was multifocal coagulative necrosis (Figure 2f ). Immunohistochemistry showed tumor cells to be diffusely and strongly immunoreactive for CD34 (Figure 2g) and CD99 (Figure 2h), whereas keratin, epithelial membrane antigen, and smooth muscle actin were negative. These findings were again diagnostic of an HPC, WHO grade III. DISCUSSION The multifocal presentation of intracranial HPCs can have three explanations: 1) recurrence of a previously resected HPC; 2) metastasis of an HPC to other intracranial, dural-based locations; or 3) development of independent HPCs at different sites. In the present case, it is most likely that the second tumor was a recurrence of the primary tumor resected 10 years earlier since the second HPC arose at a site very close to the first HPC (left frontoparietal region). The third dural-based HPC, however, developed in an entirely separate area of the brain (in the right middle Figure 1. Ten years after the first mass was resected, the patient presented with worsening neurological symp- fossa), relatively distant from the site of toms. (a) An axial contrast-enhanced T1-weighted image showed a left frontal, extra-axial, avidly enhancing, the first two HPCs. There is no specific partially cystic tumor resulting in significant mass effect on the left frontal lobe and lateral ventricles. (b) An vascular connection favoring this paraxial T2-weighted image demonstrated the extent of vasogenic edema in the frontal lobes and genu of the ticular spread; however, there is a poscorpus callosum. The dark signal in the cystic portion of the mass posteriorly represents dependently layering sible, although distant, cerebrospinal hemorrhage. (c) In addition, axial contrast-enhanced T1-weighted imaging showed a right middle cranial fossa, extra-axial, avidly enhancing mass distant from the left frontal mass. (d) An axial contrast-enhanced T1- fluid connection. It is less likely that the weighted image acquired 9 months later showed the right middle cranial fossa mass to have increased in size. third HPC developed independently of the first two HPCs. In most cases of intracranial HPC with reported recurrence and/or metastases, recurrence at the primary tumor site is usuCD34 reactivity and negative epithelial membrane antigen. ally followed by systemic rather than intracranial metastases. The morphology and immunostaining patterns supported a The interesting feature of this particular case is the lack of diagnosis of an HPC, WHO grade III. systemic metastases in the setting of an unusual intracranial The patient’s mass in the left frontal region, which was remetastasis from one dural-based location to another without moved 10 years later, showed histopathology characteristics an obvious connection. Since recurrence with a greater degree similar to those of the first tumor (Figure 2b). Reticulin staining of malignancy can develop following an extended disease-free highlighted the rich microvascular network (Figure 2c). As with interval, this case highlights the importance of careful long-term the original tumor, CD34 reactivity was diffusely positive and follow-up for patients with HPC. epithelial membrane antigen was negative. The morphology and 192 Baylor University Medical Center Proceedings Volume 29, Number 2 a b 1. 2. 3. c d 4. 5. e f 6. 7. g h Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring Zimmerman’s pericytes. Ann Surg 1942;116(1):26–33. Begg CF, Garret R. Hemangiopericytoma occurring in the meninges: case report. Cancer 1954;7(3):602–606. Guthrie BL, Ebersold MJ, Scheithauer BW, Shaw EG. Meningeal hemangiopericytoma: histopathological features, treatment, and long-term follow-up of 44 cases. Neurosurgery 1989;25(4):514–522. Giannini C, Rushing EJ, Hainfeller JA. Haemangiopericytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavanee WK, eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC, 2007:178–180. Rutkowski MJ, Sughrue ME, Kane AJ, Aranda D, Mills SA, Barani IJ, Parsa AT. Predictors of mortality following treatment of intracranial hemangiopericytoma. J Neurosurg 2010;113(2):333–339. Rutkowski MJ, Jian BJ, Bloch O, Chen C, Sughrue ME, Tihan T, Barani IJ, Berger MS, McDermott MW, Parsa AT. Intracranial hemangiopericytoma: clinical experience and treatment considerations in a modern series of 40 adult patients. Cancer 2012;118(6):1628–1636. Tian R, Hao S, Hou Z, Bian L, Zhang Y, Wu W, Xu F, Li H, Liu B. Clinical characteristics and prognostic analysis of recurrent hemangiopericytoma in the central nervous system: a review of 46 cases. J Neurooncol 2013;115(1):53–59. Figure 2. (a) Hematoxylin and eosin (H&E)–stained section of the original tumor showing a rich vascular network with a staghorn-like appearance. (b) H&E-stained section of the second tumor removed 10 years later showing patternless sheets of plump cells with indistinct cell borders and abundant vasculature with a staghorn-like appearance. (c) Reticulin stain of the second tumor, highlighting the rich microvascular network and pericellular reticulin fibers. (d–f) H&E-stained section of the third tumor 9 months later, showing a highly cellular tumor composed of sheets of cells in a highly vascular background with (d, e) a vaguely staghorn-like configuration and (f) multifocal coagulative necrosis. Immunohistochemistry showed tumor cells to be diffusely and strongly immunoreactive for (g) CD34 and (h) CD99. April 2016 Multiple dural-based hemangiopericytomas 193 Colorectal cancer implant in an external hemorrhoidal skin tag Lampros Liasis, MD, and Harry T. Papaconstantinou, MD External hemorrhoidal skin tags are generally benign. Colorectal cancer metastases to the squamous epithelium of perianal skin tags without other evidence of disseminated disease is a very rare finding. We present the case of a 61-year-old man with metastasis to an external hemorrhoidal skin tag from a midrectal primary adenocarcinoma. This case report highlights the importance of close examination of the anus during surgical planning for colorectal cancers. Abnormal findings of the perianal skin suggesting an implant or metastatic disease warrant biopsy, as distal spread and seeding can occur. In our patient, this finding appropriately changed surgical management. E xternal hemorrhoidal skin tags are benign and are removed if they cause local problems (irrigation, pruritus, etc.) or for cosmetic reasons. We describe a patient with colon cancer where abnormal findings in an anal skin tag had survival significance. CASE REPORT A 61-year-old man was referred to the colorectal service at Baylor Scott & White Memorial Hospital in Temple, Texas, complaining of anal pain and bleeding. During perianal examination, two unremarkable acutely thrombosed external hemorrhoids were noted. Endoscopic examination of the colon revealed a locally advanced poorly differentiated rectal adenocarcinoma 5 to 7 cm from the anal verge. Endorectal ultrasound revealed a uT3N0Mx tumor. Computed tomography (CT) evaluation of the chest, abdomen, and pelvis was unremarkable for metastatic disease. The patient underwent neoadjuvant chemotherapy and radiation therapy. Radiation therapy was provided using CT-guided three-dimensional conformal therapy with 50 Gy to the tumor bed and 45 Gy to the pelvic lymph nodes. The perineal skin was spared. Two months after completing neoadjuvant therapy, the patient was reevaluated for surgical planning. During anorectal examination, he was noted to have asymptomatic external hemorrhoidal skin tags in the location of the previous thrombosed hemorrhoids. These tags, however, exhibited a hyperemic firm ulcerated mass at the tip (Figure 1a). Biopsies of the mass on the external tag demonstrated an invasive poorly differentiated adenocarcinoma. Given this result, the patient underwent abdominoperineal resection of the 194 rectum. The primary cancer in the rectum was 7 cm from the hemorrhoidal implant (Figure 1b). The hemorrhoidal tag had normal squamous epithelium with a focus of invasive poorly differentiated adenocarcinoma (Figure 1c). There was no evidence of lymphovascular invasion or tumor involvement of the hemorrhoidal vascular pedicle. The closest margin to the implant was 3 cm. The patient was discharged with no complications from surgery and underwent adjuvant chemotherapy. At 5-year follow-up, there was no recurrence of the neoplasm. DISCUSSION Rectal cancer has been shown to spread distally as far as 5 cm (1). Downstream seeding of colorectal adenocarcinoma is most commonly identified in anastomotic sites (2, 3), biopsy sites (4), and anal fistulas (5–15), as well as in perianal areas with a previous traumatic intervention (16, 17). Literature pertaining to metastatic disease to hemorrhoids is scarce and usually focuses on metastasis to hemorrhoidectomy sites (8, 18–20). Colorectal metastasis to hemorrhoidal sites that were treated with banding or sclerotherapy have been reported (21). Only 3 cases have been reported of colorectal cancer implants to hemorrhoids without previous therapeutic intervention (22, 23). It is especially remarkable that in all 3 case reports, implants were noted during the follow-up period after the operation for primary colorectal adenocarcinoma. Furthermore, all implants involved the internal hemorrhoidal plexus where adenomatous epithelium is normally found. Our case report is the first to describe the downstream colorectal metastasis to an external hemorrhoidal skin tag that was discovered after neoadjuvant therapy and before surgical intervention. This also is the only case of downstream metastasis affecting a nonoperated site of squamous epithelium. In our patient, repeat examination of the anal canal prior to the operation allowed for diagnosis of the metastasis, which changed the surgical strategy. The patient received the optimal From the Department of Surgery, Northwick Park Hospital, London North West Healthcare NHS Trust, and Imperial College School of Medicine, London, UK (Liasis); and Department of Surgery, Baylor Scott & White Memorial Hospital, Temple, Texas (Papaconstantinou). Corresponding author: Harry T. Papaconstantinou, MD, Glen E. and Rita K. Roney Professor and Chairman, Department of Surgery, Baylor Scott & White Memorial Hospital, 2401 South 31st Street, Temple, TX 76508 (e-mail: hpapaconstantinou@ sw.org). Proc (Bayl Univ Med Cent) 2016;29(2):194–195 a b c Figure 1. (a) Abnormal external anal skin tag with hyperemic ulcerated tip (white arrow). (b) Surgical specimen after abdominoperineal resection. The black arrow shows the site of primary adenocarcinoma of the rectum, and the white arrow shows the adenocarcinoma implant in an external hemorrhoidal skin tag. (c) Photomicrograph of normal squamous epithelium of an anal skin tag with a focus of invasive adenocarcinoma (hematoxylin and eosin stain at 10× magnification). abdominal-perineal resection of the rectum instead of the previously planned low anterior resection. It is important to note that if there was evidence of the tumor implant in the hemorrhoidal tag before neoadjuvant therapy, the field of radiation therapy would have included the perineal skin, inguinal lymph nodes, and ischiorectal fossa. This would be in direct response to the pattern of lymph node drainage exhibited in the distal rectum and anus. 1. Scott N, Jackson P, al-Jaberi T, Dixon MF, Quirke P, Finan PJ. Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg 1995;82(8):1031–1033. 2. Basha G, Penninckx F. Exfoliated tumour cells and locally recurrent colorectal cancer. Acta Chir Belg 1996;96(2):66–70. 3. Futami R, Shimanuki K, Sugiura A, Tsuchiya Y, Kaneko M, Okawa K, Mineta S, Sugiyama Y, Akimaru K, Tajiri T. Recurrence of colonic cancer twice at the site of stapled colorectal anastomosis. J Nippon Med Sch 2007;74(3):251–256. 4. Basha G, Ectors N, Penninckx F, Filez L, Geboes K. Tumor cell implantation after colonoscopy with biopsies in a patient with rectal cancer: report of a case. Dis Colon Rectum 1997;40(12):1508–1510. 5. Benjelloun B, Aitalalim S, Chbani L, Mellouki I, Mazaz K, Aittaleb K. Rectosigmoid adenocarcinoma revealed by metastatic anal fistula. The visible part of the iceberg: a report of two cases with literature review. World J Surg Oncol 2012;10(1):209. 6. Gomes RM, Kumar RK, Desouza A, Saklani A. Implantation metastasis from adenocarcinoma of the sigmoid colon into a perianal fistula: a case report. Ann Gastroenterol 2014;27(3):276–279. 7. Gupta R, Kay M, Birch DW. Implantation metastasis from adenocarcinoma of the colon into a fistula-in-ano: a case report. Can J Surg 2005;48(2):162–163. 8. Isbister WH. Unusual ‘recurrence’ sites for colorectal cancer. Dig Surg 2000;17(1):81–83. 9. Ishiyama S, Inoue S, Kobayashi K, Sano Y, Kushida N, Yamazaki Y, Yanaga K. Implantation of rectal cancer in an anal fistula: report of a case. Surg Today 2006;36(8):747–749. 10. Kouraklis G, Glinavou A, Kouvaraki M, Raftopoulos J, Karatzas G. Anal lesion resulting from implantation of viable tumour cells in a pre-existing anal fistula. A case report. Acta Chir Belg 2002;102(3):212–213. April 2016 11. Rakoto-Ratsimba HN, Rakototiana AF, Rakotosamimanana J, Ranaivozanany A. Anal adenocarcinoma revealed by a fistula-in-ano. Report of a case. Ann Chir 2006;131(9):564–566. 12. Rollinson PD, Dundas SA. Adenocarcinoma of sigmoid colon seeding into pre-existing fistula in ano. Br J Surg 1984;71(9):664–665. 13. Schaffzin DM, Stahl TJ, Smith LE. Perianal mucinous adenocarcinoma: unusual case presentations and review of the literature. Am Surg 2003;69(2):166–169. 14. Tomimaru Y, Ohue M, Noura S, Tanida T, Miyashiro I, Yano M, Ohigashi H, Sasaki Y, Ishikawa O, Imaoka S. A case of anal fistula cancer probably developing from intraluminal dissemination of rectal cancer. Gan To Kagaku Ryoho 2005;32(11):1776–1778. 15. Wakatsuki K, Oeda Y, Isono T, Yoshioka S, Nukui Y, Yamazaki K, Nabeshima S, Miyazaki M. Adenocarcinoma of the rectosigmoid colon seeding into pre-existing anal fistula. Hepatogastroenterology 2008;55(84):952–955. 16. Mekata E, Shimizu T, Endo Y, Tani T. The rapid growth of intraluminal tumor metastases at the intestinal wall sites damaged by obstructive colitis due to sigmoid colon cancer: report of a case. Surg Today 2008;38(9):862–865. 17. Tranchart H, Benoist S, Penna C, Julie C, Rougier P, Nordlinger B. Cutaneous perianal recurrence on the site of Lone Star Retractor after J-pouch coloanal anastomosis for rectal cancer: report of two cases. Dis Colon Rectum 2008;51(12):1850–1852. 18. Abbasakoor F, Srivastava V, Swarnkar K, Stephenson BM. Implantation anal metastases after out-patient treatment of haemorrhoids. Ann R Coll Surg Engl 2004;86(1):38–39. 19. Hsu TC, Lu IL. Implantation of adenocarcinoma on hemorrhoidectomy wound. Int J Colorectal Dis 2007;22(11):1407–1408. 20. Timaran CH, Sangwan YP, Solla JA. Adenocarcinoma in a hemorrhoidectomy specimen: case report and review of the literature. Am Surg 2000;66(8):789–792. 21. Cantos-Pallarés M, García-Armengol J, Mulas-Fernández C, Sancho-Moya C, Fabra-Cabrera I, Bruna-Esteban M, Roig-Vila JV. Perianal cutaneous metastases from colorectal adenocarcinoma. Rev Esp Enferm Dig 2012;104(1):41–42. 22. Gujral DM, Bhattacharyya S, Hargreaves P, Middleton GW. Metastatic rectal adenocarcinoma within haemorrhoids: a case report. J Med Case Reports 2008;2(1):128. 23. Scott NA, Taylor BA, Wolff BG, Lieber MM. Perianal metastasis from a sigmoid carcinoma—objective evidence of a clonal origin. Report of a case. Dis Colon Rectum 1988;31(1):68–70. Colorectal cancer implant in an external hemorrhoidal skin tag 195 Bilateral synchronous plasmacytoma of the testis Geetha Narayanan, MD, DM, Rona Joseph, MD, and Lali V. Soman, MBBS Extramedullary plasmacytoma (EMP) is usually seen in the head and neck regions and in the upper respiratory, gastrointestinal, and central nervous systems. Testis is a rare site for EMP, and bilateral synchronous testicular plasmacytoma occurring as an isolated event at initial presentation has been reported only once previously. We present herein the second such report in a 70-year-old man who underwent bilateral orchidectomy. P lasmacytoma is a discrete solitary mass of neoplastic monoclonal plasma cells occurring either in bone (solitary plasmacytoma of bone) or in soft tissues (extramedullary plasmacytoma, EMP). EMP represents 3% to 5% of all plasma cell neoplasms. The common sites of EMP are the head and neck, upper respiratory system, gastrointestinal system, and central nervous system (1). Testis is a rare site for EMP, and EMP accounts for only 0.03% to 0.15% of all testicular tumors (2–4). Testicular plasmacytoma usually occurs as part of multiple myeloma or as a site of recurrence. Rarely, isolated testicular plasmacytomas occur as a presenting feature, with a few cases reported (5–7). Even more rare is bilateral and synchronous testicular plasmacytoma, with only four cases reported in the literature, and in only one case it occurred as an isolated event at the initial presentation (8–11). We present the second report of isolated bilateral synchronous testicular plasmacytoma as the presenting feature in a 70-year-old man. CASE REPORT A 70-year-old man was evaluated for pain and swelling of the right testis of 6 months’ duration. Right inguinal hernia and bilateral hydrocele were initially diagnosed. He underwent right hernioplasty and hydrocelectomy and eversion of the left tunica vaginalis sac. Swelling recurred after 4 months. Doppler ultrasound of the testis showed a grossly enlarged right testis (76 × 43 × 67 mm) with multiple hypoechoic lesions, lobulations, and increased vascularity. He underwent right orchidectomy, and the testis showed a circumscribed grayish-white lobulated lesion, 7.5 × 6 cm, with no normal testicular tissue seen. The section showed immature and atypical plasma cells in sheets infiltrating the interstitial tissue and surrounding the atrophic tubules (Figure 1a). On immunohistochemistry, the cells were positive for CD138 and kappa light chain staining (Figure 1b) 196 and negative for CD20 and CD5 and lambda, suggestive of plasmacytoma. Two months later, the patient noticed swelling of his left testis. Ultrasound showed similar hypoechoic lesions, and he underwent left orchidectomy. The patient’s hemoglobin level was 13.1 g/dL; total white blood cell count, 10,200/mm3; and platelet count, 2.88 lakhs/ mm3; his total protein and renal function were normal. His serum IgG was 1838 mg/dL; IgA, 212 mg/dL; IgM, 86 mg/ dL; free kappa light chain, 33.5 mg/dL; and free lambda, 36.7 mg/dL. Serum electrophoresis and serum immunofixation did not show any abnormal bands. His bone marrow aspiration was normal, and there were no lytic lesions on skeletal survey. DISCUSSION EMP occurs in 18% of patients with multiple myeloma (12). Testicular involvement by plasmacytoma is rare but well documented, and most patients have myeloma at the time of diagnosis or develop plasmacytoma during relapse (4, 13–16). EMP occurs rarely as a solitary plasmacytoma at initial presentation in the absence of systemic myeloma (2, 4–6, 14, 15, 17). Anghel et al reported 52 cases of testicular plasmacytoma, and most had prior or concurrent multiple myeloma (4). Synchronous cancers are defined as malignant tumors that present simultaneously or within a 6-month period of identification of the original tumor. Bilateral involvement of testes by plasmacytoma is unusual, and most cases have occurred asynchronously at the time of relapse. Two cases of myeloma in remission relapsing later with bilateral testicular plasmacytoma were reported (9, 10). A 43-year-old man with myeloma was detected to have both testes involved by a positron emission tomography/computed tomography scan done prior to allogeneic transplantation (11). However, there has been only one previous report of bilateral synchronous testicular plasmacytoma presenting without evidence of myeloma occurring in a 48-year-old man (8). Our patient also presented initially with From the Department of Medical Oncology, Regional Cancer Centre, Trivandrum, India. Corresponding author: Geetha Narayanan, MD, DM, Professor and Head, Department of Medical Oncology, Regional Cancer Centre, Trivandrum 695011, Kerala, India (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):196–197 a b Figure 1. Orchidectomy section showing (a) sheets of plasma cells infiltrating interstitial tissue (hematoxylin and eosin, 100×) and (b) immunopositivity for CD138 (100×). isolated bilateral testicular plasmacytoma and did not have any evidence of myeloma. The mean age at diagnosis of testicular plasmacytoma is 55 to 60 years old (5). Patients usually present with a firm testicular mass which may be tender. Sonographic imaging has shown the masses to be either homogeneous or heterogeneous and typically hypoechoic. Hypervascularity on color flow and power Doppler imaging is a consistent finding in testicular plasmacytomas (6, 13). On microscopy, the tumor shows sheets of plasma cells with varying degrees of differentiation. The diagnosis is confirmed by immunostaining with CD138, CD79a, and light chain restriction (5). Our patient also showed positivity for CD138. Testicular plasmacytomas have a higher incidence of IgA than multiple myelomas (15, 18). The diagnosis of isolated testicular plasmacytoma requires studies to exclude systemic myeloma. Testicular plasmacytoma, like other primary testicular tumors, requires radical inguinal orchidectomy. Local radiation may be considered in patients with incomplete resection or recurrent or refractory disease (5). The overall prognosis for patients with testicular plasmacytoma is poor, with a high rate of progression to multiple myeloma (14). Hence, these patients require close monitoring. The survival of patients with multiple myeloma has improved over the years as a result of better understanding of the disease biology and advancement in targeted treatment modalities. 1. 2. 3. 4. Kapadia SB. 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J Med Case Reports 2011;5(1):494. Pham TH, Shetty SD, Stone CH, De Peralta-Venturina M, Menon M. Bilateral synchronous testicular plasmacytoma. J Urol 2000;164(3 Pt 1): 781. Garrido Abad P, Coloma Del Peso A, Bocardo Fajardo G, Jimenez Galvez M, Herranz Fernandez LM, Arellano Ganan R, Pereira Sanz I, Reina Duran T. Secondary bilateral testicular plasmacytoma. Case report and review of the literature. Actas Urol Esp 2008;32(10):1039–1042. Castagna M, Gaeta P, Cecchi M, Pagni GL, Pingitore R. Bilateral synchronous testicular involvement in multiple myeloma. Case report and review of the literature. Tumori 1997;83(4):768–771. Gonzalez de la Calle V, Alonso S, Del Carmen S, Dávila J, Antúnez P, Gomez Veiga F, Lopez-Godino O, Puig N, Gutiérrez N, Lopez-Corral L, Ocio EM, Caballero MD, Mateos MV. Bilateral synchronous testicular plasmacytoma as extramedullary relapse in high-risk multiple myeloma patient. Ann Hematol Oncol 2015;2(4):1032. Bladé J, Fernández de Larrea C, Rosiñol L, Cibeira MT, Jiménez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 2011;29(28):3805–3812. Rosenberg S, Shapur N, Gofrit O, Or R. Plasmacytoma of the testis in a patient with previous multiple myeloma: is the testis a sanctuary site? J Clin Oncol 2010;28(27):e456–e458. Turk HM, Komurcu S, Ozet A, Kuzhan O, Günhan O. An unusual presentation of extramedullary plasmacytoma in testis and review of the literature. Med Oncol 2010;27(4):1378–1380. Hathaway AR. Incidental discovery of a testicular plasmacytoma at initial presentation of multiple myeloma. Case Rep Hematol 2013;2013: 752921. Lue K, Emtage JB, Parinas MA, Dhillon J, Pow Sang J. An extramedullary plasmacytoma in the testicle: a case report and review of the literature. Can Urol Assoc J 2015;9(3–4):E240–E242. Ferry JA, Young RH, Scully RE. Testicular and epididymal plasmacytoma: a report of 7 cases, including three that were the initial manifestation of plasma cell myeloma. Am J Surg Pathol 1997;21(5):590–598. Avitable AM, Gansler TS, Tomaszewski JE, Hanno P, Goldwein MI. Testicular plasmacytoma. Urology 1989;34(1):51–54. Bilateral synchronous plasmacytoma of the testis 197 Presentation of epidermolytic acanthomas as multiple tan papules on the vulva J. Wesley Fletcher, MD, Arathi Ramamurthi, BA, and Palak Parekh, MD Epidermolytic hyperkeratosis is a histological reaction pattern seen in a variety of disease processes, including epidermolytic ichthyosis, Vorner’s epidermolytic palmoplantar keratoderma, epidermal nevus, and solitary epidermolytic acanthoma. Here we present the case of a 59-year-old woman with multiple asymptomatic papules on her vulva. Clinical differential diagnoses included condyloma acuminata, seborrheic keratoses, bowenoid papulosis, adnexal tumors, and papular acantholytic dyskeratosis. Shave biopsy revealed findings consistent with epidermolytic hyperkeratosis. This case represents an interesting presentation of focally disseminated vulvar epidermolytic acanthomas and highlights the importance of a biopsy in establishing this diagnosis. E pidermolytic hyperkeratosis (EHK) is a histological reaction pattern that may be seen in several clinical settings, including epidermolytic ichthyosis (EI), Vorner’s epidermolytic palmoplantar keratoderma (PPK), epidermal nevus (especially systematized variant), solitary epidermolytic acanthomas, and as an incidental finding. Solitary epidermolytic acanthomas may have a nonspecific presentation, making clinical diagnosis rather difficult (1, 2). Here, we present an unusual case of multiple vulvar epidermolytic acanthomas and the attendant diagnostic challenge. CASE REPORT A 59-year-old white woman presented with multiple asymptomatic papules on her vulva which she had noticed several months earlier while bathing. She denied lesions elsewhere. Previously, she had hypertension and hypercholesterolemia, and her father had melanoma. She had no history of skin cancer. She had been married to the same male partner for >10 years. After noticing one papule, she began discovering other small papules in her genital region and became concerned. These lesions never itched, bled, or bothered her. She had no fever, chills, or weight loss. A 4 mm verrucous papule was noted on the left labium majus surrounded by smaller 1 to 2 mm hyperkeratotic papules on both the left and right labia (Figure 1). The patient had no regional lymphadenopathy or similar lesions elsewhere. Shave biopsy of a lesion on the left labium majus revealed papillomatosis with hyperkeratosis, hypergranulosis with clumped keratohyaline granules, and multifocal vacuolization 198 Figure 1. A 3 mm hyperkeratotic papule located on the left labia majora surrounded by smaller 1 to 2 mm hyperkeratotic papules on both the left and right labia majora. of suprabasilar keratinocytes consistent with epidermolytic hyperkeratosis (Figure 2). The patient was relieved to learn that her lesions did not represent a sexually transmitted disease and were consistent with agminated epidermolytic acanthomas. DISCUSSION EHK is a histological finding seen in several conditions, including EI. EI is a genodermatosis characterized by blistering and erythroderma at birth or shortly thereafter with hyperkeratosis most pronounced on extensor surfaces later in life. Although this disorder usually displays an autosomal dominant inheritance pattern, 50% of cases result from spontaneous mutations (3). This form of ichthyosis is characterized by a defect of suprabasal keratinocytes due to mutations in keratins 1 and 10 and has a prevalence of approximately 1 in 200,000 to 300,000 individuals. Histologically, EHK may also be seen in Vorner’s PPK, an autosomal dominant dermatosis, which presents early in life with thickening of the skin on the palms and soles due to mutations in keratins 1 and 9. Children of patients with EI From Texas A&M Health Science Center College of Medicine, Temple, Texas (Fletcher, Ramamurthi, Parekh) and Department of Dermatology, Baylor Scott & White, Temple, Texas (Fletcher, Parekh). Corresponding author: Arathi Ramamurthi, BA, 3009 Ira Young Drive, Apt. 1306, Temple, TX 76504 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):198–199 a b Figure 2. (a) Lower-power view demonstrating hyperkeratosis, papillomatosis, clumped keratohyalin granules, and superficial epidermal vacuolization consistent with epidermolytic hyperkeratosis (hematoxylin and eosin, 10×). (b) Higher magnification revealing clumped keratohyalin granules and multifocal vacuolization of the superficial epidermis (hematoxylin and eosin, 40×). as well as those with mosaic presentations (such as epidermal nevus) with germline mutations may harbor the mutation and manifest EI. Our patient presented with grouped vulvar epidermolytic acanthomas. We hypothesize that her presentation may represent genetic mosaicism with a delayed onset; however, she did not undergo formal genetic testing. She denied any family history in her parents or children of any skin diseases and, in particular, denied any known diagnoses of EI, Vorner’s PPK, and epidermal nevi in her first-degree family members. Solitary epidermolytic acanthomas have been described in widespread locations including the face, extremities, and genitalia (4). Epidermolytic acanthomas localized to the genital area were once noted to be rare, with fewer than 10 cases reported; however, recent studies suggest that this location is more common than previously thought (5–7). The genitalia may in fact be the most common anatomic site for epidermolytic acanthomas (5). Clinically, epidermolytic acanthomas may present as sessile, flesh-colored, or brown papules, as well as exophytic verrucous papules (5). A nonspecific clinical presentation can make diagnosis challenging. Kazlouskaya et al retrospectively reviewed 64 biopsies from 60 patients and found that not a single case of EHK was diagnosed correctly on initial clinical presentation. Frequent misdiagnoses included warts, seborrheic keratoses, condylomas, molluscum, and squamous cell carcinoma (5). The clinical differential diagnoses of epidermolytic acanthomas of the genital area include viral and neoplastic entities. Patients are often concerned about sexually transmitted diseases (7). In situ hybridization studies of genital epidermolytic acanthomas have failed to show any evidence of genital human papillomavirus types in these lesions (5). Diagnosis of epidermolytic April 2016 acanthoma requires histopathological examination. Biopsy of a single lesion in our patient’s case was diagnostic. Treatment of epidermolytic acanthomas is not necessary given their benign nature. If desired, lesions may be treated with surgical excision or cryotherapy. One report noted complete resolution with topical 5% imiquimod cream after 4 weeks of use (8). Our patient noted softening of the lesions with decreased roughness with use of a topical lactic acid preparation; this has not been previously reported in the literature. Other topical therapies that can be used include glycerin, urea, and alpha-hydroxy acids, which may improve the hyperkeratotic, scaly nature of EHK (3). 1. 2. 3. 4. 5. 6. 7. 