1921
Volume 103, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with . Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5–5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.19-0846
2020-04-20
2020-09-28
Loading full text...

Full text loading...

/deliver/fulltext/14761645/103/1/tpmd190846.html?itemId=/content/journals/10.4269/ajtmh.19-0846&mimeType=html&fmt=ahah

References

  1. McCarthy JS et al., 2016. Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development. Antimicrob Agents Chemother 60: 36693675.
    [Google Scholar]
  2. Weaver RJ, Valentin JP, 2019. Today’s challenges to de-risk and predict drug safety in human “mind-the-gap”. Toxicol Sci 167: 307321.
    [Google Scholar]
  3. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), 2009. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical valuation. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/Guidances/UCM174090.pdf. Accessed September 23, 2018.
    [Google Scholar]
  4. McCarthy JS et al., 2011. A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS One 6: e21914.
    [Google Scholar]
  5. Collins KA et al., 2018. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest 128: 15511562.
    [Google Scholar]
  6. Cheng Q, Lawrence G, Reed C, Stowers A, Ranford-Cartwright L, Creasey A, Carter R, Saul A, 1997. Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines. Am J Trop Med Hyg 57: 495500.
    [Google Scholar]
  7. Rockett RJ, Tozer SJ, Peatey C, Bialasiewicz S, Whiley DM, Nissen MD, Trenholme K, Mc Carthy JS, Sloots TP, 2011. A real-time, quantitative PCR method using hydrolysis probes for the monitoring of Plasmodium falciparum load in experimentally infected human volunteers. Malar J 10: 48.
    [Google Scholar]
  8. Laterza OF, Scott MG, Garrett-Engele PW, Korenblat KM, Lockwood CM, 2013. Circulating miR-122 as a potential biomarker of liver disease. Biomark Med 7: 205210.
    [Google Scholar]
  9. World Health Organization, 1979. WHO Handbook for Reporting Results of Cancer Treatment. Available at: http://apps.who.int/iris/bitstream/handle/10665/37200/WHO_OFFSET_48.pdf?sequence=1&isAllowed=y. Accessed January 16, 2019.
    [Google Scholar]
  10. Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D, 2014. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev: CD010927.
    [Google Scholar]
  11. Pettersson J, Hindorf U, Persson P, Bengtsson T, Malmqvist U, Werkstrom V, Ekelund M, 2008. Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol 65: 253259.
    [Google Scholar]
  12. Aithal GP, Grove JI, 2015. Genome-wide association studies in drug-induced liver injury: step change in understanding the pathogenesis. Semin Liver Dis 35: 421431.
    [Google Scholar]
  13. Yuliwulandari R et al., 2016. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet 61: 533537.
    [Google Scholar]
  14. Aithal GP, 2015. Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice. Liver Int 35: 18011808.
    [Google Scholar]
  15. Chalasani N et al., 2015. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 148: 13401352 e7.
    [Google Scholar]
  16. Regev A et al., 2019. Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 49: 702713.
    [Google Scholar]
  17. Amacher DE, 2014. Female gender as a susceptibility factor for drug-induced liver injury. Hum Exp Toxicol 33: 928939.
    [Google Scholar]
  18. Liss G, Rattan S, Lewis JH, 2010. Predicting and preventing acute drug-induced liver injury: what’s new in 2010? Expert Opin Drug Metab Toxicol 6: 10471061.
    [Google Scholar]
  19. de Mast Q et al., 2009. Mild increases in serum hepcidin and interleukin-6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection. Br J Haematol 145: 657664.
    [Google Scholar]
  20. Viriyavejakul P, Khachonsaksumet V, Punsawad C, 2014. Liver changes in severe Plasmodium falciparum malaria: histopathology, apoptosis and nuclear factor kappa B expression. Malar J 13: 106.
    [Google Scholar]
  21. Anand AC, Puri P, 2005. Jaundice in malaria. J Gastroenterol Hepatol 20: 13221332.
    [Google Scholar]
  22. Woodford J, Shanks G, Griffin P, Chalon S, McCarthy J, 2018. The dynamics of liver function test abnormalities following malaria infection: a retrospective observational study. Am J Trop Med Hyg 98: 11131119.
    [Google Scholar]
  23. Reuling IJ et al., 2018. Liver injury in uncomplicated malaria is an overlooked phenomenon: an observational study. EBioMedicine 36: 131139.
    [Google Scholar]
