Login Register Cart 0
Generic placeholder image

Infectious Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Ameliorating Gonorrhea: Recent Therapeutic Adaptations and Scope to Improve its Prevailing Condition

Author(s): Munyaradzi Amon Bishi, Palwinder Kaur*, Manish Vyas* and Sandeep Sharma

Volume 24, Issue 5, 2024

Published on: 18 January, 2024

Article ID: e180124225807 Pages: 15

DOI: 10.2174/0118715265258305231124105334

Price: $65

Abstract

Background: Gonorrhea is a sexually transmitted infection (STI) caused by the bacteria Neisseria gonorrhoeae. According to recent research, the prevalence of gonorrhea has been increasing in many parts of the world, with some areas reporting high rates of antibiotic resistance. In the United States, the Centers for Disease Control and Prevention (CDC) reported that the number of reported gonorrhea cases increased by 56% between 2015 and 2019. Globally, the World Health Organization (WHO) estimated that there were 87 million new cases of gonorrhea in 2016, with the highest burden of infection in low- and middle-income countries. Research has also shown that gonorrhea is becoming increasingly resistant to conventional antibiotics, increasing the prevalence of gonorrhea. This raises concerns and challenges in disease management.

Objectives: The present review gives updated insight on the current state of the disease, challenges, and shortcomings of existing approaches along with the modern and alternative direction like vaccine development, its challenges, and scope to confront the existing state of drug resistance and increased rate of incidence. Alternative strategies like immunotherapy and phage therapy along with recent antibiotics researched for the treatment of gonorrhea.

Conclusion: The review provides a thorough insight into the current state of the disease and various available methods used currently and recommended by WHO. To overcome disease prevalence, various alternate therapies are coming into the limelight. However, scientists and researchers show a lack of interest in the drug development and research of gonorrhea, due to less commercial scope, lack of funding, and limited scope in the scientific scenario. These hurdles need to be overcome to meet the WHO vision of reducing gonorrhea by 90% by 2030. So, there is a need to optimize the drug therapy (optimizing dosing schedule, and precision monitoring) to reduce the chance of drug resistance. Also, there is a wide scope for drug and therapeutic system development.

