Medicine and Health Sciences Commons^™

Structural Variants Involving Mllt10 Fusion Are Associated With Adverse Outcomes In Pediatric Acute Myeloid Leukemia., Oussama Abla, Rhonda E. Ries, Tim Triche, Robert B. Gerbing, Betsy Hirsch, Susana Raimondi, Todd Cooper, Jason E. Farrar, Nathaniel Buteyn, Lauren M. Harmon, Hong Wen, Aniruddha J. Deshpande, E Anders Kolb, Alan S. Gamis, Richard Aplenc, Todd Alonzo, Soheil Meshinchi

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MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: (2 each of DDX3X and TEC), with 6 partners (DDX3Y, CEP164, SCN2B, …

Multicenter Study Of Long-Term Outcomes And Quality Of Life In Phace Syndrome After Age 10., Mitchell Braun, Ilona J. Frieden, Dawn H. Siegel, Elizabeth George, Christopher P. Hess, Christine K. Fox, Sarah L. Chamlin, Beth A. Drolet, Denise Metry, Elena Pope, Julie Powell, Kristen Holland, Caden Ulschmid, Marilyn G. Liang, Kelly K. Barry, Tina Ho, Chantal Cotter, Eulalia Baselga, David Bosquez, Surabhi Neerendranath Jain, Jordan K. Bui, Irene Lara-Corrales, Tracy Funk, Alison Small, Wenelia Baghoomian, Albert C. Yan, James R. Treat, Griffin Stockton Hogrogian, Charles Huang, Anita Haggstrom, Mary List, Catherine C. Mccuaig, Victoria Barrio, Anthony J. Mancini, Leslie P. Lawley, Kerrie Grunnet-Satcher, Kimberly A. Horii, Brandon D. Newell, Amy J. Nopper, Maria C. Garzon, Margaret E. Scollan, Erin F. Mathes

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OBJECTIVE: To characterize long-term outcomes of PHACE syndrome.

STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains.

RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma …

Pediatric Beta Blocker Therapy: A Comprehensive Review Of Development And Genetic Variation To Guide Precision-Based Therapy In Children, Adolescents, And Young Adults., Mollie Walton, Jonathan B. Wagner

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Beta adrenergic receptor antagonists, known as beta blockers, are one of the most prescribed medications in both pediatric and adult cardiology. Unfortunately, most of these agents utilized in the pediatric clinical setting are prescribed off-label. Despite regulatory efforts aimed at increasing pediatric drug labeling, a majority of pediatric cardiovascular drug agents continue to lack pediatric-specific data to inform precision dosing for children, adolescents, and young adults. Adding to this complexity is the contribution of development (ontogeny) and genetic variation towards the variability in drug disposition and response. In the absence of current prospective trials, the purpose of this comprehensive review …

Relationship Between Obesity And Global Longitudinal Strain In The Pediatric Single Ventricle Fontan Population Across Ventricular Morphologies., Nitin Madan, Doaa Aly, Melanie Kathol, Amulya Buddhavarapu, Thomas Rieth, Ashley K. Sherman, Daniel Forsha

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BACKGROUND: Obesity is associated with diminished myocardial function as measured by strain echocardiography in children and young adults with normal cardiac anatomy. Data are lacking about the effect of obesity on myocardial strain in patients with a single ventricle. In this study, the relationship between body mass index (BMI) and single ventricle myocardial strain in the Fontan population was assessed.