  24. James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM, 2009. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 37: 17791784.
    [Google Scholar]
  25. Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC, 2014. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol 15: 39.
    [Google Scholar]
  26. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC, 2006. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 296: 8793.
    [Google Scholar]
  27. Maddox JF, Amuzie CJ, Li M, Newport SW, Sparkenbaugh E, Cuff CF, Pestka JJ, Cantor GH, Roth RA, Ganey PE, 2010. Bacterial- and viral-induced inflammation increases sensitivity to acetaminophen hepatotoxicity. J Toxicol Environ Health A 73: 5873.
    [Google Scholar]
  28. Ganey PE, Luyendyk JP, Maddox JF, Roth RA, 2004. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact 150: 3551.
    [Google Scholar]
  29. Lu J, Jones AD, Harkema JR, Roth RA, Ganey PE, 2012. Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha. Toxicol Sci 125: 126133.
    [Google Scholar]
  30. Pryce J, Hine P, 2019. Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev 1: CD006404.
    [Google Scholar]
  31. West African Network for Clinical Trials of Antimalarial D, 2018. Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet 391: 13781390.
    [Google Scholar]
  32. Cosgriff TM, Boudreau EF, Pamplin CL 3rd, Berman JD, Shmuklarsky MJ, Canfield CJ, 1984. Evaluation of the 4-pyridinemethanol WR 180,409 (enpiroline) in the treatment of induced Plasmodium falciparum infections in healthy, non-immune subjects. Am J Trop Med Hyg 33: 767771.
    [Google Scholar]
  33. Cosgriff TM, Boudreau EF, Pamplin CL, Doberstyn EB, Desjardins RE, Canfield CJ, 1982. Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669). Am J Trop Med Hyg 31: 10751079.
    [Google Scholar]
  34. Rinehart J, Arnold J, Canfield CJ, 1976. Evaluation of two phenanthrenemethanols for antimalarial activity in man: WR 122,455 and WR 171,669. Am J Trop Med Hyg 25: 769774.
    [Google Scholar]
  35. Arnold JD, Martin DC, Carson PE, Rieckmann KH, Willerson D Jr., Clyde DF, Miller RM, 1973. A phenanthrene methanol (WR 33063) for treatment of acute malaria. Antimicrob Agents Chemother 3: 207213.
    [Google Scholar]
  36. McNamara JV, Rieckmann KH, Frischer H, Stockert TA, Carson PE, Powell RD, 1967. Acquired decrease in sensitivity to quinine observed during studies with a strain of chloroquine-resistant Plasmodium falciparum. Ann Trop Med Parasitol 61: 386395.
    [Google Scholar]
  37. Rieckmann KH, McNamara JV, Frischer H, Stockert TA, Carson PE, Powell RD, 1968. Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum. Bull World Health Organ 38: 625632.
    [Google Scholar]
  38. Rieckmann KH, Powell RD, McNamara JV, Willerson D Jr., Lass L, Frischer H, Carson PE, 1971. Effects of tetracycline against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum. Am J Trop Med Hyg 20: 811815.
    [Google Scholar]
  39. Williams RL, Trenholme GM, Carson PE, Frischer H, Rieckmann KH, 1978. The influence of acetylator phenotype on the response to sulfalene in individuals with chloroquine-resistant falciparum malaria. Am J Trop Med Hyg 27: 226231.
    [Google Scholar]
  40. Williams RL, Trenholme GM, Carson PE, Frischer H, Rieckmann KH, 1975. Acetylator phenotype and response of individuals infected with a chloroquine-resistant strain of Plasmodium falciparum to sulfalene and pyrimethamine. Am J Trop Med Hyg 24: 734739.
    [Google Scholar]
  41. Trenholme CM, Williams RL, Desjardins RE, Frischer H, Carson PE, Rieckmann KH, Canfield CJ, 1975. Mefloquine (WR 142,490) in the treatment of human malaria. Science 190: 792794.
    [Google Scholar]
  42. Martin DC, Arnold JD, Clyde DF, al-Ibrahim M, Carson PE, Rieckmann KH, Willerson D Jr., 1973. A quinoline methanol (WR 30090) for treatment of acute malaria. Antimicrob Agents Chemother 3: 214219.
    [Google Scholar]
  43. Powell RD, McNamara JV, 1970. Infection with chloroquine-resistant Plasmodium falciparum in man: prepatent periods, incubation periods, and relationships between parasitemia and the onset of fever in nonimmune persons. Ann N Y Acad Sci 174: 10271041.
    [Google Scholar]
  44. Church LW et al., 1997. Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. J Infect Dis 175: 915920.
    [Google Scholar]
  45. Verhage DF, Telgt DS, Bousema JT, Hermsen CC, van Gemert GJ, van der Meer JW, Sauerwein RW, 2005. Clinical outcome of experimental human malaria induced by Plasmodium falciparum-infected mosquitoes. Neth J Med 63: 5258.
    [Google Scholar]
  46. Epstein JE, Rao S, Williams F, Freilich D, Luke T, Sedegah M, de la Vega P, Sacci J, Richie TL, Hoffman SL, 2007. Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update. J Infect Dis 196: 145154.
    [Google Scholar]
  47. Roestenberg M, de Vlas SJ, Nieman AE, Sauerwein RW, Hermsen CC, 2012. Efficacy of preerythrocytic and blood-stage malaria vaccines can be assessed in small sporozoite challenge trials in human volunteers. J Infect Dis 206: 319323.
    [Google Scholar]
  48. Rampling T et al., 2018. Safety and efficacy of novel malaria vaccine regimens of RTS,S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP. NPJ Vaccines 3: 49.
    [Google Scholar]
  49. Brueckner RP, Coster T, Wesche DL, Shmuklarsky M, Schuster BG, 1998. Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial. Antimicrob Agents Chemother 42: 12931294.
    [Google Scholar]
  50. Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P, 1999. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 60: 831836.
    [Google Scholar]
  51. Berman JD, Nielsen R, Chulay JD, Dowler M, Kain KC, Kester KE, Williams J, Whelen AC, Shmuklarsky MJ, 2001. Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model. Trans R Soc Trop Med Hyg 95: 429432.
    [Google Scholar]
  52. Deye GA et al., 2012. Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of Plasmodium falciparum malaria in a human challenge model. Clin Infect Dis 54: 232239.
    [Google Scholar]
  53. Willerson D Jr., Rieckmann KH, Kass L, Carson PE, Frischer H, Bowman JE, 1972. The chemoprophylactic use of diformyl diaminodiphenyl sulfone (DFD) in falciparum malaria. Am J Trop Med Hyg 21: 138143.
    [Google Scholar]
  54. Willerson D Jr., Rieckmann KH, Carson PE, Frischer H, 1972. Effects of minocycline against chloroquine-resistant falciparum malaria. Am J Trop Med Hyg 21: 857862.
    [Google Scholar]
  55. Nyunt MM, Hendrix CW, Bakshi RP, Kumar N, Shapiro TA, 2009. Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites. Am J Trop Med Hyg 80: 528535.
    [Google Scholar]
  56. Rieckmann KH, McNamara JV, Kass L, Powell RD, 1969. Gametocytocidal and sporontocidal effects of primaquine upon two strains of Plasmodium falciparum. Mil Med 134: 802819.
    [Google Scholar]
  57. Rieckmann KH, Trenholme GM, Williams RL, Carson PE, Frischer H, Desjardins RE, 1974. Prophylactic activity of mefloquine hydrochloride (WR 142490) in drug-resistant malaria. Bull World Health Organ 51: 375377.
    [Google Scholar]
  58. Murphy SC et al., 2017. A randomized trial of the prophylactic activity of DSM265 against pre-erythrocytic Plasmodium falciparum controlled human malaria infection by mosquito bites and direct venous inoculation. J Infect Dis 217: 693702.
    [Google Scholar]
  59. Reuling IJ et al., 2018. A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. Elife 7: e31549.
    [Google Scholar]
  60. Talley AK et al., 2014. Safety and comparability of controlled human Plasmodium falciparum infection by mosquito bite in malaria-naive subjects at a new facility for sporozoite challenge. PLoS One 9: e109654.
    [Google Scholar]
  61. Laurens MB et al., 2013. Successful human infection with P. falciparum using three aseptic Anopheles stephensi mosquitoes: a new model for controlled human malaria infection. PLoS One 8: e68969.
    [Google Scholar]
  62. Lyke KE et al., 2010. Plasmodium falciparum malaria challenge by the bite of aseptic Anopheles stephensi mosquitoes: results of a randomized infectivity trial. PLoS One 5: e13490.
    [Google Scholar]
  63. Roestenberg M, O’Hara GA, Duncan CJ, Epstein JE, Edwards NJ, Scholzen A, van der Ven AJ, Hermsen CC, Hill AV, Sauerwein RW, 2012. Comparison of clinical and parasitological data from controlled human malaria infection trials. PLoS One 7: e38434.
    [Google Scholar]
  64. Hermsen CC, de Vlas SJ, van Gemert GJ, Telgt DS, Verhage DF, Sauerwein RW, 2004. Testing vaccines in human experimental malaria: statistical analysis of parasitemia measured by a quantitative real-time polymerase chain reaction. Am J Trop Med Hyg 71: 196201.
    [Google Scholar]
  65. Langenberg MCC et al., 2018. Controlled Human malaria infection with graded numbers of Plasmodium falciparum NF135.C10- or NF166.C8-infected mosquitoes. Am J Trop Med Hyg 99: 709712.
    [Google Scholar]
  66. Gomez-Perez GP et al., 2015. Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naive volunteers: effect of injection volume and dose on infectivity rates. Malar J 14: 306.
    [Google Scholar]
  67. Roestenberg M et al., 2013. Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg 88: 513.
    [Google Scholar]
  68. Sheehy SH et al., 2013. Optimising controlled human malaria infection studies using cryopreserved P. falciparum parasites administered by needle and syringe. PLoS One 8: e65960.
    [Google Scholar]
  69. Shekalaghe S et al., 2014. Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg 91: 471480.
    [Google Scholar]
  70. Bastiaens GJ et al., 2016. Safety, immunogenicity, and protective efficacy of intradermal immunization with aseptic, purified, cryopreserved Plasmodium falciparum sporozoites in volunteers under chloroquine prophylaxis: a randomized controlled trial. Am J Trop Med Hyg 94: 663673.
    [Google Scholar]
  71. Sulyok M et al., 2017. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis 17: 636644.
    [Google Scholar]
  72. Hodgson SH et al., 2014. Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection. Front Microbiol 5: 686.
    [Google Scholar]
  73. Mordmuller B et al., 2015. Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J 14: 117.
    [Google Scholar]
  74. Lyke KE et al., 2015. Optimizing intradermal administration of cryopreserved Plasmodium falciparum sporozoites in controlled human malaria infection. Am J Trop Med Hyg 93: 12741284.
    [Google Scholar]
  75. Obiero JM et al., 2015. Impact of malaria preexposure on antiparasite cellular and humoral immune responses after controlled human malaria infection. Infect Immun 83: 21852196.
    [Google Scholar]
  76. Hall CE et al., 2018. Mosquito-bite induced controlled human malaria infection with P. vivax or P. falciparum generates immune responses to homologous and heterologous preerythrocytic and erythrocytic antigens. Infect Immun 87: e00541-18.
    [Google Scholar]
  77. Lell B et al., 2018. Impact of sickle cell trait and naturally acquired immunity on uncomplicated malaria after controlled human malaria infection in adults in Gabon. Am J Trop Med Hyg 98: 508515.
    [Google Scholar]
  78. Low LM et al., 2019. Controlled infection immunization using delayed death drug treatment elicits protective immune responses to blood-stage malaria parasites. Infect Immun 87: e00587-18.
    [Google Scholar]
  79. Oh RC, Hustead TR, Ali SM, Pantsari MW, 2017. Mildly elevated liver transaminase levels: causes and evaluation. Am Fam Physician 96: 709715.
    [Google Scholar]
  80. Krishna S, Pukrittayakamee S, Supanaranond W, ter Kuile F, Ruprah M, Sura T, White NJ, 1995. Fever in uncomplicated Plasmodium falciparum malaria: randomized double-‘blind’ comparison of ibuprofen and paracetamol treatment. Trans R Soc Trop Med Hyg 89: 507509.
    [Google Scholar]
  81. Rainsford KD, Bjarnason I, 2012. NSAIDs: take with food or after fasting? J Pharm Pharmacol 64: 465469.
    [Google Scholar]
  82. United States National Library of Medicine, Drug record: Ibuprofen. Available at: https://livertox.nlm.nih.gov/Ibuprofen.htm. Accessed September 24, 2018.
    [Google Scholar]
  83. Douros A, Bronder E, Klimpel A, Erley C, Garbe E, Kreutz R, 2018. Drug-induced kidney injury: a large case series from the Berlin case-control surveillance study. Clin Nephrol 89: 1826.
    [Google Scholar]
  84. Church RJ et al., 2019. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: an international collaborative effort. Hepatology 69: 760773.
    [Google Scholar]
  85. European Medicines Agency, 2016. Letter of Support for Drug-Induced Liver Injury (DILI) Biomarker. Available at: https://www.ema.europa.eu/en/documents/other/letter-support-drug-induced-liver-injury-dili-biomarker_en.pdf. Accessed July 11, 2019.
    [Google Scholar]
  86. Food and Drug Administration, 2016. Letter of Support for Drug-Induced Liver Injury (DJU) Biomarker(s) Available at: https://www.fda.gov/media/99856/download. Accessed July 11, 2019.
    [Google Scholar]
  87. Merz M, Lee KR, Kullak-Ublick GA, Brueckner A, Watkins PB, 2014. Methodology to assess clinical liver safety data. Drug Saf 37 (Suppl 1): S33S45.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.19-0846
Loading
/content/journals/10.4269/ajtmh.19-0846
Loading

Data & Media loading...

Supplemental data, tables, and figures

  • Received : 11 Nov 2019
  • Accepted : 09 Mar 2020
  • Published online : 20 Apr 2020
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error