8. Banky JP, Turner RJ, Hollowood K. Multiple scrotal epidermolytic acanthomas; secondary to trauma? Clin Exp Dermatol 2004;29(5):489–491. Yang JH, Kim JK, Won CH, Chang SE, Lee MW, Choi JH, Moon KC. Isolated epidermolytic acanthoma in a renal transplant recipient. Ann Dermatol 2011;23(3):415–416. Kwak J, Maverakis E. Epidermolytic hyperkeratosis. Dermatol Online J 2006;12(5):6. Abbas O, Wieland CN, Goldberg LJ. Solitary epidermolytic acanthoma: a clinical and histopathological study. J Eur Acad Dermatol Venereol 2011;25(2):175–180. Kazlouskaya V, Lambe J, Elston D. Solitary epidermolytic acanthoma. J Cutan Pathol 2013;40(8):701–707. High WA, Miller MD. Localized epidermolytic hyperkeratosis of the female genitalia: a case report and review of an underappreciated disorder of women. MedGenMed 2005;7(4):33. Bogale SR, Chan CS, McIntire H, Hsu S. Epidermolytic acanthoma of the scrotum: A rare mimicker of condyloma acuminatum. Dermatol Online J 2011;17(1):6. Jang BS, Jang HS, Park HJ, Kim MB, Oh CK, Kwon KS. Multiple scrotal epidermolytic acanthomas successfully treated with topical imiquimod. J Dermatol 2007;34(4):267–269. Presentation of epidermolytic acanthomas as multiple tan papules on the vulva 199 Rumpel-Leede phenomenon presenting as a hypertensive urgency Daniel Varela, MS-4, Dat Tran, MS-4, Kyari Sumayin Ngamdu, MD, Brett Trullender, MD, Debabrata Mukherjee, MD, MS, and Aamer Abbas, MD Rumpel-Leede (R-L) phenomenon is the rare event in which the small dermal capillaries of an extremity rupture in response to application of a compressive device to that extremity, such as when inflating a cuff during noninvasive blood pressure monitoring or when applying a tourniquet to draw blood. This capillary rupture results in formation of a petechial rash distal to the compressive device. R-L phenomenon is believed to occur most often in patients with underlying vascular disease, such as diabetes mellitus or thrombocytopenia. R-L phenomenon is most often benign, though it may rarely be associated with pain and discomfort. There is no treatment for this condition apart from treatment of the underlying vascular disease or thrombocytopenia. We report a 57-year-old woman who presented with hypertensive urgency and experienced R-L phenomenon during blood pressure cuff inflation. T he Rumpel-Leede (R-L) phenomenon was described in 1909 by Dr. Theodor Rumpel and again in 1911 by Dr. Carl Stockbridge Leede while treating patients with scarlet fever (1), where R-L phenomenon occurred following application of a tourniquet. Currently, most cases of R-L phenomenon are reported in elderly patients with a history of diabetes and hypertension, or in patients with thrombocytopenia. We present a case of R-L phenomenon in a nondiabetic patient with a history of uncontrolled hypertension. CASE PRESENTATION A 57-year-old nondiabetic woman with a 10-year history of systemic hypertension and medication nonadherence presented with severe right-sided facial pain radiating to the occiput and neck and associated numbness and tingling affecting the right side of her face, right arm, and right leg. Noninvasive blood pressure (BP) monitoring revealed a BP of 272/124 mm Hg. While the patient’s BP was being recorded, she began to complain of sharp pain in her left upper arm, where the BP cuff had been placed. She subsequently developed an erythematous petechial rash spreading distally from her left elbow down to her fingers, and when the cuff was removed, striae were observed along the full circumference of her upper arm (Figure 1). After the cuff was removed, the patient’s arm pain rapidly resolved, but the petechial rash and striae persisted. The patient reported that this phenomenon had occurred several times in the 200 past during BP monitoring, with the initial episode occurring 10 years earlier, when hypertension was first diagnosed. The patient’s workup included a normal white blood cell count (9.78 × 109/L) and platelet count (317 × 109/L). Her serum chemistries, electrocardiogram, echocardiogram, head computed tomography (CT), magnetic resonance imaging, and magnetic resonance angiography were also normal. A CT of the patient’s face revealed a right periodontal abscess with mandibular cellulitis. The cellulitis was successfully treated with antibiotics, and the petechial rash had resolved by the time the patient returned to the clinic 1 month after discharge from the hospital. DISCUSSION The formation of petechiae distal to the BP cuff during BP monitoring is quite common, particularly in diabetic patients (2). These petechiae may be mild and often go undetected. R-L phenomenon is a more severe form of petechial hemorrhage, resulting in an apparent erythematous rash, which is much less common and is seen almost exclusively in patients with thrombocytopenia or an underlying vascular disease, most often diabetes. The present case is remarkable for the absence of either of these findings. Only 2 other cases of R-L phenomenon have been reported in patients without thrombocytopenia or vascular disease: the first was a 72-year-old woman, where the presence of R-L phenomenon was attributed to age-related capillary fragility (3); the second case was believed to have resulted from the use of a BP cuff that was too small for the patient’s arm (1). In the present case, R-L phenomenon was likely related to the patient’s state of hypertensive urgency, with a BP of 272/124 mm Hg. We believe that the BP cuff inflation in the presence of significant venous pressure resulted in the rupture of dermal capillaries, even in the absence of underlying capillary fragility. From Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, El Paso, Texas (Varela, Tran, Ngamdu, Trullender, Mukherjee, Abbas); and the Departments of Internal Medicine (Ngamdu, Mukherjee, Abbas), Emergency Medicine (Trullender), and Cardiology (Mukherjee, Abbas), University Medical Center, El Paso, Texas. Corresponding author: Daniel Varela, 6857 Granero Drive, El Paso, TX 79912 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):200–201 a Another unique finding in this case is that our patient complained of pain in her arm during BP monitoring, an uncommon finding in R-L phenomenon. Most reported cases of R-L phenomenon resolved within 2 weeks. While our patient’s most recent episode resolved within 1 month, she did report that previous episodes persisted for up to 3 months. b 1. Wang K, Lee J. Images in clinical medicine. Rumpel-Leede sign. N Engl J Med 2014;370(1):e1. 2. Eichner HL. Rumpel-Leede sign associated with a noninvasive ambulatory blood pressure monitor. JAMA 1985;254(4):506. 3. Rehman HU, Kambo J. RumpelLeede phenomenon: a case report. Can J Gen Intern Med 2014;9(4):159. c Figure 1. Views of the patient's left arm and hand, showing (a) striae along the upper arm (black arrow), followed by transition to an erythematous petechial rash distal to the elbow; (b) the demarcation between the rash and the patient's normal skin tone (red arrow); and (c) the most prominent part of the rash over the dorsal surface of the patient's wrist and hand. April 2016 Rumpel-Leede phenomenon presenting as a hypertensive urgency 201 Arm pain and erythema Brandon M. Barth, MD, and Andrew L. Juergens, MD a b Pyomyositis can be a difficult diagnosis to make, as it can mimic many other disease processes. Various laboratory studies can be abnormal with pyomyositis, but none are specific to the disease. Early disease can generally be treated with antibiotics alone, whereas advanced disease frequently requires emergent surgical intervention with significant resuscitation. We describe a case of pyomyositis of the right arm. P yomyositis is an infection of skeletal muscle that arises from a hematogenous source. Figure 1. (a) The right arm and shoulder demonstrate significant erythema and swelling. (b) Coronal computed tomography Staphylococcus aureus is the demonstrates multiple fluid-filled collections (arrows). most common pathogen (1, 2). Other organisms include Streptococcus pyogenes, Escherichia systemic symptoms such as fevers and denied involvement of coli, and mycobacteria (1, 3). This infection is associated with other joints. Examination revealed an exquisitely tender right immunosuppression, intravenous drug use, and trauma (1, 2, shoulder and proximal arm with erythema and induration 4, 5). Large muscle bodies such as the quadriceps are most (Figure 1a). Shoulder range of motion was limited secondary commonly affected (6). We present a patient with pyomyositis to patient discomfort. His erythrocyte sedimentation rate was that was initially presumed to be thrombophlebitis. 95 mm/h, and C-reactive protein was 257 mg/L. Laboratory studies were otherwise normal, including a white blood cell CASE REPORT count of 7.9 × 109/L. A 53-year-old man returned to the emergency department Computed tomography of the shoulder revealed multiple with worsening redness, swelling, and pain of the proximal intramuscular abscesses within the body of the biceps brachii right arm. His similar presentation 5 days earlier was conconsistent with pyomyositis (Figure 1b). Antibiotics were started cerning for deep venous thrombosis. He had no history of immediately. The orthopedic surgery team took the patient to similar symptoms prior to that episode but had a 30-packthe operating room for incision and drainage. Wound cultures year smoking history. He took no medication and denied a grew methicillin-sensitive Staphylococcus aureus. The patient’s history of drug abuse. Diagnostic workup at that time was positive only for a mildly elevated white blood cell count From the Department of Emergency Medicine, Scott & White Healthcare, Temple, of 11.9 × 109/L, but after a negative ultrasound the patient Texas. was discharged home on cephalexin for presumed superficial Corresponding author: Brandon M. Barth, MD, Department of Emergency thrombophlebitis. On return to the emergency department, Medicine, Scott & White Healthcare, MS-11-AG062, 2401 S. 31st Street, Temple, TX 76508 (e-mail: [email protected]). the patient was afebrile and vital signs were normal. He denied 202 Proc (Bayl Univ Med Cent) 2016;29(2):202–203 condition improved after the procedure, and he was discharged home on cephalexin several days later. DISCUSSION The clinical course of pyomyositis is typically progressive and can be divided into three stages as described by Chiedozi (1). Stage 1 is limited to localized symptoms with induration and tenderness and occasional leukocytosis. Stage 2 presents with fevers, tenderness and edema at the site, and distinct abscess. Leukocytosis is nearly always present, and inflammatory markers are typically elevated. Stage 3 presents with systemic infection such as endocarditis, septic arthritis, or brain abscess. These patients often present in septic shock. Diagnosis of pyomyositis can be difficult due to the various disease processes it can mimic, and multiple visits to a healthcare provider may be required before the diagnosis is reached. The astute clinician must have a broad differential, ranging from a simple muscle strain to necrotizing fasciitis or septic arthritis. Deep tissue abscess can be difficult to detect on physical exam. Laboratory measurements such as white blood cell count lack the sensitivity to predict disease. Patients who return for further evaluation after receiving a presumptive diagnosis require special consideration, particularly if their clinical course has worsened. The diagnosis is typically made with imaging. Magnetic resonance imaging is the most sensitive and specific study, particularly in the early stages of disease, although computed to- April 2016 mography is very good at detecting fluid collection and muscle swelling (5). Ultrasound can also be helpful, primarily in the second stage of disease with abscess formation and for repeat imaging and real-time visualization (3, 7). Treatment should begin with prompt administration of antibiotics, which are often sufficient for patients with stage 1 disease (1). Once fluid collections form, antibiotics are no longer adequate and drainage is required. In Stage 3 disease, resuscitation with vasopressor use and emergent surgical intervention are frequently required. Chiedozi LC. Pyomyositis. Review of 205 cases in 112 patients. Am J Surg 1979;137(2):255–259. 2. Koutures CG, Savoia M, Pedowitz RA. Staphylococcus aureus thigh pyomyositis in a collegiate swimmer. Clin J Sport Med 2000;10(4):297– 299. 3. Chu CK, Yang TL, Tan CT. Tuberculous pyomyositis of the temporal muscle in a nonimmunocompromised woman: diagnosis by sonography. J Laryngol Otol 2004;118(1):59–61. 4. Crum NF. Bacterial pyomyositis in the United States. Am J Med 2004;117(6):420–428. 5. Belsky DS, Teates CD, Hartman ML. Case report: diabetes mellitus as a predisposing factor in the development of pyomyositis. Am J Med Sci 1994;308(4):251–254. 6. Theodorou SJ, Theodorou DJ, Resnick D. MR imaging findings of pyogenic bacterial myositis (pyomyositis) in patients with local muscle trauma: illustrative cases. Emerg Radiol 2007;14(2):89–96. 7. Quillin SP, McAlister WH. Rapidly progressive pyomyositis. Diagnosis by repeat sonography. J Ultrasound Med 1991;10(3):181–184. 1. Arm pain and erythema 203 Rheumatoid meningitis associated with infliximab Susan Seago, MD, Edana Stroberg, DO, and Austin Metting, MD We present a patient who had rheumatoid meningitis while on infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor, which initially presented as transient ischemic attacks. Although our patient had been stable on infliximab for several years, her neurologic symptoms improved when her infliximab was held due to active infection and then recurred after reinitiation of therapy. Rheumatoid meningitis is exceedingly rare; however, there have been several other reports of rheumatoid meningitis developing in patients on TNF-α inhibitor therapy. R heumatoid meningitis is an exceedingly rare manifestation of rheumatoid arthritis (1). Though it is uncommon, there are several case reports of rheumatoid meningitis developing in patients on tumor necrosis alpha (TNF-α) inhibitor therapy (2–5). Our case is unique in that our patient’s neurologic symptoms improved when infliximab, a TNF-α inhibitor, was held due to active infection and resumed following reinitiation of therapy. CASE DESCRIPTION A 66-year-old woman with hypertension, coronary artery disease, gastroesophageal reflux, and rheumatoid arthritis on infliximab for 12 years developed acute-onset expressive aphasia in late January 2014. The episode reportedly lasted around 30 minutes and resolved without intervention. She presented to her local emergency department at that time and was diagnosed with a transient ischemic attack after a noncontrast computed tomography scan of the head was negative. Three days later, she had another episode of expressive aphasia and was again diagnosed with a transient ischemic attack. Following her second episode, ultrasound disclosed left carotid stenosis prompting a left carotid endarterectomy. She also developed a right corneal abrasion which developed into dendritic keratitis followed by infections with Staphylococcus epidermidis and yeast. The infliximab was discontinued in February 2014 prior to having a deceased-donor corneal transplant in April 2014. Following her carotid endarterectomy and corneal transplant, her neurologic symptoms and right eye infection appeared to resolve, and she was started on infliximab and methotrexate in June 2014. After resuming infliximab, she noted intermittent episodes of lower-extremity numbness and 204 tingling. Several months later, she developed a third episode of expressive aphasia, prompting hospitalization. On admission, her infliximab was held and magnetic resonance imaging (MRI) of the brain illustrated abnormal T2/FLAIR signal intensity in her bilateral frontal lobes and anterior temporal lobe with leptomeningeal enhancement (Figure 1). Notably, she was not taking nonsteroidal antiinflammatory medications or oral steroids prior to admission. A lumbar puncture illustrated 213 white blood cells, 86% lymphocytes, protein 85.9 g/dL, and glucose 41 mg/dL. She was started on empiric acyclovir for herpes simplex encephalitis. Her clinical status continued to decline, and she developed headache, nausea, vomiting, altered mental status, urinary incontinence, and intermittent bilateral lower-extremity numbness and paralysis over the next several days. Herpes simplex polymerase chain reaction from her cerebrospinal fluid (CSF) was negative, and a repeat MRI of the brain illustrated interval worsening of her abnormal T2/FLAIR signal intensity. An electroencephalogram illustrated rare sharp waves over the left temporal region consistent with focal seizure disorder, and she was loaded on levetiracetam. Serologic studies illustrated a positive antinuclear antibody, rheumatoid factor, and anti-citrullinated protein antibody with negative doublestranded DNA antibody and normal serum complement levels. Repeat lumbar puncture again illustrated a lymphocytic pleocytosis, with 216 white blood cells, 87% lymphocytes, protein 44 g/dL, and glucose 63 mg/dL. An extensive infectious, neoplastic, and autoimmune analysis of her CSF was unremarkable apart from an elevated rheumatoid factor. Brain biopsy of the dura and cerebral cortex illustrated abundant T lymphocytes and macrophages, with a small number of B lymphocytes and IgG4-positive cells consistent with hypertrophic pachymeningitis (Figure 2). She was treated with 1000 mg intravenous methylprednisolone daily for 6 days with rapid improvement of her neurologic symptoms. She ultimately made a full neurologic recovery and was discharged on 50 mg prednisone daily. From Baylor Scott & White Health, Temple, Texas. Corresponding author: Susan Seago, MD, Baylor Scott & White Health, 2401 S. 31st Street, Temple, TX 76508 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):204–206 a b Figure 1. MRI of the brain with gadolinium T2/FLAIR. (a) Sagittal image illustrating enhancement of the leptomeninges and frontal lobe. (b) Coronal image illustrating abnormal enhancement. DISCUSSION Although rheumatoid meningitis is rare, the number of biopsy-confirmed cases has increased greatly over the past several decades, due in part to improvements in imaging and increased access to MRI (6). The central nervous system manifestations of rheumatoid arthritis include vasculitis, rheumatoid nodules, and aseptic meningitis, most commonly in the form of lepto and pachymeningitis (2). Hypertrophic pachymeningitis results a b c d Figure 2. Brain biopsy findings suggesting a diagnosis of hypertrophic pachymeningitis. (a) Hematoxylin and eosin stain showing edematous cortex with attached chronically inflamed fibrous dura mater. (b) CD20 stain demonstrating scattered B lymphocytes. (c) CD68 stain demonstrating an abundance of macrophages. (d) Trichrome stain highlighting blue-staining dense fibrosis. Stains for organisms were negative, and IgG4 highlighted rare cells. April 2016 Rheumatoid meningitis associated with infliximab 205 from chronic inflammation of the dura and has been illustrated on brain biopsy and MRI in patients with confirmed rheumatoid meningitis (3). Elevated CSF rheumatoid factor has been proven to be a highly specific marker of rheumatologic central nervous system disease (1). Our patient’s negative infectious workup, elevated CSF rheumatoid factor, and brain biopsy illustrating hypertrophic pachymeningitis are all consistent with a diagnosis of rheumatoid meningitis. Although previous studies reported rheumatoid meningitis mortality rates as high as 70% (1), more recent case reports illustrate significant neurologic recovery following initiation of high-dose steroids, as seen in our patient (3–7). Multiple studies illustrate a correlation between TNF-α inhibitors and both central and peripheral neuropathies. A double-blind clinical trial using lenercept, a soluble dimeric p55 TNF-IgG fusion protein, illustrated a statistically significant increase in episodes of multiple sclerosis compared with placebo (8). Another prospective study illustrated decreased conduction velocity on electromyography after 12 months of infliximab therapy (9). Several case reports illustrate the development of biopsy-confirmed aseptic, autoimmune meningitis soon after the initiation of TNF-α inhibitors (2–4). Of these reports, one case study illustrated the recurrence of neurologic symptoms upon repeated administration of adalimumab and complete resolution of symptoms following its withdrawal (5). A recent retrospective analysis also illustrated an increased incidence of aseptic meningitis in patients on TNF-α inhibitors compared to alternative disease-modifying antirheumatic drugs (7). With the current trend towards early and long-term treatment with immunomodulating agents, over 2 million patients have been treated with TNF-α inhibitors worldwide. A recent pharmacologic review found 772 reports of neurologic side effects attributed to TNF-α inhibitors submitted to the US Food and Drug Administration between 2000 and 2009 (10). 206 While the complete neurologic effects of TNF-α inhibitors are still unknown, our case report highlights a unique clinical presentation and encourages physicians to carefully consider autoimmune etiologies for neurologic symptoms in patients on TNF-α inhibitor therapy and promptly discontinue treatment when needed. 1. Kato T, Hoshi K, Sekijima Y, Matsuda M, Hashimoto T, Otani M, Suzuki A, Ikeda S. Rheumatoid meningitis: an autopsy report and review of the literature. Clin Rheumatol 2003;22(6):475–480. 2. Huys AC, Guerne PA, Horvath J. Rheumatoid meningitis occurring during adalimumab and methotrexate treatment. Joint Bone Spine 2012;79(1):90–92. 3. Ahmed M, Luggen M, Herman JH, Weiss KL, Decourten-Myers G, Quinlan JG, Khanna D. Hypertrophic pachymeningitis in rheumatoid arthritis after adalimumab administration. J Rheumatol 2006;33(11):2344–2346. 4. Booker MJ, Flint J, Saravana S. Aseptic meningitis in a patient taking etanercept for rheumatoid arthritis: a case report. Cases J 2008;1(1):364– 365. 5. Jazeron A, Lallier JC, Rihn B, Thiercelin MC. Aseptic meningitis possibly induced by adalimumab. Joint Bone Spine 2010;77(6):618–619. 6. Hayashi Y, Namekawa M, Ohtani K, Watanabe E, Nakano I. Parkinsonism as an initial manifestation of rheumatoid meningitis. Neurol Sci 2014;35(7):1139–1141. 7. Cavazzana I, Taraborelli M, Fredi M, Tincani A, Franceschini F. Aseptic meningitis occurring during anti-TNF-alpha therapy in rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol 2014;32(5):732– 734. 8. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999;53(3):457–465. 9. Kotyla PJ, Sliwinska-Kotyla B, Kucharz EJ. Treatment with infliximab may contribute to the development of peripheral neuropathy among the patients with rheumatoid arthritis. Clin Rheumatol 2007;26(9):1595–1596. 10. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther 2013;38(4):388–396. Baylor University Medical Center Proceedings Volume 29, Number 2 Cryptococcal meningitis in a patient with sarcoidosis Traci N. Adams, MD, and Maeghan Gibson, MD Sarcoidosis is a multisystem granulomatous disease characterized by the presence of noncaseating granulomas. Case reports have previously described an association between sarcoidosis and cryptococcal infection, but many of these patients were receiving immunosuppression at the time of diagnosis or had limited cutaneous disease. We report a case of cryptococcal meningitis in a 65-year-old man with a new presentation of sarcoidosis who was not receiving immunosuppressive medications. S arcoidosis has been described as an “immune paradox” in which patients demonstrate both exaggerated inflammation and peripheral anergy as demonstrated by reduced delayed-type hypersensitivity to tuberculin skin testing and increased susceptibility to infection (1–3). We present a case that is unique in that it describes the development of cryptococcal meningitis in a patient with sarcoidosis who was not on immunosuppressive therapy and did not have extrathoracic manifestations of the disease. CASE PRESENTATION A previously healthy 65-year-old man presented with chronic cough. He had been in his usual state of health until 1 year earlier when he visited his primary care physician for a nonproductive cough. He denied any history of gastroesophageal reflux, nasal congestion, wheezing, coughing while eating, orthopnea, hemoptysis, or dyspnea on exertion. He also denied tobacco or drug use, recent travel, sick contacts, and bird or mold exposure. His only medications were acetaminophen and ibuprofen for back pain and simvastatin for hyperlipidemia. His chest radiograph was reportedly unremarkable, and he was treated with azithromycin and levofloxacin but did not improve. He was then evaluated at an outside hospital, where computed tomography (CT) of his chest revealed a spiculated left lower lobe nodule measuring 2.5 × 1.6 cm; left supraclavicular, mediastinal, and hilar adenopathy; and extensive peribronchovascular nodularity with a perihilar distribution (Figure 1). Bronchoscopy with bronchoalveolar lavage, bronchial brushings, transbronchial biopsies of the right upper lobe, and biopsies of the subcarinal lymph nodes were performed. Cytology of the bronchial brushing was negative for malignancy, and bronchoalveolar lavage fluid was negative for malignant cells and Proc (Bayl Univ Med Cent) 2016;29(2):207–208 cytomegalovirus. Transbronchial biopsies revealed focal chronic bronchiolitis, and lymph node biopsy was benign. One month later he presented to a neurologist with headache, dysarthria, and left hand numbness. His temperature was 98.5°F; heart rate, 89 beats per minute; blood pressure, 138/88 mm Hg; and oxygen saturation, 96% on room air. His jugular venous pulse was at 6 cm, crackles were heard in the bilateral lower lung fields, and lower extremities were not edematous. Neurologic examination revealed an intact mental status, normal cranial nerve function, normal strength and sensation throughout his arms and legs, 2+ reflexes, and intact finger-to-nose bilaterally. CT and magnetic resonance imaging of the brain were unremarkable. Lumbar puncture revealed an opening pressure of 20 cm of water, and cerebrospinal studies included a white blood cell count of 111/mm3, total protein of 166 g/dL, and glucose of 31 mg/dL. His cerebrospinal microbiologic studies revealed a cryptococcal antigen titer of 1:256 and were otherwise negative. Serum cryptococcal antigen was positive at 1:128. His serum HIV, QuantiFERON Gold, histoplasmosis serum antigen and serology, and viral hepatitis serologies were negative. He began treatment for cryptococcal meningitis with flucytosine and liposomal amphotericin, and his neurologic symptoms resolved. Following his recovery from cryptococcal meningitis, he underwent a CT-guided core biopsy of his left lower lobe mass, histologically containing noncaseating granulomas (Figure 2). Gomori methenamine silver and acid-fast stains as well as fungal and acid-fast cultures on the biopsy specimen were negative. His angiotensin-converting enzyme level was normal. Spirometry, total lung capacity, and diffuse capacity of carbon monoxide were within normal limits. His workup for extrapulmonary sarcoidosis including ophthalmology evaluation, 1,25-hydroxy vitamin D levels, electrocardiogram, and urine calcium-tocreatinine ratio were unremarkable. With normal pulmonary function tests and lack of extrapulmonary involvement, the From the Division of Pulmonary and Critical Care Medicine (Adams) and Department of Internal Medicine (Gibson), The University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Traci N. Adams, MD, Division of Pulmonary and Critical Care Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75219 (e-mail: [email protected]). 207 a b c Figure 1. (a) Coronal and (b, c) axial CT images demonstrating a perilymphatic nodular pattern with extensive involvement of the peribronchovascular interstitium. decision was made to manage the sarcoidosis conservatively with serial pulmonary function testing. DISCUSSION An imbalance between effector and regulatory T cells may contribute to susceptibility to infection in patients with sarcoidosis (2, 4, 5). Regulatory CD4+CD25brightFoxP3+ T cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of sarcoidosis patients (2). These cells exhibit antiproliferative activity, which may contribute to anergy; however, because they are unable to completely inhibit the production of tumor necrosis factor–α, local inflammation and granuloma formation continue to occur (2). Immunosuppressive CD8+ T cells may also accumulate in peripheral blood and produce anergy (4). Further, a reduced number of CD4+ T cells and other effector T cells such as CD1drestricted natural killer cells and a decreased CD4+/CD8+ T cell ratio are found in the peripheral blood of sarcoidosis patients, which may inhibit their T cell–mediated immunity (5). These mechanisms of impaired T cell–mediated immunity in sarcoidosis contribute to increased susceptibility to cryptococcal infection, which has been demonstrated in both in vitro studies and case reports (6–11). Cryptococcus neoformans is an opportunistic mycosis, which begins as a primary respiratory tract Figure 2. CT-guided core biopsy of the left lower lobe revealing granulomatous inflammation (hematoxylin and eosin, 100×). 208 infection and can disseminate hematogenously, with a propensity to localize to the central nervous system (6). It most frequently occurs in the setting of impaired T cell–mediated immunity, and the most common predisposing conditions include HIV, organ failure, and prolonged treatment with glucocorticoids (7–9). The largest clinical case series of C. neoformans infection revealed that sarcoidosis accounted for 0.6% of cryptococcal cases overall (8). Treatment with glucocorticoids and extrathoracic sarcoidosis are independent risk factors for cryptococcal infection in these patients (8, 11), and lung, bone, skin, and the central nervous system are the most common sites of infection (6, 9). 1. Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol 2008;181(1):746–755. 2. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Kambouchner M, Valeyre D, Chapelon-Abric C, Debré P, Piette JC, Gorochov G. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006;203(2):359–370. 3. Loke WS, Herbert C, Thomas PS. Sarcoidosis: immunopathogenesis and immunological markers. Int J Chronic Dis 2013;2013:928601. 4. Planck A, Katchar K, Eklund A, Gripenbäck S, Grunewald J. T-lymphocyte activity in HLA-DR17 positive patients with active and clinically recovered sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20(2):110–117. 5. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005;365(9464):1062–1072. 6. Botha RJ, Wessels E. Cryptococcal meningitis in an HIV negative patient with systemic sarcoidosis. J Clin Pathol 1999;52(12):928–930. 7. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, Henderson H, Kauffman CA, Haas DW, Saccente M, Hamill RJ, Holloway MS, Warren RM, Dismukes WE. Cryptococcosis in human immunodeficiency virus–negative patients in the era of effective azole therapy. Clin Infect Dis 2001;33(5):690–699. 8. Bernard C, Maucort-Boulch D, Varron L, Charlier C, Sitbon K, Freymond N, Bouhour D, Hot A, Masquelet AC, Valeyre D, Costedoat-Chalumeau N, Etienne M, Gueit I, Jouneau S, Delaval P, Mouthon L, Pouget J, Serratrice J, Brion JP, Vaylet F, Bremont C, Chennebault JM, Jaffuel S, Broussolle C, Lortholary O, Sève P; French Cryptococcosis Study Group. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM 2013;106(6):523–539. 9. Ross JJ, Katz JD. Cryptococcal meningitis and sarcoidosis. Scand J Infect Dis 2002;34(12):937–939. 10. Shih CC, Chen YC, Chang SC, Luh KT, Hsieh WC. Cryptococcal meningitis in non–HIV-infected patients. QJM 2000;93(4):245–251. 