Washington University School Of Medicine Research Articles

Commentary: the role of epidemiologists in funding biomedical education and research

Melissa Perry served as the president of the American College of Epidemiology from September 2014 to September 2015. This is a written version of her Presidential Address at the 2015 Annual Meeting. Her speech was inspired by a 2014 Wall Street Journal commentary by Dr. Ferric Fang of the Washington University School of Medicine and Dr. Arturo Casadevall of the Albert Einstein College of Medicine of Yeshiva University. They likened the process of submitting a research proposal to the National Institutes of Health to playing the Powerball lottery. In her speech, Dr. Perry argued for the urgent need for epidemiology researchers to reach out to policymakers and the public in support of our field to ensure the continuation of research projects that can help improve the health of citizens everywhere.

Abstract 5225: CDK11B, PTPRN2 and WDPCP were frequently duplicated genes in refractory/relapsed normal karyotype AML patients: Identifying structural variations using whole genome sequencing

Abstract Background According to the NCCN guideline, the prognosis of acute myeloid leukemia with normal karyotype (NK-AML) is classified based on the mutational status of NPM1, FLT3-ITD or CEBPA. However, patients with NK-AML without the above mutations, who are in intermediate risk, still show various clinical outcomes. Unfortunately, refractory/relapsed patients with intermediate risk NK-AML cannot be predicted before cytotoxic chemotherapy, yet. With the advent of next generation sequencing technology, we tried to reveal prognostic molecular marker in intermediate risk NK-AML, especially focusing on large structural variations (SVs). Methods A total of nine patients with intermediate risk NK-AML patients were included. Whole genome sequencing (WGS) was performed using a pair of tumor and germline DNA of the patients. Leukemic blasts were obtained from bone marrow aspiration specimens of each patient at the time of diagnosis. As a germline control, epithelial cells were collected from saliva of each patient at the time of complete remission. Then, genomic DNA was massively sequenced using HiSeq X10 system (Illumina Inc., San Diego, CA, USA). Possible SVs including inversion, duplication and translocation were identified with BreakDancer (Washington University School of Medicine, St. Louis, MO, USA), Pindel (The Wellcome Trust Sanger Institute, Cambridge, UK) and Delly (European Molecular Biology Laboratory, Heidelberg, Germany). Possible SVs were considered when they were recurrently identified from the three pipelines. Results This cohort consisted of 7 males and 2 females (median age = 55.6 years old). None of them had secondary AML. Eight patients were relapsed after complete remission and the other patient was refractory to 1st line induction chemotherapy. Through WGS, 25 inversions, 67 duplications and 10 translocations were identified in nine patients. Among them, 4 inversions, 13 duplications and 2 translocations were recurrently mutated. Especially, CDK11B, PTPRN2 and WDPCP were frequently duplicated more than 40% of the patients. Conclusions In this study, we performed WGS to investigate SVs of refractory/relapsed NK-AML patients with intermediate risk. Among various mutations, duplications of CDK11B, PTPRN2 and WDPCP were highly prevalent, so they could be a possible prognostic biomarker in NK-AML with intermediate risk. Further functional validation is required in order to clarify their roles. Citation Format: Jeonghwan Youk, Sunghoon Cho, Daeyoon Kim, Youngil Koh, Inho Kim, Murim Choi, Sung-Soo Yoon. CDK11B, PTPRN2 and WDPCP were frequently duplicated genes in refractory/relapsed normal karyotype AML patients: Identifying structural variations using whole genome sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5225.

Development and Evaluation of an Online Risk Communication Teaching Program for Medical Students

