{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T03:19:11Z","timestamp":1763695151436,"version":"3.45.0"},"reference-count":46,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Gates Foundation","doi-asserted-by":"publisher","award":["OPP1196642"],"award-info":[{"award-number":["OPP1196642"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Departament d\u2019Universitats i Recerca de la Generalitat de Catalunya"}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"<ns3:p>\n                    Background Monitoring parasite resistance to antimalarial drugs is essential for detecting potential changes in drug efficacy. This study assessed the prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine (SP), chloroquine, and artemisinin in Sierra Leone, where SP is used for intermittent preventive treatment in pregnancy (IPTp) and perennial malaria chemoprevention (PMC) in young children, while artemisinin is used to treat malaria episodes. Methods A cross-sectional survey was conducted between June and August 2021 in three districts of Sierra Leone. A total of 440 febrile children aged 2-5 years attending the health facilities were screened for\n                    <ns3:italic>P. falciparum<\/ns3:italic>\n                    malaria using a rapid diagnostic test, and 300 participants with positive RDT were enrolled. Capillary blood samples were collected as dried blood spots, analyzed using quantitative PCR to confirm\n                    <ns3:italic>P. falciparum,<\/ns3:italic>\n                    and sequenced for resistance markers in\n                    <ns3:italic>pfdhfr, pfdhps, pfcrt, pfmdr1,<\/ns3:italic>\n                    and\n                    <ns3:italic>pfK13.<\/ns3:italic>\n                    Results Of 298 blood samples, 237 (79.5%) were qPCR-positive and 230 samples were successfully genotyped. The\n                    <ns3:italic>pfdhfr<\/ns3:italic>\n                    triple mutant (N51I\/C59R\/S108N) was detected in 99.5% of samples (217\/218), while\n                    <ns3:italic>pfdhps<\/ns3:italic>\n                    mutations A437G and K540E were detected in 92.1% (211\/229) and 19.1% (42\/220), respectively. The\n                    <ns3:italic>pfdhfr\/dhps<\/ns3:italic>\n                    quintuple mutant (triple mutant + A437G\/K540E) prevalence was 4.6% (7\/151), and no sextuple mutants (quintuple +\n                    <ns3:italic>pfdhps<\/ns3:italic>\n                    -A581G) were observed. Chloroquine resistance-associated mutations in\n                    <ns3:italic>pfcrt<\/ns3:italic>\n                    (CVIET haplotype) were detected in 36.6% of samples, while\n                    <ns3:italic>pfmdr1<\/ns3:italic>\n                    mutations at codon 86, 184, 1042, and 1246 occurred in 2.3%, 71.7%, 0.9% and 1.8%, respectively. No validated\n                    <ns3:italic>pfK13<\/ns3:italic>\n                    markers of artemisinin resistance were detected. Conclusion In this study, the sustained low prevalence of\n                    <ns3:italic>pfdhfr\/dhps<\/ns3:italic>\n                    quintuple mutant justifies the continued use of SP- containing IPTp and PMC, as well as its expansion in the country into the second year of life with additional SP doses. Importantly, no validated\n                    <ns3:italic>pfK13<\/ns3:italic>\n                    markers were found supporting the use of artemisinin-based combination therapies in Sierra Leone. Trial registration Clinicaltrials.gov NCT04235816. Registered on January 17, 2020\n                  <\/ns3:p>","DOI":"10.12688\/gatesopenres.16367.1","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:55:16Z","timestamp":1763686516000},"page":"81","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prevalence of Molecular Markers of Resistance to Antimalarial Drugs Three Years After Perennial Malaria Chemoprevention in Sierra Leone"],"prefix":"10.12688","volume":"9","author":[{"given":"Haily","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3733-7936","authenticated-orcid":false,"given":"Kwabena","family":"Owusu-Kyei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Augustin E.","family":"Fombah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Garc\u00eda-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduard","family":"Rovira-Vallbona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreu","family":"Bofill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-6951","authenticated-orcid":false,"given":"Lloren\u00e7","family":"Quint\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4682-1421","authenticated-orcid":false,"given":"Ant\u00eda","family":"Figueroa-Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Falama","family":"Mac-Abdul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Samai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Mayor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-6907","authenticated-orcid":false,"given":"Clara","family":"Men\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"ref2","article-title":"WHO Malaria Guidelines: Treatment of Malaria.","author":"P Olumese","year":"2023"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"64-70","DOI":"10.4314\/gmj.v56i2.2","article-title":"Effectiveness of seasonal malaria chemoprevention in reducing under-five malaria morbidity and mortality in the Savannah Region, Ghana.","volume":"56","author":"M Adjei","year":"2022 Jun 1","journal-title":"Ghana Med. J."