11. Jamilloux Y, Valeyre D, Lortholary O, Bernard C, Kerever S, Lelievre L, Neel A, Broussolle C, Seve P. The spectrum of opportunistic diseases complicating sarcoidosis. Autoimmun Rev 2015;14(1):64–74. Baylor University Medical Center Proceedings Volume 29, Number 2 Thyroid hormone resistance and its management Ana Marcella Rivas, MD, and Joaquin Lado-Abeal, MD, PhD Table 1. Thyroid function panel from 2009 to 2014 The syndrome of impaired sensitivity to thyroid hormone, also known as syndrome of thyroid hormone Reference resistance, is an inherited condition that occurs in value 12/2009 10/2010 08/2011 04/2012 02/2013 07/2014 1 of 40,000 live births characterized by a reduced TSH (mcIntUnit/mL) 0.27–4.20 10.37 42.41 46.62 37.70 26.39 39.00 responsiveness of target tissues to thyroid horFT4 (ng/dL) 0.93–1.70 3.00 1.81 2.07 1.91 1.82 1.05 mone due to mutations on the thyroid hormone FT3 (pg/mL) 2.3–4.2 N/A N/A N/A N/A 8.86 3.64 receptor. Patients can present with symptoms of hyperthyroidism or hypothyroidism. They usually FT3 indicates free triiodothyronine; FT4, free thyroxine; NA, not available; TSH, thyroid-stimulating hormone. have elevated thyroid hormones and a normal or elevated thyroid-stimulating hormone level. Due to their nonspecific symptomatic presentation, these patients can be misdifor the patient. Her family history was relevant for a son with agnosed if the primary care physician is not familiar with the condition. “hypothyroidism.” The patient’s thyroid function panels from 2009 to 2014 This can result in frustration for the patient and sometimes unnecessary were reviewed and are presented in Table 1. During this peinvasive treatment such as radioactive iodine ablation, as in the case riod of time she was on different doses of thyroid replacement presented herein. T he syndrome of impaired sensitivity to thyroid hormone (ISTH) is a condition of decreased tissue sensitivity to thyroid hormone action usually caused by germline mutations of the thyroid hormone receptor beta (THRB) gene. The mutant receptor has lower binding affinity for thyroid hormone and, as a consequence, serum thyroid-stimulating hormone (TSH) levels remain nonsuppressed despite elevated thyroid hormones (1–3). We present the case of a 66-year-old woman who was referred for evaluation of an abnormal thyroid function panel that suggested ISTH. CASE REPORT A 66-year-old woman was referred for evaluation of thyroid dysfunction. Her complaints were memory loss and intermittent gastrointestinal symptoms with alternating diarrhea and constipation attributed to irritable bowel syndrome. In 1998, she had been diagnosed with “a thyroid condition that no one was able to fix.” At that time, she had a goiter and was treated with radioactive iodine (I-131) and was subsequently started on thyroid replacement therapy. For nearly 30 years, she was seen by multiple physicians who continuously modified her thyroid hormone replacement but had been unable to “normalize” her thyroid hormone levels, and this resulted in frustration Proc (Bayl Univ Med Cent) 2016;29(2):209–211 therapy, her TSH remained elevated despite normal or elevated free T4 levels. She also had magnetic resonance imaging of the head, which showed a possible right-sided pituitary microadenoma. A thyroid ultrasound showed a normal thyroid gland with some nonspecific nodules. PCR amplification of THRB gene exons 10, 9, and 8 followed by gene sequencing showed a heterozygous missense mutation C>A located at exon 10. The mutation caused a change in thyroid hormone receptor beta protein amino acid 453 proline to threonine, P453T (Figure 1). We recommended that the patient resume thyroid hormone replacement with liothyronine 10 mg twice a day and levothyroxine 75 mcg daily; unfortunately, she was lost to follow up thereafter. DISCUSSION We describe a case of ISTH caused by a common germline mutation located at THRB exon 10 hot spot (4). The patient went undiagnosed for many years. When reviewing her thyroid From the Department of Medicine, Division of Endocrinology and Metabolism, Mayo Clinic, Jacksonville, Florida (Rivas); and the Department of Medicine, Division of Endocrinology, Texas Tech University Health Science Center, Lubbock, Texas (Lado-Abeal). Corresponding author: Ana Marcella Rivas, MD, 4500 San Pablo Road, Jacksonville, FL 32224 (e-mail: [email protected]). 209 Figure 1. Sequence analysis of the thyroid hormone receptor beta (THRB) gene showing a heterozygous mutation C>A located in exon 10. The mutation results in a change of proline for threonine at amino acid position 453, P453T. function tests, we noted a nonsuppressed serum TSH despite a normal or elevated free T4 level. These abnormal values led us to suspect THRB mutation and proceed with genetic studies, which confirmed the diagnosis. The diagnosis of ISTH requires a high degree of suspicion, and we therefore believe it is important for the general practitioner to be able to recognize the syndrome to avoid delay in diagnosis and unnecessary invasive treatments, such as thyroid surgery or radioactive iodine ablation. Thyroid hormone genomic actions are exerted by thyroid hormone binding mostly to nuclear receptors located in the nuclei and interaction with DNA to regulate the transcription of target genes. Most of the cases of ISTH are caused by mutations in the THRB gene located in chromosome 3, and these mutations most often clustered in three hot spots located in exons 8, 9, and 10. The mutant thyroid hormone receptor beta protein has either reduced affinity for T3 or abnormal interaction with cofactors involved in thyroid hormone action, making the target tissues refractory to thyroid hormones (5–7). In 15% of cases of ISTH, a gene mutation is not identified (6). Mutations affecting thyroid hormone cell membrane transporters and thyroid hormone metabolism have now been described, and the concept of syndrome of reduced sensitivity to thyroid hormone is used to encompass any defect causing reduced effectiveness of the thyroid hormone (3). The clinical presentation of patients with THRB mutations is variable. Patients may present with symptoms of hyperthyroidism, hypothyroidism, or a combination of symptoms of thyroid hormone deficiency and excess depending on the level of THRB and THRA gene expression in the target tissues (5, 6, 8). 210 Symptoms tend to decrease with age, and patients eventually become clinically euthyroid. Goiter is one of the most common findings for which patients seek medical attention. It’s usually refractory and recurs after surgery or treatment with radioactive iodine. Other common complaints include tachycardia, learning disabilities, and hyperactivity (8). The classic pattern of thyroid function test that these patients present with is elevated thyroid hormones with nonsuppressed TSH in serum. The response of TSH to thyrotropin-releasing hormone is normal or exaggerated, and thyroidal radioiodine uptake may be elevated (5). ISTH can be difficult to differentiate from TSH-producing pituitary tumors, which present with a similar thyroid function profile. A case of coexistence of both conditions has been reported (9). TSH-producing pituitary tumors present elevated serum levels of T4, T3, and nonsuppressed TSH. In contrast to patients with ISTH who may be clinically euthyroid, patients with TSHomas usually present with symptoms of mild to severe hyperthyroidism and compression symptoms resulting from tumor growth (7). When treating these patients, one should concentrate on the patient’s symptoms and clinical picture instead of aiming to normalize thyroid hormone levels (5, 8). Most patients, if left alone, adequately overcome the resistance by increased thyroid hormone secretion and therefore do not require treatment (8, 10). Treating patients who present with normal TSH is more challenging; in these patients, administration of supraphysiological doses of thyroid hormone might be required and, if so, should be closely monitored. Patients who present with symptoms of hyperthyroidism should be treated symptomatically with Baylor University Medical Center Proceedings Volume 29, Number 2 beta-blockers or antianxiety medications, among others, depending on their predominant symptoms (10). 1. 2. 3. 4. Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosineguanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest 1993;91(6):2408–2415. McDermott MT, Ridgway EC. Thyroid hormone resistance syndromes. Am J Med 1993;94(4):424–432. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830(7):3987–4003. Lado Abeal J, Albero Gamboa R, Araujo Vilar D, Barca Mallo O, Bernabeú Moron I, Calvo MT, Castro Piedras I, Martin Calamata J, Palos Paz F, Peinó R, Peteiro D, Victoria B. Clinical and molecular study of five families with resistance to thyroid hormones. Med Clin (Barc) 2011;137(12):551–554. April 2016 5. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007;21(2):277–305. 6. Gonçalves AP, Aragüés JM, Nobre E, Barbosa AP, Mascarenhas M. A case of thyroid hormone resistance: a rare mutation. Arq Bras Endocrinol Metabol 2014;58(9):962–966. 7. Melmed S, Kleinberg D. Pituitary masses and tumors. In Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology, 12th ed. Philadelphia: Elsevier Saunders; 2011: chap 9. 8. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14(3):348–399. 9. Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab 2015;100(7):2511–2514. 10. Weiss RE, Refetoff S. Treatment of resistance to thyroid hormone— primum non nocere. J Clin Endocrinol Metab 1999;84(2):401–404. Thyroid hormone resistance and its management 211 The price of a 15-year delay in diagnosis of Sheehan’s syndrome Rohan Parikh, MD, Varun Buch, BMBCh, Mitesh Makwana, MD, and Harit N. Buch, FRCP We describe a case of a 48-year-old woman who presented with a 15-year history of recurrent episodes of hypoglycemia and hyponatremia leading to altered behavior and generalized seizures. She underwent full clinical assessment, endocrine tests, and a pituitary magnetic resonance scan that showed pananterior hypopituitarism secondary to postpartum pituitary necrosis (Sheehan’s syndrome). She was commenced on appropriate hormone replacement therapy, which led to significant improvement in lethargy, anorexia, muscle weakness, and episodes of hypoglycemia. In addition to the alleviation of her physical symptoms, she experienced a significant improvement in her psychological wellbeing and reduction in hospital visits. This case illustrates the impact of delay in diagnosis of an easily treatable medical condition and its socioeconomic implications, especially for the population of a developing country like India. P ostpartum pituitary necrosis has an insidious course with varied manifestations. We present a case where a delay in its diagnosis resulted in significant morbidity to the patient. CASE REPORT A 48-year-old woman was brought to the endocrine clinic following transfer from an intensive care unit of another hospital, where she was being managed for lower respiratory infection complicated by severe hyponatremia (serum sodium 105 mEq/L [reference range 135–155 mEq/L]) and hypoglycemia (blood glucose 36 mg/dL [2 mmol/L]) leading to altered behavior and generalized seizures. She had a long history of lethargy, anorexia, and episodic vomiting, which began insidiously a few months after her last pregnancy and had gradually progressed over the past 15 years. She had consulted local and regional specialists and had received symptom-driven management with no long-term benefit. Four years before presentation, she had developed persistent and progressive back pain, stooping posture, and reduced mobility. Imaging studies showed an osteoporotic spine with spondylolisthesis and deformity. She required two surgical operations over 2 years for spinal fixation, with short-term symptomatic relief. One year before presentation she was started on 50 mcg thyroxine for hypothyroidism but 212 discontinued it due to worsening of symptoms. Over the past 2 years during intercurrent illnesses or procedures, she developed hypotension, hyponatremia, and hypoglycemia requiring hospital admissions and had been managed with sodium and glucose replacement. She delivered three children at home in a rural setting. Her last delivery had been complicated by significant bleeding, requiring hospitalization for blood transfusion. She had postpartum failure of lactation and her periods did not return after the delivery, but she never sought evaluation since she had completed her family. On examination, she appeared well oriented but lethargic, withdrawn, and pale. She was tachycardic with a blood pressure of 110/70 mm Hg with a postural fall of >20 mm Hg systolic. She was weak and could not sit or stand due to dizziness. Axillary and pubic hair was scanty, and her skin was cold, pale, and wrinkled. Her hemoglobin was 10.3 g/dL, with normocytic blood tests, and her renal and liver function tests were normal. As a result of the treatment she had received, her serum sodium had risen to 121 mEq/L, and her serum potassium was normal. Anterior pituitary hormone values, listed in Table 1, confirmed the diagnosis of pananterior hypopituitarism. Review of previous spinal x-rays showed spinal implant in situ extending from L4, L5 to S1 with osteopenic bones. Dualenergy x-ray absorptiometry confirmed significant osteoporosis, with a spinal T score of –2.9. Magnetic resonance imaging of the pituitary gland showed an empty sella. A diagnosis of Sheehan’s syndrome was made and the patient was commenced on 75 mcg of thyroxine and 20 mg of hydrocortisone in three divided doses. She was not started on estrogen in view of her age and was prescribed alendronate 70 mg once a week. Within 2 weeks, she showed marked improvement in general well-being with no hypoglycemia or hyponatremia. A repeat thyroid function test confirmed adequate replacement (Table 1). Three months later, she remained well and had regained full mobility. From the Department of Medicine, Civil Hospital, Ahmedabad, India (Parikh, Makwana, H. Buch), and SAL Hospital, Ahmedabad, India (V. Buch). Corresponding author: Harit N. Buch, MBBS, Diabetes Centre, New Cross Hospital, Wednesfield Road, Wolverhampton, West Midlands, England, United Kingdom WV10 0QP (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(2):212–213 Table 1. The patient’s pituitary function tests confirming anterior hypopituitarism Reference range At presentation On replacement Thyroid-stimulating hormone (uIU/mL) 0.35–4.94 1.85 1.1 Free thyroxine (ng/dL) 0.70–1.48 0.73 1.40 Hormone Estradiol (pg/mL) 21–312 10 Luteinizing hormone (mIU/mL) 0.90–9.33 0.95 Follicle-stimulating hormone (IU/mL) 3.03–8.08 3.82 Prolactin (ng/mL) 1.20–29.93 5.23 Peak 0.28 at 0 min Peak plasma cortisol (ug/dL) cortisol >20 1.36 at 30 min after intravenous injec2.23 at 60 min tion of 250 ug synthetic adrenocorticotrophic hormone (cosyntropin) DISCUSSION Sheehan’s syndrome is caused by pituitary necrosis secondary to hemorrhagic hypovolemic shock during the peripartum period (1). Enlargement of the pituitary gland, small sella size, disseminated intravascular coagulation, and autoimmunity have been suggested to play a role in the pathogenesis of Sheehan’s syndrome in women who suffer from severe postpartum hemorrhage (2). Improvement in obstetric care and the availability of blood transfusion have led to a significant reduction in the frequency of Sheehan’s syndrome in the developed world. However, the entity remains one of the most common causes of hypopituitarism in the developing world (2). Failure of postpartum lactation and failure of resumption of menses after delivery are the most common presenting symptoms (2). However, patients can present with a wide variety of symptoms, including feeling generally unwell, or with symptoms attributable to deficiency of individual hormones, e.g., constipation, fatigue, lethargy, dizziness, depression, or weight loss (3–7). Rarely, patients may present with hypoglycemic coma (5, 6). Although a small percentage of patients have an abrupt onset of severe hypopituitarism immediately after delivery, typically the onset of Sheehan’s syndrome is insidious (7, 8). This could make an early diagnosis difficult, and a high index of suspicion is needed when patients present with a combination of the above symptoms with a history of peripartum hemorrhage. Once suspected, the diagnosis can be confirmed with pituitary April 2016 function tests and imaging, which are accessible and affordable for most patients, even in the developing world (2). In our patient, there was a long delay in arriving at the diagnosis despite several clues, including secondary amenorrhea, premature osteoporosis, unexplained significant hyponatremia, hypoglycemia during acute stress, and worsening symptoms after thyroxine administration indicating concomitant hypocortisolemia. Several possible reasons could have contributed to this delay. Appropriate guidance was not provided on discharge after her eventful delivery and postpartum hemorrhage. The patient did not seek help for secondary amenorrhea for several years. Once she presented to health professionals, her management remained symptom-driven for a number of years without an attempt to diagnose the underlying cause. The patient and her family had to pay a heavy price for this delay in diagnosis in the form of a physical, psychological, social, and financial burden. The patient endured poor health for several years, as well as impaired mobility, spinal deformity requiring two operations, repeated hospitalizations, and episodes of life-threatening acute illness related to adrenal crises. She had to frequently travel long distances, in a state of failing health, to seek specialist help. Her husband, who was her main caregiver, needed to be off work for a combined period of over 100 days during the previous 2 years. There was a considerable strain in family relationships due to the patient’s chronic ill health. Lastly, the financial burden on the lower-middle-class family was immense, with a combined cost of Rs.600,000 (>US$10,000), which was >2 years of the family’s annual income. Once the correct diagnosis was made, her monthly cost for medications was reduced to Rs.700 (US$14) a month. Sheehan HL. Postpartum necrosis of the anterior pituitary. J Pathol Bacteriol 1937;45:189–214. 2. Keleştimur F. Sheehan’s syndrome. Pituitary 2003;6(4):181–188 3. Sanyal D, Raychaudhuri M. Varied presentations of Sheehan’s syndrome at diagnosis: a review of 18 patients. Indian J Endocrinol Metab 2012;16(Suppl 2):S300–S301 4. Qadri MI, Mushtaq MB, Qazi I, Yousuf S, Rashid A. Sheehan’s syndrome presenting as major depressive disorder. Iran J Med Sci 2015;40(1):73–76. 5. Dosi RV, Bhatt NR, Patell RD, Raj RR. Recurrent hypoglycemia . . . : a less well-known presentation of Sheehan’s syndrome J Postgrad Med 2013;59(4):318–320. 6. Kumar N, Singh P, Kumar J, Dhanwal DK. Recurrent hypoglycaemia: a delayed presentation of Sheehan syndrome. BMJ Case Rep 2014;2014:bcr2013200991. 7. Schrager S, Sabo L. Sheehan syndrome: a rare complication of postpartum hemorrhage. J Am Board Fam Pract 2001;14(5):389–391. 8. Boulanger E, Pagniez D, Roueff S, Binaut R, Valat AS, Provost N, Leroy R, Codaccioni X, Dequiedt P. Sheehan syndrome presenting as early post-partum hyponatraemia. Nephrol Dial Transplant 1999;14(11):2714–2715. 1. The price of a 15-year delay in diagnosis of Sheehan’s syndrome 213 Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists Jacob Sutton, DO, Jeff Stroup, PharmD, BCPS, and Mo Som, DO, MS Linezolid is an oxazolidinone antibiotic with weak monoamine oxidase (MAO) type A and MAO type B inhibitory effects. Linezolid has been associated with serotonin toxicity when used concomitantly with multiple medications that are known to increase serotonin concentrations. We report the case of a 65-year-old woman with signs and symptoms of serotonin toxicity following administration of linezolid for treatment of methicillin-resistant Staphylococcus aureus pneumonia. L inezolid is the first oxazolidinone antibiotic approved for use in the United States for treatment of resistant gram-positive bacterial infections including vancomycin-resistant enterococci, Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae (1). It has nonselective monoamine oxidase (MAO) type A and MAO type B inhibitory effects (2). It has been associated with serotonin toxicity with concomitant use of multiple medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, MAO inhibitors, tricyclic antidepressants, meperidine, and carbidopalevodopa (1). CASE REPORT A 65-year-old woman dependent on oxygen initially presented to the emergency department complaining of dyspnea, fevers, chills, and productive cough for 3 to 4 days. She was febrile on arrival, with a temperature of 39.3°C, and tachycardic, with a heart rate of 122 beats/minute. Her serum creatinine was 1.95 mg/dL. She was admitted to the intensive care unit and started on piperacillin-tazobactam and levofloxacin. After volume resuscitation, her acute kidney injury resolved. Blood cultures drawn on admission remained negative. IgG serologies for Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumonia were negative. The patient continued to improve. On the date of discharge, an expectorated sputum culture taken on admission grew MRSA. She was discharged home with 10 days of linezolid 600 mg twice daily for treatment of MRSA pneumonia. She was not given a dose of linezolid prior to discharge from the hospital. The patient presented to the emergency department 5 days later following a syncopal episode at home. She had injuries to 214 her left scalp, left shoulder, left elbow, and bilateral hands. Computed tomography (CT) of the brain and multiple extremity x-rays showed no acute pathology. An electrocardiogram showed nonspecific T wave changes, with QTc, QRS, and PR intervals within normal limits. She was given intravenous lorazepam for agitation. Her vital signs remained stable and she was admitted to the hospital. Her family reported that she began having increasing agitation following her first dose of linezolid 5 days earlier. The patient reported new-onset insomnia, increased restlessness, increased bowel movements, tremor, and visual hallucinations after her first dose of linezolid. She also reported a feeling of increasing warmth, but denied any subjective or documented fevers. Physical exam was positive for ocular clonus, equal mydriasis with reactive pupils, and muscular clonus in the bilateral lower extremities. She did not have autonomic instability or hyperthermia. She reported taking fluoxetine 14 months prior to her admission. Otherwise, she was not prescribed any medications that are known to increase serotonin concentrations, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, MAO inhibitors, and tricyclic antidepressants. Her linezolid was discontinued. She was treated with an oral benzodiazepine. The day following admission, her signs and symptoms of serotonin toxicity completely resolved. She was discharged home later that day to complete a 10-day course of clindamycin for MRSA pneumonia. DISCUSSION Linezolid inhibits protein synthesis by binding to 23S on the 50S subunit of bacterial ribosomal DNA (3). Linezolid has activity against aerobic and anaerobic gram-positive organisms, including MRSA, vancomycin-resistant Enterococcus faecium, and Streptococcus pneumoniae (4, 5). Linezolid has been approved for the treatment of gram-positive infections causing nosocomial pneumonia, community-acquired pneumonia, From the Department of Medicine, Oklahoma State University Medical Center, Tulsa, Oklahoma (Sutton); and Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma (Stroup, Som). Corresponding author: Mo Som, DO, MS, Oklahoma State University Center for Health Sciences, 717 S. Houston, Tulsa, OK 714127 (e-mail: mousumi.som@ okstate.edu). Proc (Bayl Univ Med Cent) 2016;29(2):214–215 complicated and uncomplicated skin and structure infections, and vancomycin-resistant Enterococcus faecium infections including bacteremia (2). Linezolid exhibits weak, reversible MAO A and MAO B inhibition (1). MAO enzymes are responsible for metabolism of the monoamine neurotransmitters epinephrine, norepinephrine, serotonin, and dopamine (6). Serotonin toxicity was not observed with coadministration of linezolid and other serotonergic drugs in phase I, II, or III clinical trials (7). However, there are multiple postmarketing case reports of patients developing serotonin syndrome when taking linezolid concurrently with medications known to cause increases in serotonin concentrations (1). Serotonin syndrome is caused by increased serotonergic activity in the central nervous system and has been observed in all age groups with an increasing incidence (8, 9). Physical exam findings of serotonin syndrome include hyperthermia, agitation, ocular clonus, mydriasis, tremor, akathisia, hyperreflexia, muscular clonus, muscle rigidity, and increased bowel sounds (8). Serotonin syndrome is a clinical diagnosis made using the Hunter toxicity decision rules. Criteria for diagnosis include the use of a serotonergic drug and one of the following (10): • Spontaneous clonus • Inducible clonus plus agitation or diaphoresis • Ocular clonus plus agitation or diaphoresis • Tremor plus hyperreflexia • Hypertonia plus temperature <38°C plus ocular clonus or inducible clonus The Hunter criteria are 84% sensitive and 97% specific for the diagnosis of serotonin syndrome (10). Patients with severe serotonin syndrome demonstrate autonomic instability and severe hyperthermia. Serotonin syndrome management includes the initial identification of the toxidrome and discontinuation of all serotonergic April 2016 drugs. Additional management of serotonin syndrome includes supportive care and benzodiazepines for sedation. Patients with more severe cases of serotonin syndrome may benefit from the use of the serotonin receptor antagonist cyproheptadine (4 mg three times daily) (11). Patients with autonomic instability and severe hyperthermia (temperature <41°C) should be managed in the intensive care unit. These patients should be sedated, intubated, and managed with paralytic medications (8). 1. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006;42(11):1578–1583. 2. Linezolid [package insert]. New York, NY: Pfizer, 2014. 3. DeBellis RJ, Schaefer OP, Liquori M, Volturo GA. Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient. J Intensive Care Med 2005;20(6):351–353. 4. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003;42(13):1129– 1140. 5. Bozdogan B, Appelbaum PC. Oxazolidinones: activity, mode of action, and mechanism of resistance. Int J Antimicrob Agents 2004;23(2):113–119. 6. Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004;25(1–2):215–221. 7. Jones SL, Athan E, O’Brien D. Serotonin syndrome due to co-administration of linezolid and venlafaxine. J Antimicrob Chemother 2004;54(1):289– 290. 8. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352(11):1112–1120. 9. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 2000;79(4):201– 209. 10. Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96(9):635–642. 11. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16(4):615–619. Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists 215 Baylor news ■ Baylor University Medical Center at Dallas opens womb transplant clinical trial Baylor University Medical Center at Dallas (BUMC) is among the first in the US to conduct a new clinical trial that will implant wombs in 10 women with absolute uterine factor infertility, meaning their uterus is nonfunctioning or nonexistent. The hope is to give these women a chance to become pregnant and carry a child full term. The researchers, who will conduct the clinical trial through Baylor Scott & White Research Institute, anticipate that the first baby to be carried by a transplanted womb in the US could be born in 2017. The complex process involves a multidisciplinary collaboration at BUMC among obstetriciangynecologists, fertility specialists, and the transplant team. “The entire process of transplantation, fertilization, prenatal care, and delivery—they're all connected as part of this study, and they'll all take place at Baylor University Medical Center at Dallas,” said Giuliano Testa, MD, principal investigator and surgical chief of abdominal transplantation at BUMC. “All of these components are integrated with one goal in mind: helping women who've been previously unable to have a baby.” Investigators will seek recipients between ages 20 and 35 years old with absolute uterine factor infertility, intact ovaries, and the desire to carry a baby to term, among other criteria. Living donors should be between 40 and 65 years old and have previously carried at least one baby to term, among other criteria (menopause is not required). Prior to the surgery, study participants will undergo in vitro fertilization (IVF); qualified patients must have healthy and otherwise normal functioning ovaries. After surgery, the women will be monitored and may be eligible for an embryo produced from earlier IVF procedures to be transferred as early as a year following the womb transplant. If implantation is successful and the recipient becomes pregnant, she will be routinely monitored until her baby is delivered by cesarean section. Because carrying foreign body tissue can increase infection risk and requires taking regular antirejection medication, women in this study will undergo a hysterectomy after one or two successful pregnancies. For this reason, the women who want a second 216 pregnancy will have shorter windows of time between births. If 2017 brings babies successfully born from transplanted wombs, new options for women hoping to bear children may come by the end of the decade, or sooner. “If we're as successful as we believe we'll be in helping women have fullterm healthy pregnancies with the transplantations, then we will open this option to every woman who is willing to undergo a transplant to have a child,” Dr. Testa said. ■ Baylor University Medical Center at Dallas earns prestigious pancreas center designation BUMC has been named a National Pancreas Foundation (NPF) Center, one of only 30 facilities in the country to receive this prestigious designation from the health advocacy group. BUMC is the only NPF Center in Texas and all surrounding states including Arkansas, Louisiana, New Mexico, and Oklahoma. The NPF, a nonprofit group that works to provide education and hope for patients with pancreatitis and pancreatic cancer, created the designation to help patients find high-quality, multidisciplinary care. Designated centers also seek to advance research and awareness for pancreatitis and related conditions among community physicians, allied health professionals, patients, families, and the general public. “Having the NPF Center designation means patients will know that we provide a high level of patient-centered care either for the treatment of their disease or to get an expert second opinion,” said Scott Celinksi, MD, medical director of the Pancreatic Cancer Research and Treatment Center at BUMC. Approved NPF Centers must go through an extensive auditing process and meet the criteria developed by a task force of clinical specialists and patient advocates. The criteria included having required expert physician specialties, along with more patient-focused programs such as pain management, psychosocial support, and more. The clinical team at the Pancreatic Cancer Research and Treatment Center includes physicians from a variety of specialties, including gastroenterology, interventional endoscopy, surgery, oncology, radiology, pathology, pain management, and genetics. Highly trained nurses, genetic counselors, and nutritionists also serve as team members. These specialists are recognized leaders in pancreatic disease care and can offer diagnostic and treatment options that are not available at most hospitals. BUMC offers in-depth expertise for many pancreatic diseases, including treatment for chronic pancreatitis through auto-islet cell transplants, performed by medical teams within the Baylor Annette C. and Harold C. Simmons Transplant Institute. In the procedure, the pancreas and spleen are removed and the patient's own islet cells are extracted. They are then infused into the patient's liver, where they take hold and produce insulin to prevent diabetes. The Liver and Pancreas Disease Center, another unique program at BUMC, is dedicated to treating patients with liver and pancreas cancer. This center's team coordinates each patient's tumor management and plan of care among the specialists on the BUMC medical staff. Since the program's inception in 1998, more than 5000 patients have received treatment. ACCOLADES William C. Roberts, MD, director of the Baylor Heart and Vascular Institute at BUMC and editor in chief of BUMC Proceedings and The American Journal of Cardiology, received the 2016 Lifetime Achievement Award from the American College of Cardiology. The award—which honors an individual who has had a lifetime of outstanding achievements in the field of cardiovascular disease and has served as a role model through service, basic or clinical research, and teaching—was presented at the college's 65th Annual Scientific Session in Chicago on April 4. The Texas Neurological Society honored Stuart Black, MD, chief of neurology at BUMC and co-director of the Baylor Scott & White Health Neuroscience Governance Council, with a Lifetime Achievement Award at the society’s annual winter conference held February 5 to 7, 2016. The Lifetime Achievement Award is a peer recognition award to honor members who distinguish themselves as leaders in the neurological profession and contribute their time and effort on behalf of the society. Proc (Bayl Univ Med Cent) 2016;29(2):216–219 ■ Baylor Scott & White Health and Tenet complete joint venture to own five North Texas hospitals Baylor Scott & White Health and Tenet Healthcare Corporation have completed the previously announced joint venture to own five hospitals in North Texas. The facilities included are Centennial Medical Center in Frisco, Doctors Hospital at White Rock