METHODS AND RESULTS: Thirty-eight abnormal BMI Fontan cases (21 overweight and 17 obese) and 30 normal BMI Fontan controls matched based on single ventricular morphology, age, and sex were included in the study. Ventricular morphology was categorized as single right …

Characteristics And Prognostic Impact Of Idh Mutations In Aml: A Cog, Swog, And Ecog Analysis., Sara Zarnegar-Lumley, Todd A. Alonzo, Robert B. Gerbing, Megan Othus, Zhuoxin Sun, Rhonda E. Ries, Jim Wang, Amanda Leonti, Matthew A. Kutny, Fabiana Ostronoff, Jerald P. Radich, Frederick R. Appelbaum, Era L. Pogosova-Agadjanyan, Kristen O'Dwyer, Martin S. Tallman, Mark Litzow, Ehab Atallah, Todd M. Cooper, Richard A. Aplenc, Omar Abdel-Wahab, Alan S. Gamis, Selina Luger, Harry Erba, Ross Levine, E Anders Kolb, Derek L. Stirewalt, Soheil Meshinchi, Katherine Tarlock

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Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged betweenChildren's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): …

Comprehensive Molecular And Clinical Characterization Of Nup98 Fusions In Pediatric Acute Myeloid Leukemia, Eline J M Bertrums, Jenny L. Smith, Lauren Harmon, Rhonda E. Ries, Yi-Cheng J. Wang, Todd A. Alonzo, Andrew J. Menssen, Karen M. Chisholm, Amanda R. Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L. Pogosova-Agadjanyan, Gertjan J L Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. Van Den Heuvel-Eibrink, C Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, Soheil Meshinchi

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NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not …

Hlh-Like Toxicities Predict Poor Survival After The Use Of Tisagenlecleucel In Children And Young Adults With B-All., Kevin O. Mcnerney, Stephanie J. Si Lim, Kyle Ishikawa, Alexandra Dreyzin, Anant Vatsayan, John J. Chen, Christina Baggott, Snehit Prabhu, Holly L. Pacenta, Christine Philips, Jenna Rossoff, Heather E. Stefanski, Julie-An Talano, Amy Moskop, Michael Verneris, Douglas Myers, Nicole A. Karras, Patrick Brown, Challice L. Bonifant, Muna Qayed, Michelle Hermiston, Prakash Satwani, Christa Krupski, Amy K. Keating, Susanne H C Baumeister, Vanessa A. Fabrizio, Vasant Chinnabhandar, Emily Egeler, Sharon Mavroukakis, Kevin J. Curran, Crystal L. Mackall, Theodore W. Laetsch, Liora M. Schultz

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Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade …

Sexual Behaviors, Contraception Use And Barriers Among Adolescents And Young Adults In Rural Haiti., Abbey R. Masonbrink, Emily A. Hurley, Nikolaus Schuetz, Jonathan Rodean, Emily Rupe, Kemi Lewis, Marie Daphnée Boncoeur, Melissa K. Miller

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BACKGROUND: Adolescents and young adults (AYAs) in Haiti experience a high unintended pregnancy rate, in part due to unmet contraception needs. Little is known about AYA opinions of and experiences with contraception that may explain remaining gaps in coverage. We aimed to describe barriers and facilitators to contraception use among AYAs in Haiti.

METHODS: We conducted a cross-sectional survey and semi-structured qualitative interviews with a convenience sample of AYA females aged 14-24 in two rural communities in Haiti. The survey and semi-structured interviews assessed demographics, sexual health and pregnancy prevention behaviors and explored contraception opinions and experiences according to Theory …

Three-Year Update Of Tisagenlecleucel In Pediatric And Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia In The Eliana Trial., Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp

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In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free …

Randomized Clinical Trial Of A Self-Care And Communication Intervention For Parents Of Adolescent/Young Adults Undergoing High-Risk Cancer Treatment: A Report From The Children's Oncology Group., Joan E. Haase, Kristin Stegenga, Sheri L. Robb, Mary C. Hooke, Debra S. Burns, Patrick O. Monahan, Timothy E. Stump, Amanda K. Henley, Paul R. Haut, Brooke Cherven, Lona Roll, Anne-Marie Langevin, Rita H. Pickler, Karen Albritton, Deanna Hawkins, Erin Osterkamp, Pauline Mitby, Jackie Smith, Virginia R. Diaz, Erica Garcia-Frausto, Margo Moore

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BACKGROUND: Parents of adolescents and young adults (AYAs) with cancer offer primary support to their children and often experience their own high levels of distress, affecting parent-AYA communication and quality of life.