Graphical Abstract

[1]
Skerlev M. Čulav-Košćak I. Gonorrhea: New challenges. Clin Dermatol 2014; 32(2): 275-81.
[http://dx.doi.org/10.1016/j.clindermatol.2013.08.010] [PMID: 24559563]
[2]
Unemo M, Seifert HS, Hook EW, Hawkes S, Ndowa F, Dillon J A R. Gonorrhoea. Nat Rev Dis Primers 2019; 5(1): 79.
[3]
Unemo M, Golparian D, Eyre DW. Antimicrobial resistance in neisseria gonorrhoeae and treatment of gonorrhea. Methods Mol Biol 2019; 1997: 37-58.
[http://dx.doi.org/10.1007/978-1-4939-9496-0_3] [PMID: 31119616]
[4]
Yang J, Dhital S, Naderer T. Efficacy and safety of injectable and oral antibiotics in treating gonorrhea: A systematic review and network meta-analysis. J Clin Med 2019; 8(12): 2182.
[http://dx.doi.org/10.3390/jcm8122182] [PMID: 31835724]
[5]
Derbie A, Mekonnen D, Woldeamanuel Y, Abebe T. Azithromycin resistant gonococci: a literature review. Antimicrob Resist Infect Control 2020; 9(1): 138.
[http://dx.doi.org/10.1186/s13756-020-00805-7] [PMID: 32811545]
[6]
Kirkcaldy RD, Weston E, Segurado AC, Hughes G. Epidemiology of gonorrhoea: A global perspective. Sex Health 2019; 16(5): 401-11.
[http://dx.doi.org/10.1071/SH19061] [PMID: 31505159]
[7]
Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: Global prevalence and incidence estimates, 2016. Bull World Health Organ 2019; 97(8): 548-562P.
[http://dx.doi.org/10.2471/BLT.18.228486] [PMID: 31384073]
[8]
da Costa-Lourenço APR, Barros Dos Santos KT, Moreira BM, Fracalanzza SEL, Bonelli RR. Antimicrobial resistance in Neisseria gonorrhoeae: History, molecular mechanisms and epidemiological aspects of an emerging global threat. Brazilian J Microbiol 2017; 48: 617-28.
[9]
Whelan J, Abbing-Karahagopian V, Serino L, Unemo M. Gonorrhoea: a systematic review of prevalence reporting globally. BMC Infect Dis 2021; 21(1): 1152.
[http://dx.doi.org/10.1186/s12879-021-06381-4] [PMID: 34763670]
[10]
Weston EJ, Workowski K, Torrone E, Weinstock H, Stenger MR. Adherence to CDC Recommendations for the Treatment of Uncomplicated Gonorrhea — STD Surveillance Network, United States, 2016. MMWR Morb Mortal Wkly Rep 2018; 67(16): 473-6.
[http://dx.doi.org/10.15585/mmwr.mm6716a4] [PMID: 29698384]
[11]
Zheng Y, Yu Q, Lin Y, et al. Global burden and trends of sexually transmitted infections from 1990 to 2019: an observational trend study. Lancet Infect Dis 2022; 22(4): 541-51.
[http://dx.doi.org/10.1016/S1473-3099(21)00448-5] [PMID: 34942091]
[12]
Peters RPH, Chico RM, Rowley J, Low N. Estimating the global burden of sexually transmitted infections. Lancet Infect Dis 2022; 22(8): 1112-3.
[http://dx.doi.org/10.1016/S1473-3099(22)00415-7] [PMID: 35870456]
[13]
Chesson HW, Mayaud P, Aral SO. Sexually transmitted infections: Impact and cost-effectiveness of prevention. Washington, DC: The International Bank for Reconstruction and Development 2017.
[14]
Sharma M, Rewari BB, Aditama TY, Turlapati P, Dallabetta G, Steen R. Control of sexually transmitted infections and global elimination targets, South-East Asia Region. Bull World Health Organ 2021; 99(4): 304-11.
[http://dx.doi.org/10.2471/BLT.20.254003] [PMID: 33953448]
[15]
Vicentini CB, Manfredini S, Maritati M, Di Nuzzo M, Contini C. Gonorrhea, a current disease with ancient roots: From the remedies of the past to future perspectives. Infez Med 2019; 27(2): 212-21.
[PMID: 31205048]
[16]
Martí-Pastor M, García de Olalla P, Barberá MJ, et al. Epidemiology of infections by HIV, Syphilis, Gonorrhea and Lymphogranuloma Venereum in Barcelona City: A population-based incidence study. BMC Public Health 2015; 15(1): 1015.