Lake in Dallas, Lake Pointe Medical Center in Rowlett, Texas Regional Medical Center at Sunnyvale, and Baylor Scott & White Medical Center– Garland. The first four hospitals will transition to Baylor Scott & White Health branding as early as the spring of 2016. Additionally, physicians, advanced practice providers, and other employees of Tenet's North Texas physician group will transition to Baylor Scott & White Health's physician group, HealthTexas Provider Network. “We have already made meaningful progress in advancing population health through our physicians' participation in the Baylor Scott & White Quality Alliance, a leading local accountable care organization, and the completion of this joint venture is an important next step in coordinating top-quality, value-based care in North Texas,” said Trevor Fetter, chairman and CEO of Tenet Healthcare. UPCOMING CME PROGRAMS The A. Webb Roberts Center for Continuing Education of Baylor Scott & White Health is offering the following programs: Second Annual Skin Cancer Conference, April 2, 2016, Baylor Charles A. Sammons Cancer Center, Dallas, Texas IBD Conference, April 16, 2016, Roberts Hospital, 17th Floor Conference Center, Dallas, Texas Palliative Care and Oncology, April 16, 2016, Baylor Charles A. Sammons Cancer Center, Dallas, Texas Third Annual Oncology Update for Primary Care Providers, April 30, 2016, Sheraton McKinney, McKinney, Texas Current Trends in Complex Specialty Care in Patients, April 30, 2016, Baylor Scott & White Medical Center–Plano Southwest Regional Primary Care Physician Education Conference, May 2, 2016, Hilton Garden Inn, Granbury, Texas Pulmonary and Critical Care Medicine Symposium, May 7, 2016, Baylor Charles A. Sammons Cancer Center, Dallas, Texas Seventh Annual Stroke and Neurological Disease Conference, May 21, 2016, Westin Galleria, Dallas, Texas Complex Care: Treatment Trends and Improved Outcomes, August 13, 2016, Santa Fe, New Mexico Complex Care: Treatment Trends and Improved Outcomes, September 17, 2016, Greenville, Texas Chest Cancer 2016, October 28, 2016, Baylor Charles A. Sammons Cancer Center, Dallas, Texas For more information, call 214.820.2317 or visit www.cmebaylor.org. RECENT GRANTS • A novel function of Itch in controlling IL-17–induced inflammation in colon cancer Principal investigator: Venuprasad Poojary, PhD Sponsor: Cancer Prevention Research Institute of Texas Funding: $900,000 Award period: 6/1/2016–5/31/2018 • Cellular therapy for cancer—C1 Principal investigator: Carlos Becerra, MD Sponsor: Cancer Prevention Research Institute of Texas Funding: $50,956 Award period: 7/1/2015–6/30/2016 • Cellular therapy for cancer—AC Principal investigator: Carlos Becerra, MD Sponsor: Cancer Prevention Research Institute of Texas Funding: $6,629 Award period: 7/1/2015–6/30/2016 April 2016 • Cellular therapy for cancer—C2 Principal investigator: Joseph Fay, MD Sponsor: Cancer Prevention Research Institute of Texas Funding: $112,127 Award period: 7/1/2015–6/30/2016 • Louisiana clinical data research network subcontract agreement Principal investigator: Andrew Masica, MD Sponsor: Louisiana Public Health Institute/Patient Centered Oral Research Institute Funding: $307,300 Award period: 9/18/2015–9/17/2016 • Nurse-driven acute stroke care study Principal investigator: Jamee Gatzemeier Sponsor: UT Southwestern Medical Center/Lone Star Stroke Consortium Funding: $15,000 Award period: 8/1/2015–1/31/2017 Baylor news • A policy-relevant US trauma care system pragmatic trial for PTSD and comorbidity Principal investigator: Ann Marie Warren, PhD Sponsor: University of Washington/ National Institutes of Health Funding: $7,925 Award period: 8/1/2015–7/31/2016 • Metabolomic salivary biomarkers for oral cancer detection Principal investigator: Teodoro Bottiglieri, PhD Sponsor: Texas A&M University/National Institutes of Health Funding: $49,914 Award period: 6/1/2015–5/31/2017 217 PHILANTHROPY NOTES ■ Trisha Wilson estate gift will leave lasting impact on heart patients Trisha Wilson knows a thing or two about building a legacy that will last for generations. As the founder of interior architectural design firm Trisha Associates, she has designed interiors for some of the world's most luxurious hotels, palaces, casinos, private residences, resorts—even 747s. More than 1 million fivestar hotel rooms worldwide feature interiors dreamed up by Trisha and her team. Trisha will leave a legacy in her hometown of Dallas, too, through a $5 million estate gift to establish the Trisha Wilson Distinguished Chair in Cardiology at BUMC. This chair will support research, education, and programmatic initiatives benefiting heart and vascular patients for many years to come. “I know a lot of people donate to cardiology causes,” Trisha said, “but I just don’t think you can do enough. Heart disease is the biggest killer there is.” This estate gift is the latest in Trisha's history of giving to Baylor. Her support began in 1994 and has grown over the years, including a $250,000 gift for the Emergency Department at BUMC in 2008 in honor of close friend Leonard Riggs, MD. Trisha also has served for many years on the Baylor Health Care System Foundation board. Giving away a meaningful percentage of her estate is important to Trisha. “I have godchildren and nieces and now I’ll have a husband with children, but it's really important for me to give back. Even if I had children, I wouldn’t leave it all to them—and wouldn’t expect them to know what I would want them to do with my estate. It was also important for me to get this done now because you never know what's going to happen. You could get hit by a bus tomorrow!” ■ Baylor to offer innovative clinical trial for one of the deadliest cancers A generous contribution from The Jeanne Shelby Fund for Cancer Research at ■ New cardiac device reduces stroke risk for patients with atrial fibrillation The WatchmanTM Left Atrial Appendage Closure, a new implantable cardiac device the size of a quarter, is offering patients with atrial 218 Communities Foundation of Texas is funding a new, more effective clinical trial option that aims to make inoperable pancreas cancer operable. Under the direction of research investigators Carlos Becerra, MD, medical director of the Swim Across America Innovative Clinical Trials Center and assistant chief of oncology, and Scott Celinski, MD, director of the Pancreas Cancer Research and Treatment Center, this clinical trial will combine the inflammation-reducing drug anakinra with a three-drug chemotherapy regimen that was recently proven highly effective in a clinical trial. Anakinra has shown great promise in a breast cancer clinical trial at Baylor, and since all the drugs to be used in this trial are already FDA approved, it is expected to begin before the end of the year. “By giving patients the most effective chemotherapy available before surgery, we can kill microscopic cancer that has spread away from the original tumor and maximize our chances for a surgical cure of pancreas cancer,” said Dr. Celinski. “This trial is important in our pursuit of defeating pancreas cancer.” As additional funding becomes available, the samples collected from patients in the clinical trial will be analyzed for circulating tumor-specific DNA. The aim of these analyses is to help identify reliable biomarkers that can be used as a screening test for early detection or monitoring of the disease. Caroline Greenstone was just 8 years old when her dad, David, had to share some bad news. Her mother had cancer. Within weeks, he had more bad news. His own mother was also diagnosed with cancer. “Caroline didn’t know what was going to happen,” said David, a trial attorney and one of the founding members of Simon Greenstone Panatier Bartlett, PC. His wife, Joanna, had transitional cell carcinoma, a type of bladder cancer, and began treatment at BUMC. His mother, Karen Stern, was diagnosed with myelofibrosis and receives care at another hospital. “Caroline wanted to know: What can we do to help mommy? What can we do to help other people that are dealing with this type of thing? How can we fight back?” David said. She fought back by forming the Cancer Fighters Club with her little sister, Olivia, then 5. They formed the club to raise money to help their mother, grandmother, and others going through cancer. “This organization started as a way for her to try to get some control,” said David, who helped his girls establish the Cancer Fighters Club as an official fund through the Dallas Jewish Community Foundation. The Cancer Fighters Club hosts special fundraising events, and the Greenstone girls choose where the money goes. They’ve selected charities such as the American Cancer Society and Myeloproliferative Research Foundation. “Every time we’ve done a fundraiser, we’ve given to Baylor,” David said. “That's important to us because it made such a difference in our lives.” After surgery and intense chemotherapy at Baylor, Joanna is doing well. The girls’ fundraising efforts started with lemonade and coffee stands outside their house. In the past 3 years, though, they’ve had a roller skating party to “roll over cancer,” and after their mother finished her cancer treatments, the family hosted a party with a waterslide at their house and invited friends, family, and neighbors. Admission was free, and donations were welcome. The girls, who’ve raised nearly $20,000 so far, have no plans for slowing down, leaving plenty of room for Emma, now 3, to get involved as she gets older. “The most important thing they’ve learned is that they can actually make a difference,” David said. “They actually can fight back.” For information on how you can support these or other initiatives at Baylor, please contact the Foundation at 214.820.3136. fibrillation an alternative to long-term blood thinner use to reduce the risk of stroke. The approach was first tested in clinical trials in 2010 through 2013 at Baylor Jack and Jane Hamilton Heart and Vascular Hospital. Now physicians on the medical staff are early adopters of the technology they helped assess during clinical trials. “Our greatest worry is that patients who have atrial fibrillation will have a stroke,” said Kevin Wheelan, MD, chief of staff at Baylor Hamilton ■ After mom's diagnosis, Greenstone girls give back to Baylor Baylor University Medical Center Proceedings Volume 29, Number 2 Heart and Vascular Hospital. “Research has shown that patients with this type of heart arrhythmia are five times more likely to have a stroke. Blood thinners have been the standard course of treatment, but, for some patients, an alternative such as this device is a better longterm approach.” The parachute-shaped Watchman device is implanted using minimally invasive techniques. Cardiologists perform the hour-long procedure in a catheterization lab while the patient is under light general anesthesia. Generally patients are released from the hospital in less than 24 hours after the procedure and gradually decrease their use of blood thinner medication over time, under supervision of their cardiologist. ■ Caring for the special heart: new adult congenital heart disease center opens A new center at the Baylor Jack and Jane Hamilton Heart and Vascular Hospital is focused on caring for the rising number of adults with health complications due to congenital heart disease. Led by Medical Director Ari M. Cedars, MD, who recently joined the medical staff at BUMC, the new Center for Adult Congenital Heart Disease cares for patients born with a defect in one or more structures of the heart or blood vessels. These are the most common type of birth defects, affecting about 1% of all babies born each year. Thanks to rapidly advancing technology and new methods of treatment, these children can now live into adulthood. But while survival rates are rising, so is the incidence of complications in adults with the condition, even after repair in childhood. “One of the problems physicians face in treating these conditions in adults is the misperception that corrective surgery in childhood permanently cures congenital heart defects,” Dr. Cedars said. “Surgical technology and techniques were not nearly as refined in the 1950s and 1960s, when many of the procedures to treat pediatric heart problems were developed. And even under optimal conditions, patients born with abnormal cardiac anatomy are going to be subject to long-term consequences as a result of their repair.” Not only do those operative repairs deteriorate over time, but another factor begins to April 2016 have an effect in adult patients: the aging process. Adult congenital heart disease patients can face a triple threat: an abnormal heart structure, a deteriorating surgical repair, and the acquired heart problems that many older people develop. “There’s nothing about being born with a heart defect that protects you from ultimately developing coronary heart disease, heart failure, or abnormal heart rhythms,” said Dr. Cedars. (See Dr. Cedars’ commentary on adult congenital heart disease on pp. 174–175 of this issue.) ■ Renowned cardiothoracic surgeon joins The Heart Hospital Baylor Plano Bruce Lytle, MD, a cardiothoracic surgeon who until recently served as chairman of Cleveland Clinic's Sydell and Arnold Miller Family Heart & Vascular Institute, has joined The Heart Hospital Baylor Plano (THHBP). He will serve in the newly created role of chairman of cardiovascular strategic development and planning for cardiovascular medicine and surgery. “Based on Dr. Lytle’s previous experience of leading an internationally recognized heart and vascular institute, he brings a unique combination of talent and expertise to the leadership of our institution,” said Mark Valentine, president, TTHBP. Dr. Lytle joined Cleveland Clinic’s thoracic and cardiovascular surgery department in 1978 after receiving his medical degree from Harvard and completing residencies at Massachusetts General Hospital. While chairman of Cleveland Clinic's heart and vascular institute, he oversaw nearly 100 cardiologists and 25 heart and vascular surgeons who performed more than 7600 surgeries a year. He is credited with the conception and growth of the heart center’s national affiliation program. Baylor Jack and Jane Hamilton Heart and Vascular Hospital, BUMC, and TTHBP are affiliated with the Cleveland Clinic to share best practices, coordinate care, and develop programs to improve quality and patient safety. ■ Dallas, Plano researchers test new device to treat advanced heart failure Researchers at the Baylor Annette C. and Harold C. Simmons Transplant Institute and TTHBP have begun studying a next-generation Baylor news heart device that could give long-term solutions for patients with advanced heart failure. At about the size of a small doorknob, the device—the HeartMate III™ Left Ventricular Assist System— helps circulate blood through the body and could help certain patients avoid heart transplant surgery. The research is part of Momentum III, a nationwide trial by Thoratec Corporation, which also manufactured the HeartMate I and HeartMate II. The new trial compares the HeartMate III with the FDA-approved HeartMate II to determine if the new device is both safer and more effective for people whose hearts don’t function properly and either don’t want or don’t qualify for a heart transplant. Half the size of its HeartMate II predecessor, the HeartMate III device attaches to the heart's wall, with one end connecting to the aorta. An external battery system powers the device, which can pump up to 10 L of blood per minute. The new version of the technology is designed to reduce complications, which can include infection, bleeding, and thromboembolic events. “The science behind the new design is sound, so we hope this will decrease the risk of complications,” said Shelley A. Hall, MD, FACC, chief of transplant cardiology and mechanical circulatory support/heart failure at BUMC. “Technology is continuing to move forward at a much faster rate than our ability to treat heart failure with pills or by modifying the immune system after transplant. This is a very promising therapy for our patients with advanced heart failure.” ■ The Heart Hospital Baylor Plano earns top rating for cardiovascular care THHBP was recognized by The Society of Thoracic Surgeons as a three-star quality program in coronary bypass surgery, aortic valve replacement, and aortic valve replacement and coronary bypass grafting. A three-star rating is the highest achievable, and those three procedural groupings are the only ones where such ratings are awarded. Only 1% of the 1013 cardiac surgery hospitals in the United States reporting to the Society of Thoracic Surgeons’ registry received three-star ratings in all categories based on the society's quality methodology. 219 On John Keats and Blue Zones John Davis Cantwell, MD E n route to Sardinia, to visit hill towns in the so-called longevity “Blue Zones,” we had a brief stopover in Rome. It allowed time only to see the apartment where physician-poet John Keats spent the last 3 months of his life (separated from his fiancee, Fanny Brawne) and to reflect upon his all-too-brief life. I also wanted to visit his grave, to place some daisies on it, as did his physician, Dr. James Clark. It seemed to me the least the latter could have done, having misdiagnosed his pulmonary consumption and maltreating the weak and severely ill patient with “blood lettings” and a nearstarvation diet. JOHN KEATS Keats was just 5′1″, a handsome lad (Figure 1) who seemed anything but an athlete and a fighter. He was good at games and (according to a classmate) “would fight anyone, morning, noon, and night.” He flailed away at the butcher’s son when he caught the latter tormenting a kitten. Born in 1795, he was orphaned at a young age, after his father had a fatal riding accident and his mother succumbed to “consumption” (tuberculosis). Keats nursed his dying mother and probably contracted the disease as a result. A year after her death, Keats became an apprentice to Thomas Hammond, an apothecary-surgeon practicing in a northern suburb of London. He clashed with Hammond, apparently an alcohol abuser, and moved to separate lodging. Keats began to write poetry in his teens. Several years later he continued to pursue a medical career at Guy’s Hospital, where he met a lifelong friend, Joseph Severn. The patients at Guy’s Hospital were largely drawn from the nearby slums. Observing the various diseases, Keats once concluded that worldly honors seemed meaningless when one considers young women with cancer. While at the hospital, Keats discovered the great books and became influenced by the likes of Shakespeare and Wordsworth. He differed from his fellow medical students in expression, dress, and actions. The stomach appeared to him “like a brood of callow nestlings, opening their capacious mouths, yearning and gasping for sustenance.” He started to dress like poets did, turning his collar down and wearing a ribbon around his neck. He also grew a moustache. 220 Figure 1. John Keats. Source: National Portrait Gallery, London. In the lecture hall, Keats “seemed to sit apart and to be absorbed in something else.” During one lecture he observed “a sunbeam into the room and with it a whole troop of creatures floating in the ray; and I was off with them to fairyland.” From Piedmont Heart Institute, Atlanta, Georgia. Corresponding author: John Davis Cantwell, MD, Piedmont Heart Institute, 275 Collier Road, NW, Suite 500, Atlanta, GA 30309 (e-mail: john.cantwell@ piedmont.org). Proc (Bayl Univ Med Cent) 2016;29(2):220–223 His physician in Rome, Dr. Clark, initially thought a gastric condition was causing “mental exertion.” A detailed family history should have alerted Clark as to the correct diagnosis. Clark’s treatment likely hastened Keats’ death. He was “bled” (despite his weakness and bloody sputum) and placed on a literally starvation diet, consisting of an anchovy and a piece of bread daily. As a poet, Keats sold only several hundred copies of his books in his brief lifetime. Several were severely criticized in reviews. In one, published in Blackwood’s Magazine, the reviewer wrote: It is better and a wiser thing to be a starved apothecary (and physician) than a starved poet; so back to the shop, Mr. John, back to the plasters, pills and ointments. Figure 2. Keats’ apartment building in Rome (on the right of the Spanish Steps). A rotation with Dr. William Lucas, Jr., called by some “the butcher of the hospital,” seemed to turn Keats away from medicine. Lucas “cut amongst the most important parts as though they were only skin, making us all shutter from apprehension of his opening arteries or committing some other error.” Keats felt his own dexterity was limited, so he put down the lancet for good and turned to poetry. Keats met Fanny Brawne, the love of his life, in 1818, the same year his brother died of tuberculosis. In February 1820, Keats began having hemoptysis into the bedsheets. He illuminated the latter with a candle and, drawing from his medical background, stated: “This is very unfortunate. I know the color of that blood. It’s arterial blood. There’s no mistaking that color. That blood is my death warrant. I must die.” His physician sent him to Rome, thinking that the warm weather would help. Joseph Severn accompanied him. It took several months to arrive, in November, when the weather had turned cold. Keats and Severn rented an apartment on the second floor of a building near the Spanish Steps (Figure 2). He was essentially confined to a small bedroom (Figure 3), nursed by Severn. It became too painful for Keats to read Fanny Brawne’s last letters, which remained unopened and were later buried with him. Figure 3. The bedroom where Keats was confined in Rome. April 2016 Little wonder that for his epitaph Keats requested that no name be placed on his tomb in the Protestant Cemetery in Rome (Figure 4), only “Here lies one whose name was writ in water.” In his own mind, however, Keats had confidence in his writing skills, once correctly defiantly declaring to one of his brothers that he would be “among the English poets after his death.” Keats died quietly in Severn’s arms. Years later Severn would request to be buried next to Keats. One of Keats’ biggest champions was Percy Shelley, who continued to correspond with Keats while the latter was in Rome, and who wrote an elegy (“Adonais”) to Keats a few months after the latter’s death. Shelley was to die in a boating accident only a year after Keats, his body washing ashore “with a copy of Keats’ poems open in his pocket.” Keats’ works have endured the test of time. His Endymion (“A thing of beauty is a joy forever”) and Ode on a Grecian Urn (“Beauty is truth, truth beauty”) will no doubt remain popular for years to come. Figure 4. Keats’ grave in the Protestant Cemetery in Rome. On John Keats and Blue Zones 221 BLUE ZONES Leaving Keats behind, we flew to Sardinia to experience one of the so-called “Blue Zones” of longevity, popularized by Dan Buettner, a National Geographic fellow, and his team of researchers. They have identified at least five areas around the world where individuals have a multifold likelihood of living to age 100 compared to most Americans. These Blue Zones include 1) the Greek island of Ikaria, 2) the Nicoya Peninsula of Costa Rica, 3) Loma Linda, California, 4) Okinawa, and 5) Sardinia, the focus of our trip. A greeting in Sardinia is akea, meaning “may you live to 100.” Along with Dr. Ocie and Jo Ella Harris, friends from internship days, my wife, Marilyn, and I wanted to view personally the lifestyle of the Sardinian inhabitants which enabled many to remain active and vibrant well into old age. What did Dan Buettner find in his research and what did we observe in our hiking trip with Classic Journeys? In the Supramonte and Barbagia mountainous villages, Buettner’s staff found 21 centenarians per 10,000 population, versus only 4 per 10,000 Americans. The men:women ratio was about even, unlike in America where it is 1:4. In the village of Perdasdefogu, nine living siblings in the Melis family hold the Guinness world record of combined age–828 years. In studying the lifestyles of the Sardinians, Buettner highlighted seven key findings: 1. Their diet was lean, plant-based, with little meat. 2. They drank goat’s milk, which they felt might help combat inflammation. 3. Their family ties were strong. 4. They celebrated and cared for their elders. 5. They typically walked about 5 miles per day. 6. They drank several glasses of Cannonau red wine, believed to be high in flavonoids. 7. They had a sardonic sense of humor, laughing with and at each other and themselves. Missing from Buettner’s books was information on the smoking habits in the Blue Zones (beyond the Seventh Day Adventists from Loma Linda) and the results of blood pressure, blood sugar, and lipid levels. Our experience We spent 3 nights in the Blue Zone area of Barbagia, in the small hilltop town of Oliena, and drove cross-country to the town of Silanus, in hopes of visiting a shepherd featured in the Buettner publications. With the help of our guide, Fabricio, who seemed to know everyone in town, we tried to visit several extremely elderly shepherds. Two possibilities, both in their mid-80s, were unavailable. One was high in the Supramonte Mountains with his sheep and goats. The other was off at a cattle auction. We did enjoy meeting 93-year-old Francesca (Figure 5), who was walking back from a shopping trip. Her grandson was graduating from the medical school in Sassari, so the grandmother and other family members were celebrating with a dinner the next evening. Francesca had a sparkling person222 Figure 5. The author with 93-year-old Francesca. ality, walked and stood erect, and showed a good recall for recent and remote events, the latter including trips to Mexico, Israel, and Egypt. Our group hiked for nearly an hour up to a shepherd’s hut and a view of the nearby Nuragic ruins (dating back over 3500 years). The shepherd, Giovanni, was 50 and took care of 100 sheep and 15 goats. His father, also a shepherd, had died of throat cancer in his late 70s. Giovanni’s mother had adult-onset diabetes but was otherwise in good health at age 88. Giovanni had some central obesity, but otherwise seemed robust but at risk for future diabetes. We headed west, across Sardinia, passing through the “Valley of the Nuraghe.” We stopped at the village of Silanus, in hopes of meeting the shepherd, Tonino Tola. Our contact, who knew him, stated he was now age 93. He gave us Tonino’s telephone number. Our guide spoke with Tonino’s wife, who said he was off working in the fields with his sheep and goats and would be unable to meet with us. It seems that he had become sort of famous since the publications, and multiple groups had sought him out. One, from Japan, stayed all week and kept him from his work, so his wife now protected him from outside interference. In any event, I was happy to learn that he was still not only alive but thriving. I made a list of Blue Zone foods and drinks (Figure 6) I wanted to try: • Pasta • Pecorino cheese (from sheep’s milk) • Fava beans • Chickpeas, zucchini, tomatoes, eggplant • Fennel • Milk thistle tea • Sourdough bread • Papassini cookies (with raisins, grape juice, almonds, and fennel) • Local olive oils • Minestrone soup We visited a home in Oliena to see how they made Carasau bread (Figure 7), also known as shepherd’s bread. Shepherds take it with them up high in the Supramonte Mountains, for Baylor University Medical Center Proceedings Volume 29, Number 2 Figure 7. Ladies in Oliena making Carasau bread, also known as “shepherd's bread.” In the Blue Zone area of Sardinia, we were able to sample the food, especially the Cannonau wine, and view the active lifestyle of the inhabitants. I found it both disappointing and amusing that the few elderly shepherds we hoped to meet and to interview were too busy to accommodate us, still tending their sheep and goats in their 80s and early 90s, high in the mountains. Acknowledgment My thanks to Karen Galloway for preparing the manuscript and to Stacie Waddell for gathering the figures. Figure 6. A buffet of some “Blue Zone” foods. it will provide nourishment for weeks at a time (washed down with Cannonau wine). SUMMARY A trip to Italy enabled me to visit the small apartment in Rome where John Keats spent his final months and to visit his grave in the Protestant Cemetery. I was only sorry that I was unable to find a nice bouquet of daisies to lay on his grave. April 2016 SOURCES Gittings R. John Keats, physician and poet. JAMA 1973;224(1):51–55. Cantwell JD. Six physicians and their common mistress. Atlanta Med 1994;68 65–70. John Keats. Wikipedia. Available at https://en.wikipedia.org/wiki/John_Keats; accessed December 28 2015. Buettner D. The Blue Zone. Washington, DC: National Geographic, 2008. Buettner D. The Blue Zones Solution. Washington, DC: National Geographic, 2015. On John Keats and Blue Zones 223 Book Review In Vitro Fertilization Comes to America by Howard W. Jones Jr., MD Williamsburg, VA: Jamestown Bookworks, 2014. 