Digital Commons Network^™

Equine Arteritis Virus Elicits A Mucosal Antibody Response In The Reproductive Tract Of Persistently Infected Stallions, Mariano Carossino, Bettina Wagner, Alan T. Loynachan, R. Frank Cook, Igor F. Canisso, Lakshman Chelvarajan, Casey L. Edwards, Bora Nam, John F. Timoney, Peter J. Timoney, Udeni B. R. Balasuriya

Maxwell H. Gluck Equine Research Center Faculty Publications

Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal …

Systems Biology Approach To Late-Onset Alzheimer's Disease Genome-Wide Association Study Identifies Novel Candidate Genes Validated Using Brain Expression Data And Caenorhabditis Elegans Experiments, Shubhabrata Mukherjee, Joshua C. Russell, Daniel T. Carr, Jeremy D. Burgess, Mariet Allen, Daniel J. Serie, Kevin L. Boehme, John S. K. Kauwe, Adam C. Naj, David W. Fardo, Dennis W. Dickson, Thomas J. Montine, Nilufer Ertekin-Taner, Matt R. Kaeberlein, Paul K. Crane

Biostatistics Faculty Publications

Introduction—We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

Methods—We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

Results—We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ …

Pretreatment Ethyl Glucuronide Levels Predict Response To A Contingency Management Intervention For Alcohol Use Disorders Among Adults With Serious Mental Illness., Michael Gerard Mcdonell, Emily Leickly, Sterling Mcpherson, Jordan Skalisky, Katherine Hirchak, Oladunni Oluwoye, Debra Srebnik, John Michael Roll, Richard Kirkland Ries

Articles, Abstracts, and Reports

BACKGROUND AND OBJECTIVES: This study investigated if pretreatment ethyl glucuronide (EtG) levels corresponding to light (100 ng/mL), heavy (500 ng/mL), and very heavy (1,000 ng/mL) drinking predicted longest duration of alcohol abstinence (LDA) and proportion of EtG-negative urine tests in outpatients receiving a 12-week EtG-based contingency management (CM) intervention for alcohol dependence.

METHODS: Participants were 40 adults diagnosed with alcohol use disorders and serious mental illness who submitted up to 12 urine samples for EtG analysis during a 4-week observation period and were then randomized to 12-weeks of CM for alcohol abstinence and addiction treatment attendance. Alcohol use outcomes during …

Correcting For Tissue Nitrogen Excretion In Multiple Breath Washout Measurements., Mica Kane, Jonathan H. Rayment, Renee Jensen, Reginald Mcdonald, Sanja Stanojevic, Felix Ratjen

Student Papers, Posters & Projects

Nitrogen excreted from body tissues impacts the calculation of multiple breath nitrogen washout (MBWN2) outcomes. The aim of this study was to determine the effect of tissue N2 on MBWN2 outcomes in both healthy subjects and patients with CF and to assess whether it is possible to correct for tissue N2. The contribution of tissue N2 to MBWN2 outcomes was estimated by comparing MBWN2-derived functional residual capacity (FRCN2) to FRC measured by body plethysmography (FRCpleth) and by comparing MBW outcome measures derived from MBWN2 and sulfur hexafluoride MBW (MBWSF6). Compared to plethysmography and MBWSF6, MBWN2 overestimated FRC and lung clearance …

Association Of Disease Location And Treatment With Survival In Diffuse Large B-Cell Lymphoma Of The Eye And Ocular Adnexal Region., Aseef H H. Ahmed, C. Stephen Foster, Carol L. Shields

Wills Eye Hospital Papers

Importance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved.

Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL.

Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, …

Hmgb1-Rage Pathway Drives Peroxynitrite Signaling-Induced Ibd-Like Inflammation In Murine Nonalcoholic Fatty Liver Disease, Varun Chandrashekaran, Ratanesh K. Seth, Diptadip Dattaroy, Firas Alhasson, Jacek Ziolenka, James Carson, Franklin G. Berger, Balaraman Kalyanaraman, Anna Mae Diehl, Saurabh Chatterjee

Faculty Publications

Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly …

Single-Base Resolution Mapping Of 5-Hydroxymethylcytosine Modifications In Hippocampus Of Alzheimer's Disease Subjects, Elizabeth M. Ellison, Melissa A. Bradley-Whitman, Mark A. Lovell

