{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T21:20:42Z","timestamp":1794259242966,"version":"4.9.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Lung"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Antimicrobial-resistant pathogens such as\n                      <jats:italic>Pseudomonas aeruginosa\u00a0(P. aeruginosa)<\/jats:italic>\n                      represent a significant challenge to patients with respiratory diseases including Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), where treatment of such infections is exacerbated by a shortage of new and effective antibiotic classes. One novel approach utilises \u2018antibiotic enhancers\u2019 that potentiate the antimicrobial activity of existing antibiotics. HT61, a small quinolone-derived compound, potentiates the activity of the aminoglycosides tobramycin and gentamicin against\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      and\n                      <jats:italic>P. aeruginosa.<\/jats:italic>\n                      In this study, we have investigated synergism between tobramycin and HT61 using a panel of tobramycin-sensitive and -resistant clinical isolates of\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      from CF patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Microdilution methods and chequerboard analysis were used to evaluate antimicrobial synergy of drug combinations against 63 isolates. Bacterial time-kill assays and biofilm eradication assays were then used to further characterise antimicrobial synergy against 13 selected isolates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>74% of isolates (47\/63) demonstrated evidence of either positive interactions (29\/63) determined by a Fractional Inhibitory Concentration Index (FICI)\u2009\u2264\u20091.0, or synergy (18\/63) determined by an FICI value of\u2009\u2264\u20090.5. Using a sub-selection of these isolates, clear augmentation of tobramycin\u2019s antimicrobial activity was observed in both time-kill assays and biofilm eradication assays regardless of FICI classification with significant reductions observed in combination therapies vs monotherapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The expansion of previous studies highlighting the potentiating capabilities of HT61 on\/with antibiotics in vivo across a further 63 clinical isolates of\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      in a laboratory setting further highlights the potential therapeutic benefits of HT61-tobramycin combinations in respiratory diseases associated with drug-resistant\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00408-025-00855-x","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:34:58Z","timestamp":1764221698000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic Interactions Between the Quinolone-Derived Compound HT61 and Tobramycin Against a Range of Clinical Isolates of Pseudomonas aeruginosa In Vitro"],"prefix":"10.1007","volume":"203","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8951-4349","authenticated-orcid":false,"given":"B.","family":"Ramsden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9160-367X","authenticated-orcid":false,"given":"A. V.","family":"Kelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7554-0317","authenticated-orcid":false,"given":"M.-E.","family":"Faure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-3799","authenticated-orcid":false,"given":"C. P.","family":"Page","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6616-4599","authenticated-orcid":false,"given":"R. T.","family":"Amison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"issue":"1","key":"855_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep10241","volume":"5","author":"B Coburn","year":"2015","unstructured":"Coburn B, Wang PW, Diaz Caballero J, Clark ST, Brahma V, Donaldson S et al (2015) Lung microbiota across age and disease stage in cystic fibrosis. Sci Rep 5(1):1\u201312","journal-title":"Sci Rep"},{"key":"855_CR2","unstructured":"Shaikh N, Lee A, Charma S, Cosgriff R, Carr S. UK cystic fibrosis registry 2020 annual data report UK Cystic fibrosis registry 2020 annual data report. 