OBJECTIVE: To reduce parent distress and improve communication during high-risk cancer treatment, we examined efficacy of a self-care and communication intervention for parents and indirect benefit for AYAs receiving a therapeutic music video (TMV) intervention.

METHODS: In this study, we conducted a multisite, randomized controlled trial with AYAs and parents enrolled as dyads (n = 110). Parents were randomized to intervention or low-dose control; all AYAs received TMV. …

Demographic, Clinical, And Treatment Characteristics Of The Juvenile Primary Fibromyalgia Syndrome Cohort Enrolled In The Childhood Arthritis And Rheumatology Research Alliance Legacy Registry., Jennifer E. Weiss, Kenneth N. Schikler, Alexis D. Boneparth, Mark Connelly, Carra Registry Investigators

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BACKGROUND: To describe the demographic, clinical, and treatment characteristics of youth diagnosed with juvenile primary fibromyalgia syndrome (JPFS) who are seen in pediatric rheumatology clinics.

METHODS: Information on demographics, symptoms, functioning, and treatments recommended and tried were obtained on patients with JPFS as part of a multi-site patient registry (the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry). Data were summarized using descriptive statistics. In a subset of patients completing registry follow-up visits, changes in symptoms, pain, and functioning were evaluated using growth modeling.

RESULTS: Of the 201 patients with JPFS enrolled in the registry, most were Caucasian/White (85%), non-Hispanic …

Developing Comparative Effectiveness Studies For A Rare, Understudied Pediatric Disease: Lessons Learned From The Carra Juvenile Localized Scleroderma Consensus Treatment Plan Pilot Study., Suzanne C. Li, Robert C. Fuhlbrigge, Ronald M. Laxer, Elena Pope, Maria Ibarra, Katie Stewart, Thomas Mason, Mara L. Becker, Sandy Hong, Fatma Dedeoglu, Kathryn S. Torok, C Egla Rabinovich, Polly J. Ferguson, Marilynn Punaro, Brian M. Feldman, Tracy Andrews, Gloria C. Higgins, Carra Registry Investigators

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BACKGROUND: We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases.

METHODS: This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015. A series of virtual and physical meetings were held to design the study, standardize …

Hospital Readmission Of Adolescents And Young Adults With Complex Chronic Disease., Peter Dunbar, Matt Hall, James C. Gay, Clarissa Hoover, Jessica L. Markham, Jessica L. Bettenhausen, James M. Perrin, Karen A. Kuhlthau, Morgan Crossman, Brigid Garrity, Jay G. Berry

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Importance: Adolescents and young adults (AYA) who have complex chronic disease (CCD) are a growing population that requires hospitalization to treat severe, acute health problems. These patients may have increased risk of readmission as demands on their self-management increase and as they transfer care from pediatric to adult health care practitioners.

Objective: To assess variation across CCDs in the likelihood of readmission for AYA with increasing age.

Design, Setting, and Participants: Retrospective 1-year cross-sectional study of the 2014 Agency for Healthcare Research and Quality Nationwide Readmissions Database for all US hospitals. Participants were 215 580 hospitalized individuals aged 15 to …

Evaluation Of Clinical Outcomes In An Interdisciplinary Abdominal Pain Clinic: A Retrospective, Exploratory Review., Amanda D. Deacy, Craig A. Friesen, Vincent S. Staggs, Jennifer Verrill Schurman

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Background: Pediatric functional gastrointestinal disorders (FGIDs) are common and well-accepted to be etiologically complex in terms of the contribution of biological, psychological, and social factors to symptom presentations. Nonetheless, despite its documented benefits, interdisciplinary treatment, designed to address all of these factors, for pediatric FGIDs remains rare. The current study hypothesized that the majority of pediatric patients seen in an interdisciplinary abdominal pain clinic (APC) would demonstrate clinical resolution of symptoms during the study period and that specific psychosocial variables would be significantly predictive of GI symptom improvement.