Chemistry Faculty Publications

Epigenetic modifications to cytosine have been shown to regulate transcription in cancer, embryonic development, and recently neurodegeneration. While cytosine methylation studies are now common in neurodegenerative research, hydroxymethylation studies are rare, particularly genome-wide mapping studies. As an initial study to analyze 5-hydroxymethylcytosine (5-hmC) in the Alzheimer’s disease (AD) genome, reduced representation hydroxymethylation profiling (RRHP) was used to analyze more than 2 million sites of possible modification in hippocampal DNA of sporadic AD and normal control subjects. Genes with differentially hydroxymethylated regions were filtered based on previously published microarray data for altered gene expression in hippocampal DNA of AD subjects. Our …

Optical Coherence Tomography Angiography Features Of Iris Racemose Hemangioma In 4 Cases., Jason L. Chien, Kareem Sioufi, Sandor Ferenczy, Emil Anthony T. Say, Carol L. Shields

Wills Eye Hospital Papers

Importance: Optical coherence tomography angiography (OCTA) allows visualization of iris racemose hemangioma course and its relation to the normal iris microvasculature.

Objective: To describe OCTA features of iris racemose hemangioma.

Design, Setting, and Participants: Descriptive, noncomparative case series at a tertiary referral center (Ocular Oncology Service of Wills Eye Hospital). Patients diagnosed with unilateral iris racemose hemangioma were included in the study.

Main Outcomes and Measures: Features of iris racemose hemangioma on OCTA.

Results: Four eyes of 4 patients with unilateral iris racemose hemangioma were included in the study. Mean patient age was 50 years, all patients were white, and …

Long-Term Detection Of Atrial Fibrillation With Insertable Cardiac Monitors In A Real-World Cryptogenic Stroke Population., Paul D Ziegler, John D Rogers, Scott W Ferreira, Allan J Nichols, Mark Richards, Jodi L Koehler, Shantanu Sarkar

Heart and Vascular Articles

BACKGROUND: The long-term incidence of atrial fibrillation (AF) in cryptogenic stroke (CS) patients has been explored in carefully controlled clinical trials but real-world data are limited. We investigated the two-year incidence of AF in real-world clinical practice among a large cohort of patients with an insertable cardiac monitor (ICM) placed for AF detection following CS.

METHODS: Patients in the de-identified Medtronic Discovery™ Link database who received an ICM (Reveal LINQ™) for the purpose of AF detection following CS were included and monitored for up to 2years. All detected AF episodes (≥2min) were adjudicated. We quantified the AF detection rate using …

Predictors Of High-Sensitivity Cardiac Troponin T Elevation In Patients With Acute Paroxysmal Supraventricular Tachycardia And Ischemic Heart Disease, Mehdi Sayadnik, Akbar Shafiee, Yaser Jenab, Arash Jalali, Saeed Sadeghian

The Texas Heart Institute Journal

We studied the predictors and patterns of high-sensitivity cardiac troponin T (hs-cTnT) elevation in patients with paroxysmal supraventricular tachycardia (PSVT) in the presence and absence of ischemic heart disease.

During calendar year 2013, we enrolled 70 of 72 consecutive adult patients with PSVT who presented at our center within 4 hours after the onset of tachycardia. On the basis of increased hs-cTnT at either of 2 initial measurements, we divided patients into groups (hs-cTnT–positive and hs-cTnT–negative), to study the predictors of enzyme elevation. We then divided the hs-cTnT–positive patients into 2 groups—those with and those without ischemic heart disease—and compared …

Left Circumflex Coronary Artery As The Culprit Vessel In St-Segment-Elevation Myocardial Infarction, Diab Ghanim, Fabio Kusniec, Wadi Kinany, Dahud Qarawani, David Meerkin, Khaled Taha, Offer Amir, Shemy Carasso

The Texas Heart Institute Journal

The prevalence of the left circumflex coronary artery (LCx) as the culprit vessel in ST-segment-elevation myocardial infarction (STEMI) is reportedly lowest among that of the 3 main epicardial arteries, and has not been described for non-STEMI (NSTEMI) and stable angina pectoris. We sought to define the distribution of culprit arteries in these clinical presentations and suggest mechanisms for the differences.

We reviewed 189 coronary angiograms of patients with STEMI, 203 with NSTEMI, and 548 with stable angina (n=940), and compared distributions of stenotic and culprit coronary arteries (lesions prompting intervention).