2021 [cited 2022 Dec 8];(3). https:\/\/www.cysticfibrosis.org.uk\/sites\/default\/files\/2022-03\/2020 Annual data report\u2014Version 3.pdf"},{"issue":"5","key":"855_CR3","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1159\/000490190","volume":"96","author":"A Rodrigo-Troyano","year":"2018","unstructured":"Rodrigo-Troyano A, Melo V, Marcos PJ, Laserna E, Peiro M, Suarez-Cuartin G et al (2018) Pseudomonas aeruginosa in chronic obstructive pulmonary disease patients with frequent hospitalized exacerbations: a prospective multicentre study. Respiration 96(5):417\u2013424","journal-title":"Respiration"},{"issue":"6","key":"855_CR4","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.jinf.2013.09.003","volume":"67","author":"A Domenech","year":"2013","unstructured":"Domenech A, Puig C, Mart\u00ed S, Santos S, Fern\u00e1ndez A, Calatayud L et al (2013) Infectious etiology of acute exacerbations insevere COPD patients. J Infect 67(6):516\u2013523","journal-title":"J Infect"},{"issue":"5","key":"855_CR5","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1183\/09031936.00003309","volume":"34","author":"C Garcia-Vidal","year":"2009","unstructured":"Garcia-Vidal C, Almagro P, Roman\u00ed V, Rodr\u00edguez-Carballeira M, Cuchi E, Canales L et al (2009) Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective study. Eur Respir J 34(5):1072\u20131078","journal-title":"Eur Respir J"},{"issue":"4","key":"855_CR6","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1128\/CMR.00040-09","volume":"22","author":"PD Lister","year":"2009","unstructured":"Lister PD, Wolter DJ, Hanson ND (2009) Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 22(4):582\u2013610","journal-title":"Clin Microbiol Rev"},{"issue":"6","key":"855_CR7","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.ijantimicag.2015.03.001","volume":"45","author":"A Potron","year":"2015","unstructured":"Potron A, Poirel L, Nordmann P (2015) Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: mechanisms and epidemiology. Int J Antimicrob Agents 45(6):568\u2013585. https:\/\/doi.org\/10.1016\/j.ijantimicag.2015.03.001","journal-title":"Int J Antimicrob Agents"},{"issue":"Pt 1","key":"855_CR8","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1242\/jcs.97.1.59","volume":"97","author":"F Tablin","year":"1990","unstructured":"Tablin F, Castro M, Leven RM (1990) Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation. J Cell Sci 97(Pt 1):59\u201370","journal-title":"J Cell Sci"},{"issue":"2","key":"855_CR9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.gendis.2019.04.001","volume":"6","author":"P Pachori","year":"2019","unstructured":"Pachori P, Gothalwal R, Gandhi P (2019) Emergence of antibiotic resistance Pseudomonas aeruginosa in intensive care unit; a critical review. Genes Dis 6(2):109","journal-title":"Genes Dis"},{"issue":"4","key":"855_CR10","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1093\/cid\/ciu866","volume":"60","author":"C Pea","year":"2015","unstructured":"Pea C, Cabot G, G\u00f3mez-Zorrilla S, Zamorano L, Ocampo-Sosa A, Murillas J et al (2015) Influence of virulence genotype and resistance profile in the mortality of Pseudomonas aeruginosa bloodstream infections. Clin Infect Dis 60(4):539\u2013548","journal-title":"Clin Infect Dis"},{"issue":"1","key":"855_CR11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.diagmicrobio.2016.10.003","volume":"87","author":"A Walkty","year":"2017","unstructured":"Walkty A, Lagace-Wiens P, Adam H, Baxter M, Karlowsky J, Mulvey MR et al (2017) Antimicrobial susceptibility of 2906 Pseudomonasaeruginosa clinical isolates obtained from patients in Canadian hospitals over a period of 8 years: results of the Canadian ward surveillance study (CANWARD), 2008\u20132015. Diagn Microbiol Infect Dis 87(1):60\u201363","journal-title":"Diagn Microbiol Infect Dis"},{"issue":"1","key":"855_CR12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.diagmicrobio.2018.04.012","volume":"92","author":"HS Sader","year":"2018","unstructured":"Sader HS, Castanheira M, Duncan LR, Flamm RK (2018) Antimicrobial Susceptibility of Enterobacteriaceae and Pseudomonas aeruginosa isolates from United States Medical Centers stratified by infection type: results from the International network for optimal resistance monitoring (INFORM) surveillance program, 2015-2016. Diagn Microbiol Infect Dis 92(1):69\u201374","journal-title":"Diagn Microbiol Infect Dis"},{"key":"855_CR13","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1093\/jac\/dks384","volume":"68","author":"Y Hu","year":"2013","unstructured":"Hu Y, Coates ARM (2013) Enhancement by novel anti-methicillin-resistant Staphylococcus aureus compound HT61 of the activity of neomycin, gentamicin, mupirocin and chlorhexidine: in vitro and in vivo studies. J Antmicrob Chemother 68:374\u2013384","journal-title":"J Antmicrob Chemother"},{"key":"855_CR14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011818","author":"Y Hu","year":"2010","unstructured":"Hu Y, Shamaei-Tousi A, Liu Y, Coates A (2010) A new approach for the discovery of antibiotics by targeting non-multiplying bacteria: a novel topical antibiotic for Staphylococcal infections. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0011818","journal-title":"PLoS ONE"},{"key":"855_CR15","doi-asserted-by":"publisher","unstructured":"Frapwell CJ, Skipp PJ, Howlin RP, Angus EM, Hu Y, Coates ARM et al (2020) Antimicrobial activity of the quinoline derivative HT61 against Staphylococcus aureus biofilms. https:\/\/doi.org\/10.1128\/AAC","DOI":"10.1128\/AAC"},{"issue":"8","key":"855_CR16","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1021\/acs.biochem.6b01135","volume":"56","author":"ATM Hubbard","year":"2017","unstructured":"Hubbard ATM, Barker R, Rehal R, Vandera K-KA, Harvey RD, Coates ARM (2017) Mechanism of action of a membrane-active quinoline-based antimicrobial on natural and model bacterial membranes. Biochemistry 56(8):1163\u20131174. https:\/\/doi.org\/10.1021\/acs.biochem.6b01135","journal-title":"Biochemistry"},{"key":"855_CR17","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/ja.2017.90","volume":"70","author":"AT Hubbard","year":"2017","unstructured":"Hubbard AT, Coates AR, Harvey RD (2017) Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes. J Antibiot 70:1020\u20131025","journal-title":"J Antibiot"},{"issue":"61","key":"855_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2019.101884","volume":"1","author":"RT Amison","year":"2020","unstructured":"Amison RT, Faure ME, O\u2019Shaughnessy BG, Bruce KD, Hu Y, Coates A et al (2020) The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo. Pulm Pharmacol Ther 1(61):101884","journal-title":"Pulm Pharmacol Ther"},{"issue":"2","key":"855_CR19","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S0031-6997(25)00026-2","volume":"41","author":"MC Berenbaum","year":"1989","unstructured":"Berenbaum MC (1989) What is synergy? Pharmacol Rev 41(2):93\u2013141","journal-title":"Pharmacol Rev"},{"issue":"9","key":"855_CR20","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1093\/jac\/dkae233","volume":"79","author":"N Fatsis-Kavalopoulos","year":"2024","unstructured":"Fatsis-Kavalopoulos N, S\u00e1nchez-Hevia DL, Andersson DI (2024) Beyond the FIC index: the extended information from fractional inhibitory concentrations (FICs). J Antimicrob Chemother 79(9):2394\u20132396. https:\/\/doi.org\/10.1093\/jac\/dkae233","journal-title":"J Antimicrob Chemother"},{"issue":"1","key":"855_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jac\/dkg301","volume":"52","author":"FC Odds","year":"2003","unstructured":"Odds FC (2003) Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 52(1):1. https:\/\/doi.org\/10.1093\/jac\/dkg301","journal-title":"J Antimicrob Chemother"},{"issue":"10","key":"855_CR22","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.1128\/AAC.00361-08","volume":"52","author":"A Belley","year":"2008","unstructured":"Belley A, Neesham-Grenon E, Arhin FF, McKay GA, Parr TR, Moeck G (2008) Assessment by time-kill methodology of the synergistic effects of oritavancin in combination with other antimicrobial agents against Staphylococcus aureus. Antimicrob Agents Chemother 52(10):3820","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"855_CR23","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1124\/pharmrev.124.000951","volume":"76","author":"L Calzetta","year":"2024","unstructured":"Calzetta L, Page C, Matera MG, Cazzola M, Rogliani P (2024) Drug-drug interactions and synergy: from pharmacological models to clinical application. Pharmacol Rev 76(6):1159\u20131220","journal-title":"Pharmacol Rev"},{"issue":"9","key":"855_CR24","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1128\/AAC.00141-06","volume":"50","author":"L Pumbwe","year":"2006","unstructured":"Pumbwe L, Glass D, Wexler HM (2006) Efflux pump overexpression in multiple-antibiotic-resistant mutants of Bacteroides fragilis. Antimicrob Agents Chemother 50(9):3150","journal-title":"Antimicrob Agents Chemother"},{"key":"855_CR25","unstructured":"EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. https:\/\/eucast.org"},{"issue":"7","key":"855_CR26","doi-asserted-by":"publisher","first-page":"11818","DOI":"10.1371\/journal.pone.0011818","volume":"5","author":"Y Hu","year":"2010","unstructured":"Hu Y, Shamaei-Tousi A, Liu Y, Coates A (2010) A new approach for the discovery of antibiotics by targeting non-multiplying bacteria: a novel topical antibiotic for staphylococcal infections. Infect PLoS ONE 5(7):11818","journal-title":"Infect PLoS ONE"},{"issue":"8","key":"855_CR27","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1021\/acs.biochem.6b01135","volume":"56","author":"ATM