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Lisa M. Frenkel, MD

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Lisa M. Frenkel, MD

Infectious Disease

On staff since March 1995

Children's Title: Co-Director, Center for Global Infectious Disease Research

Academic Title: Professor, Pediatrics and Laboratory Medicine

Research Center: Center for Global Infectious Disease Research

Overview

Board Certification(s)
Pediatric Infectious Diseases
Pediatrics
Medical/Professional School
University of Kansas, Lawrence
Residency
Pediatrics, UCLA School of Medicine, Los Angeles
Clinical Interests

Prevention and treatment of pediatric HIV disease, neonatal herpes simplex virus (HSV) and congenital cytomegalovirus (CMV) infections

Research Description

Over the past 20 years, our group has conducted projects in Peru, Thailand, Mozambique, Kenya and South Africa. These studies aimed to better understand the transmission, selection and persistence of drug-resistant viruses and have included collaborations with other UW, national and international investigators. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, our laboratory located within Seattle Children's Research Institute (SCRI) focuses primarily on three topics and collaborates broadly with other UW, national and international investigators.
1. Persistence of HIV infection: A major research focus of our work has been to understand the mechanisms that allow HIV to persist despite effective ART. Our group documented that among ART-treated individuals with plasma HIV RNA consistently below the limits of detection included a subset that demonstrated viral evolution, implying low-level viral replication, although the vast majority demonstrated no evolution (Frenkel, JVI, 2003). We were the first to note that transient low-level viremias, or "blips," during ART were usually comprised of populations of identical env and pol sequences (Tobin, JVI, 2005), suggesting production of clonal virus. Our subsequent studies revealed that populations of identical viral sequences in PBMC and sputum (rich in pulmonary macrophages) increase over a decade of ART (Wagner, JVI, 2013), suggesting that clonal proliferation of cells with provirus sustains HIV infection during suppressive ART. Recently, we have documented that identical env sequences have identical integration sites, providing strong supportive evidence that HIV persistence is at least in part due to cellular proliferation, and with ongoing suppressive ART, that these proviruses are increasingly integrated into genes controlling immune functions, the cell cycle or cancers suggesting that interference with these genes expression allows the infected cells to proliferate and/or survive (Wagner, Science, 2014; http://www.sciencemag.org/cgi/content/abstract/science.1256304)
Ongoing projects (R01 AI091550 and R01 AI114348) are focused on understanding whether specific HIV integration events lead to the persistence of HIV DNA that is infectious or defective; use in vitro mutagenesis to determine the effects of specific integration events on cellular function; and on whether during acute HIV infection the antigen specificity of HIV-infected cells that would be targeted for cure in individuals who start ART during this time.
2. Systemic inflammation in HIV-infected individuals: Individuals whose viral replication is suppressed by ART continue to have biomarkers indicative of ongoing diffuse inflammation that accelerates atherosclerosis and cardio- and cerebral-vascular events. Given the timing of HIV acquisition by infected children, substantial morbidity could occur from inflammation despite suppressive ART. We hypothesize that ongoing production of viral RNA or proteins drives inflammation, rather than the alternative hypothesis that immune depletion of gut lymphocytes during acute infection allow bacterial translocation.
An ongoing project (funded by SCRI) aims to determine if low-level production of HIV virions or 16sDNA correlate with immune activation and help develop a short interventional trial to diminish inflammation.
3. HIV Resistance to antiretrovirals: Our group has conducted many studies aimed at better understanding the transmission, selection and persistence of drug-resistant viruses. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, we are conducting a randomized-controlled trial of our oligonucleotide ligation assay (OLA) detection of HIV-drug-resistance pre-ART in Kenya. The primary outcome is the rates of ART-associated suppression of viral replication among subjects randomized to testing or standard-of-care. In addition, we will analyze issues related to transfer of technology and will model the cost-effectiveness of the OLA in ART management. Secondly, with UW bioengineers, we are simplifying this OLA to make a simpler and faster assay.
Ongoing projects (R01 AI100037 and R01 AI110375) aim to better understand the role of specific transmitted mutant codons and define the threshold concentration of mutants that result in virologic failure of ART; to convert our PCR-based assay to an isothermal format; optimize Illumina-based sequencing for use as a clinical assay.