Obstructive coronary lesions (≥50% narrowing) were more prevalent in the …

Increased Habenular Connectivity In Opioid Users Is Associated With An Α5 Subunit Nicotinic Receptor Genetic Variant, Kaylah Curtis, Humsini Viswanath, Kenia M Velasquez, David L Molfese, Mark J Harding, Eduardo Aramayo, Philip R Baldwin, Elisa Ambrosi, Alok Madan, Michelle Patriquin, B Christopher Frueh, J Christopher Fowler, Thomas R Kosten, David A Nielsen, Ramiro Salas

Staff and Researcher Publications

Background and objectives: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive …

Genetic Moderation Of Cocaine Subjective Effects By Variation In The Tph1, Tph2, And Slc6a4 Serotonin Genes, Michelle A Patriquin, Sara C Hamon, Mark J Harding, Ellen M Nielsen, Thomas F Newton, Richard De La Garza, David A Nielsen

Staff and Researcher Publications

Objective: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine.

Methods: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used …

Pleiotropy Of Genetic Variants On Obesity And Smoking Phenotypes: Results From The Oncoarray Project Of The International Lung Cancer Consortium, Tao Wang, Jee-Young Moon, Yiqun Wu, Christopher I. Amos, Rayjean J. Hung, Adonina Tardon, Angeline Andrew, Chu Chen, David C. Christiani, Demetrios Albanes, Erik H. F. M. Van Der Heijden, Eric Duell, Gadi Rennert, Gary Goodman, Geoffrey Liu, James D. Mckay, Jian-Min Yuan, John K. Field, Jonas Manjer, Kjell Grankvist, Lambertus A. Kiemeney, Loic Le Marchand, M. Dawn Teare, Matthew B. Schabath, Mattias Johansson, Melinda C. Aldrich, Michael Davies, Mikael Johansson, Ming-Sound Tsao, Neil Caporaso, Susanne Arnold

Internal Medicine Faculty Publications

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p < 0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p < 0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) …

Effects Of Once-Weekly Exenatide On Cardiovascular Outcomes In Type 2 Diabetes, Rury R Holman, M Angelyn Bethel, Robert J Mentz, Vivian P Thompson, Yuliya Lokhnygina, John B Buse, Juliana C Chan, Jasmine Choi, Stephanie M Gustavson, Nayyar Iqbal, Aldo P Maggioni, Steven P Marso, Peter Öhman, Neha J Pagidipati, Neil Poulter, Ambady Ramachandran, Bernard Zinman, Adrian F Hernandez

Faculty, Staff and Student Publications

BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

RESULTS: …

Rabies Screen Reveals Gpe Control Of Cocaine-Triggered Plasticity., Kevin T. Beier, Christina K. Kim, Paul Hoerbelt, Lin Wai Hung, Boris D. Heifets, Katherine E. Deloach, Timothy J. Mosca, Sophie Neuner, Karl Deisseroth, Liqun Luo, Robert C. Malenka

Department of Neuroscience Faculty Papers

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the …

Erenumab (Amg 334) In Episodic Migraine: Interim Analysis Of An Ongoing Open-Label Study., Messoud Ashina, David Dodick, Peter J. Goadsby, Uwe Reuter, Stephen Silberstein, Feng Zhang, Julia R. Gage, Sunfa Cheng, Daniel D. Mikol, Robert A. Lenz

Department of Neurology Faculty Papers

OBJECTIVE: To assess long-term safety and efficacy of anti-calcitonin gene-related peptide receptor erenumab in patients with episodic migraine (EM).

METHODS: Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of ≥50%, ≥75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without …

Insights Into Onchocerca Volvulus Population Biology Through Multilocus Immunophenotyping, Carmelle T Norice-Tra, José Ribeiro, Sasisekhar Bennuru, Michael P Fay, Rahul Tyagi, Makedonka Mitreva, Thomas B Nutman

2010-2019 OA Pubs

We have developed a serologically based immunophenotyping approach to study Onchocerca volvulus (Ov) population diversity. Using genomic sequence data and polymerase chain reaction-based genotyping, we identified nonsynonymous single-nucleotide polymorphisms (SNPs) in the genes of 16 major immunogenic Ov proteins: Ov-CHI-1/Ov-CHI-2, Ov16, Ov-FAR-1, Ov-CPI-1, Ov-B20, Ov-ASP-1, Ov-TMY-1, OvSOD1, OvGST1, Ov-CAL-1, M3/M4, Ov-RAL-1, Ov-RAL-2, Ov-ALT-1, Ov-FBA-1, and Ov-B8. We assessed the immunoreactivity of onchocerciasis patient sera (n = 152) from the Americas, West Africa, Central Africa, and East Africa against peptides derived from 10 of these proteins containing SNPs. Statistically significant variation in immunoreactivity among the regions was seen in SNP-containing peptides …

Neurosyphilis Increases Human Immunodeficiency Virus (Hiv)-Associated Central Nervous System Inflammation But Does Not Explain Cognitive Impairment In Hiv-Infected Individuals With Syphilis., Emily L Ho, Clare L Maxwell, Shelia B Dunaway, Sharon K Sahi, Lauren C Tantalo, Sheila A Lukehart, Christina M Marra

Articles, Abstracts, and Reports

Background: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation.