Aim: To evaluate outcomes with interdisciplinary treatment in pediatric patients with pain-related …

Abcb1 Snp Predicts Outcome In Patients With Acute Myeloid Leukemia Treated With Gemtuzumab Ozogamicin: A Report From Children's Oncology Group Aaml0531 Trial., Roya Rafiee, Lata Chauhan, Todd A. Alonzo, Yi-Cheng Wang, Ahlam Elmasry, Michael R. Loken, Jessica Pollard, Richard Aplenc, Susana Raimondi, Betsy A. Hirsch, Irwin D. Bernstein, A S. Gamis, Soheil Meshinchi, Jatinder K. Lamba

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Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC …

Tisagenlecleucel Model-Based Cellular Kinetic Analysis Of Chimeric Antigen Receptor-T Cells., Andrew M. Stein, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Bruce L. Levine, Lori Tomassian, Sweta Shah, Mimi Leung, Pai-Hsi Huang, Rakesh Awasthi, Karen Thudium Mueller, Patricia A. Wood, Carl H. June

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Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or …

Direct Lung Sampling Indicates That Established Pathogens Dominate Early Infections In Children With Cystic Fibrosis., Peter Jorth, Zarmina Ehsan Md, Amir Rezayat, Ellen Caldwell, Christopher Pope, John J. Brewington, Christopher H. Goss, Dan Benscoter, John P. Clancy, Pradeep K. Singh

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Culture and sequencing have produced divergent hypotheses about cystic fibrosis (CF) lung infections. Culturing suggests that CF lungs are uninfected before colonization by a limited group of CF pathogens. Sequencing suggests diverse communities of mostly oral bacteria inhabit lungs early on and diversity decreases as disease progresses. We studied the lung microbiota of CF children using bronchoscopy and sequencing, with measures to reduce contamination. We found no evidence for oral bacterial communities in lung lavages that lacked CF pathogens. Lavage microbial diversity varied widely, but decreases in diversity appeared to be driven by increased CF pathogen abundance, which reduced the …

Inotuzumab Ozogamicin In Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia., Deepa Bhojwani, Richard Sposto, Nirali N. Shah, Vilmarie Rodriguez, Constance Yuan, Maryalice Stetler-Stevenson, Maureen M. O'Brien, Jennifer L. Mcneer, Amrana Quereshi, Aurelie Cabannes, Paul Schlegel, Claudia Rossig, Luciano Dalla-Pozza, Keith August, Sarah Alexander, Jean-Pierre Bourquin, Michel Zwaan, Elizabeth A. Raetz, Mignon L. Loh, Susan R. Rheingold

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Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted …

Csf Inflammatory Markers Differ In Gram-Positive Versus Gram-Negative Shunt Infections., Gwenn L. Skar, David C. Synhorst, Matthew Beaver, Jessica N. Snowden

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Background: Cerebrospinal fluid (CSF) shunt placement is frequently complicated by bacterial infection. Shunt infection diagnosis relies on bacterial culture of CSF which can often produce false-negative results. Negative cultures present a conundrum for physicians as they are left to rely on other CSF indices, which can be unremarkable. New methods are needed to swiftly and accurately diagnose shunt infections. CSF chemokines and cytokines may prove useful as diagnostic biomarkers. The objective of this study was to evaluate the potential of systemic and CSF biomarkers for identification of CSF shunt infection.

Methods: We conducted a retrospective chart review of children with …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

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Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

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PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

Evaluation Of The Hiv Infant Tracking System (Hitsystem) To Optimise Quality And Efficiency Of Early Infant Diagnosis: A Cluster-Randomised Trial In Kenya., Sarah Finocchario-Kessler, Brad Gautney, Anlin Cheng, Catherine Wexler, May Maloba, Niaman Nazir, Samoel Khamadi, Raphael Lwembe, Melinda Brown, Thomas A. Odeny, Jacinda K. Dariotis, Matthew Sandbulte, Natabhona Mabachi, Kathy Goggin

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BACKGROUND: The HIV Infant Tracking System (HITSystem) is a web-based intervention linking providers of early infant diagnosis, laboratory technicians, and mothers and infants to improve outcomes for HIV-exposed infants. We aimed to evaluate the efficacy of the HITSystem on key outcomes of early infant diagnosis.

METHODS: We did a cluster-randomised trial at six hospitals in Kenya, which were matched on geographic region, resource level, and volume of patients (high, medium, and low). We randomly allocated hospitals within a matched pair to either the HITSystem (intervention; n=3) or standard of care (control; n=3). A random number generator was used to assign …

A Multicenter Study To Evaluate Pulmonary Function In Osteogenesis Imperfecta., Allison Tam, Shan Chen, Evan Schauer, Ingo Grafe, Venkata Bandi, Jay R. Shapiro, Robert D. Steiner, Peter A. Smith, Michael B. Bober, Tracy Hart, David Cuthbertson, Jeffrey Krischer, Mary Mullins, Peter H. Byers, Robert A. Sandhaus, Michaela Durigova, Francis H. Glorieux, Frank Rauch, Vernon Reid Sutton, Brendan Lee, Members Of The Brittle Bone Disorders Consortium, Eric T. Rush, Sandesh C S Nagamani

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Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV₁ ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV₁ which do not follow the expected trends of the …

Functional Brain Activation Changes Associated With Practice In Delaying Smoking Among Moderate To Heavy Smokers: Study Protocol And Rationale Of A Randomized Trial (Cope)., Andrew T. Fox, Delwyn Catley, Kimber P. Richter, Edward F. Ellerbeck, Morgan G. Brucks, Vlad B. Papa, Laura E. Martin

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BACKGROUND: Most smokers struggle to overcome tobacco addiction. Neuroscientific models of addiction emphasize the importance of brain regions associated with cognitive control and reward to understand the cycle of addiction and relapse. During an attempt at abstinence, the cognitive control system appears to be underpowered to override the heightened reward system of the addicted brain. Thus, one neural target for treatment is to strengthen the cognitive control system. It may be possible to improve the functioning of the cognitive control system via deliberate practice.

METHODS/DESIGN: This study will determine the effects of practicing delaying smoking on brain and behavioral measures …

One-Day Oral Polyethylene Glycol Based Cleanout Is Effective For Pre-Colonoscopy Preparation In Children., Ashwath S. Kumar, Brooke L. Beutler, Thomas M. Attard

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BACKGROUND: The adequacy of pre-procedure preparation is the principal determinant of the quality of colonoscopy in pediatric as in adult patients. There is a lack of consensus, among providers on a standard pre-procedure regimen. Professional society guidelines include the use of Polyethylene glycol (PEG). Herein we report on the provider-assessed adequacy of a one day, age-categorized dosing, PEG based cleanout regimen in children undergoing colonoscopy in a tertiary institution.

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METHODS: The standard bowel preparation regime at our institution includes an age dependent minimum PEG dosing regimen in addition to clear liquids the day prior to the procedure. We retrospectively …

Duet: A Phase 2 Study Evaluating The Efficacy And Safety Of Sparsentan In Patients With Fsgs., Howard Trachtman, Peter Nelson, Sharon Adler, Kirk N. Campbell, Abanti Chaudhuri, Vimal Kumar Derebail, Giovanni Gambaro, Loreto Gesualdo, Debbie S. Gipson, Jonathan Hogan, Kenneth Lieberman, Brad Marder, Kevin Edward Meyers, Esmat Mustafa, Jai Radhakrishnan, Tarak Srivastava, Miganush Stepanians, Vladimír Tesar, Olga Zhdanova, Radko Komers, Duet Study Group

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BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS.

METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 …

High Report Of Miscarriage Among Women Living With Hiv Who Want To Conceive In Uganda., Sarah Finocchario-Kessler, Kathy Goggin, Vincent S. Staggs, Rhoda K. Wanyenze, Jolly Beyeza-Kashesya, Deborah Mindry, Josephine Birungi, Glenn J Wagner

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OBJECTIVE: Data on early miscarriage incidence is limited due to various social and methodological barriers. We report on 24-month pregnancy outcomes of 299 female Ugandan HIV clients in committed relationships with an intention to conceive. Miscarriage data are reported as auxiliary findings to a larger study (5R01HD072633).

RESULTS: 127 (42%) participants reported a pregnancy during the study; among the remaining 172, 82 indicated they stopped trying to conceive, and 16 dropped out prior to month 24. Of the 127 pregnancies, 55 (43%) resulted in live births, 67 (53%) in spontaneous miscarriage, 1 (< 1%) in stillbirth, 1 (< 1%) in abortion, and 3 (2%) in unknown outcomes. Three-quarters (75%) of miscarriages for which time until miscarriage was available were reported to occur in the first trimester (mean = 11.3 weeks gestation). The 67 participants who reported a miscarriage tended to be older (mean 33 vs. 30 years), but the significance of age did not persist after adjusting for multiple tests. We observed relatively low rates of pregnancy and high rates of miscarriage among this cohort of HIV-positive women wanting to conceive. Rigorously designed studies are needed to better understand the observed high rate of early miscarriage among HIV-infected women.

Recurrence Of Nephrotic Syndrome Following Kidney Transplantation Is Associated With Initial Native Kidney Biopsy Findings., Jonathan H. Pelletier, Karan R. Kumar, Rachel Engen, Adam Bensimhon, Jennifer D. Varner, Michelle N. Rheault, Tarak Srivastava, Caroline Straatmann, Cynthia Silva, T Keefe Davis, Scott E. Wenderfer, Keisha Gibson, David Selewski, John Barcia, Patricia Weng, Christoph Licht, Natasha Jawa, Mahmoud Kallash, John W. Foreman, Delbert R. Wigfall, Annabelle N. Chua, Eileen Chambers, Christoph P. Hornik, Eileen D. Brewer, Shashi K. Nagaraj, Larry A. Greenbaum, Rasheed A. Gbadegesin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end-stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation and factors that predict response to immunosuppression following recurrence.

METHODS: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006 and 12/2015. Demographics, clinical course, and biopsy data were …

An Eqtl Landscape Of Kidney Tissue In Human Nephrotic Syndrome., Christopher E. Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T. Mcnulty, Nephrotic Syndrome Study Network (Neptune), Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G. Sampson, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map …

Influenza-Associated Parotitis During The 2014-2015 Influenza Season In The United States., Melissa A. Rolfes, Alexander J. Millman, Pamela Talley, Lina I. Elbadawi, Natalie A. Kramer, Joh R. Barnes, Lenee Blanton, Jeffrey P. Davis, Stefanie Cole, John J. Dreisig, Rebecca Garten, Thomas Haupt, Mary Anne Jackson, Anna Kocharian, Daniel Leifer, Ruth Lynfield, Karen Martin, Lisa Mchugh, Sara Robinson, George Turabelidze, Lori A. Webber, Meghan Pearce Weinberg, David E. Wentworth, Lyn Finelli, Michael A. Jhung

Manuscripts, Articles, Book Chapters and Other Papers

Background: During the 2014-2015 influenza season in the United States, 256 cases of influenza-associated parotitis were reported from 27 states. We conducted a case-control study and laboratory investigation to further describe this rare clinical manifestation of influenza.

Methods: During February 2015-April 2015, we interviewed 50 cases (with parotitis) and 124 ill controls (without parotitis) with laboratory-confirmed influenza; participants resided in 11 states and were matched by age, state, hospital admission status, and specimen collection date. Influenza viruses were characterized using real-time polymerase chain reaction and next-generation sequencing. We compared cases and controls using conditional logistic regression. Specimens from additional reported …