Lab URL

http://www.seattlechildrens.org/research/global-infectious-disease-research/frenkel-lab/

Research Focus Area

Infectious Disease, Virology

Awards and Honors

Award NameAward DescriptionAwarded ByAward Date
Best Poster of Meeting, International Workshop on HIV & Hepatitis Virus Drug Resistance 2013
Outstanding Mentor Award of 2011, University of WA, Dept Pediatrics 2011
Member, (extended x2yr) NIH-NIAID AIDS Research Review Committee (AIDSRRC) 2011 - 2013
Extraordinary Professor in the Department of Immunology, Faculty of Health Sciences, 2010 - 2012
Russel Haden Medal for medical student research 1978

Publications

Validation of an oligonucleotide ligation assay for quantification of human immunodeficiency virus type 1 drug-resistant mutants by use of massively parallel sequencing.
Journal of clinical microbiology , July 2014: 52(7)2320-7
Correlation between Plasma, Intracellular, and Cervical Tissue Levels of Raltegravir at Steady-State Dosing in Healthy Women.
Antimicrobial agents and chemotherapy , June 2014: 58(6)3360-3365
Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007-2013.
Antiviral therapy , May 2014
Low Concentrations of HIV-1 DNA at Birth Delays Diagnosis, Complicating Identification of Infants for Antiretroviral Therapy to Potentially Prevent the Establishment of Viral Reservoirs.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , April 2014: 58(8)1190-3
Transmission of Nevirapine-Resistant HIV Type 1 via Breast Milk to Infants After Single-Dose Nevirapine in Beira, Mozambique.
The Journal of infectious diseases , March 2014
Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , Feb. 2014: 58(3)413-22
HIV-1 RNA levels and antiretroviral drug resistance in blood and non-blood compartments from HIV-1-infected men and women enrolled in AIDS clinical trials group study A5077.
PloS one , 2014: 9(4)e93537
Improved Detection of Rare HIV-1 Variants using 454 Pyrosequencing.
PloS one , Oct. 2013: 8(10)e76502
Simultaneous and sensitive detection of human immunodeficiency virus type 1 (HIV) drug resistant genotypes by multiplex oligonucleotide ligation assay.
Journal of virological methods , Sept. 2013: 192(1-2)39-43
Development of a novel codon-specific polymerase chain reaction for the detection of CXCR4-utilizing HIV type 1 subtype B.
AIDS research and human retroviruses , May 2013: 29(5)814-25
Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time.
The Journal of infectious diseases , April 2013: 207(8)1206-15
HIV drug resistance in mothers and infants following use of antiretrovirals to prevent mother-to-child transmission.
Current HIV research , March 2013: 11(2)126-36
Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women.
Journal of acquired immune deficiency syndromes (1999) , Feb. 2013: 62(2)143-8
An increasing proportion of monotypic HIV-1 DNA sequences during antiretroviral treatment suggests proliferation of HIV-infected cells.
Journal of virology , Feb. 2013: 87(3)1770-8
Healthy Neonates Possess a CD56-Negative NK Cell Population with Reduced Anti-Viral Activity.
PloS one , 2013: 8(6)e67700
Interaction between lactobacilli, bacterial vaginosis-associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women.
AIDS research and human retroviruses , Jan. 2013: 29(1)13-9
Quantification of mitochondrial toxicity in HIV-infected individuals by quantitative PCR compared to flow cytometry.
Cytometry. Part B, Clinical cytometry , Jan. 2013: 84(1)55-8
Healthy Neonates Possess a CD56-Negative NK Cell Population with Reduced Anti-Viral Activity.
PloS one , 2013: 8(6)e67700
Nevirapine-Resistant HIV-1 DNA in Breast Milk After Single-Dose Nevirapine With or Without Zidovudine for Prevention of Mother-to-Child Transmission.
Journal of the Pediatric Infectious Diseases Society , Sept. 2012: 1(3)244-249
Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.
The New England journal of medicine , Aug. 2012: 367(5)399-410
Monitoring of HIV type 1 DNA load and drug resistance in peripheral blood mononuclear cells during suppressive antiretroviral therapy does not predict virologic failure.
AIDS research and human retroviruses , Aug. 2012: 28(8)780-8
Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine.
The Journal of infectious diseases , June 2012: 205(12)1811-5
Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru.
AIDS research and human retroviruses , April 2012: 28(4)333-8
Yet another reason to treat HIV infection.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , April 2012: 54(7)1010-2
Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum.
Journal of acquired immune deficiency syndromes (1999) , March 2012: 59(3)245-52
A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , Jan. 2012: 54(2)285-93
Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children.
The Pediatric infectious disease journal , Jan. 2012: 31(1)47-52
Selection of HIV Resistance Associated With Antiretroviral Therapy Initiated Due to Pregnancy and Suspended Postpartum.
Journal of acquired immune deficiency syndromes (1999) , Nov. 2011: 241-247