[http://dx.doi.org/10.1186/s12889-015-2344-7] [PMID: 26438040]
[17]
Pollock ED, Clay PA, Kreisel KM, Spicknall IH. Estimated incidence and prevalence of gonorrhea in the United States, 2006-2019. Sex Transm Dis 2023; 50(4): 188-95.
[http://dx.doi.org/10.1097/OLQ.0000000000001763] [PMID: 36598837]
[18]
Kreisel KM, Weston EJ, St Cyr SB, Spicknall IH. Estimates of the Prevalence and Incidence of Chlamydia and Gonorrhea Among US Men and Women, 2018. Sex Transm Dis 2021; 48(4): 222-31.
[http://dx.doi.org/10.1097/OLQ.0000000000001382] [PMID: 33492094]
[19]
Fairley CK, Hocking JS, Zhang L, Chow EPF. Frequent transmission of gonorrhea in men who have sex with men. Emerg Infect Dis 2017; 23(1): 102-4.
[http://dx.doi.org/10.3201/eid2301.161205] [PMID: 27983487]
[20]
Ribeiro S, de Sousa D, Medina D, Castro R, Lopes Â, Rocha M. Prevalence of gonorrhea and chlamydia in a community clinic for men who have sex with men in Lisbon, Portugal. Int J STD AIDS 2019; 30(10): 951-9.
[http://dx.doi.org/10.1177/0956462419855484] [PMID: 31284840]
[21]
Chow EPF, Camilleri S, Ward C, et al. Duration of gonorrhoea and chlamydia infection at the pharynx and rectum among men who have sex with men: a systematic review. Sex Health 2016; 13(3): 199-204.
[http://dx.doi.org/10.1071/SH15175] [PMID: 26886136]
[22]
Lutz AR. Screening for asymptomatic extragenital gonorrhea and chlamydia in men who have sex with men: Significance, recommendations, and options for overcoming barriers to testing. LGBT Health 2015; 2(1): 27-34.
[http://dx.doi.org/10.1089/lgbt.2014.0056] [PMID: 26790015]
[23]
Lenz JD, Dillard JP. Pathogenesis of Neisseria gonorrhoeae and the Host Defense in Ascending Infections of Human Fallopian Tube. Front Immunol 2018; 9: 2710.
[http://dx.doi.org/10.3389/fimmu.2018.02710] [PMID: 30524442]
[24]
Château A, Seifert HS. Neisseria gonorrhoeae survives within and modulates apoptosis and inflammatory cytokine production of human macrophages. Cell Microbiol 2016; 18(4): 546-60.
[http://dx.doi.org/10.1111/cmi.12529] [PMID: 26426083]
[25]
Quillin SJ, Seifert HS. Neisseria gonorrhoeae host adaptation and pathogenesis. Nat Rev Microbiol 2018; 16(4): 226-40.
[http://dx.doi.org/10.1038/nrmicro.2017.169] [PMID: 29430011]
[26]
Whiley DM, Lahra MM, Unemo M. Prospects of untreatable gonorrhea and ways forward. Future Microbiol 2015; 10(3): 313-6.
[http://dx.doi.org/10.2217/fmb.14.138] [PMID: 25812453]
[27]
Suay-García B, Pérez-Gracia MT. Neisseria gonorrhoeae Infections. Pathogens 2020; 9(8): 647.
[http://dx.doi.org/10.3390/pathogens9080647] [PMID: 32806522]
[28]
Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 2014; 27(3): 587-613.
[http://dx.doi.org/10.1128/CMR.00010-14] [PMID: 24982323]
[29]
Unemo M. Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis 2015; 15(1): 364.
[http://dx.doi.org/10.1186/s12879-015-1029-2] [PMID: 26293005]
[30]
Cyr SS, Barbee L, Workowski KA, Bachmann LH, Pham C, Schlanger K. CDC STI Gonorrhea treatment guidelines. Morb Mortal Wkly Rep Updat 2020; 69: 1911-6.
[31]
Mathew R, Chahin M, Isache C. Neisseria gonorrhoeae: An Unexpected Cause of Polyarthritis and Meningitis. J Investig Med High Impact Case Rep 2021; 9.
[http://dx.doi.org/10.1177/23247096211012194] [PMID: 33928799]
[32]
Creighton S. Gonorrhoea. BMJ Clin Evid 2014.
[33]
WHO WHO guidelines for the treatment of Neisseria gonorrhoeae. 2016. Available from https://www.who.int/publications/i/item/9789241549691
[34]