The objective of this study was to develop, pilot, and evaluate an online program for teaching clinical risk communication skills to medical students. A new teaching program, “Risk Talk Online,” was developed and piloted at Tufts University School of Medicine (TUSM) and Washington University School of Medicine (WUSM) in 2014–2015. The program’s content was based on “Risk Talk,” a risk communication curriculum previously developed at TUSM, and consisted of didactic and observational instruction using videorecordings of physician-patient discussions illustrating key elements of effective risk communication. The program was implemented among students at the beginning of the second medical school year at TUSM and the end of the first medical school year at WUSM. The program’s feasibility, acceptability, and efficacy in improving subjective and objective risk communication competence were assessed. A total of 204 TUSM and 115 WUSM students completed the program. Average time of completion was approximately 40 min, and students rated the program’s educational value very highly. Subjective (self-reported) competence in risk communication significantly improved (P < 0.001), as did objective risk communication competence (P < 0.001) assessed by students’ performance on a skills-oriented knowledge assessment administered before and after completion of the program. A new online risk communication teaching program was feasible, acceptable, and efficacious in improving subjective and objective risk communication competence among first- and second-year students at two medical schools. More research is needed to refine the program and determine optimal strategies for integrating risk communication training in medical education.

James Moores Ball: Ophthalmologist, medical historian, bibliophile.

James Moores Ball (1862-1929) was an ophthalmologist in St. Louis, Missouri, who excelled as a medical historian and collector of rare and historic books about the history of anatomy. During his lifetime, he was best known as the author of a comprehensive, authoritative, and popular textbook titled Modern Ophthalmology First published in 1904, there were five further editions. Ball was very interested in the history of anatomy and wrote two books on this subject, the first being a biography of Andreas Vesalius, one of the earliest in English, and the second a history of the resurrection men or grave robbers who sold corpses to professors of anatomy and surgery for teaching purposes. His legacy today is the 470 volumes of his personal library, which are now in the Archives and Rare Books department of the Becker Medical Library of the Washington University School of Medicine. These texts are one of their major collections, concentrating on the history of anatomy, beginning with a first edition of Vesalius's De Humani Corporis Fabrica and holding many important and beautiful landmark volumes of anatomical atlases.

Forging Connections

Forging Connections

Gastrorenal Axis.

Gastrorenal Axis.

CMMI Demonstration to Reduce NH Hospitalizations Moves to Phase 2

CMMI Demonstration to Reduce NH Hospitalizations Moves to Phase 2

Editorial introductions

Editorial introductions

Biosimilars: potential implications for clinicians

With the expiration of patent protection for several biologics looming, the production of highly similar therapeutic agents has begun to emerge on the pharmaceutical market. These alternative drugs are referred to as biosimilars. Many anticipate that the introduction of these agents will result in a reduction in health care costs, which may create a more affordable biopharmaceutical market and also improve patient access. In contrast to generics, which are exact copies of their original products, biosimilars are not identical to their reference products. Due to concern about the safety and efficacy of biosimilars, separate regulatory approval pathways have been developed and implemented by several countries, including the US and Europe. Europe has led the way in acceptance of biosimilars into mainstream clinical practice. Biosimilars are not generic products and require extensive clinical and nonclinical bioequivalence studies before receiving marketing approval. Not only is there a lengthy developmental process, but also they will likely be required to have postmarketing surveillance and ongoing safety monitoring to keep track of issues that may arise, such as immunogenicity. Although US Food and Drug Administration approved the first biosimilar product in March 2015, physicians remain unfamiliar about their indications.

Evaluation to Improve a High School Summer Science Outreach Program.

The goal of the Young Scientist Program (YSP) at Washington University School of Medicine in St. Louis (WUSM) is to broaden science literacy and recruit talent for the scientific future. In particular, YSP seeks to expose underrepresented minority high school students from St. Louis public schools (SLPS) to a wide variety of careers in the sciences. The centerpiece of YSP, the Summer Focus Program (SFP), is a nine-week, intensive research experience for competitively chosen rising high school seniors (Scholars). Scholars are paired with volunteer graduate student, medical student, or postdoctoral fellow mentors who are active members of the practicing scientific community and serve as guides and exemplars of scientific careers. The SFP seeks to increase the number of underrepresented minority students pursuing STEM undergraduate degrees by making the Scholars more comfortable with science and science literacy. The data presented here provide results of the objective, quick, and simple methods developed by YSP to assess the efficacy of the SFP from 2006 to 2013. We demonstrate that the SFP successfully used formative evaluation to continuously improve the various activities within the SFP over the course of several years and in turn enhance student experiences within the SFP. Additionally we show that the SFP effectively broadened confidence in science literacy among participating high school students and successfully graduated a high percentage of students who went on to pursue science, technology, engineering, and mathematics (STEM) majors at the undergraduate level.

