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Evolution Of The Epigenetic Landscape In Childhood B Acute Lymphoblastic Leukemia And Its Role In Drug Resistance, Shella Saint Fleur-Lominy, Nikki A. Evensen, Teena Bhatla, Gunjan Sethia, Sonali Narang, Jun H. Choi, Xiaotu Ma, Jun J. Yang, Stephen Kelly, Elizabeth Raetz, Richard C. Harvey, Cheryl Willman, Mignon L. Loh, Stephen P. Hunger, Patrick A. Brown, Kylie M. Getz, Cem Meydan, Christopher E. Mason, Aristotelis Tsirigos, William Carroll

Pathology Research and Scholarship

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of …

Postmortem Computed Tomography In Firearm Homicides: A Retrospective Case Series, Marloes E M Vester, Kurt B Nolte, Gary M. Hatch, Chandra Y. Gerrard, Reinoud D. Stoel, Rick R. Van Rijn

Pathology Research and Scholarship

Postmortem computed tomography (PMCT) is integrated into the evaluation of decedents in several American medical examiner offices and medicolegal death investigative centers in many other countries. We retrospectively investigated the value of PMCT in a series of firearm homicide cases from a statewide centralized medical examiner's office that occurred during 2016. Autopsies were performed or supervised by board-certified forensic pathologists who reviewed the PMCT scans prior to autopsy. PMCT scans were re-evaluated by a forensic radiologist blinded to the autopsy findings and scored by body region (head-neck, thoracoabdominal, and extremities). Injury discrepancies were scored using a modified Goldman classification and …

Integrating Quality Improvement Into The Echo Model To Improve Care For Children And Youth With Epilepsy, Sucheta Joshi, Kari Gali, Linda Radecki, Amy Shah, Sarah Hueneke, Trisha Calabrese, Alexis Katzenbach, Ramesh Sachdeva, Lawrence Brown, Eve Kimball, Patience White, Peggy Mcmanus, David Wood, Eve-Lynn Nelson, Pattie Archuleta

Project ECHO Bibliography

OBJECTIVE: Project ECHO (Extension for Community Healthcare Outcomes), a telementoring program, utilizes lectures, case-based learning, and an "all teach-all learn" approach to increase primary care provider (PCP) knowledge/confidence in managing chronic health conditions. The American Academy of Pediatrics (AAP) Epilepsy and Comorbidities ECHO incorporated quality improvement (QI) methodology to create meaningful practice change, while increasing PCP knowledge/self-efficacy in epilepsy management using the ECHO model.

METHODS: Monthly ECHO sessions (May 2018 to December 2018) included lectures, case presentations/discussion, and QI review. Pediatric practices were recruited through the AAP. Practices engaged in ECHO sessions and improvement activities including monthly Plan-Do-Study-Act cycles, team …

Heterogeneity Of Mild To Moderate Persistent Asthma In Children: Confirmation By Latent Class Analysis And Association With 1-Year Outcomes, Anne M. Fitzpatrick, Leonard B. Bacharier, Daniel J. Jackson, Stanley J. Szefler, Avraham Beigelman, Michael Cabana, Ronina Covar, Theresa Guilbert, Fernando Holguin, Robert F. Lemanske, Fernando D. Martinez, Wayne Morgan, Wanda Phipatanakul, Jacqueline A. Pongracic, Hengameh H. Raissy, Robert S. Zeiger, David T. Mauger

Pediatrics Research and Scholarship

BACKGROUND: Compared with adults, phenotypic characterization of children with asthma is still limited and it remains difficult to predict which children with asthma are at highest risk for poor outcomes.

OBJECTIVE: To identify latent classes in a large population of treatment-adherent children with mild to moderate asthma enrolled in clinical trials and determine whether latent class assignment predicts future lung function abnormalities and exacerbation rate.

METHODS: Latent class analysis was performed on 2593 children with mild to moderate asthma aged 5 18 years, with 19 variables encompassing demographic characteristics, medical history, symptoms, lung function, allergic sensitization, and type 2 inflammation. …

Self-Regulation And Emotional Reactivity In Infants With Prenatal Exposure To Opioids And Alcohol, Kathryn G Beauchamp, Jean Lowe, Ronald M Schrader, Shikhar Shrestha, Crystal Aragón, Natalia Moss, Julia M Stephen, Ludmila N Bakhireva

Pediatrics Research and Scholarship

BACKGROUND: Infants with prenatal substance exposure are at increased risk for developmental problems, with self-regulatory challenges being some of the most pronounced. The current study aimed to investigate the extent to which prenatal substance exposure (alcohol, opioids) impacts infant self-regulation during a relational stressor and the association between self-regulation and infant affect.