Methods: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that …

Causes, Timing, And Impact Of Dual Antiplatelet Therapy Interruption For Surgery (From The Paris Registry), Mikkel Schoos, Jaya Chandrasekhar, Usman Baber, Aarti Bhasin, Samantha Sartori, Melissa Aquino, Birgit Vogel, Serdar Farhan, Sabato Sorrentino, Annapoorna Kini, Mitchell Kruckoff, David J. Moliterno, Timothy D. Henry, Giora Weisz, C. Michael Gibson, Ioannis Iakovou, Antonio Colombo, P. Gabriel Steg, Bernhard Witzenbichler, Alaide Chieffo, David Cohen, Thomas Stuckey, Cono Ariti, George Dangas, Stuart Pocock, Roxana Mehran

Internal Medicine Faculty Publications

Temporary interruption of dual antiplatelet therapy (DAPT) is not infrequently required in patients undergoing percutaneous coronary intervention (PCI). We sought to describe the procedures and outcomes associated with DAPT interruption in patients treated with DAPT following successful PCI from the Patterns of non-adherence to anti-platelet regimens in stented patients registry (n = 5018). DAPT interruption was prespecified as physician recommended cessation forcohort, 490 patients (9.8%) experienced 594 DAPT interruptions over 2 years following PCI. Only 1 antiplatelet agent was interrupted in 57.2% cases and interruption was frequently recommended by noncardiologists (51.3%). Where type of surgery was reported, majority of DAPT …

Gucy2c Signaling Opposes The Acute Radiation-Induced Gi Syndrome., Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. …

Impact Of Vitamin A And Carotenoids On The Risk Of Tuberculosis Progression, Omowunmi Aibana, Molly F Franke, Chuan-Chin Huang, Jerome T Galea, Roger Calderon, Zibiao Zhang, Mercedes C Becerra, Emily R Smith, Alayne G Ronnenberg, Carmen Contreras, Rosa Yataco, Leonid Lecca, Megan B Murray

Faculty, Staff and Student Publications

BACKGROUND: Low and deficient levels of vitamin A are common in low- and middle-income countries where tuberculosis burden is high. We assessed the impact of baseline levels of vitamin A and carotenoids on tuberculosis disease risk.

METHODS: We conducted a case-control study nested within a longitudinal cohort of household contacts (HHCs) of pulmonary tuberculosis case patients in Lima, Peru. We defined case patients as human immunodeficiency virus (HIV)-negative HHCs with blood samples in whom tuberculosis disease developed ≥15 days after enrollment of the index patient. For each case patient, we randomly selected 4 controls from among contacts in whom tuberculosis …

Direct Oral Anticoagulant- Vs Vitamin K Antagonist-Related Nontraumatic Intracerebral Hemorrhage, Georgios Tsivgoulis, Vasileios-Arsenios Lioutas, Panayiotis N. Varelas, Aristeidis H. Katsanos, Nitin Goyal, Robert Mikulik, Kristian Barlinn, Christos Krogias, Vijay K. Sharma, Konstantinos Vadikolias, Efthymios Dardiotis, Theodore Karapanayiotides, Alexandra Pappa, Christina Zompola, Sokratis Triantafyllou, Odysseas Kargiotis, Michael Ioakeimidis, Sotirios Giannopoulos, Ali Kerro, Argyrios Tsantes, Chandan Mehta, Mathew Jones, Christoph Schroeder, Casey Norton, Anastasios Bonakis, Jason Chang, Anne W. Alexandrov, Panayiotis Mitsias, Andrei V. Alexandrov

Neurology Articles

OBJECTIVE: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF).

METHODS: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH.

RESULTS: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke …

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As A Graft Source For T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide., Asad Bashey, Mei-Jie Zhang, Shannon R Mccurdy, Andrew St Martin, Trevor Argall, Claudio Anasetti, Stefan O Ciurea, Omotayo Fasan, Sameh Gaballa, Md, Mehdi Hamadani, Pashna Munshi, Monzr M Al Malki, Ryotaro Nakamura, Paul V O'Donnell, Miguel-Angel Perales, Kavita Raj, Rizwan Romee, Scott Rowley, Vanderson Rocha, Rachel B Salit, Melhem Solh, Robert J Soiffer, Ephraim Joseph Fuchs, Mary Eapen

Department of Medicine Faculty Papers

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil …

A Pilot Clinical Trial Of Recombinant Human Angiotensin-Converting Enzyme 2 In Acute Respiratory Distress Syndrome., Akram Khan, Cody Benthin, Brian Zeno, Timothy E Albertson, John Boyd, Jason D Christie, Richard Hall, Germain Poirier, Juan J Ronco, Mark Tidswell, Kelly Hardes, William M Powley, Tracey J Wright, Sarah K Siederer, David A Fairman, David A Lipson, Andrew I Bayliffe, Aili L Lazaar

Trauma and Acute Care Articles

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.

METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. …

Serum D-Dimer Test Is Promising For The Diagnosis Of Periprosthetic Joint Infection And Timing Of Reimplantation., Alisina Shahi, Michael M. Kheir, Majd Tarabichi, Hamid R.S. Hosseinzadeh, Timothy L. Tan, Javad Parvizi

Rothman Institute Papers

BACKGROUND: Despite the availability of a battery of tests, the diagnosis of periprosthetic joint infection (PJI) continues to be challenging. Serum D-dimer assessment is a widely available test that detects fibrinolytic activities that occur during infection. We hypothesized that patients with PJI may have a high level of circulating D-dimer and that the presence of a high level of serum D-dimer may be a sign of persistent infection in patients awaiting reimplantation.

METHODS: This prospective study was initiated to enroll patients undergoing primary and revision arthroplasty. Our cohort consisted of 245 patients undergoing primary arthroplasty (n = 23), revision for …

Therapeutic And Prognostic Implications Of Braf V600e In Pediatric Low-Grade Gliomas., Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara Mckeown, Jim Loukides, Ofelia Cruz, Carmen De Torres, Cheng-Ying Ho, Roger J Packer, Ruth Tatevossian, Ibrahim Qaddoumi, Julie H Harreld, James D Dalton, Jean Mulcahy-Levy, Nicholas Foreman, Matthias A Karajannis, Shiyang Wang, Matija Snuderl, Amulya Nageswara Rao, Caterina Giannini, Mark Kieran, Keith L Ligon, Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, Alessandro Raso, Sabine Mueller, Theodore Nicolaides, Karen Silva, Romain Perbet, Alexandre Vasiljevic, Cécile Faure Conter, Didier Frappaz, Sarah Leary, Courtney Crane, Aden Chan, Ho-Keung Ng, Zhi-Feng Shi, Ying Mao, Elizabeth Finch, David Eisenstat, Bev Wilson, Anne Sophie Carret, Peter Hauser, David Sumerauer, Lenka Krskova, Valerie Larouche, Adam Fleming, Shayna Zelcer, Nada Jabado, James T Rutka, Peter Dirks, Michael D Taylor, Shiyi Chen, Ute Bartels, Annie Huang, David W Ellison, Eric Bouffet, Cynthia Hawkins, Uri Tabori

Paediatrics Publications

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown.

Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180).

Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a …

Activating Transcription Factor 3 Promotes Loss Of The Acinar Cell Phenotype In Response To Cerulein-Induced Pancreatitis In Mice, Elena N Fazio, Claire C Young, Jelena Toma, Michael Levy, Kurt R Berger, Charis L Johnson, Rashid Mehmood, Patrick Swan, Alphonse Chu, Sean P Cregan, F Jeffrey Dilworth, Christopher J Howlett, Christopher L Pin

Paediatrics Publications

Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. …

The Natural History Of Severe Acute Liver Injury., David G Koch, J L Speiser, V Durkalski, R J Fontana, T Davern, B Mcguire, R T Stravitz, A M Larson, I Liou, Oren K Fix, M L Schilsky, T Mccashland, J E Hay, N Murray, O S Shaikh, D Ganger, A Zaman, S B Han, R T Chung, R S Brown, S Munoz, K R Reddy, L Rossaro, R Satyanarayana, A J Hanje, J Olson, R M Subramanian, C Karvellas, B Hameed, A H Sherker, W M Lee, A Reuben

Articles, Abstracts, and Reports

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death.

METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × …

Sustained Efficacy, Safety And Patient-Reported Outcomes Of Certolizumab Pegol In Axial Spondyloarthritis: 4-Year Outcomes From Rapid-Axspa., Désirée Van Der Heijde, Maxime Dougados, Robert Landewé, Joachim Sieper, Walter P Maksymowych, Martin Rudwaleit, Filip Van Den Bosch, Jürgen Braun, Philip Mease, Alan J Kivitz, Jessica Walsh, Owen Davies, Lars Bauer, Bengt Hoepken, Luke Peterson, Atul Deodhar

Articles, Abstracts, and Reports

Objective: The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA.

Methods: RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further …