Toledano Medina MÁ, Merinas-Amo T, Fernández-Bedmar Z, et al. Physicochemical characterization and biological activities of black and white garlic: In vivo and in vitro assays. Foods 2019; 8.
[35]
Silva O, Caldeira G, Serrano R. A review of the role of medicinal plants on Neisseria gonorrhoeae infection. Eur J Integr Med 2020; 39: 101211.
[http://dx.doi.org/10.1016/j.eujim.2020.101211]
[36]
Mahira A, Mahbuba Nabi V. In infectious diseases, Echinacea comes to the rescue Ann. Syst Biol 2022; 5: 8-9.
[37]
Shokeen P, Bala M, Tandon V. Evaluation of the activity of 16 medicinal plants against Neisseria gonorrhoeae. Int J Antimicrob Agents 2009; 33(1): 86-91.
[http://dx.doi.org/10.1016/j.ijantimicag.2008.07.022] [PMID: 18819776]
[38]
Mollik AH, Islam T, Khatun A, et al. Medicinal plants used against syphilis and gonorrhea by traditional medicinal practitioners of Bangladesh. Planta Med 2009; 75(9): PH40.
[http://dx.doi.org/10.1055/s-0029-1234757]
[39]
Khoshkharam M, Shahrajabian MH, Singh RB, et al. Sumac: A functional food and herbal remedy in traditional herbal medicine in the Asia. In: Singh RB, Watanabe S, Isaza AA, Eds. Functional Foods and Nutraceuticals in Metabolic and Non-Communicable Diseases. Academic Press 2022; pp. 261-6.
[40]
Acharya GS. Clinical indications of avipattikara choorna an experiential and scientific view. Int Res J Ayurveda Yoga 2022; 05: 83-5.
[41]
Prasathkumar M, Anisha S, Dhrisya C, Becky R, Sadhasivam S. Therapeutic and pharmacological efficacy of selective Indian medicinal plants – A review. Phytomedicine Plus 2021; 1: 100029.
[42]
Ranjbar R, Bagheri H, Ghasemi F, Guest PC, Sahebkar A. Effects of Curcumin and Its Analogues on Infectious Diseases Studies on Biomarkers and New Targets in Aging Research in Iran: Focus on Turmeric and Curcumin. Cham: Springer 2021; pp. 75-101.
[43]
Judson FN. Treatment of uncomplicated gonorrhea with ceftriaxone: a review. Sex Transm Dis 1986; 13(3): 199-202.
[http://dx.doi.org/10.1097/00007435-198607000-00021] [PMID: 3094173]
[44]
Balduck M, Laumen JGE, Abdellati S, et al. Tolerance to Ceftriaxone in Neisseria gonorrhoeae: Rapid Induction in WHO P Reference Strain and Detection in Clinical Isolates. Basel, Switzerland: Antibiot 2022; p. 11.
[45]
Kuehn BM. Updated recommendations for gonorrhea treatment. JAMA 2021; 325(6): 523.
[PMID: 33560331]
[46]
Fan W, Zhang Q. Risk factors for male patients with gonorrhoea complicated by inflammation of the paraurethral glands around the external urethral orifice. Int J STD AIDS 2012; 23: 400-2.
[47]
Lewis DA. New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance. Sex Health 2019; 16(5): 449-56.
[http://dx.doi.org/10.1071/SH19034] [PMID: 31292063]
[48]
Lancaster JW, Mahoney MV, Mandal S, Lawrence KR. Update on treatment options for gonococcal infections. Pharmacotherapy 2015; 35(9): 856-68.
[http://dx.doi.org/10.1002/phar.1627] [PMID: 26343813]
[49]
Anon . Update to CDC’s sexually transmitted diseases treatment guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. JAMA 2012; 308: 1850-3.
[http://dx.doi.org/10.1001/2012.jama.11292]
[50]
Pleininger S, Indra A, Golparian D, et al. Extensively drug-resistant (XDR) Neisseria gonorrhoeae causing possible gonorrhoea treatment failure with ceftriaxone plus azithromycin in Austria, April 2022. Euro Surveill 2022; 27(24): 1-5.
[http://dx.doi.org/10.2807/1560-7917.ES.2022.27.24.2200455] [PMID: 35713023]
[51]
Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill 2011; 16(14): 1-4.