234 pages, $11.99, paperback. Reviewed by Samuel P. Marynick, MD I t is very exciting to be present when a major change in the practice of medicine occurs. It is more exciting and rewarding to be the individual who is discovering and directing such a change. Howard W. Jones Jr., MD, was such an individual. In his book, In Vitro Fertilization Comes to America, Dr. Jones chronicles the development of a new arena of medical practice in North America. Medical care, by its very nature, is constantly changing. On occasion a breakthrough occurs that is revolutionary, and it takes medical care forward with greater than a baby step. Such a change occurred in the practice of reproductive medicine in the timeframe between 1970 and 1990. Several new disciplines made this leap possible. These included, not necessarily in order of importance (because they are all important), the development of a radioimmunoassay that allowed hormones to be accurately measured in small concentrations; the development of ultrasound to allow assessment of follicular development and endometrial development; the development of accurate gas sensing devices; the development of incubators that could maintain near constant temperature, humidity, and gas concentrations; and the development of tissue culture media that allowed for pre-embryo development and other advances. Howard Jones Jr. was a trained surgeon and surgical gynecologist. He was present for many discoveries made over the last 80 years, as he lived to 104 years of age. Many of these discoveries are chronicled in this volume. This book is a brief recording of the events of Howard Jones Jr.’s life, and it details how he became interested in so many different areas of medicine and medical care. It chronicles how he met his wife Georgeanna in childhood, how he completed his training, and how he became interested in human embryology, and it describes his unique relationship with Bob Edwards, 224 PhD, who is responsible for much of what we know about human embryo development. Dr. Jones was a very humble and thoughtful man, and this is evident in the humble way he describes the events leading up to the birth of the first in vitro fertilization (IVF) embryo transfer baby to be born in North America. Through this book, the reader is able to travel back in time and experience the climate that was present when potential human beings started being created outside of the body, “in vitro.” It was not a time of peace and cooperation. Some individuals felt that egg fertilization outside of the body was to be opposed, as it was too invasive. There was opposition that was theologically and ethically based, and the opponents were sometimes physical in their opposition. This led to somewhat of a bunker mentality at Eastern Virginia Medical College in Norfolk, Virginia, where this work was under way. One chapter of the book deals with the Catholic Church and its stance on assisted reproduction. The book includes the letter that Howard Jones’ wife, Georgeanna, wrote to Pope John Paul II. The letter explains and examines the many issues related to the stance of the Catholic Church on assisted reproduction. I will not spoil this unique insight, but will instead let you read the volume to understand. The next chapter discusses ethical issues related to human IVF and reproduction, particularly the issue of personhood. For the last 30 years of his life, Dr. Jones was deeply concerned about ethical and legal issues and was an author or coauthor of books regarding these subjects (Legal Conceptions: The Evolving Law and Policy of Assisted Reproduction Technologies, with S. L. Crockin, Johns Hopkins University Press, 2009; Personhood Revisited—Reproductive Technology, Bioethics, Religion and the Law, Langdon Street Press, 2013). One item that is not covered in this book is how generous Dr. Jones and his staff were to visiting scientists. They gladly accepted visitors from all over the world to help them understand the process by which human life could be created in vitro. The first time I personally visited the Jones Institute in Norfolk was in 1986. Security was present. Different areas of the reproductive center at the institute had doors mislabeled to throw off curious outsiders. For example, the embryology laboratory had a door label that said “Soiled Linen.” The foreword to this volume was written by Ms. Elizabeth Carr, the fi rst IVF individual born from this technology in America. Ms. Carr and Dr. Jones had a relationship of 34 years that spanned from her birth until Dr. Jones’ untimely death. I had the pleasure of visiting with Ms. Carr at the annual meeting of the American Society for Reproductive Medicine in the fall of 2015 (Figure). Ms. Carr told me that Dr. Jones nearly always attended her birthday party, and from Proc (Bayl Univ Med Cent) 2016;29(2):224–225 her birth on he prepared her to manage the publicity that came with being the first IVF baby in America. Ms. Carr had many touching stories about how Dr. Jones had positively influenced her life. The final chapter relates to how this science has changed the practice of reproductive medicine. Prior to IVF, a couple coming to a fertility specialist had around a 50% chance of having a child. Now the chance of being successful approaches 100%. Anyone interested in contemporary medicine, philosophy, law, reproductive medicine, and the history of medicine in general will benefit from reading this work. I am so delighted that this humble man, Howard W. Jones Jr., MD, took time at the age of 103 to complete this enlightening project. The reviewer, Samuel P. Marynick, MD, is medical director of the Texas Center for Reproductive Health in Dallas, Texas. Figure 1. Dr. Marynick with Elizabeth Carr, the first individual born through in vitro fertilization in America. April 2016 Book review 225 Reader comments HEARTS CONSIDERED FOR TRANSPLANTATION AND TAKOTSUBO SYNDROME read with interest the report by Ravi et al, in the January 2016 issue of Proceedings, about the successful transplantation of the heart of a 17-year-old woman to a 61-year-old man with end-stage ischemic cardiomyopathy (1) and the accompanying thoughtful commentary by Lima (2). The authors referred to the currently prevailing restrictive approach in considering donor hearts for procurement for cardiac transplantation (3) and stated that “to date, there are no reports of takotsubo syndrome (TS) in the context of cardiac transplantation” (1). In fact, several such cases have been published and discussed in the literature (4–7). Indeed, a similarity has been suspected to be present in donor hearts of resuscitated cardiac arrest victims, patients with neurogenic stress cardiomyopathy, and patients with TS (6). Accordingly, it is relevant to ask the authors about other triggering or inciting TS factors beyond the motor vehicle accident, like the use of catecholamines (6, 7), in the clinical management of this unfortunate 17-year-old girl. A lesson should be to proceed with procurement of donors’ hearts for cardiac transplantation when underlying heart disease in the potential donors is unlikely. Also, we should start using echocardiography serially and frequently during the clinical management of potential donors, and we should consider emphasizing mechanical device–based hemodynamic support while deemphasizing use of catecholamines (6, 7). —John E. Madias, MD Icahn School of Medicine at Mount Sinai New York, NY E-mail: [email protected] I 1. 2. 3. 4. 5. 6. 7. 226 Ravi Y, Campagna R, Rosas PC, Essa E, Hasan AK, Higgins RS, Emani S, Sai-Sudhakar CB. Successful heart transplantation using a donor heart afflicted by takotsubo cardiomyopathy. Proc (Bayl Univ Med Cent) 2016;29(1):73–74. Lima B. Using “broken hearts” for cardiac transplantation: a risky venture or fruitful endeavor? Proc (Bayl Univ Med Cent) 2016;29(1):74–75. Taylor DO, Edwards LB, Aurora P, Christie JD, Dobbels F, Kirk R, Rahmel AO, Kucheryavaya AY, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult heart transplant report—2008. J Heart Lung Transplant 2008;27(9):943–956. Guglin M, Novotorova I. Neurogenic stunned myocardium and takotsubo cardiomyopathy are the same syndrome: a pooled analysis. Congest Heart Fail 2011;17(3):127–132. Guglin M. How to increase the utilization of donor hearts? Heart Fail Rev 2015;20(1):95–105. Madias JE. “Neurogenic stress cardiomyopathy in heart donors” is a form of takotsubo syndrome. Int J Cardiol 2015;184:612–613. Madias JE. Donor hearts, hearts of resuscitated cardiac arrest victims, hearts of patients with neurogenic stress cardiomyopathy, and hearts of patients with takotsubo syndrome: any commonalities? Int J Cardiol 2015;199:33. I enjoyed reading the interesting case report recently published by Ravi et al (1). The authors have described a successful heart transplantation using the heart of a 17-year-old girl involved in a motor vehicle accident. Echocardiography revealed apical ballooning of the left ventricle consistent with takotsubo syndrome (TS). The left ventricular apical ballooning was also directly observed at procurement. One striking finding is the very rapid resolution (within hours after donor cardiectomy) of the left ventricular dysfunction. It occurred after the completion of heart transplantation, where intraoperative echocardiogram revealed complete resolution of the left ventricular ballooning. Could the resolution have occurred directly after donor cardiectomy before transplantation? The disease resolved in spite of continued inotropic support during the first 48 hours. It is justifiable to wonder whether this rapid recovery has to do with the simultaneous surgical sympathectomy during donor cardiectomy. Surgical sympathectomy may have resulted in relief of the apical myocardial cramp (stunning) caused by the brain death–induced disinhibited cardiac sympathetic tone. If this is true, this observation strengthens the hypothesis about the involvement of the local cardiac sympathetic overactivation disruption in the pathogenesis of TS. The authors have appropriately stated that a loss of brainstem parasympathetic outflow/ disinhibition of sympathetic tone may occur in brain death– induced TS. Actually, there is substantial evidence supporting the hypothesis that the local cardiac sympathetic overactivation disruption with norepinephrine seethe and spillover is causing TS, as has been discussed in detail elsewhere (2). The authors directly observed the apical ballooning at procurement; I wonder if this observation was done before or after donor cardiectomy. If it was before, could the authors observe any change in the apical ballooning after cardiectomy? Furthermore, could the authors describe the palpation findings of the ballooned apical region and the remainder of the left ventricle if palpation of the left ventricle was done? Endomyocardial biopsy was done 1 week after heart transplantation. Have the authors tried to take biopsies from the apical region? If so, did they find signs of contraction bands and vacuolization, which characterize the histopathological findings of TS, or did they find signs of complete healing of the disease (TS) histopathologically? Transplantation of donor hearts afflicted with TS opens an excellent opportunity for research into the pathogenesis of TS. This author recommends that the heart transplantation team first inspect and palpate the left ventricle followed by surgical sympathectomy of the heart and then inspect and palpate the left ventricle again before donor cardiectomy and repeat the same procedure during completion of the heart transplantation, with intraoperative echocardiography, as the authors of the current case have appropriately done. The analysis of the Proc (Bayl Univ Med Cent) 2016;29(2):226–229 biopsy for TS changes in addition to rejection changes is also highly recommended. —Shams Y-Hassan, MD Karolinska University Hospital Stockholm, Sweden E-mail: [email protected] 1. 2. Ravi Y, Campagna R, Rosas PC, Essa E, Hasan AK, Higgins RS, Emani S, Sai-Sudhakar CB. Successful heart transplantation using a donor heart afflicted by takotsubo cardiomyopathy. Proc (Bayl Univ Med Cent) 2016;29(1):73–74. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date. Cardiovasc Revasc Med 2014;15(1):35–42. The authors respond We thank Dr. Madias for his comments and acknowledge the presence of other reports pertaining to this topic. It is certainly possible that the use of catecholamines following the motor vehicle accident could have potentially caused the development of takotsubo syndrome, and we agree with Dr. Madias’ comments on serial echocardiography in the assessment of potential donors with such a presentation and the use of mechanical device–based hemodynamic support. We thank Dr. Y-Hassan for his comments. It is conceivable that the surgical sympathectomy secondary to donor cardiectomy could have resulted in the resolution of the apical ballooning. At procurement, the apex was felt to be normal, did not appear to be thinned out following cardioplegic arrest, and was comparable to the rest of the left ventricle. A biopsy was not performed on the left ventricular wall at the apex. We agree with Dr. Y-Hassan that detailed evaluation in the perioperative period is important to monitor the progress and improvement of the syndrome. —Yazhini Ravi, MD Division of Cardiothoracic Surgery Baylor Scott & White Healthcare, Temple, Texas E-mail: [email protected] ELECTRONIC MEDICAL RECORDS Dr. Couch's commentary (1) in the January 2016 issue of Proceedings on the electronic health record (EHR) is correct. However, it fails to mention the full cost of the EHR in terms of the loss of physician productivity. For example, Dallas Diagnostic Association experienced the premature retirement of 12 physicians in large part due to the adverse impact of the EHR. No one at HealthTexas Provider Network did exit interviews with these physicians. Almost all of the currently practicing physicians at Dallas Diagnostic Association have reported decreased productivity and decreased satisfaction with the practice of medicine due to the burdens imposed by the EHR. Certainly, the economics of the practice of internal medicine also play a significant role in the dissatisfaction of internists and internal medicine subspecialists with their professions. It is hoped that you and your colleagues will be effective in improving the April 2016 usability of the EHR to enhance the experience of both patients and providers. —Lannie Hughes, MD Baylor University Medical Center at Dallas 1. Couch C. Invited commentary to “Surgeons’ perspective of a newly initiated electronic medical record.” Proc (Bayl Univ Med Cent) 2016;29(1):23. FACTS AND IDEAS Regarding the January “Facts and ideas” comment on health care savings accounts and high-deductible plans, do you know if the requirements for lower deductibles came from the legislation or the “regs”? Very nice article. Thank you again. I practically tear open the journal to get to the “Facts and ideas from anywhere.” One of my thoughtful friends (our mayor, an attorney; we serve together on our LaGrange City Council) felt that people who can analyze their costs and reduce costs self-select into higher-deductible plans. He felt it was not truly because of the effect of the deductible itself. I thought that was a very good idea. I’m not sure if there is data to answer the question either way. —Tom Gore, MD LaGrange, Georgia I always enjoy your Facts and Ideas comments, but especially the review of David McCullough's book Americans in Paris. I had him autograph my copy when it first came out. Mason Warren comes from a long line of surgeons which continued into the 20th century. I have read his letters in The Parisian Education of an American Surgeon published some time ago by the American Philosophical Society. You might enjoy it as well, or perhaps you’ve read it. —Jeanie Woods Waynesboro, Pennsylvania CUBA I really did enjoy reading your article on the trip to Cuba that you made in February 2015 (1). As best I can tell, not much has changed in Cuba from 2001 to 2015. I have never recorded the experience that my wife and I had in 2001 when we accompanied the Haverford College baseball team and students for a 2-week daily baseball trip and cultural exchange in Cuba. Our oldest son, Laird, played baseball for Haverford. My wife and I served as the doctor and nurse for the Haverford delegation. We were required to enter Cuba from Jamaica. Therefore, we flew from Philadelphia to Montego Bay and then returned to Havana. During the time we were flying from Philadelphia to Montego Bay, Cuban aircraft shot down two airplanes from the US that were dropping leaflets over Cuba. Prior to our arrival in Cuba, baseball games and meetings had been prearranged. When we arrived in Havana, the delegation was informed that, because of the incident regarding the American airplanes, all previously arranged games and meetings were canceled. These prearranged baseball games were to be the spring training for the Haverford baseball team. Reader comments 227 The Haverford delegation was given two tourist buses for transportation. During the ride from the airport to our hotel, we learned from our bus driver, a former professional baseball player, that it was possible to find baseball games in Cuba 247-365. We would just need permission to leave Havana and drive into the country and find a city team for a game. The next day we had permission to leave the city to tour the country. Our bus driver headed straight for Santa Clara (about 50 miles west of Havana). There, at the base of some significant mountains, was a beautiful baseball field. The mountains were the backdrop looking out from Figure 1. The Haverford team playing in Cuba. home plate. The word went out that The Haverford College team gave the retired Cuban Nationa ball game was to be played that day. It required a couple of als, most of whom had gray hair, a good game and won the game hours for the Santa Clara team to be in position to start the 9 to 7. The Haverford team was able to beat the level III team game. During that time, the Haverford team took batting practwice, and they split the games with the level II team. Playing tice and fielding practice. against the level I team and the Reforma Plaza team were like It was quite something to see young men walking up in their playing the New York Yankees. The Reforma Plaza team had a civilian clothes and work boots, some knee-high rubber work player that was the spirit and image of the Ranger's slugger Juan boots, and changing into uniforms and putting on their cleats. Gonzalez. This gentleman hit a couple of moon-shots out of The children of the town, mainly young boys, were all over the the Reforma Plaza Park. The score was not pretty: 14 to 2. The Haverford dugout. The game was played, and it was very comfour games played against the medical school team were split. petitive. I cannot remember who won the game, but the score I was able to visit with many of the medical student baseball was close. As the Haverford team was loading its equipment, players. This was quite rewarding. it was discovered that significant numbers of gloves, bats, and The hotel we stayed in, the Ambos Mundos, was where balls were missing. After the game, the children of Santa Clara Ernest Hemingway lived before he purchased his estate. As disappeared quickly. This led to the realization that no one could we stayed in this hotel 2 weeks, we got to know the personnel be allowed in the dugout from the community where the team fairly well. When the workers at the hotel learned that I was a was playing. Following this game, the team had a wonderful physician, I saw several of the hotel employees who had quesmeal at a restaurant beside the natural waterfall in the mountains tions about their medical problems. The main conditions that that were the backdrop for the baseball field. I treated during the trip were bug bites and sprains. The Ambos On the road back to Havana, the bus driver started thinking Mundos Hotel had bedbugs. Insect repellent works wonderfully of how to play games against other teams. He mentioned that to prevent bedbug bites. You need to get a good coating of insect Cuba had an athletic training complex. At this complex was repellent before retiring for the evening. training for all the Olympic sports, with a wonderful baseball The day before our return to the US, the lady who had cared stadium and baseball teams of several levels of expertise. The for our room at Ambos Mundos said to Sharon and me, “Would bus driver detoured to the facility, and the director of athletics you like to see Mr. Hemingway's room?” We answered that we at Haverford College, Mr. Greg Kannerstein, discussed playing would, and we walked up a stairwell to the third floor of the games against the various level baseball teams at the academy. hotel. This lady opened the door and a room was revealed that Contests were set for the next several days (Figure 1). The had a single bed, a nightstand, and a small desk on which sat first game would be played against a group of retired Cuban a Royal typewriter, human powered. There was blank typing national players in the main stadium of the facility. This would paper on the desk. The Ambos Mundos has not touched this be followed by daily games against the level III players, the room except to clean it since Mr. Hemingway left the hotel in level II players, and then the level I players. The team was the 1950s. set to play Fidel Castro's personal team, the Reforma Plaza When we were in Cuba, there were policemen every half team, at the baseball field adjacent to Reforma Plaza. Also, block. The city was not safe. We were counseled to not walk by since every professional school in Cuba has a baseball team, ourselves and to take taxis when possible. The only problematic several games were scheduled against the medical school team time of the trip came the night we went to the national stadium from Havana. 228 Baylor University Medical Center Proceedings Volume 29, Number 2 to watch two professional teams play a game. The two teams were from Havana and a city in eastern Cuba (I do not remember the name of the city). During the game, I was fortunate to be able to purchase a locally made baseball bat from one of the players on the visiting team. I cannot recall how much the purchase price was. The bat was quite heavy. A dollar bill went a long way in Cuba in 2001. The ballgame went into extra innings and did not finish until after midnight. As it was a very good game, we stayed to watch. When we exited the stadium, there were no taxis to be seen. The policeman at the stadium entrance spoke pretty good English and explained that we would need to walk several blocks to the closest all-night taxi stand. He took a piece of paper and drew a map for us. As there was no ability to use credit or debit cards in Cuba in 2001, Mr. Kannerstein had several thousand dollars in a satchel which he carried everywhere on his person to pay bills as they materialized. We were a ways from the stadium when three young men and two boys started to follow us. They taunted us and then produced knives and demanded Mr. Kannerstein's satchel. Mr. Kannerstein told the young men that they would not get his satchel and they needed to leave. By this time, we could see the taxi station about a half block away. I told Kannerstein to make a run for it and I would use my baseball bat to retard these young thugs. Kannerstein took off running with his satchel, and I loaded my bat and was ready to swing. A miracle occurred. The young fellows with the knives ran. I start running to catch up with Kannerstein. We got our taxi and went back to the Ambos Mundos. The next to last day in Cuba, the Haverford baseball team played the hotel team from the Ambos Mundos. The pitcher for the Ambos Mundos team was a former National Team player for Cuba. He was close to 50 years old, I would guess, and was a lefty. He had a younger brother in the US pitching for the New York Yankees. Following the game, as the players were visiting, my oldest son, Laird, observed that he and this pitcher had similar size feet. The pitcher's shoes were not in good condition and were patched together. Laird had a spare pair of baseball shoes in his bag. He took the pair of shoes out of his bag and asked this gentleman if they would fit, and they did. The gentleman took off his Cuban National jersey and gave it to Laird. I am sure Laird still has that jersey. One of my favorite pictures is of Laird pitching in the Cuba jersey during a practice game the Haverford team had the next day prior to the plane ride home (Figure 2). There was so much more to this trip than I have recorded, but I would agree with you that Cuba and the United States of April 2016 Figure 2. Laird Marynick pitching a game in Cuba. America will be best served by exchange rather than isolation. I could discuss politics, philosophy, and economics. To do so only upsets most people because they have an opinion and their opinion is correct. They can’t comprehend how anyone with half of a brain could have a different point of view. It is a human failing that we believe individuals who do not agree with us are always wrong. Sometimes, there is more than one correct answer for the same question, sometimes not. However, history shows us that certain policies generally work better than others over time. Communism has shown that it is a recipe for economic and cultural failure. From the Pilgrims to Cuba, the result is the same. —Samuel P. Marynick, MD Texas Center for Reproductive Health Dallas, Texas 1. Roberts WC. A week in Havana, Cuba, in February 2015. Proc (Bayl Univ Med Cent) 2015;28(4):538–540. Reader comments 229 From the Editor Facts and ideas from anywhere COSTS OF DRUGS IN THE USA VERSUS OTHER COUNTRIES Norway, one of the world’s richest economies, is an expensive place to live (1). A Big Mac costs $5.65; a gallon of gasoline, $6.00. In 2015, a vial of the cancer drug Rituxan, however, cost Norway’s taxpayerfunded health system $1527, while the US William C. Roberts, MD. Medicare program paid $3678; an injection of the asthma drug Xolair cost Norway $463, 46% less than what Medicare paid for it. Drug prices in the US usually are shrouded in mystery, obscured by confidential rebates, multiple middlemen, and the strict guarding of trade secrets. But for certain drugs—those paid for by Medicare Part B—prices are public. By stacking these Medicare prices against pricing in three foreign health systems, The Wall Street Journal was able to determine drug cost differences in several countries and what lies behind them. The US prices were higher for 93% of 40 top-branded drugs available in both Norway and the USA in 2015. Similar patterns appeared when US prices were compared with those in the UK and Canada. Throughout the developed world, branded prescription drugs are generally less expensive in non-US countries than in the USA. The state-run health systems in Norway and in many other developed countries drive hard bargains with drug companies: setting price caps, demanding proof of a new drug’s value in comparison to existing ones, and sometimes refusing to cover medicines they doubt are worth the cost. The governments’ health systems also are the only large drug buyers in most of these countries, giving them substantial negotiating power. The US market, by contrast, is highly fragmented, with bill-payers ranging from employers to insurance companies to federal and state governments. Medicare, the largest single US payer for prescription drugs, is by law prevented from negotiating prices. For Medi230 care Part B, companies report the average price for which they sell medicines to distributors. By law, Medicare adds 6% to these prices. Beneficiaries are responsible for 20% of the costs. The arrangement means that Medicare essentially forfeits its buying power. In the US, few payers, public or private, cite cost as a reason to deny drug coverage. Medicare Part B typically covers drugs and services deemed “reasonable and necessary.” If it is a Food and Drug Administration (FDA)-approved drug and prescribed by a duly licensed physician, Medicare will usually cover it. The pharmaceutical industry says controls, such as those seen in Europe, discourage investment in research and deny patients access to some drugs. If US pricing fell to European levels, the industry would almost certainly cut its research and development spending. The higher US prices also help drug makers afford hefty marketing budgets that in the US include consumer advertising, something Europe does not allow. Pharmaceutical and biotechnology companies in the US earn an average net profit of 16%, compared with an average of about 7% for all companies in the Standard & Poor 1500 Index. Norway had a gross domestic product per capita of $97,000 in 2015 vs. $55,000 in the USA. In Norway, the state pays for most prescription drugs, although patients pay for some used for short periods. The government controls costs in part by setting maximum prices. To do that, it reviews prices in nine neighboring countries and takes the average of the three lowest. The Norwegian Medicines Agency then reviews patient data to decide whether a new drug is cost-effective. The drug maker must request a reimbursement price at or under the maximum that Norway has set and submit a detailed comparison of the drug’s costs and benefits vs. existing treatments. Norway recommends that companies describe a drug’s cost per quality-adjusted life year, a gauge used by many government health systems. Medicare is barred from using this gauge as a threshold in determining coverage. Drug companies know that Norway will sometimes deny coverage, and this threat is often enough to get them to offer a discount. The UK sometimes controls prices by capping the level of National Health Service spending on drugs each year and requiring the pharmaceutical industry to reimburse the National Health Service for any spending over those limits. Proc (Bayl Univ Med Cent) 2016;29(2):230–237 Of 40 branded drugs covered by Medicare Part B and also available in the UK in 2015, 98% were more expensive in the USA. Canada does not have a single large pharmaceutical payer, but drug prices are substantially lower than in the USA, held in check by regulation. Its federal agency, the Patented Medicine Prices Review Board, sets a maximum price for new drugs, based on their therapeutic benefits and the prices in six European countries and the USA. Once a drug’s maximum price is set, the maker can’t raise prices faster than the national inflation rate or above the highest price in the seven other countries. Countries with national health systems tend to feel they cannot afford everything for everybody at any price. That is not the health philosophy in the USA. FLU SHOTS FOR HOSPITAL WORKERS Drs. M. Todd Greene and Sanjay Saint of the Veterans Administration Ann Arbor Healthcare System had a piece in The Wall Street Journal indicating that seasonal flu caused as many as 55,000 deaths in 2014 according to the Centers for Disease Control and Prevention (CDC) (2). Some of these deaths almost certainly were the result of health care workers transmitting the influenza virus to patients. Some hospitals began requiring their staff to get vaccinated or wear masks if they could not or would not get vaccinated. A CDC survey in late 2015 showed that hospitals, physicians’ offices, long-term care facilities, and other clinics with mandatory vaccinations achieved 96% coverage for their workers compared with 44% coverage in institutions without mandatory vaccinations. A 2014 CDC study showed that health care worker vaccinations reduced patients’ risk of influenza-like illness by just over 40%. The CDC has long recommended annual influenza vaccinations for all health care personnel. The US Department of Health and Human Services wants 90% of health care workers vaccinated by 2020. The US, however, appears to be a long way from reaching that goal. Now, only about 43% of the 386 responding nonfederal hospitals require health care personnel to be vaccinated against the flu. Only 1% of the 77 Department of Veterans Affairs hospitals that answered the survey required health care personnel to get flu vaccinations! Mandates that allow exemptions for religious or health reasons and require unvaccinated workers to use masks can protect both patients and workers’ rights. In September 2015, Kaiser Permanente, the giant managed care organization, came to an agreement with a coalition of unions representing 105,000 health care workers, including nurses, medical assistants, custodial maintenance and food service workers, lab technicians, scientists, and clerical staff, to either receive the annual flu vaccine or wear a surgical mask while providing patient care during the flu season. Other public unions need to get on board. The Department of Veterans Affairs is considering a proposal to mandate influenza vaccinations for health care workers. It needs to adopt the proposal now. Veterans Affairs is the largest health care system in the US and one of the largest in the world. If it and its unions agree to mandatory vaccinations, that would send a strong message to the rest of the health care industry. April 2016 ZIKA VIRUS The Zika virus, a mosquito-borne infection, has already spread to numerous countries and territories in the Americas (3). It poses particular danger to pregnant women. The virus is linked to an outbreak of birth defects in Brazil. It has spread to the USA and to every country in the Western Hemisphere where the Aedes mosquitos are known to live. International travel, of course, will help the virus spread quickly. Zika does not spread from person to person, but people infected while traveling can spread the virus in the USA if they are bitten by local mosquitos which then may spread the infection here. The CDC has issued a travel alert warning pregnant women to avoid travel to the countries where Zika is present. Fortunately, the condition in nonpregnant adults is usually quite mild. CONCUSSIONS IN THE NATIONAL FOOTBALL LEAGUE According to the National Football League, there were 182 reported concussions from the 2015 regular season games, 58% more than the 115 in 2014, 148 in 2013, and 173 in 2012 (4). Among the possible explanations for the increase was a doubling in the number of players screened for possible concussions. Surely, not all concussions are equal. There must be small ones that are not noticed by anyone or realized by the player. The longer one plays in the National Football League, the greater the acquisition of concussions. MAJOR ORTHOPEDICS PROCEDURES PERFORMED AT RURAL CRITICAL-ACCESS HOSPITALS The Wall Street Journal in December 2015 reported its investigation of major orthopedic surgeries at small rural hospitals (5). It found that inpatient joint replacement operations covered by Medicare rose 43% at the critical-access hospitals from 2008 to 2013, far outpacing the 9% growth of those services at general hospitals. The trend reflects financial incentives built into the way Medicare pays the nation’s roughly 1300 critical-access hospitals, generally isolated facilities with 25 or fewer beds. Many studies show that patients generally get better results when their procedures are done at hospitals that perform them frequently. The average critical-access hospital performing inpatient joint replacements in 2013 did about 26 that year compared with about 130 at general hospitals. Hospitals doing >100 procedures a year have the lowest risks. The risk-adjusted