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease

Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: β estimate, 0.29; P = .001; global composite scores: β estimate, -0.11; P = .001; episodic memory scores: β estimate, -0.18; P < .001; and semantic memory scores: β estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.

New technologies of molecular engineering and screening for cell signaling studies.

New technologies of molecular engineering and screening for cell signaling studies.

California Dreamin': the Future of Genomic Medicine.

The recent cold weather in St. Louis has me anticipating a trip in early March (3rd–4th) to sunny La Jolla, California, where I will attend and speak at the Future of Genomic Medicine (FOGM) IX meeting. As always, FOGM has a highly unique format that conveys the latest results from translational genomic (aka “precision”) medicine, with the goal of aiding clinicians and researchers in making clinical decisions of individual patients more precise and personal. The meeting informs participants about how next-generation sequencing methods and analytical computational analyses can be combined for clinically relevant studies ushering genomics into evidence-based medicine. The meeting also provides perspectives on the social impact of genomic medicine as told by journalists, media personalities, and advocates. In the session on cancer, I will discuss our newest technological advances to understand the changes in DNA alterations and RNA expression that occur during cancer progression and provide specific examples from patients on how these data can influence clinical care. The format of the meeting is a vibrant mixture of patient stories told by the patients themselves with the gentle coaxing of Dr. Eric Topol and faculty lectures that communicate current and cutting-edge approaches. The early morning introductory patient stories are always memorable and complement our vision at CSH Molecular Case Studies (MCS) to communicate important case studies in precision medicine. I was particularly moved by my colleague, Dr. Lukas Wartman, who discussed his own case with Dr. Topol at FOGM in 2012. Lukas was diagnosed with acute lymphoblastic leukemia (ALL) in 2003, and after being treated with a multidrug chemotherapy regimen, he suffered two relapses several years apart. At the time of the second relapse, he was able to enroll in a research study at Washington University School of Medicine, allowing next-generation sequencing of his bone marrow and ultimately identification of an apparent driver in the overexpression of FLT3, a druggable kinase target. By virtue of treatment with the corresponding therapy, Lukas was able to achieve complete remission and receive a lifesaving stem cell transplant. He has also written about his experience as both a patient and a cancer researcher in the inaugural issue of MCS. Another unique aspect of the meeting is the participants. Attendees are an interactive, inquisitive group composed of academic researchers, community physicians, physician–scientists, pharmaceutical and biotechnology researchers, and undergraduates from local STEM programs. I always enjoy this meeting because it illustrates the current excitement, reality, and promise of precision medicine, and supports the idea that there is value in understanding individual patients and their disease from an “N of 1” perspective. This notion, of course, stands in stark contrast to the typical “one size fits all” approach that medicine has pursued for years and acknowledges the individual nature of diseases with a genetic component. With the journal's launch in the autumn of 2015, I will attend this year's meeting with a new purpose in mind. Much like FOGM, the journal provides a forum for communicating the results of translational medicine across the community of medical research and practice. Our aim is to encourage sharing of patient data broadly and rapidly and to reinforce the value of communicating “N of 1” cases so that our collective knowledge becomes an N of many. Competing Interest Statement The author has declared no competing interest.

Insect sugar could treat fatty liver disease

Cells in the body sometimes need a spring cleaning to clear out unwanted or dysfunctional proteins, fats, and other biomolecules cluttering their insides. The regulated cleaning process cells use is called autophagy. Scientists think compounds that can trigger autophagy could lead to therapeutics for a range of diseases, including diabetes and Alzheimer’s disease, that involve the buildup of malfunctioning molecules in cells. In a new study, researchers report that the disaccharide trehalose initiates autophagy by blocking glucose from entering cells. They show that trehalose can help liver cells in mice remove excess fat, preventing fatty liver disease in the animals (Sci. Signal. 2016, DOI: 10.1126/scisignal.aac5472). “There are about 1 billion people walking around the world with nonalcoholic fatty liver disease, whether they know it or not,” says gastroenterologist Brian J. DeBosch of Washington University School of Medicine in St. Louis. People with the disease have excess fat in their livers,