[http://dx.doi.org/10.2807/ese.16.14.19833-en] [PMID: 21492528]
[52]
Butler MM, Waidyarachchi SL, Connolly KL, et al. Aminomethyl spectinomycins as therapeutics for drug-resistant gonorrhea and chlamydia coinfections. Antimicrob Agents Chemother 2018; 62(5): e00325-18.
[http://dx.doi.org/10.1128/AAC.00325-18] [PMID: 29483122]
[53]
Unemo M, Jensen JS. Antimicrobial-resistant sexually transmitted infections: Gonorrhoea and Mycoplasma genitalium. Nat Rev Urol 2017; 14(3): 139-52.
[http://dx.doi.org/10.1038/nrurol.2016.268] [PMID: 28072403]
[54]
Lewis DA. Global resistance of Neisseria gonorrhoeae. Curr Opin Infect Dis 2014; 27(1): 62-7.
[http://dx.doi.org/10.1097/QCO.0000000000000025] [PMID: 24275696]
[55]
Fernandes P, Craft JC. Phase 3 trial of treating gonorrhoea with solithromycin. Lancet Infect Dis 2019; 19(9): 928.
[http://dx.doi.org/10.1016/S1473-3099(19)30430-X] [PMID: 31478511]
[56]
Chen MY, McNulty A, Avery A, et al. Solithromycin versus ceftriaxone plus azithromycin for the treatment of uncomplicated genital gonorrhoea (SOLITAIRE-U): A randomised phase 3 non-inferiority trial. Lancet Infect Dis 2019; 19(8): 833-42.
[http://dx.doi.org/10.1016/S1473-3099(19)30116-1] [PMID: 31196813]
[57]
Chung PY. Current technology in the discovery and development of novel antibacterials. Curr Drug Targets 2018; 19(7): 832-40.
[http://dx.doi.org/10.2174/1389450118666170911114604] [PMID: 28891454]
[58]
Penchovsky R, Traykovska M. Designing drugs that overcome antibacterial resistance: Where do we stand and what should we do? Expert Opin Drug Discov 2015; 10(6): 631-50.
[http://dx.doi.org/10.1517/17460441.2015.1048219] [PMID: 25981754]
[59]
Suay-García B, Pérez-Gracia M. Future prospects for neisseria gonorrhoeae treatment. Antibiotics 2018; 7(2): 49.
[http://dx.doi.org/10.3390/antibiotics7020049] [PMID: 29914071]
[60]
Rice PA, Shafer WM, Ram S, Jerse AE. Neisseria gonorrhoeae: Drug resistance, mouse models, and vaccine development. Annu Rev Microbiol 2017; 71(1): 665-86.
[http://dx.doi.org/10.1146/annurev-micro-090816-093530] [PMID: 28886683]
[61]
Russell MW, Jerse AE, Gray-Owen SD. Progress toward a gonococcal vaccine: The way forward. Front Immunol 2019; 10: 2417.
[http://dx.doi.org/10.3389/fimmu.2019.02417] [PMID: 31681305]
[62]
Spellberg B, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: A call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 2008; 46(2): 155-64.
[http://dx.doi.org/10.1086/524891] [PMID: 18171244]
[63]
Renwick MJ, Brogan DM, Mossialos E. A systematic review and critical assessment of incentive strategies for discovery and development of novel antibiotics. J Antibiot 2016; 69(2): 73-88.
[http://dx.doi.org/10.1038/ja.2015.98] [PMID: 26464014]
[64]
Cook MA, Wright GD. The past, present, and future of antibiotics. Sci Transl Med 2022; 14(657): eabo7793.
[http://dx.doi.org/10.1126/scitranslmed.abo7793] [PMID: 35947678]
[65]
Mancuso AM, Gandhi MA, Slish J. Solithromycin (CEM-101): A New Fluoroketolide Antibiotic and Its Role in the Treatment of Gonorrhea. J Pharm Pract 2018; 31(2): 195-201.
[http://dx.doi.org/10.1177/0897190017708073] [PMID: 28490220]
[66]
de Vries HJC, Schim-van der Loeff MF. Solithromycin for the treatment of drug-resistant gonorrhoea. Lancet Infect Dis 2019; 19(8): 791-2.
[http://dx.doi.org/10.1016/S1473-3099(19)30115-X] [PMID: 31196808]
[67]
Taylor SN, Morris DH, Avery AK, et al. Gepotidacin for the treatment of uncomplicated urogenital gonorrhea: A phase 2, randomized, dose-ranging, single-oral dose evaluation. Clin Infect Dis 2018; 67(4): 504-12.