Hubbard","year":"2017","unstructured":"Hubbard ATM, Barker R, Rehal R, Vandera KKA, Harvey RD, Coates ARM (2017) Mechanism of action of a membrane-active quinoline-based antimicrobial on natural and model bacterial membranes. Biochemistry 56(8):1163\u20131174","journal-title":"Biochemistry"},{"issue":"10","key":"855_CR28","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/ja.2017.90","volume":"70","author":"AT Hubbard","year":"2017","unstructured":"Hubbard AT, Coates AR, Harvey RD (2017) Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes. J Antibiot 70(10):1020\u20131025","journal-title":"J Antibiot"},{"key":"855_CR29","doi-asserted-by":"publisher","unstructured":"Ontong JC, Ozioma NF, Voravuthikunchai Id SP, Chusri Id S (2021) Synergistic antibacterial effects of colistin in combination with aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, tetracyclines, fosfomycin, and piperacillin on multidrug resistant Klebsiella pneumoniae isolates. https:\/\/doi.org\/10.1371\/journal.pone.0244673","DOI":"10.1371\/journal.pone.0244673"},{"key":"855_CR30","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jgar.2019.04.012","volume":"18","author":"MM Montero","year":"2019","unstructured":"Montero MM, Domene Ochoa S, L\u00f3pez-Causap\u00e9 C, VanScoy B, Luque S, Sorl\u00ed L et al (2019) Colistin plus meropenem combination is synergistic in vitro against extensively drug-resistant Pseudomonas aeruginosa, including high-risk clones. J Glob Antimicrob Resist 18:37\u201344","journal-title":"J Glob Antimicrob Resist"},{"issue":"5","key":"855_CR31","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1093\/femsre\/fuz014","volume":"43","author":"M Laws","year":"2019","unstructured":"Laws M, Shaaban A, Rahman KM (2019) Antibiotic resistance breakers: current approaches and future directions. FEMS Microbiol Rev 43(5):490\u2013516","journal-title":"FEMS Microbiol Rev"},{"key":"855_CR32","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.2c00193","author":"CMJ Wesseling","year":"2022","unstructured":"Wesseling CMJ, Martin NI (2022) Synergy by perturbing the Gram-negative outer membrane: opening the door for Gram-positive specific antibiotics. ACS Infect Dis. https:\/\/doi.org\/10.1021\/acsinfecdis.2c00193","journal-title":"ACS Infect Dis"},{"issue":"7","key":"855_CR33","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1136\/thx.2009.131532","volume":"65","author":"A Prayle","year":"2010","unstructured":"Prayle A, Watson A, Fortnum H, Smyth A (2010) Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis. Thorax 65(7):654\u2013658. https:\/\/doi.org\/10.1136\/thx.2009.131532","journal-title":"Thorax"},{"issue":"1","key":"855_CR34","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/ppul.20138","volume":"39","author":"M Al-Aloul","year":"2005","unstructured":"Al-Aloul M, Miller H, Alapati S, Stockton PA, Ledson MJ, Walshaw MJ (2005) Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 39(1):15\u201320. https:\/\/doi.org\/10.1002\/ppul.20138","journal-title":"Pediatr Pulmonol"},{"issue":"4","key":"855_CR35","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.jcf.2005.09.003","volume":"4","author":"S Glass","year":"2005","unstructured":"Glass S, Plant ND, Spencer DA (2005) The effects of intravenous tobramycin on renal tubular function in children with cystic fibrosis. J Cyst Fibros 4(4):221\u2013225","journal-title":"J Cyst Fibros"},{"key":"855_CR36","unstructured":"Alliance JL (2022) Cystic Fibrosis Refesh Top 10 Priorities. https:\/\/www.jla.nihr.ac.uk\/priority-setting-partnerships\/cystic-fibrosis-refresh\/top-10-priorities.htm"}],"container-title":["Lung"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00408-025-00855-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00408-025-00855-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00408-025-00855-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T04:43:06Z","timestamp":1766378586000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00408-025-00855-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["855"],"URL":"https:\/\/doi.org\/10.1007\/s00408-025-00855-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7235788\/v1","asserted-by":"object"}]},"ISSN":["0341-2040","1432-1750"],"issn-type":[{"value":"0341-2040","type":"print"},{"value":"1432-1750","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]},"assertion":[{"value":"28 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"CP declares that he holds equity in Helperby Therapeutics who are developing HT61. There are no other conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"101"}}