Long-term Endurance Training Increases Expression of Slow Twitch Myosin Heavy Chain and Mitochondria Biogenesis in Mouse Skeletal Muscle

Long-term Endurance Training Increases Expression of Slow Twitch Myosin Heavy Chain and Mitochondria Biogenesis in Mouse Skeletal Muscle Jin-Ho Koh, Hyun-Gyu Suh, Ki-Jin Kim Division of Geriatrics and Nutritional Sciences, Section of Applied Physiology, Department of Medicine, Washington University School of Medicine; Department of Health, Human Performance & Rec; Department of Physical Education, Keimyung University, Daegu, Korea

Prognostic Significance of FDG-PET/CT Metabolic Parameters After Induction Chemotherapy in Squamous Cell Carcinoma of the Head and Neck

Prognostic Significance of FDG-PET/CT Metabolic Parameters After Induction Chemotherapy in Squamous Cell Carcinoma of the Head and Neck R.I. Chin, C.R. Spencer, J. Ley, T.A. DeWees, H.A. Gay, B.H. Haughey, B. Nussenbaum, J.S. Lewis, Jr, F. Dehdashti, B. Siegel, M.D. Daly, L. Michel, T. Wildes, D. Adkins, and W.L. Thorstad; Saint Louis University School of Medicine, St. Louis, MO, Washington University School of Medicine, St. Louis, MO, Vanderbilt University, Nashville, TN

A Randomized Trial Comparing Skin Antiseptic Agents at Cesarean Delivery

BackgroundPreoperative skin antisepsis has the potential to decrease the risk of surgical-site infection. However, evidence is limited to guide the choice of antiseptic agent at cesarean delivery, which is the most common major surgical procedure among women in the United States.MethodsIn this single-center, randomized, controlled trial, we evaluated whether the use of chlorhexidine–alcohol for preoperative skin antisepsis was superior to the use of iodine–alcohol for the prevention of surgical-site infection after cesarean delivery. We randomly assigned patients undergoing cesarean delivery to skin preparation with either chlorhexidine–alcohol or iodine–alcohol. The primary outcome was superficial or deep surgical-site infection within 30 days after cesarean delivery, on the basis of definitions from the Centers for Disease Control and Prevention.ResultsFrom September 2011 through June 2015, a total of 1147 patients were enrolled; 572 patients were assigned to chlorhexidine–alcohol and 575 to iodine–alcohol. In an intention-to-treat analysis, surgical-site infection was diagnosed in 23 patients (4.0%) in the chlorhexidine–alcohol group and in 42 (7.3%) in the iodine–alcohol group (relative risk, 0.55; 95% confidence interval, 0.34 to 0.90; P=0.02). The rate of superficial surgical-site infection was 3.0% in the chlorhexidine–alcohol group and 4.9% in the iodine–alcohol group (P=0.10); the rate of deep infection was 1.0% and 2.4%, respectively (P=0.07). The frequency of adverse skin reactions was similar in the two groups.ConclusionsThe use of chlorhexidine–alcohol for preoperative skin antisepsis resulted in a significantly lower risk of surgical-site infection after cesarean delivery than did the use of iodine–alcohol. (Funded by the National Institutes of Health and Washington University School of Medicine in St. Louis; ClinicalTrials.gov number, NCT01472549.)

Life as an early career researcher: interview with Catherine Martel.

Catherine Martel speaks to Francesca Lake, Managing Commissioning Editor: Catherine Martel obtained her PhD from the Université de Montréal and pursued a postdoctoral fellowship first at Mount Sinai School of Medicine in New York (NY, USA), then at Washington University School of Medicine in St Louis (MO, USA), and obtained the Junior Investigator Award for Women from the Arteriosclerosis, Thrombosis and Vascular Biology council of the American Heart Association. Her postdoctoral work is certainly groundbreaking and brings forward new considerations in the field: she discovered that the lymphatic vessel route, the network that runs in parallel with the blood vessels, is critical for removing cholesterol from multiple tissues, including the aortic wall. In 2013, she joined the Arteriosclerosis, Thrombosis and Vascular Biology Early Career Committee, eager to bring a Canadian perspective to the group and get involved in council activities. Since 2014, she is an Assistant Professor at the Department of Medicine at the Université de Montréal, and a research scientist at the Montreal Heart Institute. Her research program now focuses on characterizing the physiopathologic role of the lymphatics in the initiation, progression and regression of atherosclerosis. Basic and translational research will allow her team to identify the causes of lymphatic dysfunction, and eventually target potential therapeutic strategies aiming at improving lymphatic function at the different levels of the atherothrombotic disease. You can follow her laboratory at @LaboMartel_ICM.