Oral acyclovir suppression and neurodevelopment after neonatal herpes.
The New England journal of medicine , Oct. 2011: 1284-92
Herpes simplex virus type 2 suppressive therapy with acyclovir or valacyclovir does not select for specific HIV-1 resistance in HIV-1/HSV-2 dually infected persons.
The Journal of infectious diseases , Jan. 2011: 117-21
Postpartum viral load rebound in HIV-1-infected women treated with highly active antiretroviral therapy: AIDS Clinical Trials Group Protocol A5150.
HIV clinical trials , Jan. 2011: 9-23
Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.
PloS one , 2011: 6(12)e28952
Antiretroviral treatment for HIV-infected infants exposed to nevirapine.
JAMA : the journal of the American Medical Association , Dec. 2010: 2589; author reply 2589-90
Two clusters of HIV-1 infection, rural Idaho, USA, 2008.
Emerging infectious diseases , Nov. 2010: 1807-9
Genetic analyses of HIV-1 env sequences demonstrate limited compartmentalization in breast milk and suggest viral replication within the breast that increases with mastitis.
Journal of virology , Oct. 2010: 10812-9
Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old.
Journal of acquired immune deficiency syndromes (1999) , Oct. 2010: 197-204
Comment on "The origins of sexually transmitted HIV among men who have sex with men".
Science translational medicine , Sept. 2010: 50le1; author reply 50lr1
Nevirapine resistance by timing of HIV type 1 infection in infants treated with single-dose nevirapine.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , May 2010: 1405-14
Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , May 2010: 1397-404
Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , March 2010: 898-908
Cross-contamination during processing of dried blood spots used for rapid diagnosis of HIV-1 infection of infants is rare and avoidable.
Journal of virological methods , Feb. 2010: 489-91
Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention.
AIDS research and human retroviruses , Nov. 2009: 1099-106
Virologic and immunologic correlates with the magnitude of antibody responses to the hepatitis A vaccine in HIV-infected children on highly active antiretroviral treatment.
Journal of acquired immune deficiency syndromes (1999) , Sept. 2009: 17-24
Compartmentalization of HIV-1 within the female genital tract is due to monotypic and low-diversity variants not distinct viral populations.
PloS one , Sept. 2009: e7122
Mental health treatment patterns in perinatally HIV-infected youth and controls.
Pediatrics , Aug. 2009: 627-36
Increased detection of HIV-1 drug resistance at time of diagnosis by testing viral DNA with a sensitive assay.
Journal of acquired immune deficiency syndromes (1999) , July 2009: 283-9
Monotypic human immunodeficiency virus type 1 genotypes across the uterine cervix and in blood suggest proliferation of cells with provirus.
Journal of virology , June 2009: 6020-8
Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses.
AIDS (London, England) , May 2009: 923-8
Assessment of mitochondrial toxicity by analysis of mitochondrial protein expression in mononuclear cells.
Cytometry. Part B, Clinical cytometry , May 2009: 181-90
Early postpartum pharmacokinetics of lopinavir initiated intrapartum in Thai women.
Antimicrobial agents and chemotherapy , May 2009: 2189-91
Potential limitation of CCR5 antagonists: drug resistance more often linked to CXCR4-utilizing than to CCR5-utilizing HIV-1.
AIDS (London, England) , Nov. 2008: 2393-5
Transmission cluster of multiclass highly drug-resistant HIV-1 among 9 men who have sex with men in Seattle/King County, WA, 2005-2007.
Journal of acquired immune deficiency syndromes (1999) , Oct. 2008: 205-11
Diminished human immunodeficiency virus type 1 DNA yield from dried blood spots after storage in a humid incubator at 37 degrees C compared to -20 degrees C.
Journal of clinical microbiology , Sept. 2008: 2945-9
Optimization of the oligonucleotide ligation assay, a rapid and inexpensive test for detection of HIV-1 drug resistance mutations, for non-North American variants.
Journal of acquired immune deficiency syndromes (1999) , Aug. 2008: 418-27
Detection of nonnucleoside reverse-transcriptase inhibitor-resistant HIV-1 after discontinuation of virologically suppressive antiretroviral therapy.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America , Aug. 2008: 421-4
Cytomegalovirus and Epstein-Barr virus in breast milk are associated with HIV-1 shedding but not with mastitis.
AIDS (London, England) , July 2008: 1453-60
Structured treatment interruptions (STIs) in HIV-1 infected pediatric populations increases interferon gamma production and reduces viremia.
Vaccine , June 2008: 3086-9
Planned multiple exposures to autologous virus in HIV type 1-infected pediatric populations increases HIV-specific immunity and reduces HIV viremia.
AIDS research and human retroviruses , March 2008: 401-11
Laboratory indicators of mastitis are not associated with elevated HIV-1 DNA loads or predictive of HIV-1 RNA loads in breast milk.
The Journal of infectious diseases , Aug. 2007: 570-6
Methods used to examine compartmentalization of viral populations between the genital tract and peripheral blood.
The Journal of infectious diseases , Aug. 2007: 493-4; author reply 494-5
Effectiveness of antenatal group HIV voluntary counseling and testing services in rural India.
AIDS education and prevention : official publication of the International Society for AIDS Education , June 2007: 187-97
Polymerase chain reaction diagnosis of primary human herpesvirus-6 infection in the acute care setting.
The Journal of pediatrics , Oct. 2006: 480-5
HIV type 1 zidovudine (ZDV) resistance in blood and uterine cervical secretions of pregnant women.
AIDS research and human retroviruses , Sept. 2006: 870-3
Blinded, multicenter comparison of methods to detect a drug-resistant mutant of human immunodeficiency virus type 1 at low frequency.
Journal of clinical microbiology , July 2006: 2612-4
Density-dependent decay in HIV-1 dynamics.
Journal of acquired immune deficiency syndromes (1999) , March 2006: 266-76
Detection and quantification of human immunodeficiency virus type 1 p24 antigen in dried whole blood and plasma on filter paper stored under various conditions.
Journal of clinical microbiology , Aug. 2005: 3901-5
Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.
Journal of virology , Aug. 2005: 9625-34
Model for assessment of proficiency of human immunodeficiency virus type 1 sequencing-based genotypic antiretroviral assays.
Journal of clinical microbiology , Aug. 2005: 3963-70
Immune reconstitution after receipt of highly active antiretroviral therapy in children with advanced or progressive HIV disease and complete or partial viral load response.
The Journal of infectious diseases , July 2005: 296-302
Challenges in the diagnosis and management of neonatal herpes simplex virus encephalitis.
Pediatrics , March 2005: 795-7
A population-based study of primary human herpesvirus 6 infection.
The New England journal of medicine , Feb. 2005: 768-76
Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332.
The Journal of infectious diseases , Dec. 2004: 2167-74
Rapid HIV type 1 testing of women presenting in late pregnancy with unknown HIV status in Lima, Peru.
AIDS research and human retroviruses , Oct. 2004: 1046-52
Persistence of human immunodeficiency virus type 1 subtype B DNA in dried-blood samples on FTA filter paper.
Journal of clinical microbiology , Aug. 2004: 3847-9
Comparison of oligonucleotide ligation assay and consensus sequencing for detection of drug-resistant mutants of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and plasma.
Journal of clinical microbiology , Aug. 2004: 3670-4
Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022.
Journal of acquired immune deficiency syndromes (1999) , July 2004: 772-6
A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection.
The Journal of infectious diseases , June 2004: 1974-82
Understanding HIV-1 drug resistance.
Therapeutic drug monitoring , April 2004: 116-21
Importance and detection of virus reservoirs and compartments of HIV infection.
Current opinion in microbiology , Aug. 2003: 410-6
Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis.
AIDS (London, England) , July 2003: 1631-8
Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy.
Journal of virology , May 2003: 5721-30
Evolutionary indicators of human immunodeficiency virus type 1 reservoirs and compartments.
Journal of virology , May 2003: 5540-6
Effect of cessation of zidovudine prophylaxis to reduce vertical transmission on maternal HIV disease progression and survival.
Journal of acquired immune deficiency syndromes (1999) , Feb. 2003: 170-81
Human immunodeficiency virus drug susceptibility and resistance testing.
The Pediatric infectious disease journal , July 2002: 681-3
Human immunodeficiency virus drug susceptibility and resistance testing.
The Pediatric infectious disease journal , July 2002: 681-3
Efficacy and toxicity of antiretroviral therapy using 4 or more agents: application of a strategy for antiretroviral management in human immunodeficiency virus-infected children.
Archives of pediatrics & adolescent medicine , June 2002: 568-73
Efficacy and toxicity of antiretroviral therapy using 4 or more agents: application of a strategy for antiretroviral management in human immunodeficiency virus-infected children.
Archives of pediatrics & adolescent medicine , June 2002: 568-73
Rapid and sensitive oligonucleotide ligation assay for detection of mutations in human immunodeficiency virus type 1 associated with high-level resistance to protease inhibitors.
Journal of clinical microbiology , April 2002: 1413-9
Case report: primary human herpesvirus-6 associated with an afebrile seizure in a 3-week-old infant.
Journal of medical virology , March 2002: 384-7
T69D/N pol mutation, human immunodeficiency virus type 1 RNA levels, and syncytium-inducing phenotype are associated with CD4 cell depletion during didanosine therapy.
The Journal of infectious diseases , Feb. 2002: 448-55

Presentations

Presentations TitleEventLocationDate
Rapid inexpensive point-of-care assaysGlobal WACh Seminar Series: 2014
HIV Reservoirs and Viral Eradication Transformative Science Group 2013
Strategies Towards HIV CURE for Infected ChildrenWashington, DC 2013
Invited Speaker, XII Congreso de Enfermedades Infecciosas y Tropicales, Lima, Peru 2011
Invited Speaker, NIH US-Japan, HIV Resistance Meeting, Singapore 2010
Invited Speaker, 5th Annual Research Symposium, Seattle Children’s Research Institute 2010
Invited Speaker, 2nd Canada-Colombia Collaborative Research Wkshp HIV, Cali, Colombia 2010
Invited Speaker, HIV Pathogenesis, Prevention and Treatment 2010. Lima, Peru 2010

Research Funding

Grant TitleGrantorAmountAward Date
"A rapid point-of-treatment diagnostic assay for HIV-resistance to 1st-line ART" - R01 AI110375NIH $250,000 annual direct costsMay 1, 2014 - April 30, 2019
"Evaluation of mHealth strategies to optimize adherence and efficacy of PMTCT/ART" - R01 HD080460 (PI: John-Stewart)NIH $11,393 subcontract annual direct costsMay 1, 2014 - April 30, 2019
Mechanisms of Formation and Persistence of Active HIV Reservoirs - R01 AI111806 (PI: Mullins)NIH $114,390 subcontract annual direct costsApril 1, 2014 - March 31, 2019
"International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group" Virology Lab - UM1 AI106716 (PI: Aldrovandi)NIH $95,547 annual direct costsJan. 1, 2014 - Nov. 30, 2020
"University of Washington Center for AIDS Research" (CFAR) - P30 AI027757 (PI: Holmes)NIH $95,547 annual direct costsJune 1, 2013 - May 31, 2015
"Drug-resistance testing in Kenya to improve ART suppression of HIV replication" (PEPFAR) - R01 AI100037NIH $695,729 annual direct costsJune 3, 2012 - May 31, 2015
"Academic Pediatric Infectious Disease" - T32 HD007233NIH $277,930 annual direct costsMay 1, 2012 - April 30, 2017
"HIV-1 evolution in the female genital tract and trafficking in the blood" - R01AI091550.NIH/NIAID $254,817 annual direct costsJan. 21, 2011 - Dec. 31, 2015
"Immunologic and Virologic Events in Early HIV Infection" (SEAPIP) - P01 AI057005 (Mullins).NIH $101,000 annual direct costsJuly 15, 2010 - June 30, 2015
"Low-frequency HIV-1 Drug Resistance Mutations in Primary HIV-1 Infection" - R01 AI078802 (Steckler)NIH $61,594 annual direct costsApril 1, 2009 - June 30, 2015
"International and Domestic Pediatric and Maternal HIV Studies Coordinating Center" - NO1-DK-8-0001 (Melvin).NIH $11,360 annual direct costsDec. 16, 2007 - Nov. 30, 2014
"Occurrence and Outcome of Dual HIV-1 Infection" - R37 AI047734 (Mullins)NIH $4,987 annual direct costsJuly 5, 2005 - March 31, 2015

Primary Office

Seattle Children's Research Institute
JMB - 8 - Infectious Disease
1900 - 9th Ave
Seattle, WA 98101
206-987-2073

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