METHODS: Participants were 100 mother-child dyads recruited prenatally (Mean = 23.8 gestational weeks) and completed the Still Face Paradigm (SFP) when infants were 5 to 8 months of age (Mean = 6.9 months) as part of an ENRICH prospective birth cohort study. Based on prospective repeated assessment of …

Early Working Memory Is A Significant Predictor Of Verbal And Processing Skills At 6-7 Years In Children Born Extremely Preterm, Jean Lowe, Carla M Bann, Janell Fuller, Betty R Vohr, Susan R Hintz, Abhik Das, Rosemary D Higgins, Kristi L Watterberg, Support Study Group Of The Eunice Kennedy Shriver National Institute Of Child Health And Human Development Neonatal Research Network

Pediatrics Research and Scholarship

OBJECTIVE: The study was designed to investigate whether attainment of object permanence, a measure of early working memory used at 18-22 months corrected age, was associated with executive function at 6-7 years in a cohort of children born extremely preterm.

STUDY DESIGN: Children enrolled in the Neuroimaging and Neurodevelopmental Outcome (NEURO) study, a secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) of the NICHD NRN, were eligible for this longitudinal study. Testing completed at 18 to 22 months corrected age was compared to testing at school age with a specific focus on measures of executive …

Dna Methylation Signature For Ezh2 Functionally Classifies Sequence Variants In Three Prc2 Complex Genes, Sanaa Choufani, William T. Gibson, Andrei L. Turinsky, Brian H Y Chung, Tianren Wang, Kopal Garg, Alessandro Vitriolo, Ana S A Cohen, Sharri Cyrus, Sarah Goodman, Eric Chater-Diehl, Jack Brzezinski, Michael Brudno, Luk Ho Ming, Susan M. White, Sally Ann Lynch, Carol Clericuzio, I Karen Temple, Frances Flinter, Vivienne Mcconnell, Tom Cushing, Lynne M. Bird, Miranda Splitt, Bronwyn Kerr, Stephen W. Scherer, Jerry Machado, Eri Imagawa, Nobuhiko Okamoto, Naomichi Matsumoto, Guiseppe Testa, Maria Iascone, Romano Tenconi, Oana Caluseriu, Roberto Mendoza-Londono, David Chitayat, Cheryl Cytrynbaum, Katrina Tatton-Brown, Rosanna Weksberg

Pediatrics Research and Scholarship

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other …

Accelerating Care Through Echo: Case Examples From The Field., Mirna Becevic, Emmanuelle Wallach, Lincoln R. Sheets, Hope Misterovich, Susan Norris, Evelyn Aboagye, Jonathan A Dyer, Bruce R Bacon, Karen Edison, Kristin Sohl

Project ECHO Bibliography

In this article, we describe three life-changing patient cases demonstrating high-quality and timely care they received in their communities, thanks to the Show-Me ECHO project. Early autism diagnosis, a potentially deadly tumor manifesting as a benign-looking rash, a recalcitrant case of hepatitis C: rural and underserved Missourians now have access to state-of-the-art care through their local providers receiving interdisciplinary telementoring on evidence based practices.

Drug Resistance Of Previously Treated Tuberculosis Patients With Diabetes Mellitus In Shandong, China, Wan-Mei Song, Yi-Fan Li, Jin-Yue Liu, Ning-Ning Tao, Yao Liu, Qian-Yun Zhang, Ting-Ting Xu, Shi-Jin Li, Qi-Qi An, Si-Qi Liu, Chun-Bao Yu, Lei Gao, Cui-Xiang Yu, Min Zhang, Huai-Chen Li

Pathology Research and Scholarship

BACKGROUND: Although the association between diabetes mellitus (DM) and tuberculosis (TB) has been well-documented for centuries, evidence of the link between diabetes and drug resistance among previously treated TB patients remains limited and inconsistent.

METHODS: An observational study was performed that involved 1791 retreated TB-no DM patients (refers to TB cases without diabetes) and 93 retreated TB-DM patients (refers to TB cases with diabetes) in Shandong, China from 2004 to 2017. Baseline data including demographic and clinical characteristics, drug susceptibility test (DST) results, and diabetes status were collected. Categorical baseline characteristics were compared by Fisher's exact or Pearson Chi-square test. …

Recommendations For Clinical Laboratory Testing For Protein C Deficiency, For The Subcommittee On Plasma Coagulation Inhibitors Of The Isth, Peter C. Cooper, Anna Pavlova, Gary W. Moore, Kieron P. Hickey, Richard A. Marlar

Pathology Research and Scholarship

Inherited protein C (PC) deficiency increases risk of venous thromboembolism (VTE) by 5 to 10-fold in thrombosis-prone families; however, heterozygous PC deficiency alone does not determine that a subject has thrombophilia. Protein C deficient subjects, who lack additional inherited risk factors such as factor V Leiden or have no major acquired risk factors, may not suffer from VTE. In addition, PC deficiency may be acquired, often due to vitamin K antagonist treatment or liver disease. In contrast, homozygous or compound heterozygous PC deficiencies are rare and serious disorders, and affected infants are often in families with no history of PC …

A Multicenter Study Of The Revogene C. Difficile System For Detection Of The Toxin B Gene From Unformed Stool Specimens, Michael J. Mashock, Matthew L. Faron, Karen C. Carroll, Christina Dang, Shawna Lewis, Hossein Salimnia, Paul Lephart, Vivian G. Loo, Bryan H. Schmitt, Stephen Young, Blake W. Buchan, Nathan A. Ledeboer