Implementation of a Screening Program for Patients at Risk for Posttraumatic Stress Disorder.

INTRODUCTIONImplantable cardioverter defibrillator (ICD) recipients who suffer from posttraumatic stress disorder (PTSD) are known to be associated with significant cardiac-specific mortality. Clinical observations suggest that PTSD is frequently undetected in ICD recipients followed up at electrophysiology (EP) outpatient clinics. Early recognition of PTSD is important to reduce the risk of serious manifestations on patient outcomes.METHODSAll ICD recipients aged 19 years or older at the Washington University School of Medicine (WASHU) EP clinic, a large urban EP clinic, were invited to participate in the project. An informed consent letter with an attached primary care: posttraumatic stress disorder (PC: PTSD) survey was offered to the participants who met the inclusion criteria. Those who completed the survey were included in the project. Individuals with positive survey result were offered a referral to mental health services. Comparisons between PTSD and non-PTSD patients were done using a two-sample t-test for continuous variables. Using Fisher’s exact test, PTSD prevalence was compared to the study by Ladwig et al in which prevalence was determined as the proportion of patients with positive findings of PTSD (n = 38/147). All analyses were conducted using SAS v9.4. The proportion of patients having PTSD was determined and an exact 95% confidence interval was evaluated based on the binomial distribution.RESULTSUsing a convenience sample, 50 ICD recipients (33 males and 17 females) were enrolled. The project had a 30-day outcome period. Nine (18%) of the 50 participants had positive PC: PTSD findings and all these nine participants were referred to a mental health specialist. The current project demonstrated an 18% (9/50) PTSD prevalence rate when compared to a 26% (38/147) prevalence rate in the study by Ladwig et al (P = 0.34). Although this project did not demonstrate 20% PTSD prevalence rate, as hypothesized, the 18% PTSD prevalence rate is consistent with previous research.CONCLUSIONThe prevalence of PTSD noted in the current project is consistent with previous research and validates underrecognition of PTSD in ICD patients. Offering a referral to all ICD recipients at EP clinic visits with a positive PC: PTSD screening to a mental health specialist is an important step in reducing the risk of serious manifestations on patient outcomes.

2015 Presidential Address: 75 Years of Battling Diabetes--Our Global Challenge.

This address was delivered by Samuel Dagogo-Jack, MD, President, Medicine & Science, of the American Diabetes Association (ADA), at the Association’s 75th Scientific Sessions in Boston, MA, on 7 June 2015. Dr. Dagogo-Jack is a professor of medicine and the director of the Division of Endocrinology, Diabetes and Metabolism and the director of the Clinical Research Center at The University of Tennessee Health Science Center, Memphis, TN, where he holds the A.C. Mullins Endowed Chair in Translational Research. He has been an ADA volunteer since 1991 and has served on several national committees and chaired the Association’s Research Grant Review Committee. At the local level, he has served on community leadership boards in St. Louis, MO, and Tennessee. A physician-scientist, Dr. Dagogo-Jack’s current research focuses on the interaction of genetic and environmental factors in the prediction and prevention of prediabetes, diabetes, and diabetes complications. He is the principal investigator of the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study and also directs The University of Tennessee site for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). Dr. Dagogo-Jack earned his medical and research doctorate degrees from the University of Ibadan College of Medicine in Nigeria, holds a master’s of science from the University of Newcastle upon Tyne in England, and completed his postdoctoral fellowship training in metabolism at the Washington University School of Medicine in St. Louis in Missouri. A board-certified endocrinologist, Dr. Dagogo-Jack has been elected to the Association of American Physicians and is the 2015 recipient of the Banting Medal for Leadership from the ADA. The ADA and Diabetes Care thank Dr. Dagogo-Jack for his outstanding leadership and service to the Association.