[http://dx.doi.org/10.1093/cid/ciy145] [PMID: 29617982]
[68]
Aitolo GL, Adeyemi OS, Afolabi BL, Owolabi AO. Neisseria gonorrhoeae antimicrobial resistance: Past to present to future. Curr Microbiol 2021; 78(3): 867-78.
[http://dx.doi.org/10.1007/s00284-021-02353-8] [PMID: 33528603]
[69]
Taylor SN, Marrazzo J, Batteiger BE, et al. Single-Dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea. N Engl J Med 2018; 379(19): 1835-45.
[http://dx.doi.org/10.1056/NEJMoa1706988] [PMID: 30403954]
[70]
Veve MP, Wagner JL. Lefamulin: Review of a promising novel pleuromutilin antibiotic. Pharmacotherapy 2018; 38(9): 935-46.
[http://dx.doi.org/10.1002/phar.2166] [PMID: 30019769]
[71]
Humphries R, Bobenchik AM, Hindler JA, Schuetz AN. Overview of changes to the clinical and laboratory standards institute performance standards for antimicrobial susceptibility testing, M100. J Clin Microbiol 2021; 59: e0021321.
[72]
Jacobsson S, Golparian D, Oxelbark J, et al. Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections. Front Pharmacol 2022; 13: 1035841.
[http://dx.doi.org/10.3389/fphar.2022.1035841] [PMID: 36452226]
[73]
Baker SJ, Payne DJ, Rappuoli R, De Gregorio E. Technologies to address antimicrobial resistance. Proc Natl Acad Sci 2018; 115(51): 12887-95.
[http://dx.doi.org/10.1073/pnas.1717160115] [PMID: 30559181]
[74]
Leung E, Weil DE, Raviglione M, Nakatani H. The WHO policy package to combat antimicrobial resistance. Bull World Health Organ 2011; 89(5): 390-2.
[http://dx.doi.org/10.2471/BLT.11.088435] [PMID: 21556308]
[75]
Cater K. Międzybrodzki R, Morozova V, et al Potential for Phages in the Treatment of Bacterial Sexually Transmitted Infections. Basel, Switzerland: Antibiot 2021; p. 10.
[76]
Gottlieb SL, Johnston C. Future prospects for new vaccines against sexually transmitted infections. Curr Opin Infect Dis 2017; 30(1): 77-86.
[http://dx.doi.org/10.1097/QCO.0000000000000343] [PMID: 27922851]
[77]
Gala R, Zaman R, D’Souza M, Zughaier S. Novel whole-cell inactivated neisseria gonorrhoeae microparticles as vaccine formulation in microneedle-based transdermal immunization. Vaccines 2018; 6(3): 60.
[http://dx.doi.org/10.3390/vaccines6030060] [PMID: 30181504]
[78]
Gottlieb SL, Jerse AE, Delany-Moretlwe S, Deal C, Giersing BK. Advancing vaccine development for gonorrhoea and the Global STI Vaccine Roadmap. Sex Health 2019; 16(5): 426-32.
[http://dx.doi.org/10.1071/SH19060] [PMID: 31476278]
[79]
Edwards JL, Jennings MP, Apicella MA, Seib KL. Is gonococcal disease preventable? The importance of understanding immunity and pathogenesis in vaccine development. Crit Rev Microbiol 2016; 42(6): 928-41.
[http://dx.doi.org/10.3109/1040841X.2015.1105782] [PMID: 26805040]
[80]
Thakur SD, Levett PN, Horsman GB, Dillon JAR. Molecular epidemiology of Neisseria gonorrhoeae isolates from Saskatchewan, Canada: Utility of NG-MAST in predicting antimicrobial susceptibility regionally. Sex Transm Infect 2014; 90(4): 297-302.
[http://dx.doi.org/10.1136/sextrans-2013-051229] [PMID: 24503900]
[81]
Rodrigues MQ, Alves PM, Roldão A. Functionalizing Ferritin Nanoparticles for Vaccine Development. Pharmaceutics 2021; 13(10): 1621.
[http://dx.doi.org/10.3390/pharmaceutics13101621] [PMID: 34683914]
[82]
Ladner JT, Grubaugh ND, Pybus OG, Andersen KG. Precision epidemiology for infectious disease control. Nat Med 2019; 25(2): 206-11.
[http://dx.doi.org/10.1038/s41591-019-0345-2] [PMID: 30728537]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy