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Article: Drug repurposing through virtual screening and in vitro validation identifies tigecycline as a novel putative HCV polymerase inhibitor

ElHefnawi, Mahmoud / Jo, Eunji / Tolba, Mahmoud M. / Fares, Mohamed / Yang, Jaewon / Shahbaaz, Mohd / Windisch, Marc P.

Virology. 2022 May, v. 570

2022

Abstract: The repurposing of marketed drugs for new indications is an elegant strategy to quickly and cost-efficiently address unmet medical needs. The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been shown to be a valid drug target. We ... ...

Abstract	The repurposing of marketed drugs for new indications is an elegant strategy to quickly and cost-efficiently address unmet medical needs. The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been shown to be a valid drug target. We performed structure-based virtual screening to assess the off-label utilization of existing drugs as novel HCV inhibitors. The virtual screen showed that tigecycline could potentially dock with high affinity to the palm site of the HCV RdRp. In vitro validation showed that tigecycline had therapeutic indexes (CC₅₀/EC₅₀) greater than 13 and 6.5 against infectious HCV and subgenomic HCV replicons, respectively. Furthermore, tigecycline displayed synergistic activity with sofosbuvir and daclatasvir against HCV. In silico screening identified tigecycline as a putative inhibitor of HCV RdRp, which was validated in vitro and demonstrated synergistic effects in combination with first-line anti-HCV therapies.
Keywords	Hepatitis C virus ; RNA-directed RNA polymerase ; computer simulation ; synergism ; therapeutics ; tigecycline ; virology
Language	English
Dates of publication	2022-05
Size	p. 9-17.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2022.02.006
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Determination of infectious hepatitis B virus particles by an end-point dilution assay identifies a novel class of inhibitors.

Jo, Eunji / Kim, Hyun / König, Alexander / Yang, Jaewon / Yoon, Seung Kew / Windisch, Marc P

Antiviral research

2021 Volume 196, Page(s) 105195

Abstract: The quantification of infectious virus particles is fundamental to perform in vitro virology studies. To determine the number of hepatitis B virus (HBV) genome-containing particles in vitro, the genome equivalents (GEq) are measured using quantitative ... ...

Abstract	The quantification of infectious virus particles is fundamental to perform in vitro virology studies. To determine the number of hepatitis B virus (HBV) genome-containing particles in vitro, the genome equivalents (GEq) are measured using quantitative PCR (qPCR). However, in addition to infectious virions, HBV DNA-containing, non-infectious HBV particles are also produced in vitro, which can lead to an over-estimation of the number of infectious HBV particles when analyzed by qPCR. Here, we establish an end-point dilution assay that can precisely determine the number of infectious HBV particles. The cell-based HBV infection assay uses a 384-well plate format and enables the calculation of the 50% tissue culture infective dose (TCID
MeSH term(s)	Biological Assay/methods ; Cell Culture Techniques/methods ; DNA, Viral/analysis ; Hep G2 Cells ; Hepatitis B/virology ; Hepatitis B virus/genetics ; Hepatitis B virus/isolation & purification ; Hepatocytes/virology ; Humans ; Virion ; Virus Replication
Chemical Substances	DNA, Viral
Language	English
Publishing date	2021-11-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2021.105195
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Article: A Simple and Cost-Effective DNA Preparation Method Suitable for High-Throughput PCR Quantification of Hepatitis B Virus Genomes

Jo, Eunji / Yang, Jaewon / Koenig, Alexander / Yoon, Seung Kew / Windisch, Marc P

Viruses. 2020 Aug. 24, v. 12, no. 9

2020

Abstract: Hepatitis B virus (HBV) is a para-retrovirus that reverse transcribes its pregenomic RNA into relaxed circular DNA inside viral nucleocapsids. The number of HBV genomes produced in vitro is typically quantified using commercial silica-membrane-based ... ...

Abstract	Hepatitis B virus (HBV) is a para-retrovirus that reverse transcribes its pregenomic RNA into relaxed circular DNA inside viral nucleocapsids. The number of HBV genomes produced in vitro is typically quantified using commercial silica-membrane-based nucleic acid purification kits to isolate total DNA followed by HBV-specific quantitative PCR (qPCR). However, despite the convenience of commercial kits, this procedure is costly and time-consuming due to multiple centrifugation steps, which produce unnecessary waste. Here, we report a rapid, cost-effective, and environmentally friendly total DNA preparation method. The assay is based on the simple incubation of detergent and proteinase K with cells or cell-free supernatants to permeabilize cells and disrupt viral particles. After heat inactivation and subsequent centrifugation to clear the lysates, DNA samples are directly subjected to qPCR to quantify HBV genomes. As a proof of concept, the assay was developed in 12-well plates to assess intra- and extracellular HBV genome equivalents (GEqs) of stably viral-replicating cell lines (e.g., HepAD38) and HBV-infected HepG2-NTCP cells, both treated with lamivudine (LMV), an HBV replication inhibitor. Viral DNA was also prepared from the serum of patients chronically infected with HBV. To validate the assay, a representative commercial DNA isolation kit was used side-by-side to isolate intra- and extracellular HBV DNA. Both methods yielded comparable amounts of HBV GEqs with comparable LMV 50% efficient concentration (EC₅₀) values. The assay was subsequently adapted to 96- and 384-well microtiter plates using HepAD38 cells. The EC₅₀ values were comparable to those obtained in 12-well plates. In addition, the calculated coefficient of variation, Z’ values, and assay window demonstrated high reproducibility and quality. We devised a novel, robust, reproducible, high-throughput microtiter plate DNA preparation method suitable for quantifying HBV GEqs by qPCR analysis. This strategy enables rapid and convenient quantitative analysis of multiple viral DNA samples in parallel to investigate intracellular HBV replication and the secretion of DNA-containing viral particles.
Keywords	Hepatitis B virus ; RNA ; analytical kits ; blood serum ; cell lines ; centrifugation ; circular DNA ; cost effectiveness ; detergents ; genome ; heat inactivation ; lamivudine ; median effective concentration ; nucleocapsid ; patients ; peptidase K ; quantitative analysis ; quantitative polymerase chain reaction ; secretion ; transcription (genetics) ; virion ; wastes
Language	English
Dates of publication	2020-0824
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12090928
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Performance of QuantaMatrix Microfluidic Agarose Channel system integrated with mycobacteria growth indicator tube liquid culture

Kim, Hyejin / Lee, Sangyeop / Jo, EunJi / Kim, Suyeoun / Kim, Haeun / Kim, Eun-Geun / Kwon, Sunghoon / Shin, Soyoun

Appl Microbiol Biotechnol. 2021 Aug., v. 105, no. 14-15 p.6059-6072

2021

Abstract: The QuantaMatrix Microfluidic Agarose Channel (QMAC) system was used for rapid drug susceptibility testing (DST). Here, we performed DST using QMAC integrated with the mycobacteria growth indicator tube (MGIT) liquid culture employing a specially ... ...

Abstract	The QuantaMatrix Microfluidic Agarose Channel (QMAC) system was used for rapid drug susceptibility testing (DST). Here, we performed DST using QMAC integrated with the mycobacteria growth indicator tube (MGIT) liquid culture employing a specially designed cross agarose channel for the tuberculosis chip. MGIT-, QMAC-, and Löwenstein–Jensen (LJ)-DSTs were performed using 13 drugs. The protocol for QMAC-DST was optimized using the inoculum obtained after the disaggregation of Mycobacterium tuberculosis clumps in MGIT culture. The completion times of QMAC-DST and MGIT-DST were analyzed, and the results of all three DSTs were compared. Discrepant results were analyzed using line probe assays and DNA sequencing. Nontuberculous mycobacteria were distinguished using the ρ-nitrobenzoic acid inhibition test. The overall agreement rate of QMAT-DST and LJ-DST was 97.0% and that of QMAT-DST and MGIT-DST was 86.3%. An average turnaround time for DST was 5.4 days, which was considerably less than the time required for MGIT-DST. The overall time required to obtain DST results using QMAC-DST integrated with MGIT culture was an average of 18.6 days: 13.2 days for culture and identification and 5.4 days for DST. Hence, QMAC-DST integrated with liquid culture can be used to perform DSTs with short turnaround times and effective detection. KEY POINTS: • QMAC system can simultaneously perform phenotypic DST with 13 anti-TB drugs and PNB. • An optimized DST protocol led to a marked decrease in clumping in MGIT culture. • QMAC system integrated with MGIT liquid culture system reduced the turnaround time.
Keywords	DNA ; Mycobacterium tuberculosis ; agarose ; drugs ; inoculum ; liquids ; phenotype ; tuberculosis
Language	English
Dates of publication	2021-08
Size	p. 6059-6072.
Publishing place	Springer Berlin Heidelberg
Document type	Article ; Online
ZDB-ID	392453-1
ISSN	1432-0614 ; 0171-1741 ; 0175-7598
ISSN (online)	1432-0614
ISSN	0171-1741 ; 0175-7598
DOI	10.1007/s00253-021-11446-0
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Article ; Online: Drug repurposing through virtual screening and in vitro validation identifies tigecycline as a novel putative HCV polymerase inhibitor.

ElHefnawi, Mahmoud / Jo, Eunji / Tolba, Mahmoud M / Fares, Mohamed / Yang, Jaewon / Shahbaaz, Mohd / Windisch, Marc P

Virology

2022 Volume 570, Page(s) 9–17

Abstract	The repurposing of marketed drugs for new indications is an elegant strategy to quickly and cost-efficiently address unmet medical needs. The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been shown to be a valid drug target. We performed structure-based virtual screening to assess the off-label utilization of existing drugs as novel HCV inhibitors. The virtual screen showed that tigecycline could potentially dock with high affinity to the palm site of the HCV RdRp. In vitro validation showed that tigecycline had therapeutic indexes (CC
MeSH term(s)	Antiviral Agents/pharmacology ; Drug Repositioning ; Hepacivirus/genetics ; Hepatitis C ; Humans ; RNA-Dependent RNA Polymerase/genetics ; Tigecycline/pharmacology ; Viral Nonstructural Proteins/genetics ; Virus Replication
Chemical Substances	Antiviral Agents ; Viral Nonstructural Proteins ; Tigecycline (70JE2N95KR) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2022-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2022.02.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Selected ginsenosides interfere efficiently with hepatitis B virus mRNA expression levels and suppress viral surface antigen secretion

Duraisamy, Ganesh Selvaraj / Jo, Eunji / Huvarová, Ivana / Park, Kyu-Ho P. / Heger, Zbyněk / Adam, Vojtěch / Ruzek, Daniel / Windisch, Marc P. / Miller, Andrew D.

Heliyon. 2022 Sept., v. 8, no. 9 p.e10465-

2022

Abstract: Ginsenosides are a class of natural steroid glycosides and triterpene saponins found in Panax ginseng. After screening of a commercial ginsenoside compound library for low cellular cytotoxicity and the ability to mediate efficient reductions in hepatitis ...

Abstract	Ginsenosides are a class of natural steroid glycosides and triterpene saponins found in Panax ginseng. After screening of a commercial ginsenoside compound library for low cellular cytotoxicity and the ability to mediate efficient reductions in hepatitis B virus (HBV) mRNA expression levels in HepG2.2.15 cells, three ginsenosides (Rg6, Rh4, and Rb3) are selected. Thereafter, using the same cellular model, all three ginsenosides are shown to mediate efficient, selective inhibition of HBV mRNA expression levels, and also interfere with the secretion of both HBV particles and hepatitis B surface antigen (HBsAg). Drug combination studies are performed in both HepG2.2.15 and HBV-infected HepG2-NTCPsec+ cell models with the selected ginsenosides and lamivudine (LMV), a nucleoside analogue used to treat chronic hepatitis B (CHB) infections. These studies, involving RT-qPCR and ELISA, suggest that Rh4/LMV combinations in particular act synergistically to inhibit the secretion of HBV particles and HBsAg. Therefore, on the assumption that appropriate in vivo data are in future agreement, Rh4, in particular, might be used in combination with nucleoside/nucleotide analogues (NUCs) to devise an effective, cost-efficient combination therapy for the treatment of patients with CHB infections.
Keywords	Hepatitis B virus ; Panax ginseng ; chronic hepatitis B ; cost effectiveness ; cytotoxicity ; drugs ; gene expression ; ginsenosides ; hepatitis B antigens ; lamivudine ; models ; secretion ; surface antigens ; therapeutics ; triterpenoid saponins ; Ginsenoside ; Nucleoside/nucleotide analogues ; Hepatitis B surface protein ; Hepatitis B surface antigen ; Chronic hepatitis B virus ; Drug combinations
Language	English
Dates of publication	2022-09
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2022.e10465
Database	NAL-Catalogue (AGRICOLA)

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Article: Effects of thermal aging on the electronic and structural properties of Pt-Pd and toluene oxidation activity

Kim, Seung-Ik / Im, Mintaek / Jo, Eunji / Jang, Haneul / Jang, Seo Yun / Kim, Dong Woo / Kim, Ki Wang / Heo, Iljeong / Kim, Young Jin / Lee, Jin Hee

Science of the total environment. 2022 July 14,

2022

Abstract: Catalytic oxidation is a feasible method for remediating volatile organic compounds (VOCs), due to its lower energy consumption and mineralization of VOCs into H₂O and CO₂. Noble metal-based catalysts are preferred for the catalytic oxidation of VOCs ... ...

Abstract	Catalytic oxidation is a feasible method for remediating volatile organic compounds (VOCs), due to its lower energy consumption and mineralization of VOCs into H₂O and CO₂. Noble metal-based catalysts are preferred for the catalytic oxidation of VOCs because of their superior activity, but they are usually deactivated by thermal aging which sinters the metal particles. Here, we report that Pt-Pd/Al₂O₃ thermally aged at 700–900 °C in air showed enhanced catalytic activity for toluene oxidation in humid conditions. There were electronic and structural changes in the thermally aged Pt-Pd/Al₂O₃, as confirmed by numerous analyses. Both Pt and Pd existed in a metallic rather than oxidized state without additional reduction steps. The noble metal particles were assembled to form Pt-Pd alloy, in the form of isolated Pd atoms surrounded by Pt atoms. This specific alloy structure was found to be crucial to the observed enhancement in catalytic toluene oxidation at low temperature.
Keywords	air ; alloys ; carbon dioxide ; catalytic activity ; energy ; environment ; mineralization ; oxidation ; temperature ; toluene ; volatile organic compounds
Language	English
Dates of publication	2022-0714
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2022.157482
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Article ; Online: A Simple and Cost-Effective DNA Preparation Method Suitable for High-Throughput PCR Quantification of Hepatitis B Virus Genomes.

Jo, Eunji / Yang, Jaewon / Koenig, Alexander / Yoon, Seung Kew / Windisch, Marc P

Viruses

2020 Volume 12, Issue 9

Abstract	Hepatitis B virus (HBV) is a para-retrovirus that reverse transcribes its pregenomic RNA into relaxed circular DNA inside viral nucleocapsids. The number of HBV genomes produced in vitro is typically quantified using commercial silica-membrane-based nucleic acid purification kits to isolate total DNA followed by HBV-specific quantitative PCR (qPCR). However, despite the convenience of commercial kits, this procedure is costly and time-consuming due to multiple centrifugation steps, which produce unnecessary waste. Here, we report a rapid, cost-effective, and environmentally friendly total DNA preparation method. The assay is based on the simple incubation of detergent and proteinase K with cells or cell-free supernatants to permeabilize cells and disrupt viral particles. After heat inactivation and subsequent centrifugation to clear the lysates, DNA samples are directly subjected to qPCR to quantify HBV genomes. As a proof of concept, the assay was developed in 12-well plates to assess intra- and extracellular HBV genome equivalents (GEqs) of stably viral-replicating cell lines (e.g., HepAD38) and HBV-infected HepG2-NTCP cells, both treated with lamivudine (LMV), an HBV replication inhibitor. Viral DNA was also prepared from the serum of patients chronically infected with HBV. To validate the assay, a representative commercial DNA isolation kit was used side-by-side to isolate intra- and extracellular HBV DNA. Both methods yielded comparable amounts of HBV GEqs with comparable LMV 50% efficient concentration (EC
MeSH term(s)	Cell Line ; Cost-Benefit Analysis ; DNA, Viral/analysis ; DNA, Viral/isolation & purification ; Genome, Viral/genetics ; Hepatitis B/virology ; Hepatitis B virus/genetics ; Hepatitis B virus/isolation & purification ; Humans ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Virology/economics ; Virology/methods
Chemical Substances	DNA, Viral
Language	English
Publishing date	2020-08-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12090928
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Outcomes Among Minority Patients With Metastatic Colorectal Cancer in a Safety-net Health Care System.

Lau-Min, Kelsey / Prakash, Preeti / Jo, Eunji / Thrift, Aaron P / Hilsenbeck, Susan / Musher, Benjamin L

Clinical colorectal cancer

2020 Volume 19, Issue 2, Page(s) e49–e57

Abstract: Background: Metastatic colorectal cancer (CRC) outcomes continue to improve, but they vary significantly by race and ethnicity. We hypothesize that these disparities arise from unequal access to care.: Materials and methods: The Harris Health System ( ...

Abstract	Background: Metastatic colorectal cancer (CRC) outcomes continue to improve, but they vary significantly by race and ethnicity. We hypothesize that these disparities arise from unequal access to care. Materials and methods: The Harris Health System (HHS) is an integrated health delivery network that provides medical care to the underserved, predominantly minority population of Harris County, Texas. As the largest HHS facility and an affiliate of Baylor College of Medicine's Dan L. Duncan Comprehensive Cancer Center, Ben Taub Hospital (BTH) delivers cancer care through multidisciplinary subspecialty that prioritize access to care, adherence to evidence-based clinical pathways, integration of supportive services, and mitigation of financial toxicity. We performed a retrospective analysis of minority patients diagnosed with and treated for metastatic CRC at BTH between January 2010 and December 2012. Kaplan-Meier survival curves were compared with survival curves from randomized control trials reported during that time period. Results: We identified 103 patients; 40% were black, 49% were Hispanic, and 12% were Asian or Middle Eastern. Thirty-five percent reported a language other than English as their preferred language. Seventy-four percent of patients with documented coverage status were uninsured. Eighty-four percent of patients received standard chemotherapy with a clinician-reported response rate of 63%. Overall survival for BTH patients undergoing chemotherapy was superior to that of subjects enrolled in the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial (median, 24.0 vs. 19.9 months; P = .014). Conclusion: HHS provides a health delivery infrastructure through which minority patients with socioeconomic challenges experience clinical outcomes comparable with highly selected patients enrolled in randomized control trials. Efforts to resolve CRC disparities should focus on improving access of at-risk populations to high-quality comprehensive cancer care.
MeSH term(s)	Academic Medical Centers/economics ; Academic Medical Centers/statistics & numerical data ; Adult ; African Americans/statistics & numerical data ; Aged ; Asian Americans/statistics & numerical data ; Colorectal Neoplasms/economics ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/therapy ; European Continental Ancestry Group/statistics & numerical data ; Female ; Healthcare Disparities/statistics & numerical data ; Hispanic Americans/statistics & numerical data ; Humans ; Kaplan-Meier Estimate ; Male ; Medically Uninsured/statistics & numerical data ; Middle Aged ; Minority Groups/statistics & numerical data ; Patient Acceptance of Health Care/statistics & numerical data ; Randomized Controlled Trials as Topic/statistics & numerical data ; Retrospective Studies ; Safety-net Providers/economics ; Safety-net Providers/statistics & numerical data ; Socioeconomic Factors
Language	English
Publishing date	2020-01-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2112638-0
ISSN	1938-0674 ; 1533-0028
ISSN (online)	1938-0674
ISSN	1533-0028
DOI	10.1016/j.clcc.2019.09.002
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Zs.A 5798: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A multicellular liver organoid model for investigating hepatitis C virus infection and nonalcoholic fatty liver disease progression.

Lee, Jaeseo / Gil, Dayeon / Park, Hyeyeon / Lee, Youngsun / Mun, Seon Ju / Shin, Yongbo / Jo, Eunji / Windisch, Marc P / Kim, Jung-Hyun / Son, Myung Jin

Hepatology (Baltimore, Md.)

2023

Abstract: Background and aims: HCV infection can be successfully managed with antiviral therapies; however, progression to chronic liver disease states, including NAFLD, is common. There is currently no reliable in vitro model for investigating host-viral ... ...

Abstract	Background and aims: HCV infection can be successfully managed with antiviral therapies; however, progression to chronic liver disease states, including NAFLD, is common. There is currently no reliable in vitro model for investigating host-viral interactions underlying the link between HCV and NAFLD; although liver organoids (LOs) show promise, they currently lack nonparenchymal cells, which are key to modeling disease progression. Approach and results: Here, we present a novel, multicellular LO model using a coculture system of macrophages and LOs differentiated from the same human pluripotent stem cells (PSCs). The cocultured macrophages shifted toward a Kupffer-like cell type, the liver-resident macrophages present in vivo , providing a suitable model for investigating NAFLD pathogenesis. With this multicellular Kupffer-like cell-containing LO model, we found that HCV infection led to lipid accumulation in LOs by upregulating host lipogenesis, which was more marked with macrophage coculture. Reciprocally, long-term treatment of LOs with fatty acids upregulated HCV amplification and promoted inflammation and fibrosis. Notably, in our Kupffer-like cell-containing LO model, the effects of 3 drugs for NASH that have reached phase 3 clinical trials exhibited consistent results with the clinical outcomes. Conclusions: Taken together, we introduced a multicellular LO model consisting of hepatocytes, Kupffer-like cells, and HSCs, which recapitulated host-virus intercommunication and intercellular interactions. With this novel model, we present a physiologically relevant system for the investigation of NAFLD progression in patients with HCV.
Language	English
Publishing date	2023-11-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1097/HEP.0000000000000683
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