rate of 30-day mortality per 1000 patients was 5.0 at general hospitals but 9.0 at critical-access hospitals. Critical-access hospitals are exempt from federal rules that require most facilities to report quality measures, such as rate of surgical complications! SCHOLARSHIP AND LIFE EXPECTANCY Scott Burns of The Dallas Morning News was one of the 837 graduates of the Massachusetts Institute of Technology in 1962 (6). He found that only 126 of his classmates were known to be dead, producing a survival of well over 80%, a rate much better than that of the broad US population. According to US life tables, only 62% of all men alive at age 22 survive to age 75. He opined that if the survival rate of his class of 1962 continues on its current path, life expectancy for the class would be Facts and ideas from anywhere 231 92 years. He indicated that the survival of the more educated is greater than that of the less educated. According to Social Security actuaries, the top half of the Social Security wage base can expect to live nearly 5 years longer than the bottom half. Those in the top 10% of the wage base can expect to live about 10 years longer than the bottom 10%. In 2015, Nobel laureate Augers Deaton and his wife, Anne Case, published an article showing that life expectancy for less educated, lower-income white men and women had actually declined by 5 years. The life expectancy of white women without a high school diploma was only 73.5 years; the life expectancy for white men without a high school diploma was 67.5 years. Study hard and live longer! UPGRADING PHYSICAL ACTIVITY Berra and colleagues (7) made the case that physical activity counseling should be upgraded to the equivalent of vital signs. The reason of course is that there is overwhelming evidence that regular physical activity is one of the most powerful healthpromoting practices that people can do. For decades, research has shown that regular physical activity protects against major chronic diseases including systemic hypertension, type II diabetes mellitus, obesity, heart disease, stroke, cognitive decline, select cancers, and depression. No other single intervention or treatment is associated with such a diverse array of benefits. In a recent “call to action” for the National Physical Activity Plan of the American Heart Association, a lack of physical activity was highlighted as a leading cause of death worldwide. The report emphasized that advice from health professionals significantly influences adoption of healthy lifestyle behaviors, including regular physical activity, and can increase satisfaction with medical care. Given the overwhelming evidence of benefits from physical activity and the vital role of health professionals in motivating behavior change, the lack of physical activity counseling in the clinical setting represents a lost opportunity to improve the health and well-being of patients, and with minimal costs. In 2012, there were >506 million primary care visits in the USA, most of which were for prevention and treatment of preventable chronic health conditions. Yet, only 34% of adults reported being counseled about physical activity at their last physician visit. Even among adults with prediabetes and other vascular risk factors, only 40% reported receiving such counseling. Technology, of course, provides numerous ways to improve the adoption of health promotion behaviors. The TEXTME study randomized 810 adults with coronary artery disease to receive or not receive motivational and informational text messages related to physical activity, diet, and smoking cessation. At 6 months, the investigators found improvements in all of the above outcomes as well as blood pressure and body mass index in the active message group compared with the control group. Clinicians can recommend pedometers or other wearable measurement devices, have resources available at the office visit (such as self-monitoring forms and reminders), and provide patients with a list of selected apps and websites to encourage physical activity. Because physicians and other health care 232 professionals are trusted sources of health information and can help patients set priorities for improving their health, physical activity counseling affords a vitally important opportunity to improve patients’ health and well-being. PETER MARK ROGET, MD, AND HIS THESAURUS Roget’s Thesaurus of English Words and Phrases first appeared in June 1852 and subsequently has emerged as one of the most recognizable books in the English language (8). The book has sold nearly 40 million copies. Although almost everyone is familiar with his book, few people know anything about Peter Mark Roget (1779–1869), the eminent 19th century polymath—physician, physiologist, mathematician, inventor, writer, editor, and chess whiz—and what motivated him to write this immortal book. Roget was obsessed with words ever since he began studying Latin as a schoolboy. Roget completed a first draft of the Thesaurus (the Latin word for “treasure” or “treasury”) in 1805 when he was 26 years old and working as a physician in Manchester, England. It was not until his retirement from medical practice, however, in 1848 at the age of 69 that Roget set out to finish the Thesaurus. The still spry Roget worked nonstop for nearly 4 years to complete the book. He tinkered with his masterpiece until his death at age 90, having watched over the publication of 28 editions. Roget’s Thesaurus of English Words and Phrases classified and arranged ideas so as to facilitate writers. He put both a book of synonyms and a topical dictionary (a compendium of thematically arranged concepts) under one cover. Borrowing the principles of zoological classification, Roget organized all knowledge, not just words. Just as his hero, the 18th century naturalist Carl Linnaeus, divided animals into six classes, Roget divided his 1000 concepts as follows: 1) abstract relations, 2) space, 3) matter, 4) intellect, 5) volition, and 6) affections. The 1000 headings of the 1852 edition, from which are culled the epigraphs to each chapter in the book, were arranged not alphabetically but according to where a given idea fit within Roget’s classification system. In that edition, the first entry is “existence,” which falls under the first class “abstract relations.” The purpose of the classification was to help readers find the right word for a given idea. Shortly before publication, Roget decided to insert an alphabetical index as an appendix, thus enabling readers to use the Thesaurus as a conventional book of synonyms. Scholars immediately began fawning over his prodigious efforts. One reviewer stated, “Roget will rank with Samuel Johnson as a literary instrument-maker of the first-class.” Generations of British writers would thereafter look up to Roget as a kindred soul who could offer both emotional and intellectual substance. An American version of the Thesaurus appeared in 1854 and initially appealed mainly to scholars. The crossword puzzle craze of the 1920s, however, turned Roget into a celebrity in the US as well as in the UK. In February 1925, The New York Times magazine described Roget as “Saint of Crosswordia.” In the days before every laptop became equipped with a thesaurus, Roget had a market all to himself and was an icon. Baylor University Medical Center Proceedings Volume 29, Number 2 Roget’s new world of 1000 concepts was not only his monumental gift to posterity, it was, first and foremost, the primary means by which he preserved his own sanity. Overwhelmed by the early death of his father and the emotional instability of his mother, Roget was constantly burying himself in books to cope with his sadness, anxiety, and anger. As a boy Roget kept dreaming up new worlds in the hope of escaping the dreary one in which he found himself. Commenting on his embrace of astronomy when he was 12, his mother remarked, “Peter ever eager after new studies, has for this while left this world and lived wholly in the starry regions.” Madness ran in the immediate family. Roget’s maternal grandmother, Margaret Garnault Romily, who suffered from an unidentified mental disorder thought to be severe depression or schizophrenia, was in an almost vegetative state for most of her life. In his memoir published in 1840, Roget’s uncle, the distinguished member of Parliament Sir Samuel Romily, mentioned that she had a nervous collapse when her parents initially objected to her marriage to his father. Romily also revealed that he and his two siblings, Thomas and Catherine (Peter’s mother), were raised jointly by an aunt, Margaret Facquier, and a nurse, Mary Evans, adding that “as far as my mother, she was incapable, from the bad state of her health, of taking any part in our education.” Romily himself committed suicide at the age of 61, at which time Roget’s mother, until then merely temperamental and emotionally demanding, lapsed into paranoia. For the last 15 years of her life, Catherine Romily Roget engaged in increasingly bizarre behavior. She lived her later years with her sister, Annette, who, like her mother, suffered frequent bouts of depression. Roget’s daughter, Kate, followed a similar trajectory. Roget himself was not immune, as his uncle once wrote him, “Despondency is, I have always thought, the great defect of our family, and I do not think that you are more exempt from it than the rest.” Described at 14 by his mother as “awkwardly bashful,” the young Roget was slow to make friends and felt most comfortable in his own company. Unlike his mother or his uncle, however, Roget managed to stave off madness. As a boy he stumbled upon a remarkable recovery—that compiling lists of words could provide solace, no matter what misfortunes might befall him. He was particularly fond of cataloguing the objects, both animate and inanimate, in his environment. As an adult he kept returning to the classification of words and concepts. Emerging in the nuances of language invariably both energized him and kept his persistent anxiety at bay. As he grew older, though he had satisfying relationships with both his wife, Mary, and the governess, Margaret Spowers, who became his unofficial second wife after Mary’s early death, Roget remained more interested in words than in people. After he had published his Thesaurus, Roget stated, “Men are odd animals; I have never felt as at home around them as around their words; without these, they’re monkeys. The other day I was going through my book and it struck me that I have more words for ‘disapprobation’ than ‘approbation.’ Why is this?” Over the course of his scientific career, Roget would specialize in physiology, and in 1834 he published the two-volume Animal and Vegetable Physiology: Considered with Reference to April 2016 Figure. Stamp issued by Belgium to commemorate the centenary of the death of Adolphe Quetelet (1796–1874), who in 1832 developed the “Quetelet Index,” now known as the body mass index. Natural Theology, also known as his Bridgewater Treatise. This work, held in highest esteem by 19th century academics, consisted of nothing but a catalog of specific plants and animals. ADOLPHE QUETELET AND BODY MASS INDEX The quest for a practical index of relative body weight began shortly after actuaries reported the increased mortality for their overweight policyholders after World War II, when the relation between weight and cardiovascular disease became the subject of epidemiological studies (9). It became evident then that the best index was the ratio of the body weight in kilograms divided by the square of the height in meters, or the Quetelet Index, described in 1832 by Adolphe Quetelet (1796–1874) (Figure). He was a Belgium mathematician, astronomer, and statistician who developed a passionate interest in probability calculus that he applied to study human physical characteristics and social aptitudes. His pioneering cross-sectional studies of human growth led him to conclude that other than the spurts of growth after birth and during puberty, the weight increases as the square of the height, known as the Quetelet Index, until it was termed the body mass index in 1972 by Ancil Keys (1904–2004). For his application of comparative statistics to social conditions and moral issues, Quetelet is considered a founder of the social sciences. His principal work, A Treatise of Man and the Development of His Facilities, published in 1835, is considered one of the greatest books of the 19th century. A tireless promoter of statistical data collection, Quetelet organized in 1853 the first International Statistical Congress, which launched the development of a uniform nomenclature of the causes of death applicable to all countries, the progenitor of the current International Classification of Diseases. HEALTH RANKINGS OF TEXAS In America’s Health Rankings, a composite index of >20 factors, Texas ranked 34th in overall health in 2015 (10). The report, put out by United Health Foundation, established by UnitedHealth Group, parent of insurer UnitedHealth Care, showed that Texas had one of the largest declines among US Facts and ideas from anywhere 233 states for 2015. The five healthiest states were Hawaii, Vermont, Massachusetts, Minnesota, and New Hampshire, and the five least healthy states were Alabama, West Virginia, Arkansas, Mississippi, and Louisiana. Texas’ rank among states in smoking was 5th (14.5%); excessive alcohol drinking, 25th (17.4%); obesity (body mass index >30 kg/m²), 40th (32%); physical inactivity, 43rd (28%); childhood immunizations, 48th (64%); and lack of health insurance, 50th (21%). Texas had the seventh lowest rate of drug-related deaths (10 per 100,000 population). Of high school students graduating within 4 years of starting the ninth grade, Texas had the third highest percentage (88%), trailing only Iowa and Nebraska. Consumers with more education are less likely to smoke, drink alcohol heavily, or be overweight or obese. They are also likely to have higher earning potential and better employment opportunities, factors generally associated with access to healthier food, better health insurance, better medical care, and safer neighborhoods. INTERRUPTED LONG SLEEP VERSUS CONTINUOUS SHORTER SLEEP In a study published in November 2015 in the journal Sleep, researchers from The Johns Hopkins University School of Medicine found that people forced to awaken multiple times during the night showed a greater decline in positive mood than those forced to go to bed later (11). They also had less slow-wave or deep sleep, the third stage of non-rapid eye movement sleep. A 2013 study from Israel found that a fragmented night of sleep for a full 8 hours impacted mood and attention as much as sleeping continuously 4 hours a night. A study from the University of Pittsburgh showed that the cognitive performance of elderly people was impaired when their sleep was disrupted but not when they slept a shorter amount of time straight through. The recent study from Hopkins included healthy people without any diagnosed sleep problems. The 62 subjects were brought into the lab and randomized into three groups: a group whose sleep was repeatedly disrupted; a group whose bedtime was delayed; and a control group. The subjects were given 8 hours to sleep in the lab for three consecutive nights. Those in the disrupted group were awakened each hour. Those in the forced awakening group showed a decline in mood during the 3 days, while those in the delayed bedtime group saw their moods stabilized over the 3 days. Thus, a good night’s sleep is not just about how long one sleeps; uninterrupted short sleep time may be better or at least equivalent to long interrupted sleep time. DIABETES DECLINING According to researchers at the CDC, the first decline in 25 years in the rate of new cases of diabetes mellitus was noted between 2008 and 2014, a 20% decrease (12). There were 1.4 million new cases of diabetes in 2014, down from 1.7 million in 2008. There is growing evidence that eating habits, after decades of deterioration, have finally begun to improve. The amount of soda Americans drink has declined by about 25% since the late 1990s, and the average number of daily calories children and adults consume also has fallen. Physical activity has started to rise and once-surging rates of obesity have flat234 tened. Type I diabetes mellitus, usually diagnosed in childhood and adolescents and usually not associated with excessive body weight, was included in the data. The portion of Americans with diabetes is still more than double what it was in the early 1990s! Educated Americans have seen improvements, while the rates for the less educated have flattened but not declined. The number of new cases is dropping for whites, but the change has not been statistically significant for blacks or Hispanics, although both show a downward trend. Diabetes still affects 1 in every 10 American adults and is the country’s leading cause of blindness, limb amputations, and kidney dialysis. SYNAPTIC PRUNING AND SCHIZOPHRENIA In the January 2016 issue of Nature was a report indicating that researchers had pieced together the steps by which genes can increase a person’s risk of developing schizophrenia, a condition affecting >2 million Americans and characterized by delusional thinking and hallucinations (13). The investigators found that the risk of schizophrenia is tied to a natural process called synaptic pruning in which the brain sheds weak or redundant connections between neurons as it matures. Their finding helps explain why this disorder often begins in adolescence or young adulthood. During this time, synaptic pruning takes place primarily in the section of the brain where thinking and planning skills are centered, known as the prefrontal cortex. People who carry genes that accelerate or intensify that pruning are at higher risk of developing schizophrenia than those who do not. Earlier studies with patients with schizophrenia had shown that the prefrontal areas tended to have fewer neural connections compared with those of unaffected people. The new study not only strongly supports this earlier belief but also describes how pruning probably goes wrong and why and identifies the genes responsible. People with schizophrenia have a gene variant that apparently facilitates aggressive “tagging” of connections for pruning, in effect accelerating the process. THE END OF THE ONE-CHILD POLICY IN CHINA The Chinese government announced in December 2015 that it has ended its one-child policy and will replace it with a universal two-child policy (14). The one-child policy profoundly affected the lives of 20% of the world’s population for 35 years! The one-child policy introduced in 1979 by Deng Xiao Ping (who saw population containment as essential to his ambitious economic reform program) was designed to improve standards of living after decades of economic stagnation. The decision to introduce an unpopular population policy was made despite a substantial reduction in the total fertility rate (TFR, defined as the average number of children born per woman) from an estimated 5.9 to 2.9 in the previous decade. This reduction had been achieved entirely through voluntary measures, and the TFR was still declining when the policy was introduced. Thailand’s fertility trajectory has been almost identical in the absence of a government mandate. From the outset, the one-child policy was strictly enforced for urban residents but not for rural residents. It soon became clear that a one-child rule was unenforceable because of the Baylor University Medical Center Proceedings Volume 29, Number 2 importance of labor capital in the family-based agrarian economy, dependence on children in old age, and the tradition of son preference. From 1984, most of the rural couples were allowed two children, although, in some provinces, only when the first child was a girl. The policy was enforced through a system of rewards and penalties, such as substantial fines and loss of employment, especially for public-sector workers, but with wide variations across the country. On the positive side, during the one-child policy time period, the TFR fell from 2.9 to around 1.6. The government claims that this policy prevented 400 million births while helping to lift 300 million people out of poverty. Women have benefited from fewer pregnancies and births, with consequent lower lifetime morbidity and mortality risk. The policy accelerated the move toward gender equality. Under the traditional Chinese system of patrilineal kinship, parents invested relatively little in their daughters, but in the absence of brothers, girls no longer competed for household resources. Recent studies have found no significant differences between single girl and single boy families in education, in terms of access, aspiration, or achievement. Women now account for 52% of undergraduates and 48% of postgraduates, as well as 25% of chief executive officers of medium and large Chinese companies. From the negative standpoint, the one-child policy may be viewed as a violation of the right to reproductive choice. Its implementation has resulted in well-documented atrocities, such as forced abortions and sterilizations. The policy has contributed to the highest sex ratio at birth in the world, peaking in 2005 at 121 male to 100 female births. The sex ratio at birth started to increase after the onset of the policy, but this trend accelerated after sex-selective technology (ultrasound followed by abortion of the female fetus) became available, even in the rural areas, from the late 1980s. The latest estimates show a decline to 116 male births to 100 female births, still the highest in the world, and with ratios up to 140 in parts in rural China. The number of excess men in the reproductive age group is estimated at around 30 million, with large numbers of unmarriageable men in high sex-ratio areas. Evidence indicates that these men have higher levels of depression, are more prone to aggression than married men, and may be more easily drawn into crime. The policy has also created the so-called 4:2:1 phenomenon, with many couples solely responsible for the care of one child and four grandparents. One-quarter of the world’s population ≥65 years, or 140 million people, live in China, and the number is estimated to increase to >200 million by 2030. The pressure on the health system resulting from the increasing burden of noncommunicable diseases and degenerative disorders is one of China’s most serious challenges. Because out-of-pocket health costs are high in China and approximately 70% of this age group lacks adequate pension coverage, they are highly financially dependent on offspring. This is further compounded by the fact that approximately 40% of the elderly now live away from their children and 10% live alone. This is a particular problem in rural areas because of mass migration of the young to cities. This occurs in a setting where Confucian tradition still dictates that care of the elderly is a filial duty. China is probably April 2016 unique in having laws that make care of the elderly a family responsibility, and adult children may be compelled to provide financial support. It is ironic that after decades of draconian restrictions on fertility, the government is now concerned about the economic consequences of future labor shortages, concomitant with a high age-dependency ratio, and will now encourage couples to have two children. “NATURAL” FOOD What is it? About 60% of the US population regularly buys food labeled “natural,” yet there is confusion as to what that word means. The word has never been legally defined. At least 60% of people believe a natural label means packaged and processed foods that have no genetically modified organisms, no artificial ingredients or colors, no chemicals, and no pesticides. About 45% think that natural is a verified claim. It is not! In fact, according to a piece in USA Today by Hadley Malcolm (15), none of these attributes is necessarily true because the use of the word is not regulated. The FDA apparently is going to take a closer look sometime this year at how the word is used and whether it should be defined and how. According to the FDA website, “a long-standing policy” interprets “natural” to mean nothing artificial or synthetic has been added to a food that would not normally be expected in that food. The FDA does not intend to address food production, processing, or manufacturing methods. Shoppers unfortunately appear to be on the lookout for certain words and use them as purchase signals regardless of whether the claims are regulated or not. If there is a health claim on the front of the package, that is what we zero in on apparently. Consumer Reports identified seven products with “natural” claims that also contain artificial ingredients or chemicals: Del Monte Fruit Naturals, All-Natural Alexia Sweet Potato Fries, Krakus Polish Sliced Ham, Natural Brew Draft Root Beer, Tyson Grilled & Ready Frozen Southwestern Chicken Breast Strips, Kraft Natural Cheese, and Wesson Vegetable Oil. Definitions are wonderful things. That’s why the dictionary has been around so long. LIMITED CALORIC DIVERSITY Simran Sethi discussed our dwindling food variety (16). In 1903, US commercial seed houses offered hundreds of varieties. The following numbers were offered in 1903, followed by the numbers (in parentheses) offered in 1983: muskmelon, 338 (227); lettuce, 497 (236); sweet corn, 307 (12); cabbage, 544 (28); beets, 288 (217); peas, 408 (25); radish, 463 (27); squash, 341 (40); tomato, 408 (279); cucumber, 285 (16). There are now 7500 varieties of apples grown all over the world, <100 of which are grown commercially in the USA. Bananas, America’s most popular fruit, have 1000 varieties grown in the world. The only one on grocery store shelves in the USA is not the one that has the best texture or taste but the one that transports easily and is immune to certain diseases. There are 30,000 edible plant species, and we cultivate about 150. Of the 30 domesticated mammalian and bird species, 14 provide 90% of the human food supply. Of the world’s food, 75% comes from 12 plants Facts and ideas from anywhere 235 and 5 animal species. Plants account for over 80% of the human diet: 30,000 terrestrial plants are known to be edible, but only 7000 are cultivated or collected by humans for food. Thirty crops feed the world. DAILY WRITING Charlie Kempthorne, now 78 years old, began writing in his “My Journal” at age 26 in 1964 and has logged about 1000 to 3000 words daily on his computer during each of these past 52 years (17). By his rough calculations, his journal is about 10 million words long. Every month, he prints the last 30 days of entries (single-spaced, two-sided) and puts it in a three-ring binder. His collective writings occupy about 15 feet of shelf space in a storage unit in Manhattan, Kansas, where he lived before moving last year. No one, including his wife of 41 years, has read it. Mr. Kempthorne, who quit a university teaching job in his 30s to run a farm and small housecleaning business, says his writing helps him understand his life better. It makes him simply feel better and gets him started on the day in a better mood. Psychology professor James Pennebaker at the University of Texas and author of several books, including Writing to Heal, says, “Taking 15 or 20 minutes to write freely about emotions, secrets or upheaval can be a powerful tonic.” “Writing privately about traumatic experiences, even for as few as 4 consecutive days, can reduce stress, help people sleep, and improve their immune system,” says Dr. Pennebaker. “When you translate an emotional experience into words, it organizes them in ways not organized before. It makes them simpler and easier to get past.” When Charlie Kempthorne sits down to write every morning, he often has no idea what he will write until he opens the folder labeled “My Journal” on his computer. One day he might write about going to the Goodwill Store in Olympia, where he now lives. The next day he might recall fighting with a boy named Jimmy over whose dad was best and telling Jimmy his father didn’t get anything to eat but vegetables. He will sometimes consult a list of phrases kept in another computer file or on paper that refers to events in his past that he might want to write about. Once he starts writing he begins to remember things, people, and conversations. It reminds him of his farm in Kansas, which was covered with rocks that needed to be cleared before he could plow. He prefers the computer to longhand because typing is faster. “The faster I write the better I write. If I don’t write each day I feel something is missing.” His wife, June, says he is ‘out of sorts’ if he skips a session. Charlie Kempthorne has some advice on how to build a daily writing habit: Write 500 words every day for 28 consecutive days, preferably at the same time and same place to create a routine. Don’t worry about grammar or punctuation. Be willing to write badly. Authenticity is more important than excellence. Use prompts to get you going. Make a list of six stories you commonly tell. Get a photo and tell the story of that picture. Keep it private. If you show it to others you might worry about what they will say and never start. If you can’t think of what to write, describe the room you are in, what you are wearing or a room from your 236 childhood home, or what it felt like to brush your teeth. Carry a notebook to jot down ideas or a recollection, conversation, or image. KONDOING Marie Kondo is the author of The Life-Changing Magic of Tidying Up (2014) and Spark Joy: An Illustrated Master Class on the Art of Organizing and Tidying Up (2016) (18). Marie Kondo, who refers to herself as KonMari, is a phenomenon in Japan and becoming one in the USA. Her view in essence is that a neat home is a happy home. Kondo offers her tips with a side of existential advice. She counsels that “the best way to choose what to keep and what to throw away is to take each item in one’s hand and ask: ‘Does this spark joy?’ If it does, keep it. If not, dispose of it.” Kondo instructs her readers to ask themselves of each item in their home, “Am I having trouble getting rid of this because of an attachment to the past or because of a fear for the future? Tidying is the act of confirming yourself.” Kondo writes in her new book, “Cleaning is the act of confronting nature.” In the US, women take on more domestic responsibilities than their male partners. Women in the USA spend an average of 2 hours more on chores a week than men. In one British survey, men acknowledged deliberately doing a poor job of cleaning the toilet, loading the dishwasher, and vacuuming so that their female partners would be more inclined to tackle those chores themselves. Even the most equally minded heterosexual couples can find themselves defaulting to familiar roles when it comes to the mundane tasks of homemaking. GLOBAL WARMING US agencies released figures in January 2016 showing that 2015 was the warmest year since 1880, when the global record began (19, 20). The previous record was in 2014. December 2015 was especially remarkable in the US, with virtually every state east of the Mississippi River having a record warm month often accompanied by heavy rains. A warmer atmosphere can hold more water vapor, and intensification of rain storms was one of the fundamental predictions made by climate scientists decades ago as a consequence of human-produced emissions. That prediction has come true with the rains growing more intense in every region of the US, especially in the East. The term “global warming” is generally taken to refer to the temperature trend at the surface of the planet. Some additional measurements of shorter duration are available for the ocean depths and the atmosphere above the surface, both generally showing an inexorable long-term warming trend. The intense warmth of 2015 produced a heat wave in India that turned out to have been the second worst in that country’s history, killing an estimated 2500 people. Of the 10 deadliest heatwaves, eight have occurred since 1997. Although only rough estimates of heat deaths are available, according to figures from the Center for Research on the Epidemiology of Disasters in Brussels, the toll over the last 2 decades is approaching 140,000 people, with most of those deaths occurring during a European heat wave in 2003 and a Russian heat wave in 2010. The strong El Niño has continued into 2016, raising the possibility that this year will yet again set a global temperature Baylor University Medical Center Proceedings Volume 29, Number 2 record. The El Niño pattern also is disturbing the circulation of the atmosphere, contributing to worldwide weather extremes that include a drought in Southern Africa threatening the food supply of millions. The National Oceanic and Atmospheric Administration calculated the 2015 global temperature at 58.62°, or 1.62° above the 20th century average. 