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"203","DOI":"10.3390\/diseases12090203","article-title":"Uptake and Effectiveness of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine during Pregnancy in Africa: A Scoping Review.","volume":"12","author":"G Berchie","year":"2024 Sep 4","journal-title":"Diseases."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12936-022-04115-8","article-title":"Malaria chemoprevention and drug resistance: A review of the literature and policy implications.","volume":"21","author":"C Plowe","year":"2022","journal-title":"Malar. J."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"9114-9118","DOI":"10.1073\/pnas.85.23.9114","article-title":"Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria (Plasmodiumfakiparum\/drug resistance\/folic acid antagonists\/genetic linkage analysis\/polymerase chain reaction).","volume":"85","author":"D Peterson","year":"1988","journal-title":"Proc. Nati. Acad. Sci. USA."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"45-59","DOI":"10.1016\/0163-7258(90)90017-V","article-title":"The dihydrofolate reductase-thymidylate synthetase gene in the drug resistance of malaria parasites.","volume":"48","author":"J Hyde","year":"1990 Jan 1","journal-title":"Pharmacol. Ther."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"164-169","DOI":"10.1128\/AAC.42.1.164","article-title":"Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity in vitro and Point Mutations in the Dihydrofolate Reductase Domain.","volume":"42","author":"A Nzila-Mounda","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"183-193","DOI":"10.1016\/j.actatropica.2005.06.015","article-title":"Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine-pyrimethamine resistance in malaria-infected patients from Nigeria.","volume":"95","author":"C Happi","year":"2005 Sep","journal-title":"Acta Trop."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1629-1630","DOI":"10.1016\/S0140-6736(98)24022-0","article-title":"Molecular assays for surveillance of antifolate-resistant malaria.","volume":"351","author":"J Kublin","year":"1998 May 30 cited 2021 Mar 3","journal-title":"Lancet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"546-556","DOI":"10.1016\/S1473-3099(18)30732-1","article-title":"Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: A systematic review and meta-analysis.","volume":"19","author":"A Eijk","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref14","article-title":"U.S. President\u2019s Malaria Initiative: Sierra Leone Malaria Operational Plan FY 2023.","year":"2023"},{"key":"ref17","article-title":"Ministry of Health. Sierra Leone Malaria Control Strategic Plan 2016-2020.","year":"2015"},{"key":"ref18","article-title":"WHO list of Prequalified in vitro Diagnostic Products|WHO - Prequalification of Medical Products (IVDs, Medicines, Vaccines and Immunization Devices, Vector Control).","year":"cited 2025 Mar 3"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1038\/s41467-024-46535-x","article-title":"Genomic malaria surveillance of antenatal care users detects reduced transmission following elimination interventions in Mozambique.","volume":"15","author":"N Brokhattingen","year":"2024 Dec 1","journal-title":"Nat. Commun."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1-10","DOI":"10.1186\/1475-2875-8-9","article-title":"Sub-microscopic infections and long-term recrudescence of Plasmodium falciparum in Mozambican pregnant women.","volume":"8","author":"A Mayor","year":"2009 Jan 9","journal-title":"Malar. J."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"247-251","DOI":"10.1016\/S0166-6851(01)00379-6","article-title":"Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR.","volume":"118","author":"C Hermsen","year":"2001","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"10737","DOI":"10.1038\/s41598-025-94716-5","article-title":"Sensitive and modular amplicon sequencing of Plasmodium falciparum diversity and resistance for research and public health.","volume":"15","author":"A Aranda-D\u00edaz","year":"2025 Mar 28","journal-title":"Sci. Rep."},{"key":"ref23","doi-asserted-by":"crossref","DOI":"10.12688\/verixiv.444.1","article-title":"Antimalarial drug resistance and population structure of Plasmodium falciparum in Mozambique using genomic surveillance at health facilities (2021-2022).","author":"S Boene","year":"2024"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"27-38","DOI":"10.1093\/biomet\/80.1.27","article-title":"Bias Reduction of Maximum Likelihood Estimates.","volume":"80","author":"D Firth","year":"1993","journal-title":"Biometrika."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2409-2419","DOI":"10.1002\/sim.1047","article-title":"A solution to the problem of separation in logistic regression.","volume":"21","author":"G Heinze","year":"2002 Aug 30","journal-title":"Stat. Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s12936-023-04575-6","article-title":"Coverage of intermittent preventive treatment of malaria in infants after four years of implementation in Sierra Leone.","volume":"22","author":"A Fombah","year":"2023 Dec 1","journal-title":"Malar. J."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"363-370","DOI":"10.1016\/j.actatropica.2018.06.016","article-title":"Efficacy of artemisinin-based combination therapies and prevalence of molecular markers associated with artemisinin, piperaquine and sulfadoxine-pyrimethamine resistance in Sierra Leone.","volume":"185","author":"S Smith","year":"2018 Sep 1","journal-title":"Acta Trop."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12936-021-03615-3","article-title":"Evaluation of health system readiness and coverage of intermittent preventive treatment of malaria in infants (IPTi) in Kambia district to inform national scale-up in Sierra Leone.","volume":"20","author":"M Lahuerta","year":"2021 Dec 1","journal-title":"Malar. J."},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01927-18","article-title":"Mutation Profile of pfdhfr and pfdhps in Plasmodium falciparum among Returned Chinese Migrant Workers from Africa.","volume":"63","author":"C Xu","year":"2019 May 1","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref34","article-title":"Prevalence of molecular markers of drug resistance in an area of seasonal malaria chemoprevention in children in Senegal.","author":"A Lo","year":"2013"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e0162718","DOI":"10.1371\/journal.pone.0162718","article-title":"Seasonal malaria chemoprevention with sulphadoxine-pyrimethamine and amodiaquine selects Pfdhfr-dhps quintuple mutant genotype in Mali.","volume":"11","author":"H Maiga","year":"2016 Sep 1","journal-title":"PLoS One."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e003217","DOI":"10.1136\/bmjgh-2020-003217","article-title":"Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in Africa: A systematic analysis of national trends.","volume":"5","author":"F Amimo","year":"2020 Nov 19","journal-title":"BMJ Glob. Health."},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.1059695","article-title":"Prevalence of malaria resistance-associated mutations in Plasmodium falciparum circulating in 2017\u20132018, Bo, Sierra Leone.","volume":"13","author":"T Leski","year":"2022 Dec 2","journal-title":"Front. Microbiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12936-022-04140-7","article-title":"Artesunate\u2013amodiaquine and artemether\u2013lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: In vivo efficacy and frequency of molecular markers.","volume":"21","author":"V Koko","year":"2022 Dec 1","journal-title":"Malar. J."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s12879-022-07112-z","article-title":"Biennial surveillance of Plasmodium falciparum anti-malarial drug resistance markers in Democratic Republic of Congo, 2017 and 2019.","volume":"22","author":"D Yobi","year":"2022 Dec 1","journal-title":"BMC Infect. Dis."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1186\/s12936-021-04000-w","article-title":"Temporal evolution of the resistance genotypes of Plasmodium falciparum in isolates from Equatorial Guinea during 20 years (1999 to 2019).","volume":"20","author":"P Berzosa","year":"2021 Dec 1","journal-title":"Malar. J."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s12936-024-04922-1","article-title":"Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine and prevalence of molecular markers of anti-malarial drug resistance in children in Togo in 2021.","volume":"23","author":"A Dorkenoo","year":"2024 Dec 1","journal-title":"Malar. J."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e000999","DOI":"10.1136\/bmjgh-2018-000999","article-title":"Emerging implications of policies on malaria treatment: Genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether\u2013lumefantrine and artesunate\u2013amodiaquine in Africa.","volume":"3","author":"L Okell","year":"2018 Nov 1","journal-title":"BMJ Glob. Health."},{"key":"ref43","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01423-19","article-title":"Antimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation Sequencing.","author":"B Mensah","year":"2020"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"59-66","DOI":"10.1007\/s12639-023-01640-4","article-title":"Increase of Plasmodium falciparum parasites carrying lumefantrine-tolerance molecular markers and lack of South East Asian pfk13 artemisinin-resistance mutations in samples collected from 2013 to 2016 in C\u00f4te d\u2019Ivoire.","volume":"48","author":"A Konat\u00e9-Tour\u00e9","year":"2024 Mar 1","journal-title":"J. Parasit. Dis."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s12936-023-04645-9","article-title":"Plasmodium falciparum drug resistance-associated mutations in isolates from children living in endemic areas of Burkina Faso.","volume":"22","author":"C Tarama","year":"2023 Dec 1","journal-title":"Malar. J."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"833-843","DOI":"10.4269\/ajtmh.14-0031","article-title":"Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: Parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.","volume":"91","author":"M Venkatesan","year":"2014 Oct 1","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"991-997","DOI":"10.1128\/AAC.00875-06","article-title":"Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria.","volume":"51","author":"G Humphreys","year":"2007 Mar","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref48","article-title":"Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine.","author":"J S\u00e1"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"562-569","DOI":"10.1016\/j.meegid.2007.03.005","article-title":"Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa.","volume":"7","author":"G Holmgren","year":"2007 Sep","journal-title":"Infect. Genet. Evol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1120-1128","DOI":"10.1016\/S1473-3099(21)00142-0","article-title":"Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: An open-label, single-arm, multicentre, therapeutic efficacy study.","volume":"21","author":"A Uwimana","year":"2021 Aug 1 cited 2024 Jul 9","journal-title":"Lancet Infect. Dis."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"e441-e449","DOI":"10.1016\/S2666-5247(21)00085-9","article-title":"Drug susceptibility of Plasmodium falciparum in eastern Uganda: A longitudinal phenotypic and genotypic study.","volume":"2","author":"P Tumwebaze","year":"2021 Sep 1","journal-title":"Lancet Microbe."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"41-49","DOI":"10.1016\/j.ijid.2023.11.026","article-title":"Identification of the PfK13 mutations R561H and P441L in the Democratic Republic of Congo.","volume":"139","author":"G Mesia Kahunu","year":"2024 Feb 1","journal-title":"Int. J. Infect. Dis."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"e0099424","DOI":"10.1128\/spectrum.00994-24","article-title":"Slow clearance of histidine-rich protein-2 in Gabonese with uncomplicated malaria.","volume":"12","author":"C Lamsfus Calle","year":"2024 Oct 3","journal-title":"Microbiol Spectr."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s12936-020-03163-2","article-title":"Use of real-time multiplex PCR, malaria rapid diagnostic test and microscopy to investigate the prevalence of Plasmodium species among febrile hospital patients in Sierra Leone.","volume":"19","author":"T Leski","year":"2020 Feb 21","journal-title":"Malar. J."},{"key":"ref55","article-title":"Updated WHO recommendations for malaria chemoprevention among children and pregnant women.","year":"2022 cited 2024 Aug 23"}],"container-title":["Gates Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-81\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-81\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-81\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:55:23Z","timestamp":1763686523000},"score":1,"resource":{"primary":{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-81\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":46,"URL":"https:\/\/doi.org\/10.12688\/gatesopenres.16367.1","relation":{"has-preprint":[{"id-type":"doi","id":"10.12688\/verixiv.1155.1","asserted-by":"subject"}]},"ISSN":["2572-4754"],"issn-type":[{"value":"2572-4754","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"assertion":[{"value":"Awaiting Peer Review","URL":"https:\/\/gatesopenresearch.org\/articles\/9-81\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"This work was financially supported by the Gates Foundation (OPP1196642 and INV-067310, A.M.), La Caixa Foundation and the Departament d\u2019Universitats i Recerca de la Generalitat de Catalunya (AGAUR; grant 2021 SGR 01517, A.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":0,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}