Pathology Research and Scholarship

Clostridioides difficile is the leading cause of diarrhea in hospitalized U.S. patients and results in over 400,000 cases of C. difficile infection per year. C. difficile infections have mortality rates of 6 to 30% and significantly increase health care costs, because of increased length of stay and increased frequency of readmissions due to recurrences. Efforts to reduce the spread of C. difficile in hospitals have led to the development of rapid sensitive diagnostic methods. A multicenter study was performed to establish the performance characteristics of the Revogene C. difficile test (Meridian Bioscience, Cincinnati, OH, USA) for use in detection of …

A Randomized Trial Of Erythropoietin For Neuroprotection In Preterm Infants, Sandra E Juul, Bryan A Comstock, Rajan Wadhawan, Dennis E Mayock, Sherry E Courtney, Tonya Robinson, Kaashif A Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F Lagamma, L Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D Frantz Iii, Janine Y Khan, Michael Weiss, Maureen M Gilmore, Robin K Ohls, Nishant Srinivasan, Jorge E Perez, Victor Mckay, Phuong T Vu, Jean Lowe, Karl Kuban, T Michael O'Shea, Adam L Hartman, Patrick J Heagerty, Penut Trial Consortium

Pediatrics Research and Scholarship

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.

METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for …

Clinical Diagnostics And Treatment Strategies For Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia, Richard C. Harvey, Sarah K. Tasian

Pathology Research and Scholarship

Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) accounts for 15% to 30% of B-cell acute lymphoblastic leukemia in older children, adolescents, and adults and is associated with high rates of conventional treatment failure and relapse. Current clinical trials are assessing the efficacy of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy for children and adults with Ph-like ALL harboring ABL class translocations or CRLF2 rearrangements and other JAK pathway alterations. However, real-time diagnosis of patients can be quite challenging given the genetic heterogeneity of this disease and the often cytogenetically cryptic nature of Ph-like ALL-associated alterations. In this …

Recommendations For Clinical Laboratory Testing For Antithrombin Deficiency; Communication From The Ssc Of The Isth, Elizabeth M. Van Cott, Christelle Orlando, Gary W. Moore, Peter C. Cooper, Piet Meijer, Richard Marlar, Subcommittee On Plasma Coagulation Inhibitors

Pathology Research and Scholarship

Hereditary deficiency of antithrombin, a natural anticoagulant, causes a thrombophilia with a high risk for venous thromboembolism. Guidance for laboratory testing to diagnose antithrombin deficiency include the use of an activity assay for initial testing, performing an antigen test and activity-to-antigen ratio when the activity level is low, using pediatric reference ranges until the age of 6 months, excluding acquired causes of low antithrombin (e.g. liver dysfunction, proteinuria, heparin, disseminated intravascular coagulation, thrombosis, surgery) or falsely normal/elevated results (e.g. argatroban, bivalirudin, dabigatran in factor IIa-based assays; rivaroxaban, apixaban, edoxaban, but not betrixaban in Xa-based assays). Molecular testing, if available, may …

Therapeutic Plasma Exchange For Neuromyelitis Optica Spectrum Disorder: A Multicenter Retrospective Study By The Asfa Neurologic Diseases Subcommittee, Tina S. Ipe, Jay S. Raval, Leonor P. Fernando, Amit Gokhale, Cyril Jacquot, Andrew D. Johnson, Haewon C. Kim, Grace F. Monis, Yunchun D. Mo, Shanna M. Morgan, Monica B. Pagano, Huy P. Pham, Kimberly Sanford, Amy E. Schmidt, Joseph Schwartz, Jennifer Webb, Jeffrey L. Winters, Yanyun Wu, Chisa Yamada, Edward C C Wong, Amy Waldman

Pathology Research and Scholarship

IMPORTANCE: Neuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized.

OBJECTIVE: Our study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE.

DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease.

MAIN OUTCOMES AND MEASURES: The primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were …

A Multicenter Evaluation Of A Sample To Answer Real-Time Pcr Assay For Toxigenic C. Difficile In Symptomatic Subjects, Preeti Pancholi, Steve Young, R Widen, Suzane Silbert, B Schmitt, R Dunn, A Drain, S A. Weissfeld

Pathology Research and Scholarship

We evaluated the performance of the Luminex ARIES® C. difficile Assay on 984 stool specimens prospectively collected from patients being tested for CDI at 4 clinical laboratories in the United States. Results were compared to direct and enriched toxigenic culture. Positive percent agreement (PPA) of the ARIES® C. difficile Assay was 98.1% versus direct toxigenic culture, and sensitivity versus direct plus enriched toxigenic culture was 90.5%. Negative percent agreement (NPA) of the ARIES® C. difficile Assay against direct culture was 92.6%, and specificity versus direct plus enriched toxigenic culture was 95.8%. The ARIES® C. difficile Assay was also compared to …