5. 6. 7. 8. ROGER STAUBACH AND “HAIL MARY” It was on December 28, 1975, with only 32 seconds remaining in a National Football Conference playoff game (Dallas Cowboys vs. Minnesota Vikings) when Roger Staubach completed a winning 50-yard touchdown pass to wide receiver Drew Pearson (21). After the game, Staubach, a lifelong Catholic, said, “I closed my eyes and said a Hail Mary.” And now, nearly half a century later, the phrase is often used. We owe it to Roger Staubach. 9. 10. 11. 12. 13. 14. 15. 16. William Clifford Roberts, MD February 9, 2016 1. 2. 3. 4. Whalen J. US drug prices dwarf other nations’. Wall Street Journal, December 1, 2015. Greene MT, Saint S. Flu shots for hospital workers save lives. Wall Street Journal, December 14, 2015. Szabo L. Zika virus threatens to hit USA. USA Today, January 28, 2016. AP. NFL briefs: Concussions increase. Dallas Morning News, January 30, 2016. April 2016 17. 18. 19. 20. 21. Weaver C, Wilde Mathews C, McGinty T. New risks at rural hospitals. Wall Street Journal, December 26–27, 2015. Burns S. For a longer life, try being a nerd. Dallas Morning News, January 24, 2016. Berra K, Rippe J, Manson JE. Making physical activity counseling a priority in clinical practice: the time for action is now. JAMA 2015;314(24):2617– 2618. Kendall J. The Man Who Made Lists: Love, Death, Madness, and the Creation of Roget’s Thesaurus. New York: Penguin Group, 2008 (297 pp.). Eknoyan G. Adolphe Quetelet (1796–1874)—the average man and indices of obesity. Nephrol Dial Transplant 2008;23(1):47–51. Robinson-Jacobs K. Texans bigger but not better in health rankings. Dallas Morning News, December 10, 2015. Reddy S. Less sleep can feel better than interruptions. Wall Street Journal, December 1, 2015. Tavernise S. New cases of diabetes in US decline. New York Times, December 1, 2015. Carey B. Schizophrenia’s cause explored. New York Times, January 29, 2016. Hesketh T, Zhou X, Wang Y. The end of the one-child policy: lasting implications for China. JAMA 2015;314(24):2619–2620. Malcolm H. More buying ‘natural’ food, but it’s unclear what that is. USA Today, January 29, 2016. Sethi S. Your varied diet isn’t really so varied. Dallas Morning News, January 24, 2016. Ansberry C. 52 years and counting: the power of daily writing. Wall Street Journal, January 27, 2016. Friedman A. Men miss “Magic of Tidying Up.” Dallas Morning News, January 31, 2016. Wire reports. 2015: hottest year on record. Dallas Morning News, January 21, 2016. Englis B. Conservatives need to thaw on warming. USA Today, January 22, 2016. Granberry M. All hail the Hail Mary at 40. Dallas Morning News, December 29, 2015. Facts and ideas from anywhere 237 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff ANESTHESIOLOGY AND PAIN MANAGEMENT 1. Barker SJ, Shander A, Ramsay MA. Continuous noninvasive hemoglobin monitoring: a measured response to a critical review. Anesth Analg 2015 Mar 5 [Epub ahead of print]. 2. Idris AH, Guffey D, Pepe PE, Brown SP, Brooks SC, Callaway CW, Christenson J, Davis DP, Daya MR, Gray R, Kudenchuk PJ, Larsen J, Lin S, Menegazzi JJ, Sheehan K, Spoko G, Stiell I, Nichol G, Aufderheide TP; Resuscitation Outcomes Consortium Investigators [Ramsay M]. Chest compression rates and survival following out-of-hospital cardiac arrest. Crit Care Med 2015;43(4):840–848. 3. Nichol G, Leroux B, Wang H, Callaway CW, Sopko G, Weisfelt M, Stiell I, Morrison LJ, Aufderheide TP, Cheskes S, Christenson J, Kudenchuk P, Vaillancourt C, Rea TD, Idris AH, Colella R, Isaacs M, Straight R, Stephens S, Richardson J, Condle J, Schmicker RH, Egan D, May S, Ornato JP; Resuscitation Outcomes Consortium Investigators [Ramsay M]. Trial of continuous or interrupted chest compressions during CPR. N Engl J Med 2015 Nov 9 [Epub ahead of print]. 4. Ramsay M. Breathing is good. J Clin Monit Comput 2015;29(2):221–222. 5. Rauck R, Parikh N, Dillaha L, Barker J, Stearns L. Patient satisfaction with fentanyl sublingual spray in opioid-tolerant patients with breakthrough cancer pain. Pain Pract 2015;15(6):554–563. 16. 17. 18. 19. 20. 21. 22. 23. CARDIOLOGY/CARDIAC, VASCULAR, AND THORACIC SURGERY 6. Abramowitz Y, Jilaihawi H, Chakravarty T, Mack MJ, Makkar RR. Mitral annulus calcification. J Am Coll Cardiol 2015;66(17):1934–1941. 7. Abramowitz Y, Jilaihawi H, Chakravarty T, Mack MJ, Makkar RR. Porcelain aorta: a comprehensive review. Circulation 2015;131(9):827–836. 8. Adams R, Adams J, Qin H, Bilbrey T, Schussler JM. Virtual coaching for the high-intensity training of a powerlifter following coronary artery bypass grafting. Proc (Bayl Univ Med Cent) 2015;28(1):75–77. 9. Afzal AM, Alsahhar J, Podduturi V, Schussler JM. Undifferentiated intimal sarcoma of the inferior vena cava with extension to the right atrium and renal vasculature. Case Rep Cardiol 2015;2015:812374. 10. Afzal AM, Sarmast SA, Weber NA, Schussler JM. Spontaneous coronary artery dissection in a 22-year-old man on lisdexamfetamine. Proc (Bayl Univ Med Cent) 2015;28(3):367–368. 11. Alli O, Rihal CS, Suri RM, Greason KL, Waksman R, Minha S, Torguson R, Pichard AD, Mack M, Svensson LG, Rajeswaran J, Lowry AM, Ehrlinger J, Tuzcu EM, Thourani VH, Makkar R, Blackstone EH, Leon MB, Holmes D. Learning curves for transfemoral transcatheter aortic valve replacement in the PARTNER-I trial: technical performance. Catheter Cardiovasc Interv 2015 Aug 10 [Epub ahead of print]. 12. Anker SD, Kosiborod M, Zannad F, Piña IL, McCullough PA, Filippatos G, van der Meer P, Ponikowski P, Rasmussen HS, Lavin PT, Singh B, Yang A, Deedwania P. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail 2015;17(10):1050–1056. 13. Arko FR, Gable DR. Why build an aortic center? EndoVasc Today 2015;8(S2):5–10. 14. Armstrong D, Gonzalez-Stawinski GV, Ko JM, Hall SA, Roberts WC. The two extremes of cardiac sarcoidosis and the effect of prednisone therapy. Am J Cardiol 2015;115(1):150–153. 15. Arnold SV, Spertus JA, Vemulapalli S, Dai D, O’Brien SM, Baron SJ, Kirtane AJ, Mack MJ, Green P, Reynolds MR, Rumsfeld JS, Cohen DJ. 238 24. 25. 26. 27. 28. 29. 30. Association of patient-reported health status with long-term mortality after transcatheter aortic valve replacement: report from the STS/ACC TVT registry. Circ Cardiovasc Interv 2015;8(12). Arsalan M, Mack M. Coronary artery bypass grafting in patients with diabetes: the weight is on us. J Thorac Cardiovasc Surg 2015;150(2):284–285. Arsalan M, Mack MJ. Durability of devices: long-term results and clinical outcomes. EuroIntervention 2015;11(Suppl W):W119–W122. Arsalan M, Squiers JJ, DiMaio JM, Mack MJ. Catheter-based or surgical repair of the highest risk secondary mitral regurgitation patients. Ann Cardiothorac Surg 2015;4(3):278–283. Arsalan M, Squiers JJ, Walther T. Preimplantation valvuloplasty in transcatheter aortic valve replacement: to BAV or not to BAV? J Thorac Cardiovasc Surg 2015;150(5):1118–1119. Arsalan M, Walther T, Smith RL 2nd, Grayburn PA. Tricuspid regurgitation diagnosis and treatment. Eur Heart J 2015 Sep 10 [Epub ahead of print]. Asgar AW, Mack MJ, Stone GW. Secondary mitral regurgitation in heart failure: pathophysiology, prognosis, and therapeutic considerations. J Am Coll Cardiol 2015;65(12):1231–1248. Asgar AW, Mack MJ, Stone GW. Reply: Secondary mitral regurgitation. J Am Coll Cardiol 2015;66(17):1947. Barbin CM, Grayburn PA, Choi JW. Successful MitraClip® implantation after angioplasty of a chronic inferior vena cava filter thrombosis. Catheter Cardiovasc Interv 2015 Jun 23 [Epub ahead of print]. Barbin CM, Weissenborn MR, Ko JM, Guileyardo JE, Roberts WC. Computed tomographic and morphologic features of syphilis of the aorta. Am J Cardiol 2015;116(8):1311–1314. Bavaria JE, Brinkman WT, Hughes GC, Khoynezhad A, Szeto WY, Azizzadeh A, Lee WA, White RA. Outcomes of thoracic endovascular aortic repair in acute type B aortic dissection: results from the Valiant United States investigational device exemption study. Ann Thorac Surg 2015;100(3):802–808. Bhak RH, Wininger M, Johnson GR, Lederle FA, Messina LM, Ballard DJ, Wilson SE; Aneurysm Detection and Management (ADAM) Study Group. Factors associated with small abdominal aortic aneurysm expansion rate. JAMA Surg 2015;150(1):44–50. Blackstone EH, Suri RM, Rajeswaran J, Babaliaros V, Douglas PS, Fearon WF, Miller DC, Hahn RT, Kapadia S, Kirtane AJ, Kodali SK, Mack M, Szeto WY, Thourani VH, Tuzcu EM, Williams MR, Akin JJ, Leon MB, Svensson LG. Propensity-matched comparisons of clinical outcomes after transapical or transfemoral transcatheter aortic valve replacement: a placement of aortic transcatheter valves (PARTNER)-I trial substudy. Circulation 2015;131(22):1989–2000. Blanke P, Naoum C, Webb J, Dvir D, Hahn RT, Grayburn P, Moss RR, Reisman M, Piazza N, Leipsic J. Multimodality imaging in the context of transcatheter mitral valve replacement: establishing consensus among modalities and disciplines. JACC Cardiovasc Imaging 2015;8(10):1191–1208. Bourantas CV, Zhang YJ, Garg S, Mack M, Dawkins KD, Kappetein AP, Mohr FW, Colombo A, Holmes DR, Ståhle E, Feldman T, Morice MC, de Vries T, Morel MA, Serruys PW. Prognostic implications of severe coronary calcification in patients undergoing coronary artery bypass surgery: an analysis of the SYNTAX study. Catheter Cardiovasc Interv 2015;85(2):199–206. Brinkman WT, Squiers JJ, Covington KR, Wheeler DA, Arsalan M, Smith RL, Mack MJ, DiMaio J. Mini-extracorporeal circulation and off-pump Proc (Bayl Univ Med Cent) 2016;29(2):238–258 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. techniques associated with less inflammatory gene expression as compared to on-pump in the 24-hour postoperative window following coronary artery bypass grafting. J Cardiothorac Surg 2015;10(Suppl 1):A101. Brinkman WT, Squiers JJ, Filardo G, Arsalan M, Smith RL, Moore D, Mack MJ, DiMaio JM. Perioperative outcomes, transfusion requirements, and inflammatory response after coronary artery bypass grafting with off-pump, mini-extracorporeal, and on-pump circulation techniques. J Investig Med 2015;63(8):916–920. Busken CJ, Grimsley BR, Shutze WP. Iliac artery stenosis complicating iliac vein stenting in a patient with a history of radiation and cancer: case report and literature review. Ann Vasc Surg 2015;29(4):843.e7–15. Carroll JD, Shuren J, Jensen TS, Hernandez J, Holmes D, Marinac-Dabic D, Edwards FH, Zuckerman BD, Wood LL, Kuntz RE, Mack MJ. Transcatheter valve therapy registry is a model for medical device innovation and surveillance. Health Aff (Millwood) 2015;34(2):328–334. Chan RH, Maron BJ, Olivotto I, Assenza GE, Haas TS, Lesser JR, Gruner C, Crean AM, Rakowski H, Rowin E, Udelson J, Lombardi M, Tomberli B, Spirito P, Formisano F, Marra MP, Biagini E, Autore C, Manning WJ, Appelbaum E, Roberts WC, Basso C, Maron MS. Significance of late gadolinium enhancement at right ventricular attachment to ventricular septum in patients with hypertrophic cardiomyopathy. Am J Cardiol 2015;116(3):436–441. Charytan DM, Fishbane S, Malyszko J, McCullough PA, Goldsmith D. Cardiorenal syndrome and the role of the bone-mineral axis and anemia. Am J Kidney Dis 2015;66(2):196–205. Chen S, Chen J, Huang P, Meng XL, Clayton S, Shen JS, Grayburn PA. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction. Biochem Biophys Res Commun 2015;458(4):823–829. Chen J, Chen S, Huang P, Meng XL, Clayton S, Shen JS, Grayburn PA. In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. Diabetologia 2015;58(5):1036–1044. Coylewright M, Mack MJ, Holmes DR Jr, O’Gara PT. A call for an evidence-based approach to the heart team for patients with severe aortic stenosis. J Am Coll Cardiol 2015;65(14):1472–1480. Cumbie TA, Kedora JC, Pearl GJ, Shutze WP. A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion. Proc (Bayl Univ Med Cent) 2015;28(3):355–357. Cutlip DE, Kereiakes DJ, Mauri L, Stoler R, Dauerman HL; EDUCATE Investigators. Thrombotic complications associated with early and late nonadherence to dual antiplatelet therapy. JACC Cardiovasc Interv 2015;8(3):404–410. Douglas PS, Hahn RT, Pibarot P, Weissman NJ, Stewart WJ, Xu K, Wang Z, Lerakis S, Siegel R, Thompson C, Gopal D, Keane MG, Svensson LG, Tuzcu EM, Smith CR, Leon MB. Hemodynamic outcomes of transcatheter aortic valve replacement and medical management in severe, inoperable aortic stenosis: a longitudinal echocardiographic study of cohort B of the PARTNER trial. J Am Soc Echocardiogr 2015;28(2):210–217.e1–9. Falcone AM, Varghese JJ, Stoler RC, Choi JW. Effectiveness of balloon valvuloplasty for stenosis of a bioprosthesis in the tricuspid valve position. Proc (Bayl Univ Med Cent) 2015;28(4):502–503. Fallahzadeh MK, McCullough PA. Cardiac electromechanical abnormalities in hemodialysis patients: indicators of cardiomyopathy and future risk. Am J Nephrol 2015;42(3):237–238. Farber A, Tan TW, Hu B, Dember LM, Beck GJ, Dixon BS, Kusek JW, Feldman HI; Dialysis Access Consortium (DAC) Study Group. The effect of location and configuration on forearm and upper arm hemodialysis arteriovenous grafts. J Vasc Surg 2015;62(5):1258–1264. Feldman T, Kar S, Elmariah S, Smart SC, Trento A, Siegel RJ, Apruzzese P, Fail P, Rinaldi MJ, Smalling RW, Hermiller JB, Heimansohn D, Gray WA, Grayburn PA, Mack MJ, Lim DS, Ailawadi G, Herrmann HC, Acker MA, Silvestry FE, Foster E, Wang A, Glower DD, Mauri L; EVEREST II Investigators. Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5-year results of EVEREST II. J Am Coll Cardiol 2015;66(25):2844–2854. Filardo G, Powell JT, Martinez MA, Ballard DJ. Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst Rev 2015;2:CD001835. April 2016 47. Flack JM, Bhatt DL, Kandzari DE, Brown D, Brar S, Choi JW, D’Agostino R, East C, Katzen BT, Lee L, Leon MB, Mauri L, O’Neill WW, Oparil S, Rocha-Singh K, Townsend RR, Bakris G; SYMPLICITY HTN-3 Investigators. An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and non-African Americans in the SYMPLICITY HTN-3 trial. J Am Soc Hypertens 2015;9(10):769–779. 48. Frost PA, Chen S, Mezzles MJ, Voruganti VS, Nava-Gonzalez EJ, ArriagaCazares HE, Freed KA, Comuzzie AG, DeFronzo RA, Kent JW Jr, Grayburn PA, Bastarrachea RA. Successful pharmaceutical-grade streptozotocin (STZ)induced hyperglycemia in a conscious tethered baboon (Papio hamadryas) model. J Med Primatol 2015;44(4):202–217. 49. Gable DR. Covered stent grafts in the SFA are still the endovascular champion in long lesions. Vasc Spec 2015;11(4):8. 50. Garcia MJ, Blankstein R, Budoff MJ, Dent JM, Drachman DE, Lesser JR, Grover-McKay M, Schussler JM, Voros S, Wann LS. COCATS 4 Task Force 7: training in cardiovascular computed tomographic imaging. J Am Coll Cardiol 2015;65(17):1810–1812; J Nucl Cardiol 2015;22(4):826–839. 51. Généreux P, Campos CM, Farooq V, Bourantas CV, Mohr FW, Colombo A, Morel MA, Feldman TE, Holmes DR Jr, Mack MJ, Morice MC, Kappetein AP, Palmerini T, Stone GW, Serruys PW. Validation of the SYNTAX revascularization index to quantify reasonable level of incomplete revascularization after percutaneous coronary intervention. Am J Cardiol 2015;116(2):174–186. 52. Gillinov AM, Gelijns AC, Parides MK, DeRose JJ Jr, Moskowitz AJ, Voisine P, Ailawadi G, Bouchard D, Smith PK, Mack MJ, Acker MA, Mullen JC, Rose EA, Chang HL, Puskas JD, Couderc JP, Gardner TJ, Varghese R, Horvath KA, Bolling SF, Michler RE, Geller NL, Ascheim DD, Miller MA, Bagiella E, Moquete EG, Williams P, Taddei-Peters WC, O’Gara PT, Blackstone EH, Argenziano M; CTSN Investigators. Surgical ablation of atrial fibrillation during mitral-valve surgery. N Engl J Med 2015;372(15):1399–1409. 53. Gopal A, Grayburn PA, Mack M, Chacon I, Kim R, Montenegro D, Phan T, Rudolph J, Filardo G, Mack MJ, Gopalakrishnan D. Noncontrast 3D CMR imaging for aortic valve annulus sizing in TAVR. JACC Cardiovasc Imaging 2015;8(3):375–378. 54. Grayburn PA, Carabello B, Hung JW, Gillam LD, Liang D, Mack MJ, McCarthy PM, Miller DC, Trento A, Siegel RJ. Reply: When to call it severe mitral regurgitation? J Am Coll Cardiol 2015;65(25):2767–2768. 55. Grayburn PA, She L, Roberts BJ, Golba KS, Mokrzycki K, Drozdz J, Cherniavsky A, Przybylski R, Wrobel K, Asch FM, Holly TA, Haddad H, Yii M, Maurer G, Kron I, Schaff H, Velazquez EJ, Oh JK. Comparison of transesophageal and transthoracic echocardiographic measurements of mechanism and severity of mitral regurgitation in ischemic cardiomyopathy (from the Surgical Treatment of Ischemic Heart Failure Trial). Am J Cardiol 2015;116(6):913–918. 56. Green P, Arnold SV, Cohen DJ, Kirtane AJ, Kodali SK, Brown DL, Rihal CS, Xu K, Lei Y, Hawkey MC, Kim RJ, Alu MC, Leon MB, Mack MJ. Relation of frailty to outcomes after transcatheter aortic valve replacement (from the PARTNER trial). Am J Cardiol 2015;116(2):264–269. 57. Hahn RT, Kodali S, Tuzcu EM, Leon MB, Kapadia S, Gopal D, Lerakis S, Lindman BR, Wang Z, Webb J, Thourani VH, Douglas PS. Echocardiographic imaging of procedural complications during balloonexpandable transcatheter aortic valve replacement. JACC Cardiovasc Imaging 2015;8(3):288–318. 58. Hamm CW, Arsalan M, Mack MJ. The future of transcatheter aortic valve implantation. Eur Heart J 2015 Nov 17 [Epub ahead of print]. 59. Harrison JK, Hughes GC, Reardon MJ, Stoler RC, Grayburn PA, Hebeler RF, Popma JJ. Balloon post-dilation of the self-expanding CoreValve transcatheter aortic valve bioprosthesis: procedural results and in hospital outcomes from 3532 patients in the CoreValve US pivotal and continued access trials. J Am Coll Cardiol 2015;66(15S). 60. Harskamp RE, Alexander JH, Ferguson TB Jr, Hager R, Mack MJ, Englum B, Wojdyla D, Schulte PJ, Kouchoukos NT, de Winter RJ, Gibson CM, Peterson ED, Harrington RA, Smith PK, Lopes RD. Frequency and predictors of internal mammary artery graft failure and subsequent clinical outcomes: insights from the PREVENT IV Trial. Circulation 2015 Dec 8 [Epub ahead of print]. 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff 239 61. Harskamp RE, Halkos ME, Xian Y, Szerlip MA, Poston RS, Mick SL, Lopes RD, Tijssen JG, de Winter RJ, Peterson ED. A nationwide survey on perception, experience, and expectations of hybrid coronary revascularization among top-ranked US hospitals. Am Heart J 2015;169(4):557–563.e6. 62. Head SJ, Parasca CA, Mack MJ, Mohr FW, Morice MC, Holmes DR Jr, Feldman TE, Dawkins KD, Colombo A, Serruys PW, Kappetein AP; SYNTAX Investigators. Differences in baseline characteristics, practice patterns and clinical outcomes in contemporary coronary artery bypass grafting in the United States and Europe: insights from the SYNTAX randomized trial and registry. Eur J Cardiothorac Surg 2015;47(4):685–695. 63. Hess CN, Lopes RD, Gibson CM, Hager R, Wojdyla DM, Englum BR, Mack MJ, Kouchoukos NT, Peterson ED, Alexander JH. Response to letters regarding article, “Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV.” Circulation 2015;132(4):e29. 64. Hijazi ZM, Ruiz CE, Zahn E, Ringel R, Aldea GS, Bacha EA, Bavaria J, Bolman RM 3rd, Cameron DE, Dean LS, Feldman T, Fullerton D, Horlick E, Mack MJ, Miller DC, Moon MR, Mukherjee D, Trento A, Tommaso CL. SCAI/AATS/ACC/STS operator and institutional requirements for transcatheter valve repair and replacement, part III: pulmonic valve. J Am Coll Cardiol 2015;65(23):2556–2563; Ann Thorac Surg 2015;99(5):1857–1864; J Thorac Cardiovasc Surg 2015;149(5):e71–e78; Catheter Cardiovasc Interv 2015;86(1):85–93. 65. Holmes DR Jr, Brennan JM, Rumsfeld JS, Dai D, O’Brien SM, Vemulapalli S, Edwards FH, Carroll J, Shahian D, Grover F, Tuzcu EM, Peterson ED, Brindis RG, Mack MJ; STS/ACC TVT registry. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA 2015;313(10):1019–1028. 66. Holmes DR Jr, Mack MJ. Moore’s law: apples and oranges. JACC Cardiovasc Interv 2015;8(13):1667–1669. 67. Holmes DR Jr, Nishimura RA, Grover FL, Brindis RG, Carroll JD, Edwards FH, Peterson ED, Rumsfeld JS, Shahian DM, Thourani VH, Tuzcu EM, Vemulapalli S, Hewitt K, Michaels J, Fitzgerald S, Mack MJ; STS/ACC TVT Registry. Annual outcomes with transcatheter valve therapy: from the STS/ACC TVT registry. J Am Coll Cardiol 2015;66(25):2813–2823. 68. Husain-Syed F, McCullough PA, Birk HW, Renker M, Brocca A, Seeger W, Ronco C. Cardio-pulmonary-renal interactions: a multidisciplinary approach. J Am Coll Cardiol 2015;65(22):2433–2448. 69. Iqbal J, Zhang YJ, Holmes DR, Morice MC, Mack MJ, Kappetein AP, Feldman T, Stahle E, Escaned J, Banning AP, Gunn JP, Colombo A, Steyerberg EW, Mohr FW, Serruys PW. Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year followup. Circulation 2015;131(14):1269–1277. 70. Jacobs JP, O’Brien SM, Pasquali SK, Gaynor JW, Mayer JE Jr, Karamlou T, Welke KF, Filardo G, Han JM, Kim S, Quintessenza JA, Pizarro C, Tchervenkov CI, Lacour-Gayet F, Mavroudis C, Backer CL, Austin EH 3rd, Fraser CD, Tweddell JS, Jonas RA, Edwards FH, Grover FL, Prager RL, Shahian DM, Jacobs ML. The Society of Thoracic Surgeons congenital heart surgery database mortality risk model: part 2—clinical application. Ann Thorac Surg 2015;100(3):1063–1068. 71. Kapadia S, Stewart WJ, Anderson WN, Babaliaros V, Feldman T, Cohen DJ, Douglas PS, Makkar RR, Svensson LG, Webb JG, Wong SC, Brown DL, Miller DC, Moses JW, Smith CR, Leon MB, Tuzcu EM. Outcomes of inoperable symptomatic aortic stenosis patients not undergoing aortic valve replacement: insight into the impact of balloon aortic valvuloplasty from the PARTNER trial (Placement of AoRtic TraNscathetER Valve trial). JACC Cardiovasc Interv 2015;8(2):324–333. 72. Kapadia SR, Leon MB, Makkar RR, Tuzcu EM, Svensson LG, Kodali S, Webb JG, Mack MJ, Douglas PS, Thourani VH, Babaliaros VC, Herrmann HC, Szeto WY, Pichard AD, Williams MR, Fontana GP, Miller DC, Anderson WN, Akin JJ, Davidson MJ, Smith CR; PARTNER trial investigators. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable 240 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385(9986):2485–2491. Kapadia SR, Tuzcu EM, Makkar RR, Svensson LG, Agarwal S, Kodali S, Fontana GP, Webb JG, Mack M, Thourani VH, Babaliaros VC, Herrmann HC, Szeto WY, Pichard A, Williams MR, Anderson WN, Akin JJ, Miller DC, Smith CR, Leon MB. Response to letter regarding article, “Long-term outcomes of inoperable patients with aortic stenosis randomly assigned to transcatheter aortic valve replacement or standard therapy.” Circulation 2015;132(6):e118–e119. Kassis HM, Minsinger KD, McCullough PA, Block CA, Sidhu MS, Brown JR. A review of the use of iloprost, a synthetic prostacyclin, in the prevention of radiocontrast nephropathy in patients undergoing coronary angiography and intervention. Clin Cardiol 2015;38(8):492–498. Keshavamurthy S, Shafii AE, Soltesz E. Spectroscopic limb monitoring in peripheral extracorporeal membrane oxygenation. Asian Cardiovasc Thorac Ann 2015;23(3):347–348. Khan MA, Ullah I, Khan A. How healthy is your heart? There is a scan for that. InSight in Medicine 2015(Fall), 1–3. Khouri Y, Stephens T, Ayuba G, Ameri H, Juratli N, McCullough PA. Understanding and managing atrial fibrillation in patients with kidney disease. J Atrial Fibrillation 2015;7(6):62–68. Ko JM, Guileyardo JM, Zhang J, Roberts WC. Morphologic demonstration of spontaneous and surgical closure of membranous ventricular septal defect. Proc (Bayl Univ Med Cent) 2015;28(4):514–515. Kron IL, Hung J, Overbey JR, Bouchard D, Gelijns AC, Moskowitz AJ, Voisine P, O’Gara PT, Argenziano M, Michler RE, Gillinov M, Puskas JD, Gammie JS, Mack MJ, Smith PK, Sai-Sudhakar C, Gardner TJ, Ailawadi G, Zeng X, O’Sullivan K, Parides MK, Swayze R, Thourani V, Rose EA, Perrault LP, Acker MA; CTSN Investigators. Predicting recurrent mitral regurgitation after mitral valve repair for severe ischemic mitral regurgitation. J Thorac Cardiovasc Surg 2015;149(3):752–761.e1. Kurlansky P, Herbert M, Prince S, Mack MJ. Improved long-term survival for diabetic patients with surgical versus interventional revascularization. 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Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, Papp K, Spelman L, Toth D, Kerdel F, Armstrong AW, Stingl G, Kimball AB, Bachelez H, Wu JJ, Crowley J, Langley RG, Blicharski T, Paul C, Lacour JP, Tyring S, Kircik L, Chimenti S, Callis Duffin K, Bagel J, Koo J, Aras G, Li J, Song W, Milmont CE, Shi Y, Erondu N, Klekotka P, Kotzin B, Nirula A. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 2015;373(14):1318–1328. Lim HW, Silpa-archa N, Amadi U, Menter A, Van Voorhees AS, Lebwohl M. Phototherapy in dermatology: a call for action. J Am Acad Dermatol 2015;72(6):1078–1080. Lloyd AA, Witheiler D, Menter A. Nodular fasciitis of the lip mucosa: a rare but clinically important entity. Clin Exp Dermatol 2015;40(4):408–412. Mahmood T, Horner M, Menter A. Polymorphic blistering eruption and stomatitis in a patient with non-Hodgkin lymphoma. JAMA Dermatol 2015;151(4):439–440. Mahmood T, Mansouri B, Menter A. Successful treatment of generalized granuloma annulare with adalimumab. Clin Exp Dermatol 2015;40(5):537–539. Mahmood T, Menter A. The Laugier-Hunziker syndrome. Proc (Bayl Univ Med Cent) 2015;28(1):41–42. Mahmood T, Zaghi D, Menter A. Emerging oral drugs for psoriasis. Expert Opin Emerg Drugs 2015:1–12. Mansouri B, Horner ME, Menter A. Tumor necrosis factor-α inhibitor use in psoriasis patients with a first-degree relative with multiple sclerosis. J Drugs Dermatol 2015;14(8):876–878. Mansouri B, Kivelevitch D, Campa M, Menter A. Palmoplantar pustular psoriasis unresponsive to the interleukin-1β antagonist canakinumab. Clin Exp Dermatol 2015 Sep 7 [Epub ahead of print]. Mansouri B, Kivelevitch D. Re: Complete clinical remission of psoriasis 6 months after renal transplantation. Transplant Proc 2015;47(6):2074–2075. Mansouri B, Menter A. Reporting of MABp1 for the treatment of psoriasis. JAMA Dermatol 2015;151(10):1143–1144. Mansouri B, Richards L, Menter A. Treatment of two patients with generalized pustular psoriasis with the interleukin-1β inhibitor gevokizumab. Br J Dermatol 2015;173(1):239–241. Mayer JE, Menter MA. Reply to: “Review of drug-related causes of oculocutaneous disease.” J Am Acad Dermatol 2015;72(2):362–363. McFall MJ, Griffin JR, Elston DM. A solitary auricular polyp. Indian Dermatol Online J 2015;6(4):284–285. Menter A. Best practices: an oral treatment for moderate to severe plaque psoriasis. Dermatology News Best Practices Supplement, October 22, 2015. Menter A, Thaçi D, Papp KA, Wu JJ, Bereswill M, Teixeira HD, Rubant S, Williams DA. Five-year analysis from the ESPRIT 10-year postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriasis. J Am Acad Dermatol 2015;73(3):410–419.e6. Menter MA, Griffiths CE. Psoriasis: the future. Dermatol Clin 2015;33(1):161–166. Menter MA, Griffiths CE. The International Psoriasis Council: advancing knowledge, enhancing care. 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Advanced Hip Arthroscopy. Philadelphia: Elsevier, 2015. Baylor University Medical Center Proceedings Volume 29, Number 2 546. Martin HD, ed. Mini symposium: evolving concepts in extra-articular hip pathology. J Hip Pres Surg 2015;2(2):91–122. 547. Martin H, Palmer IJ, Hatem MA. Deep gluteal space syndrome. In Nho S, Leuning M, Kelly B, Bedi A, Larson C, eds., Hip Arthroscopy and Hip Joint Preservation Surgery. New York: Springer, 2015. 548. Martin H, Palmer IJ, Hatem MA. Physical examination of the hip. In Nho S, Leuning M, Kelly B, Bedi A, Larson C, eds., Hip Arthroscopy and Hip Joint Preservation Surgery. New York: Springer, 2015. 549. Martin H, Palmer IJ, Hatem MA. Surgical technique: endoscopic sciatic nerve release. In Nho S, Leuning M, Kelly B, Bedi A, Larson C, eds., Hip Arthroscopy and Hip Joint Preservation Surgery. New York: Springer, 2015. 550. Martin HD, Larson CM, Trousdale RT. Orthopedic round table: panel discusses new types and treatments of hip impingement. Orthopedics Today, May 2015. 551. Martínez D, Gómez-Hoyos J, Márquez W, Gallo J. Factors associated with the failure of arthroscopic surgery treatment in patients with femoroacetabular impingement: a cohort study. Rev Esp Cir Ortop Traumatol 2015;59(2):112–121. 552. Tenenbaum S, Stockton KG, Bariteau JT, Brodsky JW. Salvage of avascular necrosis of the talus by combined ankle and hindfoot arthrodesis without structural bone graft. Foot Ankle Int 2015;36(3):282–287. 566. 567. 568. 569. 570. 571. 572. OTOLARYNGOLOGY 553. Chan D, Ducic Y. A simplified, reliable approach for advancement genioplasty. JAMA Facial Plast Surg 2015 Dec 23 [Epub ahead of print]. 554. Ducic Y. Intraoperative free flap monitoring using indocyanine green. JAMA Facial Plast Surg 2015;17(6):427. 555. Gordin E, Lee TS, Ducic Y, Arnaoutakis D. Facial nerve trauma: evaluation and considerations in management. Craniomaxillofac Trauma Reconstr 2015;8(1):1–13. 556. Kadakia S, Ducic Y, Marra D, Saman M. The role of elective superficial parotidectomy in the treatment of temporal region squamous cell carcinoma. Oral Maxillofac Surg 2015 Dec 21 [Epub ahead of print]. 557. Kadakia S, Saman M, Gordin E, Marra D, Ducic Y. The role of parotidectomy in the treatment of auricular squamous cell carcinoma. Otolaryngol Head Neck Surg 2015;152(6):1048–1052. 558. Mourad M, Saman M, Ducic Y. Internal to external jugular vein bypass allowing for simultaneous bilateral radical neck dissection. Laryngoscope 2015;125(11):2480–2484. 559. Mourad M, Saman M, Sawhney R, Ducic Y. Management of the thyroid gland during total laryngectomy in patients with laryngeal squamous cell carcinoma. Laryngoscope 2015;125(8):1835–1838. 560. Mourad M, Saman M, Stroman D, Lee T, Ducic Y. Carotid artery sacrifice and reconstruction in the setting of advanced head and neck cancer. Otolaryngol Head Neck Surg 2015;153(2):225–230. 561. Saman M, Kadakia S, Ducic Y. Does the use of an acellular dermal graft in abdominal closure after rectus flap harvest impact the occurrence of post-operative hernia? Oral Maxillofac Surg 2015;19(4):347–351. PATHOLOGY Note: See also Oncology and other departments in which pathologists were first authors or coauthors. 562. Armstrong-Briley D, Hozhabri NST, Armstrong K, Puthottile J, Benavides R, Beal S. Comparison of length of stay and outcomes of patients with positive versus negative blood culture results. Proc (Bayl Univ Med Cent) 2015;28(1):10–13. 563. Atta MG, Estrella MM, Skorecki KL, Kopp JB, Winkler CA, Wasser WG, Shemer R, Racusen LC, Kuperman M, Foy MC, Lucas GM, Fine DM. Association of APOL1 genotype with renal histology among black HIV-positive patients undergoing kidney biopsy. Clin J Am Soc Nephrol 2015 Dec 14 [Epub ahead of print]. 564. Beal SG, Thomas C, Dhiman N, Nguyen D, Qin H, Hawkins JM, Dekmezian M, Benavides R, Njoku J. Antibiotic utilization improvement with the Nanosphere Verigene Gram-Positive Blood Culture assay. Proc (Bayl Univ Med Cent) 2015;28(2):139–143. 565. Dekmezian M, Beal SG, Damashek MJ, Benavides R, Dhiman N. The SUCCESS model for laboratory performance and execution of rapid April 2016 molecular diagnostics in patients with sepsis. Proc (Bayl Univ Med Cent) 2015;28(2):144–150. Guileyardo JM. Probability and uncertainty in clinical and forensic medicine. Proc (Bayl Univ Med Cent) 2015;28(2):247–249. Kang X, Hu DY, Li CB, Li XH, Fan SL, Liu Y, Tang GY, Ai ZS, Wu T, Mohan C, Zhou XJ, Liu JY, Peng A. The volume ratio of ground glass opacity in early lung CT predicts mortality in acute paraquat poisoning. PLoS One 2015;10(4):e0121691. Podduturi V, Guileyardo JM. Sickle cell trait as a contributory cause of death in natural disease. J Forensic Sci 2015;60(3):807–811. Podduturi V, Guileyardo JM, Soto LR, Krause JR. A case series of clinically undiagnosed hematopoietic neoplasms discovered at autopsy. Am J Clin Pathol 2015;143(6):854–860. Podduturi V, Tran T, Champion KJ, Onur N, Shiller SM. Microcystic stromal tumor of the ovary: a case report of a newly described ovarian neoplasm with a β-catenin (CTNNB1) G34E mutation. Int J Gynecol Pathol 2015;34(6):541–545. Rauhauser AA, Ren C, Lu D, Li B, Zhu J, McEnery K, Vadnagara K, Zepeda-Orozco D, Zhou XJ, Lin F, Jetten AM, Attanasio M. Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury. Am J Physiol Renal Physiol 2015;309(9):F770–F778. Ye T, Zhen J, Du Y, Zhou JK, Peng A, Vaziri ND, Mohan C, Xu Y, Zhou XJ. Green tea polyphenol-epigallocatechin-3-gallate restores Nrf2 activity and ameliorates crescentic glomerulonephritis. PLoS One 2015;10(3):e0119543. PEDIATRICS/NEONATOLOGY 573. Chiruvolu A, Tolia VN, Qin H, Stone GL, Rich D, Conant RJ, Inzer RW. Effect of delayed cord clamping on very preterm infants. Am J Obstet Gynecol 2015;213(5):676.e1–7. 574. Jacob J, Kamitsuka M, Clark RH, Kelleher AS, Spitzer AR. Etiologies of NICU deaths. Pediatrics 2015;135(1):e59–e65. 575. Patel SD, Pierce L, Ciardiello A, Hutton A, Paskewitz S, Aronowitz E, Voss HU, Moore H, Vannucci SJ. Therapeutic hypothermia and hypoxia-ischemia in the term-equivalent neonatal rat: characterization of a translational preclinical model. Pediatr Res 2015;78(3):264–271. 576. Tolia VN, Patrick SW, Bennett MM, Murthy K, Sousa J, Smith PB, Clark RH, Spitzer AR. Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl J Med 2015;372(22):2118–2126. 577. Tower P, Tolia VN. Another preemie with hypoglycemia? BeckwithWiedemann syndrome—a case study. Neonatal Netw 2015;34(3):178–182. PULMONOLOGY 578. Modrykamien AM, Gupta P. The acute respiratory distress syndrome. Proc (Bayl Univ Med Cent) 2015;28(2):163–171. 579. Mora A Jr. The masquerading pulmonary embolism: why a high index of suspicion remains even today. Proc (Bayl Univ Med Cent) 2015;28(1):71. 580. Mora A Jr, Arroyo M, Gummelt KL, Colbert G, Ursales AL, Van Vrancken MJ, Snipes GJ, Guileyardo JM, Columbus C. West Nile virus and the 2012 outbreak: the Baylor University Medical Center experience. Proc (Bayl Univ Med Cent) 2015;28(3):291–295. 581. Rokadia HK, Adams JR, McCarthy K, Aboussouan LS, Mireles-Cabodevila E. Cough augmentation in a patient with neuromuscular disease. Ann Am Thorac Soc 2015;12(12):1888–1891. 582. Russo R, Coultas D, Ashmore J, Peoples J, Sloan J, Jackson BE, Uhm M, Singh KP, Blair SN, Bae S. Chronic obstructive pulmonary disease self-management activation research trial (COPD-SMART): results of recruitment and baseline patient characteristics. Contemp Clin Trials 2015;41:192–201. 583. Schuller D. Lung abscess. In Bope ET, Kellerman RD, eds. Conn’s Current Therapy 2015, 67th ed. Philadelphia: Elsevier, 2015:401–403. RADIOLOGY Note: See also Oncology and other departments in which radiologists were first authors or coauthors. 584. Bahador FM, Latifi HR, Grossman SJ, Oza UD, Xu H, Griffeth LK. Optimal interpretative strategy for preoperative parathyroid scintigraphy. Clin Nucl Med 2015;40(2):116–122. 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff 255 585. Bell BM Jr, Bruner A, Landaverde C, Rees CR. Prone positioning for transjugular intrahepatic portosystemic shunt revision to prevent exacerbation of existing radiation dermatitis. J Vasc Interv Radiol 2015;26(5):764–765. 586. Bell BM Jr, Cura M, Shaw CJ, Rees CR. Transjugular intrahepatic portosystemic shunt creation using a three-dimensional fluoroscopy guidance system in patients with the Budd-Chiari syndrome. Proc (Bayl Univ Med Cent) 2015;28(4):484–487. 587. dePrisco G. MRI local staging and restaging in rectal cancer. Clin Colon Rectal Surg 2015;28(3):194–200. 588. Evans AJ, Kip KE, Brinjikji W, Layton KF, Jensen ML, Gaughen JR, Kallmes DF. Randomized controlled trial of vertebroplasty versus kyphoplasty in the treatment of vertebral compression fractures. J Neurointerv Surg 2015 Jun 24 [Epub ahead of print]. 589. Mason C, Yokubaitis K, Howard E, Shah Z, Wang J. Impact of Henda’s law on the utilization of screening breast magnetic resonance imaging. Proc (Bayl Univ Med Cent) 2015;28(1):7–9. 590. Weir VJ, Zhang J, Bruner AP. Dosimetric characterization and image quality evaluation of the AIRO mobile CT scanner. J Xray Sci Technol 2015;23(3):373–381. 591. West JA, Louis TH. Radiographic findings in the nail-patella syndrome. Proc (Bayl Univ Med Cent) 2015;28(3):334–336. RHEUMATOLOGY 592. Bykerk VP, Cush J, Winthrop K, Calabrese L, Lortholary O, de Longueville M, van Vollenhoven R, Mariette X. Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials. Ann Rheum Dis 2015;74(1):96–103. 593. Clowse ME, Wolf DC, Förger F, Cush JJ, Golembesky A, Shaughnessy L, De Cuyper D, Mahadevan U. Pregnancy outcomes in subjects exposed to certolizumab pegol. J Rheumatol 2015;42(12):2270–2278. 594. Dalal DS, Lin YC, Brennan DM, Borkar N, Korman N, Husni ME. Quantifying harmful effects of psoriatic diseases on quality of life: cardiometabolic outcomes in psoriatic arthritis study (COMPASS). Semin Arthritis Rheum 2015;44(6):641–645. 595. Kavanaugh A, Cush JJ. Pregnancy: data, outcomes, and treatment paradigms in rheumatology. J Rheumatol 2015;42(8):1357–1358. 596. Kavanaugh A, Cush JJ, Ahmed MS, Bermas BL, Chakravarty E, Chambers C, Clowse M, Curtis JR, Dao K, Hankins GD, Koren G, Kim SC, Lapteva L, Mahadevan U, Moore T, Nolan M, Ren Z, Sammaritano LR, Seymour S, Weisman MH. Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res (Hoboken) 2015;67(3):313–325. SURGERY Note: Most surgery articles are subclassified by specialty, even if general surgeons were first authors or coauthors. Surgery articles related to cancer appear under Oncology. 597. Argun OB, Chrouser K, Chauhan S, Monga M, Knudsen B, Box GN, Lee DI, Gettman MT, Poniatowski LH, Wang Q, Reihsen TE, Sweet RM. Multi-institutional validation of an OSATS for the assessment of cystoscopic and ureteroscopic skills. J Urol 2015;194(4):1098–1105. 598. Gardner AK, Willis RE, Dunkin BJ, Van Sickle KR, Brown KM, Truitt MS, Uecker JM, Gentry L, Scott DJ. What do residents need to be competent laparoscopic and endoscopic surgeons? Surg Endosc 2015 Oct 20 [Epub ahead of print]. 599. Graziano K, Islam S, Dasgupta R, Lopez ME, Austin M, Chen LE, Goldin A, Downard CD, Renaud E, Abdullah F. Asymptomatic malrotation: diagnosis and surgical management: an American Pediatric Surgical Association Outcomes and Evidence Based Practice Committee systematic review. J Pediatr Surg 2015;50(10):1783–1790. 600. King DR, Li W, Squiers JJ, Mohan R, Sellke E, Mo W, Zhang X, Fan W, DiMaio JM, Thatcher JE. Surgical wound debridement sequentially characterized in a porcine burn model with multispectral imaging. Burns 2015;41(7):1478–1487. 601. Perez M, Xu S, Chauhan S, Tanaka A, Simpson K, Abdul-Muhsin H, Smith R. Impact of delay on telesurgical performance: study on the ro- 256 botic simulator dV-Trainer. Int J Comput Assist Radiol Surg 2015 Oct 8 [Epub ahead of print]. 602. Smallwood NR, Fleshman JW, Leeds SG, Burdick JS. The use of endoluminal vacuum (E-Vac) therapy in the management of upper gastrointestinal leaks and perforations. Surg Endosc 2015 Sep 30 [Epub ahead of print]. 603. Steele SR, Varma MG, Prichard D, Bharucha AE, Vogler SA, Erdogan A, Rao SS, Lowry AC, Lange EO, Hall GM, Bleier JI, Senagore AJ, Maykel J, Chan SY, Paquette IM, Audett MC, Bastawrous A, Umamaheswaran P, Fleshman JW, Caton G, O’Brien BS, Nelson JM, Steiner A, Garely A, Noor N, Desrosiers L, Kelley R, Jacobson NS. The evolution of evaluation and management of urinary or fecal incontinence and pelvic organ prolapse. Curr Probl Surg 2015;52(2):17–75; 52(3):92–136. 604. Williams SB, Matin SF, Matin S, Subbarao CD. Implementation of a very low calorie diet in patients undergoing urologic surgery: room for improvement? Clin Genitourin Cancer 2015;13(4):e203–e204. TRANSPLANTATION (ORGAN AND PANCREATIC CELLS) 605. Asrani SK, Kamath PS. Model for end-stage liver disease score and MELD exceptions: 15 years later. Hepatol Int 2015;9(3):346–354. 606. Asrani SK, O’Leary JG. Can one pill a day keep rejection away? Am J Transplant 2015;15(5):1135–1136. 607. Asrani SK, O’Leary JG. The changing liver transplant waitlist: an emerging liver purgatory? Gastroenterology 2015;148(3):493–496. 608. Bellin MD, Gelrud A, Arreaza-Rubin G, Dunn TB, Humar A, Morgan KA, Naziruddin B, Rastellini C, Rickels MR, Schwarzenberg SJ, Andersen DK. Total pancreatectomy with islet autotransplantation: summary of an NIDDK workshop. Ann Surg 2015;261(1):21–29. 609. Campos-Varela I, Lai JC, Verna EC, O’Leary JG, Todd Stravitz R, Forman LM, Trotter JF, Brown RS, Terrault NA; Consortium to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C). Hepatitis C genotype influences post-liver transplant outcomes. Transplantation 2015;99(4):835–840. 610. Chapman WC, Klintmalm G, Hemming A, Vachharajani N, Majella Doyle MB, DeMatteo R, Zaydfudim V, Chung H, Cavaness K, Goldstein R, Zendajas I, Melstrom LG, Nagorney D, Jarnagin W. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified? J Am Coll Surg 2015;220(4):628–637. 611. Chinnakotla S, Klintmalm GB. Induction and maintenance of immunosuppression. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 612. Curry MP, Forns X, Chung RT, Terrault NA, Brown R Jr, Fenkel JM, Gordon F, O’Leary J, Kuo A, Schiano T, Everson G, Schiff E, Befeler A, Gane E, Saab S, McHutchison JG, Subramanian GM, Symonds WT, Denning J, McNair L, Arterburn S, Svarovskaia E, Moonka D, Afdhal N. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology 2015;148(1):100–107.e1. 613. Demetris AJ, Zeevi A, O’Leary JG. ABO-compatible liver allograft antibody-mediated rejection: an update. Curr Opin Organ Transplant 2015;20(3):314–324. 614. Elgharably H, Shafii AE, Mason DP. Expanding the donor pool: donation after cardiac death. Thorac Surg Clin 2015;25(1):35–46. 615. Engels EA, Jennings L, Kemp TJ, Chaturvedi AK, Pinto LA, Pfeiffer RM, Trotter JF, Acker M, Onaca N, Klintmalm GB. Circulating TGF-β1 and VEGF and risk of cancer among liver transplant recipients. Cancer Med 2015;4(8):1252–1257. 616. Fernandez H, Weber J, Barnes K, Wright L, Levy M. Financial impact of liver sharing and organ procurement organizations’ experience with Share 35: implications for national broader sharing. Am J Transplant 2015 Sep 15 [EPub ahead of print]. 617. Fernandez HT, Kim PT, Anthony TL, Hamman BL, Goldstein RM, Testa G. Inferior vena cava reconstruction for leiomyosarcoma of Zone I-III requiring complete hepatectomy and bilateral nephrectomy with autotransplantation. J Surg Oncol 2015;112(5):481–485. 618. Ghobrial RM, Klintmalm GB. Outcome predictors in liver transplantation. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. Baylor University Medical Center Proceedings Volume 29, Number 2 619. Hasse JM. Nutritional aspects of transplantation in adults. In Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver, 3rd ed. Philadelphia: WB Saunders, 2015:494–509. 620. Hasse JM, Chinnakotla S. Solid organ transplantation. In Cresci GA, ed. Nutrition Support for the Critically Ill: A Guide to Practice, 2nd ed. Boca Raton, FL: CRC Press, 2015:433–454. 621. International Genetics & Translational Research in Transplantation Network (iGeneTRAiN). Design and implementation of the International Genetics and Translational Research in Transplantation Network. Transplantation 2015;99(11):2401–2412. 622. Kanak MA, Takita M, Shahbazov R, Lawrence MC, Chung WY, Dennison AR, Levy MF, Naziruddin B. Evaluation of microRNA375 as a novel biomarker for graft damage in clinical islet transplantation. Transplantation 2015;99(8):1568–1573. 623. Kappel DF, Chapman WC, Conrad S, Reed A, Linderer R, Dunn S, Niles P, Levy MF, Cawiezell T. Organ procurement organization liver acquisition costs could more than double with proposed redistricts. Am J Transplant 2015;15(8):2269–2270. 624. Kim PT, Marquez M, Jung J, Cavallucci D, Renner EL, Cattral M, Greig PD, McGilvray ID, Selzner M, Ghanekar A, Grant DR. Long-term follow-up of biliary complications after adult right-lobe living donor liver transplantation. Clin Transplant 2015;29(5):465–474. 625. Klein J, Kuperman M, Haley C, Barri Y, Chandrakantan A, Fischbach B, Melton L, Rice K, Saim M, Yango A, Klintmalm G, Rajagopal A. Late presentation of adenovirus-induced hemorrhagic cystitis and ureteral obstruction in a kidney-pancreas transplant recipient. Proc (Bayl Univ Med Cent) 2015;28(4):488–491. 626. Klintmalm GB. Antibody-mediated rejection: immunology phenomenon looking for a clinical phenotype. Liver Transpl 2015;21(Suppl 1):S24. 627. Klintmalm GB, Busuttil RW. The recipient hepatectomy and grafting. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 628. Lawrence MC, Borenstein-Auerbach N, McGlynn K, Kunnathodi F, Shahbazov R, Syed I, Kanak M, Takita M, Levy MF, Naziruddin B. NFAT targets signaling molecules to gene promoters in pancreatic β-cells. Mol Endocrinol 2015;29(2):274–288. 629. Levy MF, Cowling T, Klintmalm GB. Long-term functional recovery and quality of life: childhood, adulthood, employment, pregnancy, and family planning. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 630. Lima B, Chamogeorgakis T, MacHannaford JC, Gonzalez-Stawinski GV. Hypothermic circulatory arrest in cardiac transplantation. Transplant Proc 2015;47(9):2719–2721. 631. Lloyd A, Klintmalm G, Qin H, Menter A. Skin cancer evaluation in transplant patients: a physician opinion survey with recommendations. Clin Transplant 2015;29(2):110–117. 632. McKenna GJ. Making the extraordinary, ordinary: renoportal bypass for complete portal vein thrombosis. Liver Transpl 2015;21(3):275–276. 633. Mehrotra S, Kilambi V, Gilroy R, Ladner DP, Klintmalm GB, Kaplan B. Modeling the allocation system: principles for robust design before restructuring. Transplantation 2015;99(2):278–281. 634. Mehrotra S, Kilambi V, Gilroy R, Ladner DP, Klintmalm GB, Kaplan B. The authors’ reply. Transplantation 2015;99(9):e160–e161. 635. O’Leary JG. Donor-specific alloantibodies in liver transplantation: how should we define and improve long-term success? Transpl Int 2015;28(12):1359–1361. 636. O’Leary JG, Kaneku H, Banuelos N, Jennings LW, Klintmalm GB, Terasaki PI. Impact of IgG3 subclass and C1q-fixing donor-specific HLA alloantibodies on rejection and survival in liver transplantation. Am J Transplant 2015;15(4):1003–1013. 637. O’Leary JG, Orloff SL, Levitsky J, Martin P, Foley DP. Keeping high model for end-stage liver disease score liver transplantation candidates alive. Liver Transpl 2015;21(11):1428–1437. 638. Rahimi RS, O’Leary JG. Post-liver transplant hepatitis C therapy. Curr Treat Options Gastroenterol 2015;13(2):249–258. 639. Rahimi RS, O’Leary JG. Transfusing common sense instead of blood products into coagulation testing in patients with cirrhosis: overtreatment ≠ safety. Hepatology 2015 Oct 16 [Epub ahead of print]. April 2016 640. Rahimi RS, Trotter JF. Liver transplantation for hepatocellular carcinoma: outcomes and treatment options for recurrence. Ann Gastroenterol 2015;28(3):323–330. 641. Randell HB, Klintmalm GB. Postoperative intensive care unit management: adult liver transplant recipients. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 642. Reddy KR, O’Leary JG, Kamath PS, Fallon MB, Biggins SW, Wong F, Patton HM, Garcia-Tsao G, Subramanian RM, Thacker LR, Bajaj JS; North American Consortium for the Study of End-Stage Liver Disease. High risk of delisting or death in liver transplant candidates following infections: Results from the North American Consortium for the Study of End-Stage Liver Disease. Liver Transpl 2015;21(7):881–888. 643. Reed A, Chapman WC, Knechtle S, Chavin K, Gilroy R, Klintmalm GB. Equalizing MELD scores over broad geographies is not the most efficacious way to allocate a scarce resource in a value-based environment. Ann Surg 2015;262(2):220–223. 644. Reinhold SM, Lima B, Khalid A, Gonzalez-Stawinski GV, Stoler RC, Hall SA, Chamogeorgakis T. Heart transplantation in the Ehlers-Danlos syndrome. Proc (Bayl Univ Med Cent) 2015;28(4):492–493. 645. Sanchez EQ, Klintmalm GB. Combined liver-kidney transplantation. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 646. Sanchez EQ, Klintmalm GB. Postoperative management beyond the intensive care unit: adults. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 647. Serrano PE, Cleary SP, Dhani N, Kim PT, Greig PD, Leung K, Moulton CA, Gallinger S, Wei AC. Improved long-term outcomes after resection of pancreatic adenocarcinoma: a comparison between two time periods. Ann Surg Oncol 2015;22(4):1160–1167. 648. Shahbazov R, Kanak MA, Takita M, Kunnathodi F, Khan O, Borenstein N, Lawrence MC, Levy MF, Naziruddin B. Essential phospholipids prevent islet damage induced by proinflammatory cytokines and hypoxic conditions. Diabetes Metab Res Rev 2015 Sep 17 [Epub ahead of print]. 649. Singh N, Sifri CD, Silveira FP, Miller R, Gregg KS, Huprikar S, Lease ED, Zimmer A, Dummer JS, Spak CW, Koval C, Banach DB, Shroff M, Le J, Ostrander D, Avery R, Eid A, Razonable RR, Montero J, Blumberg E, Alynbiawi A, Morris MI, Randall HB, Alangaden G, Tessier J, Wagener MM, Sun HY. Cryptococcosis in patients with cirrhosis of the liver and posttransplant outcomes. Transplantation 2015;99(10):2132–2141. 650. SoRelle JA, Kanak MA, Itoh T, Horton JM, Naziruddin B, Kane RR. Comparison of surface modification chemistries in mouse, porcine, and human islets. J Biomed Mater Res A 2015;103(3):869–877. 651. Stone MJ, Fuller JM, Klintmalm GB. Transplantation for Budd-Chiari syndrome. In Busuttil RW, Klintmalm GB. Transplantation of the Liver, 3rd ed. Philadelphia: Elsevier Saunders, 2015. 652. Takita M, Lara LF, Naziruddin B, Shahbazov R, Lawrence MC, Kim PT, Onaca N, Burdick JS, Levy MF. Effect of the duration of chronic pancreatitis on pancreas islet yield and metabolic outcome following islet autotransplantation. J Gastrointest Surg 2015;19(7):1236–1246. 653. Trotter JF, Levy G. Sotrastaurin in liver transplantation: has it had a fair trial? Am J Transplant 2015;15(5):1137–1138. 654. Verna EC, O’Leary JG. Hepatitis C treatment in patients on the liver transplant waiting list. Curr Opin Organ Transplant 2015;20(3):242–250. 655. Verna EC, Saxena V, Burton JR Jr, O’Leary JG, Dodge JL, Stravitz RT, Levitsky J, Trotter JF, Everson GT, Brown RS Jr, Terrault NA; CRUSH-C Consortium. Telaprevir- and boceprevir-based triple therapy for hepatitis C in liver transplant recipients with advanced recurrent disease: a multicenter study. Transplantation 2015;99(8):1644–1651. 656. Woods T, Jennings NB, Fernandez HT, Onaca N, Carlile BK, Levy MF, Gould DL, Ruiz R. Renal autotransplantation in Lynch syndrome: a viable option in a patient with contralateral metachronous ureteral cancer. Am J Transplant 2015;15(9):2507–2510. TRAUMA/PHYSICAL MEDICINE AND REHABILITATION/EMERGENCY MEDICINE 657. Cleveland S, Driver S, Swank C, Macklin S. Classifying physical activity research following stroke using the behavioral epidemiologic framework. Top Stroke Rehabil 2015;22(4):289–298. 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff 257 658. Cochran G, Field C, Foreman M, Ylioja T, Brown CV. Effects of brief intervention on subgroups of injured patients who drink at risk levels. Inj Prev 2015 Jun 29 [Epub ahead of print]. 659. Dodd Z, Driver S, Warren AM, Riggs S, Clark M. Effects of adult romantic attachment and social support on resilience and depression in individuals with spinal cord injuries. Top Spinal Cord Inj Rehabil 2015;21(2):156–165. 660. Driver S, Rachal L, Swank C, Dubiel R. Objective assessment of activity in inpatients with traumatic brain injury: initial findings. Brain Impairment 2015. Available at http://dx.doi.org/10.1017/BrImp.2015.20 661. Driver SJ, Warren AM, Agatrap S, Reynolds M, Trost Z, Monden K, Hamilton R. Identifying predictors of resilience at inpatient and three months post spinal cord injury. J Spinal Cord Med 2015. DOI: 10.1179/2045772314Y.0000000270 662. Ewing M, Funk GA, Warren AM, Rapier N, Reynolds M, Bennett M, Mastropieri C, Foreman ML. Improving National Trauma Data Bank® coding data reliability for traumatic injury using a prospective systems approach. Health Informatics J 2015 Oct 29 [Epub ahead of print]. 663. Fann JR, Bombardier CH, Richards JS, Wilson CS, Heinemann AW, Warren AM, Brooks L, McCullumsmith CB, Temkin NR, Warms C, Tate DG; PRISMS Investigators. Venlafaxine extended-release for depression following spinal cord injury: a randomized clinical trial. JAMA Psychiatry 2015;72(3):247–258. 664. Fox N, Schwartz D, Salazar JH, Haut ER, Dahm P, Black JH, Brakenridge SC, Como JJ, Hendershot K, King DR, Maung AA, Moorman ML, Nagy K, Petrey LB, Tesoriero R, Scalea TM, Fabian TC. Evaluation and management of blunt traumatic aortic injury: a practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Nurs 2015;22(2):99–110; J Trauma Acute Care Surg 2015;78(1):136–146. 665. Fromm NM, Salisbury DB, Driver SJ, Dahdah MN, Monden KR. Functional recovery from neuroinvasive West Nile virus: a tale of two courses. Rehabil Psychol 2015;60(4):383–390. 666. Hamm J, Driver S. Strategies to increase physical activity participation of young adults with Asperger syndrome in the community. Strategies 2015;28(3):3–8. 667. Klakeel M, Thompson J, Srinivasan R, McDonald F. Anterior spinal cord syndrome of unknown etiology. Proc (Bayl Univ Med Cent) 2015;28(1):85–87. 668. Le D, Shafi S, Gwirtz P, Bennett M, Reeves R, Callender L, Dunklin C, Cleveland S. Effect of obesity on motor functional outcome of rehabilitating traumatic brain injury patients. Am J Phys Med Rehabil 2015;94(8):627–632. 669. Petrey LB, Weddle RJ, Richardson B, Gilder R, Reynolds M, Bennett M, Cook A, Foreman M, Warren AM. Trauma patient readmissions: why do they come back for more? J Trauma Acute Care Surg 2015;79(5):717–724. 670. Roden-Foreman JW, Warren AM, Reynolds M, Foreman ML. Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer. Proc (Bayl Univ Med Cent) 2015;28(3):331–333. 671. Salisbury DB, Driver S, Parsons TD. Brain-computer interface targeting non-motor functions after spinal cord injury: a case report. Spinal Cord 2015;53(Suppl 1):S25–S26. 672. Stiers W, Barisa M, Stucky K, Pawlowski C, Van Tubbergen M, Turner AP, Hibbard M, Caplan B. Guidelines for competency development and measurement in rehabilitation psychology postdoctoral training. Rehabil Psychol 2015;60(2):111–122. 673. Trost Z, Agtarap S, Scott W, Driver S, Guck A, Roden-Foreman K, Reynolds M, Foreman ML, Warren AM. Perceived injustice after traumatic 258 injury: associations with pain, psychological distress, and quality of life outcomes 12 months after injury. Rehabil Psychol 2015;60(3):213–221. 674. Wang H, Robinson RD, Garrett JS, Bunch K, Huggins CA, Watson K, Daniels J, Banks B, D’Etienne JP, Zenarosa NR. Use of the SONET score to evaluate high volume emergency department overcrowding: a prospective derivation and validation study. Emerg Med Int 2015;2015:401757. 675. Warren AM, Boals A, Elliott TR, Reynolds M, Weddle RJ, Holtz P, Trost Z, Foreman ML. Mild traumatic brain injury increases risk for the development of posttraumatic stress disorder. J Trauma Acute Care Surg 2015;79(6):1062–1066. EDITORIALS AND MISCELLANEOUS 676. Davis M. Directions to a lost place: a parable for modern times. Proc (Bayl Univ Med Cent) 2015;28(2):254–255. 677. Ellis PR III, Roberts WC. Paul Roscoe Ellis III, MD: a conversation with the editor. Proc (Bayl Univ Med Cent) 2015;28(1):97–107. 678. Frost SM, Roberts WC. Steven Marshall Frost, MD: a conversation with the editor. Proc (Bayl Univ Med Cent) 2015;28(1):108–117. 679. Gentry L. Teaching with questions. Proc (Bayl Univ Med Cent) 2015;28(1):118–119. 680. Hellmann DB, Roberts WC. David Bruce Hellmann, MD: a conversation with the editor. Proc (Bayl Univ Med Cent) 2015;28(3):409–419. 681. Lister ED, Ledbetter TG, Warren AM. The engaged physician. Mayo Clin Proc 2015;90(4):425–427. 682. Marcus PB. Feroze Novroji Ghadially, 1920–2014: a personal remembrance. Proc (Bayl Univ Med Cent) 2015;28(4):531–537. 683. Miller AM, Roberts WC. Alan Marshall Miller, MD, PhD: a conversation with the editor. Proc (Bayl Univ Med Cent) 2015;28(2):237–246. 684. Roberts WC. Good books in cardiovascular disease received in 2014 and in early 2015. Am J Cardiol 2015;115:1623–1625. 685. Roberts WC. Proceedings of the editorial board meeting of The American Journal of Cardiology in March 15, 2015. Am J Cardiol 2015;115:1626–1629. 686. Roberts WC. A week in Havana, Cuba, in February 2015. Proc (Bayl Univ Med Cent) 2015;28(4):538–540. 687. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2015;28(1):126–133. 688. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2015;28(2):258–265. 689. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2015;28(3):421–432. 690. Roberts WC. Facts and ideas from anywhere. Proc (Bayl Univ Med Cent) 2015;28(4):541–552. 691. Roberts WC. Proliferation of online medical journals. Am J Cardiol 2015 Nov 11 [Epub ahead of print]. 692. Stefanos S, Paul A, Thakur R, Bass K, East C. The gender of authors in the Baylor Proceedings: a reflection of both current staff composition and lesser number of publications by female physicians. Proc (Bayl Univ Med Cent) 2015;28(4):457–460. 693. Warren B. Book review: Users’ Guides to the Medical Literature. Proc (Bayl Univ Med Cent) 2015;28(2):256–257. Note: This list (finalized on February 11, 2016) 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. Staff are encouraged to submit their publications each year. For more information or to submit publications for this list, please contact [email protected]. Baylor University Medical Center Proceedings Volume 29, Number 2 Instructions for authors B 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: [email protected]. 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: The journal operates on a rolling schedule, but in general authors are encouraged to aim for the following submission deadlines for each issue: 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, a case description of 0.5 to 2 double-spaced 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. Indent paragraphs. Start the Proc (Bayl Univ Med Cent) 2016;29(2):259–260 first paragraph of the text and the beginning of the reference section on a new page and place figures on separate pages. 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 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: Authors are asked to pay $100 for each color figure or table. Generally, color is suggested 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. 259 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 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 Baylor Scott & White Health, 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. 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. 260 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 [email protected]. 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, a case discussion of 0.5 to 2 double-spaced pages, and a discussion of 0.5 to 5 doublespaced 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 29, Number 2 Volume 29 Number 2 April 2016 The peer-reviewed journal of Baylor Scott & White Health Scott & White Medical Center – Temple Baylor Scott & White Medical Center - Marble Falls Baylor All Saints Medical Center at Fort Worth Baylor Medical Center at McKinney Baylor Scott & White Hospital - Hillcrest Baylor Scott & White Medical Center - Round Rock Baylor University Medical Center Proceedings Baylor University Medical Center at Dallas Volume 29, Number 2 • April 2016 Pages 117–260 www.BaylorScottandWhite.com Review Articles 131 Review of behavioral health integration in primary care at Baylor Scott and White Healthcare, Central Region by J. B. Jolly et al 137 Invited commentary by C. Couch Historical Article 138 Medical and surgical care during the American Civil War, 1861– 1865 by R. F. Reilly Baylor Regional Medical Center at Grapevine The largest not-for-profit health care system in Texas, and one of the largest in the United States, Baylor Scott & White Health was born from the 2013 combination of Baylor Health Care System and Scott & White Healthcare. For more information on our 43 hospitals and more than 500 patient care sites, please visit www.BaylorHealth.com and www.sw.org. Original Research 119 The characteristics of Mohs surgery performed by dermatologists who learned the procedure during residency training or through postgraduate courses and observational preceptorships by H. K. Steinman et al 124 Virtual reality and brain computer interface in neurorehabilitation by D. B. Salisbury et al 128 Safety and efficacy of packed red blood cell transfusions at different doses in very low birth weight infants by L. H. Mallett et al Case Studies 143 Exercise-induced acute compartment syndrome in a young man, occurring after a short race by B. Basnet et al 145 Table tipping and a near-miss fall after unlocking a surgical table holding a morbidly obese patient by R. T. Booth et al 147 Use of ultrasound guidance to remove entrapped stimulating popliteal catheters by R. K. McAllister et al 150 Baclofen-responsive hiccups after esophageal stenting for malignancy-related dysphagia by V. Sharma et al 151 Specificity of testing in a cardiac rehabilitation setting resulting in a patient’s return to high-intensity outdoor activity following aortic dissection repair by S. Bartee et al 154 Invited commentary: Simulated performance testing to determine the aortic dissection patient’s potential for vigorous physical activity by B. A. Franklin 157 Cardiovascular autonomic neuropathy by N. McCarty and B. Silverman 160 Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2) by L. R. Phillipp and F. H. Rodriguez III 163 Holter monitor recordings in a man who snores by D. L. Glancy and P. Vijitbenjaronk 165 An interesting electrocardiogram by H. H. McClure Jr. 166 Takotsubo cardiomyopathy after administration of norepinephrine by K. Sherif et al 168 Acute myocardial infarction with isolated congenitally corrected transposition of the great arteries by J. Zimmerman et al 171 Isolated congenitally corrected transposition of the great arteries with dextroversion discovered incidentally in a patient with cocaine-induced acute myocardial infarction by A. Tandon et al 174 Invited commentary: The specialty of adult congenital heart disease by A. Cedars 176 Surgical considerations for the explantation of the Parachute left ventricular partitioning device and the implantation of the HeartMate II left ventricular assist device by Y. Ravi et al 178 Intracranial aneurysm and sildenafil by A. Adiga et al 181 Infective endocarditis caused by Klebsiella oxytoca in an intravenous drug user with cancer by A. Mohamed et al 183 Rapidly enlarging neck mass in a neonate causing airway compromise by K. Schmidt et al 185 Serendipitous discovery of peritoneal mesothelioma by A. Jaster and J. Wachsmann 188 Pneumomediastinum, pneumorrhachis, and subcutaneous emphysema in Pneumocystis jiroveci pneumonia in AIDS by N. Saleem et al 191 Multiple dural-based hemangiopericytomas by E. Stroberg et al 194 Colorectal cancer implant in an external hemorrhoidal skin tag by L. Liasis and H. T. Papaconstantinou 196 Bilateral synchronous plasmacytoma of the testis by G. Narayanan et al 198 Presentation of epidermolytic acanthomas as multiple tan papules on the vulva by J. W. Fletcher et al 200 Rumpel-Leede phenomenon presenting as a hypertensive urgency by D. Varela et al 202 Arm pain and erythema by B. M. Barth and A. L. Juergens 204 Rheumatoid meningitis associated with infliximab by S. Seago et al 207 Cryptococcal meningitis in a patient with sarcoidosis by T. N. Adams and M. Gibson 209 Thyroid hormone resistance and its management by A. M. Rivas et al 212 The price of a 15-year delay in diagnosis of Sheehan’s syndrome by R. Parikh et al 214 Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists by J. Sutton et al Editorial and Book Review 220 On John Keats and Blue Zones by J. D. Cantwell 224 Book review: In Vitro Fertilization Comes to America by S. P. Marynick From the Editor 230 Facts and ideas from anywhere by W. C. Roberts Miscellany 118 Clinical research studies enrolling patients 164 In memoriam 187 Avocations: Photograph by R. Solis 216 Baylor news 226 Reader comments: Hearts considered for transplantation and takotsubo syndrome by J. E. Madias, S. Y-Hassan, author reply by Y. Ravi; Electronic medical records by L. Hughes; Facts and ideas by T. Gore, J. Woods; Cuba by S. P. Marynick 238 2015 publications of the Baylor Scott & White Health North Division medical and scientific staff 259 Instructions for authors www.BaylorHealth.edu/Proceedings Indexed in PubMed, with full text available through PubMed Central